Tag Archive: opioid


The Effect of Ketamine on Opioid-Induced Acute Tolerance: Can It Explain Reduction of Opioid Consumption with Ketamine-Opioid Analgesic Combinations?

Filed under: Uncategorized — Hinterlasse einen Kommentar
25/02/2011

Abstract

Ketamine administered intraoperatively in very small doses reduces postoperative opioid consumption. We suggest that this effect is the result of attenuation of acute tolerance to the analgesic effect of opioids. We sought to demonstrate that acute tolerance induced by alfentanil infusion can be attenuated by a dose of ketamine that is too small to produce a direct antinociceptive effect. The experiments were conducted in rats with the use of an infusion algorithm designed to maintain a constant plasma level of the opioid for 4 h. The degree of acute tolerance was determined on the basis of decline in the level of analgesia measured with a tail compression test. Ketamine (10 mg/kg) did not change the baseline pain threshold and did not increase the peak of alfentanil-induced analgesia. At the same time, it attenuated the development of acute tolerance to analgesia during alfentanil infusion and suppressed rebound hyperalgesia observed the day after the infusion. These effects were similar to those observed with dizocilpine (0.1 mg/kg). The development of acute tolerance to analgesia induced by the infusion of an opioid can be attenuated by ketamine administered in doses that are not large enough to provide a direct antinociceptive effect. Therefore, ketamine has the potential to reduce opioid consumption even in subanalgesic doses.

Abstract

Implications: Ketamine attenuated the development of acute tolerance to analgesia during alfentanil infusion and suppressed rebound hyperalgesia observed the day after the infusion.

The idea of combining an N-methyl-d-aspartate (NMDA) receptor antagonist, inhibiting pain-induced central hypersensitivity, with an opioid (1) has stirred considerable interest in analgesia research. Ketamine as a clinically available NMDA receptor antagonist has been especially attractive in this regard. The authors of a recent review summarizing studies on combined ketamine-opioid administration in postoperative pain concluded that results on the ability of ketamine to improve opioid analgesia are rather contradictory (2). Sethna et al. (3) demonstrated only simple additivity in the effects of ketamine and alfentanil on experimental pain in volunteers. The analgesic effect of ketamine in postoperative pain was observed when the drug was used in a dose range from 0.3 to 0.5 mg/kg, and the effect lasted only for 40 to 60 min (4–6).

Some of the clinical studies (7–9) revealed that ketamine administered during surgery reduced postoperative opioid consumption. These authors used small doses of ketamine (75–150 μg/kg) that could not provide analgesic concentrations in the biophase during the postoperative period. The reduction of opioid consumption was explained by the effect of ketamine on pain-induced central sensitization (7–9). An alternative explanation could be based on the ability of NMDA receptor antagonists to inhibit acute tolerance to the analgesic effect of opioids. We have reported previously (10) that the NMDA receptor antagonist dizocilpine attenuates the development of acute tolerance to analgesia induced in rats by IV infusion of alfentanil. This outcome is similar, although not identical, to the results reported in studies on chronic tolerance in which NMDA receptor antagonists (11–13) or NMDA receptor defect (14) blocked tolerance to the analgesic effect of morphine. Suppression of acute tolerance to alfentanil by dizocilpine, which does not have an analgesic effect by itself, indicates that the direct analgesic effect of ketamine and its effect on opioid-induced analgesia are not necessarily related: the opioid-induced analgesia could be enhanced by the effect of ketamine on opioid acute tolerance that reveals itself in relatively small subanalgesic doses.

Our principal purpose was to test the hypothesis that acute tolerance induced by alfentanil infusion can be attenuated by ketamine in a dose that is not large enough to provide a direct antinociceptive effect. With this aim, it will be possible to substantiate an approach to the treatment of postoperative pain that was actually used in a few clinical studies with ketamine, but the mechanism of ketamine-induced potentiation of opioid analgesia was not identified correctly. The potential of NMDA receptor antagonists to reduce acute tolerance to opioids may be a basis for a novel and important contribution to the relief of postoperative pain. An additional purpose of our study was to examine the effect of ketamine on another opioid-induced adaptive response-delayed hyperalgesia that follows the alfentanil infusion.

