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Reality, Part I
SCOTT C. ARMSTRONG, M.D. KELLY L. COZZA, M.D.
Pharmacokinetic drug-drug interactions with morphine, hydromorphone, and oxymorphone are reviewed in this column. Morphine is a naturally occurring opiate that is metabolized chiey through glucuronidation by uridine diphosphate glucuronosyl transferase (UGT) enzymes in the liver. These enzymes produce an active analgesic metabolite and a potentially toxic metabolite. In vivo drug-drug interaction studies with morphine are few, but they do suggest that inhibition or induction of UGT enzymes could alter morphine and its metabolite levels. These interactions could change analgesic efcacy. Hydromorphone and oxymorphone, close synthetic derivatives of morphine, are also metabolized primarily by UGT enzymes. Hydromorphone may have a toxic metabolite similar to morphine. In vivo drug-drug interaction studies with hydromorphone and oxymorphone have not been done, so it is difcult to make conclusions with these drugs. (Psychosomatics 2003; 44:167171)
he narcotic analgesics can be categorized into three groups. Two of the groups are synthetic chemicals: phenylpiperidines (e.g., meperidine [Demerol ] and fentanyl) and pseudopiperidines (e.g., methadone and propoxyphene [Darvon ]). The third group is related to the naturally occurring alkaloids from the seeds of the poppy plant. These natural opium derivatives include heroin, morphine, and codeine. Semi-synthetic derivatives from this group include hydromorphone (Dilaudid ), oxymorphone (Numorphan ), hydrocodone (e.g., Vicodin among others), oxycodone (e.g., OxyContin and Percocet ), dihydrocodeine, and buprenorphine (Buprenex ). This is the rst of a two-part series. In this issue, the pharmacokinetic properties of morphine and its closely related synthetic congeners, hydromorphone and oxymorphone, will be reviewed. Emphasis in this report will be placed on the enhancing or inhibiting of their metabolism by other drugs, which could potentially alter their analgesic efcacy. Part II, which will appear in an upcoming issue, will review codeine and related compounds (dihydrocodeine, hydrocodone, and oxycodone) and their pharmacokinetic drug-drug interaction proles. Morphine and mor-
phine derivatives also have the potential for pharmacodynamic drug interactions, but these interactions will not be discussed in this series. The chemical structure of morphine is shown in Figure 1. The 3 and 6 carbon atoms along with the 17 nitrogen (N) position are the three sites that have various substitutions of ester ( OCX2), hydroxyl ( OH), keto ( O), and methyl ( CH3) groups, creating other natural or synthetic opiate drugs. Morphine, as noted above, has hydroxyl groups at the 3 and 6 carbons and a methyl group at the 17 (N) position. Codeine simply adds a methyl group
Dr. Armstrong is the Co-Medical Director, Center for Geriatric Psychiatry, Tuality Forest Grove Hospital, Forest Grove, Ore., and