Methods

Experiments were performed on male Sprague-Dawley rats weighing 320–370 g. The animals were housed with a 12-h light-dark cycle, and food and water were available ad libitum. The protocol for this study was approved by the Institutional Panel on Laboratory Animal Care.

A catheter for the drug infusion was chronically implanted into the jugular vein, and its free end was exteriorized through the skin at the back of the neck. The surgical procedure for implantation was performed under pentobarbital (55 mg/kg intraperitoneally [IP]) anesthesia several days before the experiment. Alfentanil was infused with a Harvard Apparatus pump (model 55–2222; Harvard Apparatus Co., Natick, MA). Alfentanil infusion algorithm was based on the constants of one compartment model for rats derived from our previous study (15).

The responses to mechanical noxious stimulation were determined by measuring the threshold of motor response to increasing pressure applied to the tail—tail compression test (16) with the use of an Analgesy-Meter® (Ugo Basile, Milan, Italy). The rat’s tail was positioned on a Teflon platform, and the pressure plate (0.7-mm edge) attached to this device was applied to the tail while the rat was held in the experimenter’s hand. Pressure was increased at a constant rate (cutoff pressure of 2.375 kg) until coordinated struggle occurred. Three consecutive measurements were recorded, and the mean of the last two measurements was taken as the pressure threshold. For each consecutive determination of the pain threshold, the pressure plate was moved 2-mm cephalad. Measurements were made by an experimenter who was unaware of expected changes in the reaction thresholds among the treatment groups.

Animals were randomly divided into four groups: Alfentanil-Ketamine, Alfentanil-Dizocilpine, Alfentanil-Saline (bolus), and Saline (infusion)-Ketamine, each consisting of eight rats. In all groups, alfentanil was administered as described previously (15,17): a bolus dose of 50 μg/kg followed by an infusion rate of 155 μg · kg−1· h−1 for 4 h. This pattern was chosen to rapidly achieve and maintain a stable alfentanil plasma concentration. The degree of acute tolerance was determined on the basis of decline in the level of pressure threshold during the infusion period. After the alfentanil administration, the pressure threshold was measured twice: 1.5 h and 23 h after the infusion. The last measurement was made to determine the rebound hyperalgesia after the alfentanil infusion. According to preliminary experiments, the measurements made the next day revealed the maximal rebound hyperalgesia that disappeared in a few days after the infusion.

The interacting drugs were administered IV with the first injection given 60 min before the beginning of alfentanil infusion. The following doses were used: ketamine 10 mg/kg (Alfentanil Infusion-Ketamine Bolus Group); dizocilpine 0.1 mg/kg (Alfentanil Infusion-Dizocilpine Bolus Group); isotonic saline (Alfentanil Infusion-Saline Bolus Group); and ketamine 10 mg/kg (Saline Infusion-Ketamine Bolus Group).

The selection of the dose of ketamine was based on the preliminary experiments in which it was verified that 10 mg/kg was not providing an analgesic effect immediately after the drug injection. To further reduce the probability of some direct analgesic influence by ketamine, the interval between the injection of ketamine and the start of alfentanil administration was extended to 1 h. In the rat, ketamine 60 mg/kg IM provides incomplete analgesia, and only at doses of 100 to 120 mg/kg IP can it provide a complete anesthetic effect (18). A more specific NMDA receptor antagonist, dizocilpine, was used in a dose of 0.1 mg/kg.

In the above doses, neither ketamine nor dizocilpine produced behavioral effects interfering with the pressure threshold measurements. The interacting drugs were also administered 5 min after the last measurement of the pressure threshold on the day of alfentanil infusion (second administration) and on the next day, 19 h after the end of alfentanil infusion (third administration), both in the same dose as the first injection (see schedule for drug administration in Table 1).

Table 1.

Effect of Ketamine on Acute Tolerance and Rebound Hyperalgesia Induced by Alfentanil Infusion

The pressure threshold in each of the groups was determined before, and 5 min after, the administration of an interacting drug, at 30, 60, 120, 180, and 240 min after the beginning of alfentanil infusion, and at 1.5 and 23 h after the end of alfentanil infusion. Racemic ketamine hydrochloride was from Parke-Davis (Morris Plains, NJ), dizocilpine maleate (MK-801) was from Sigma Chemical Co. (St. Louis, MO), and alfentanil hydrochloride was from Taylor Pharmaceuticals (Decatur, IL).

The pressure threshold was treated as a continuous variable and was analyzed using a two-way (groups and time) analysis of variance with time treated as a repeated measures factor. Comparisons among groups at each time were performed with the use of an one-way analysis of variance. Multiple comparisons among pairs of means were made by using the Fisher’s protected least significant difference method (19). Differences were declared statistically significant if P < 0.05.

Results

Table 1 shows a summary of the data obtained in all four groups of experiments. The comparison of the pressure threshold before, and 5 min after, ketamine administration (10 mg/kg) indicates that ketamine had no significant analgesic effect. Because alfentanil administration was started 60 min after the ketamine injection, the presence of any direct analgesic effect of ketamine at that time would be even less likely. Dizocilpine also did not produce any changes in the pressure threshold measured 5 min after its injection.

The effect of ketamine on acute tolerance to alfentanil is illustrated by Figure 1, which shows a comparison of the alfentanil-induced changes in the pressure threshold. It demonstrates (A segment) that, in the Alfentanil-Saline Group, the pressure threshold before the end of alfentanil infusion was only insignificantly more than that before the start of infusion (808 ± 78 g vs 733 ± 66 g, not significant). At the same time, in the Alfentanil-Ketamine Group, the pressure threshold at the end of alfentanil infusion was much higher than that before the start of infusion (1078 ± 191 g vs 763 ± 64 g, P < 0.001); and it was higher than in the Alfentanil-Saline Group at the same time interval (1078 ± 191 g vs 808 ± 78 g, P < 0.05). The changes in the Alfentanil-Dizocilpine Group were similar to those in the Alfentanil-Ketamine Group. The Saline-Ketamine Group demonstrated a constant pressure threshold level for the whole study period.

Figure 1. The effect of ketamine on acute tolerance to continuously infused alfentanil. Alfentanil was administered as a bolus of 50 μg/kg followed by a constant-rate infusion at 155 μg · kg−1 · h−1 for 4 h. Ketamine was injected in a dose of 10 mg/kg IV 60 min before the start of alfentanil administration. A, Alf + Sal = alfentanil infusion and isotonic saline as an interacting drug; Alf + Diz = alfentanil infusion and dizocilpine 0.1 mg/kg IV 60 min before alfentanil; Alf + Ket = alfentanil infusion and ketamine 10 mg/kg IV 60 min before alfentanil; Sal + Ket = isotonic saline infusion and ketamine 10 mg/kg IV 60 min before the start of saline infusion. Each dot reflects a mean ± sd for a group of eight rats at various time intervals. *P < 0.05, +P < 0.01, both versus value at 30 min in each of the groups. B, Changes in cumulative reductions of the initial analgesic effect. Columns represent reductions in percent (mean ± sd). Cumulative reduction of the initial analgesic effect was calculated by comparing the alfentanil-induced increase in pressure threshold (from predrug baseline value) at 30 min of the infusion (initial analgesic effect) with the increases from the predrug baseline separately at 60, 120, and 240 min (gradual cumulation of the effect). *P < 0.05 versus corresponding value of Alf + Sal group.

The effects of ketamine and dizocilpine for reduction of the initial analgesic response at various time intervals during alfentanil infusion are presented in Figure 1B. Both drugs significantly (P<0.05) attenuated tolerance development at all time intervals as presented by cumulative reduction of the initial analgesic effect (explanation in the legend to Figure 1B). The effect of dizocilpine had a tendency to be more pronounced than that of ketamine, although this tendency did not reach statistical significance.

In addition to the attenuation of acute tolerance to alfentanil, ketamine inhibited the alfentanil-induced rebound hyperalgesia. After the 4-h alfentanil infusion, there was a decrease in the pressure threshold that reached its maximum the day after infusion and then gradually returned to the baseline level, usually 1–2 days later. Table 1 indicates that in the Alfentanil-Saline Group, 23 h after the end of alfentanil infusion, the pressure threshold was decreased 27% from baseline level (532 ± 65 g vs 733 ± 66 g, P < 0.001). In the Alfentanil-Ketamine Group, animals received three injections of ketamine 10 mg/kg (60 min before the start of alfentanil infusion, and 5 min and 19 h after its end). This treatment resulted in a decrease of the pressure threshold decline 23 h after the end of alfentanil infusion (539 ± 65 g in Alfentanil-Saline Group vs 692 ± 54 g in the Alfentanil-Ketamine Group, P < 0.001). Figure 2 shows a comparison of the degree of the rebound hyperalgesia with and without the NMDA receptor antagonist’s administration. Both ketamine and dizocilpine suppressed it, with dizocilpine completely suppressing it; however, statistical significance (P = 0.058) of the difference between the Dizocilpine and Ketamine Groups did not reach the accepted level of P value.

Figure 2. Effect of ketamine on rebound hyperalgesia induced by alfentanil infusion. Columns represent reductions of pressure thresholds (percent of baseline value, mean ± sd) 23 h after the end of the 4-h alfentanil infusion. Animals received three injections of interacting drugs in equal doses: 60 min before the start of alfentanil infusion, and 5 min and 19 h after its end. Ketamine was used at a dose of 10 mg/kg, and dizocilpine at a dose of 0.1 mg/kg. *P < 0.001 versus corresponding value of the alfentanil (Alf) + isotonic saline (Sal) group.

Discussion

Both alfentanil-induced adaptive changes assessed in the present study—acute tolerance and rebound hyperalgesia—were attenuated by ketamine. The development of acute tolerance to the antinociceptive effect of alfentanil was decreased by ketamine at all time-intervals of the four-hour alfentanil infusion. The ability of ketamine to attenuate chronic tolerance to morphine was reported with systematic and intrathecal drug administration in rodents (20–22).

In our experiments, ketamine 10 mg/kg was administered IV one hour before the beginning of alfentanil infusion. The baseline pressure threshold measured five minutes after ketamine was not changed (Table 1), and the peak of the alfentanil-induced antinociceptive effect with ketamine pretreatment was the same as that with the saline pretreatment (Table 1 and Figure 1A). These results indicate that the dose of ketamine we used was not large enough to provide a direct antinociceptive effect, even in combination with alfentanil. Similar results with systemic ketamine 10 mg/kg were reported in mice: ketamine did not change the response to mechanical or thermal nociceptive stimuli (23). Also, when ketamine 10 mg/kg was administered with morphine in rats, the morphine dose-response curve was not changed to any significant degree (21). With phasic pain, ketamine provides analgesia only in very large doses (24). That agrees well with the fact that, in rats, only at doses 100 to 120 mg/kg IP does it block motor nociceptive responses in minor surgical procedures (18).

The pattern of ketamine biodisposition is characterized by a very rapid redistribution from the brain to other tissue (25). In the rat, 60 minutes after an IV ketamine injection, its brain level declined 20-fold compared with the level measured immediately after the injection (26). This indicates that when attenuation of acute tolerance to alfentanil occurred (two to five hours after ketamine bolus injection), in our experiments, the ketamine biophase concentration was at least 20-fold smaller than that immediately after the injection. Thus, despite the fact that the ketamine concentration was too small to produce a direct antinociceptive effect, it effectively attenuated the development of acute tolerance to alfentanil.

Bilsky et al. (12) reported that NMDA receptor antagonists blocked chronic antinociceptive tolerance to morphine, but not however, to selective μ or δ agonists, including fentanyl. They concluded that the effect of NMDA receptor antagonists on opioid tolerance is not a general phenomenon related at all opioids. Alfentanil, used in our study, belongs to the same group of opioids as fentanyl. The difference in the results is probably related to the difference in the model of tolerance (chronic versus acute).

Rebound hyperalgesia that was present the day after the alfentanil infusion was also attenuated by ketamine. This confirms similar observations with delayed hyperalgesia induced by multiple bolus injections of fentanyl (27). The rebound hyperalgesia observed during opioid abstinence could result from reduction of a tonic inhibitory modulation that was present before opioid administration; however, the activation of modulatory neurons that facilitate nociceptive transmission could also be involved (28).

Ketamine is a nonspecific noncompetitive NMDA receptor antagonist; however, its effects on acute tolerance to alfentanil and on delayed hyperalgesia were almost the same as those of dizocilpine, a specific noncompetitive NMDA receptor antagonist. The effects of dizocilpine were only insignificantly more pronounced than those of ketamine.

The activation of NMDA receptors in the central nervous system is seen as a mechanism involved in the adaptive changes underlying both tolerance to opioids and delayed hyperalgesia. It was suggested that activation of opioid receptors leads to protein kinase C-mediated activation of NMDA receptors (29,30). The attenuation of acute tolerance and rebound hyperalgesia by the NMDA receptor antagonists is in agreement with this suggestion.

Could our results be relevant to the clinical experience with acute opioid exposure in surgery? The tolerance to analgesia during remifentanil infusion in humans is profound and develops very rapidly (31). Chia et al. (32) reported that the preoperative and intraoperative use of fentanyl in large doses (15 μg/kg plus 100 μg/h for 2–3 h) resulted in an increased postoperative fentanyl consumption via patient-controlled analgesia (up to 50%) and increased pain severity compared with preoperative administration of a small dose of fentanyl (1 μg/kg). It was also found that patients who received more morphine during the initial postoperative period had increased opioid requirements for pain relief after the initial period (33). In a recent editorial, Eisenach (34) concluded that we may be contributing to postoperative pain by the use of large doses of opioids intraoperatively. Thus, attenuation of the development of acute tolerance to opioids could be a clinically important approach for the treatment of postoperative pain, and the possible role of ketamine in this regard deserves specific attention.

The value of ketamine in the treatment of postoperative pain is a very controversial issue (2,25). To provide a direct analgesic effect, ketamine should be used in relatively large doses, which is associated with significant adverse effects. However, several authors (7–9) reported that ketamine administered during surgery in small doses (75–150 μg/kg) reduced postoperative opioid consumption. We hypothesize that this effect is the result of attenuation of acute tolerance to opioids. Figure 3 illustrates this suggestion by presenting three antinociceptive effects of ketamine that require different concentrations of the drug. Attenuation of tolerance to the analgesic effect of opioids occurs at the smallest concentration. Therefore, ketamine in subanesthetic (effect on phasic pain) or subanalgesic (effect on tonic pain) doses can still reduce opioid consumption.

Figure 3. Hypothetical dose-response relationship for the effects of ketamine related to nociception.

There is a separate pharmacologic property of ketamine that is related to the treatment of postoperative pain. NMDA receptor antagonists, including ketamine, can prevent the induction of injury-induced central sensitization and abolish hypersensitivity to pain once it is established (35). This property is a basis for the use of ketamine for preemptive analgesia (2). In a study on surgical patients, we could not demonstrate the preemptive effect of ketamine (used in a large dose of 2 mg/kg bolus + 20 μg · kg−1 · min−1 infusion during surgery) on spontaneous or movement-induced pain; however, its effect on hyperalgesia to pressure on the wound was observed even 48 hours after the surgery (36). The effect of ketamine on pain-induced central sensitization could be a factor in the decrease of postoperative pain, and consequently, in the reduction of opioid requirements (7–9). This study suggests that the ketamine-induced attenuation of acute tolerance to opioids might also be a potentially beneficial mechanism in the treatment of postoperative pain resulting in reduction of opioid requirements. It is interesting that mechanisms underlying injury-induced central sensitization and opioid-induced tolerance have close relationships. Mao et al. (30) suggested that these two seemingly unrelated phenomena may have common neural substrates that interact at the level of excitatory amino acid receptor activation and related intracellular events.

In conclusion, ketamine attenuated the development of acute tolerance to analgesia during alfentanil infusion and suppressed rebound hyperalgesia observed the day after the infusion.

Acknowledgments

Supported by National Institutes of Health Grant GM35135.

Footnotes

  • Accepted August 17, 2000.

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source: http://www.anesthesia-analgesia.org/content/91/6/1483.full

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Kommentar

Opioid Metabolism

Filed under: Uncategorized — Hinterlasse einen Kommentar
20/01/2011

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.6–9 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.6–9

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 110–18). 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.19–23 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,29–31 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%).35–39 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.46–48

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.6–9 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 410,11,16–18,28,43,53–60). 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.68–70 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.73–76 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.84–86

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.89–92

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 510,11,13–18,43). 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.35–39 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.102–104 Because most opioids are eliminated primarily in urine, dose adjustments are required in patients with renal impairment.10,11,13,16–18,43

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.105–107 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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Kommentar

Science-Based Views of Drug Addiction and Its Treatment

Filed under: Uncategorized — Hinterlasse einen Kommentar
19/03/2010

MORE THAN TWO THIRDS OF
people with addiction see a
primary care or urgent care
physician every 6 months, and many
others are regularly seen by other medical
specialists.1,2

These physicians are
therefore in a prime position to help patients
who may have drug abuse problems
by recognizing and diagnosing the
addiction, helping to direct patients to
a program that can meet their treatment
needs, and helping to monitor
progress after specialty treatment and
during recovery.3-6

Many physicians,
however, find the domain of drug abuse
particularly daunting and often avoid
the issue with their patients. This is understandable
given the relatively short
shrift drug abuse is given in formal
medical education. There is a widespread
misperception that drug abuse
treatment is not effective, which may
account for the reluctance of physicians
to even broach the subject of drug
abuse or treatment with their patients.
On the other hand, over the past 15
to 20 years, advances in science have
revolutionized our fundamental understanding
of the nature of drug abuse
and addiction and what to do about it.
In addition, there are now extensive
data showing that addiction is eminently
treatable if the treatment is welldelivered
and tailored to the needs of
the particular patient.

There is an array
of both behavioral and pharmacological
treatments that can effectively
reduce drug use, help manage drug
cravings and prevent relapses, and restore
people to productive functioning
in society.7-9
Of course, not all drug abuse treatments
are equally effective, and there
is no single treatment appropriate for
all patients. Fortunately, recent scientific
advances have provided insights
both into the nature of drug abuse and
addiction and into the principles that
characterize the most effective treatment
approaches and programs.10 These
treatment principles should make the
primary care or nonaddiction specialty
care physician’s tasks of screening
and referral much easier.

Read more: 20.03.10

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ROLE OF NIGELLA SATIVA IN OPIOID DEPENDENCE

Filed under: Uncategorized — Hinterlasse einen Kommentar
16/03/2010

Opioid dependence is a chronic disorder that produces changes in brain pathways that remain long after the patient stops taking the drug. These protracted brain changes put the dependent person at greater risk of relapse. Detoxification can be successful in cleansing the person of drugs and withdrawal symptoms; it does not address the underlying disorder, and thus is not the adequate treatment. Maintenance with methadone or naltrexone is the usual practice in the long-term management of opioid dependence but both drugs have their own disadvantages because no single medication is appropriate for every individual for treating their opioid dependence, it is important that clinicians have a variety of the therapeutic agents available to them.

Calcium channel blockers, such as verapamil, diltiazem, nifedipine, nimodipine, and felodipine are useful drugs being used in cardiovascular disorders, such as hyper-tension, arrhythmias, and ischaemic heart disease. Research on calcium channel blockers has proved their therapeutic potential in a variety of disorders such as asthma, diarrhoea, premature labour, and diseases of central nervous system such as epilepsy, and opioid dependence. Modern drugs are not only expensive and beyond the reach of majority of the population of world but also have multiple side effects. Hence there is a need to explore such drugs from indigenous sources and to observe if combination of desired therapeutic efficacy exists in nature.

Nigella Sativa is in use for the treatment of variety of ailments since ancient times. Research has based its many effects on their efficacy of blocking calcium channels. As calcium channels have been tried for the treatment of opioid dependence, so Nigella Sativa was used in this study. This study was carried out on 50 patients who were divided into two groups. Patients were admitted for 12 days and then weekly followed up for 12 weeks.

Each patient received placebo orally during day-1 and day-2 of admission. Thereafter Nigella Sativa was given to the patients from day-3 of admission to eighth week. Then the dose of each drug was tapered off during 9th and 10th weeks and then no treatment was given during last two weeks.

It was observed that Nigella Sativa showed a rapid improvement in signs and symptoms of acute opioid abstinence. It was also observed that Nigella Sativa prevented the development of significant craving and relapse. It is concluded that Nigella Sativa is effective in long term management of opioid dependence and it is suggested that further long term follow up studies may be designed with greater number of patients.

First Time the Full Research Paper here:1742 niglea sativa

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Opioid Antagonists, Naloxone & Naltrexone — Aids for Pain Management

Filed under: Uncategorized — Hinterlasse einen Kommentar
12/02/2010

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
antagonists.
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.

OpioidAntagonistsForPain

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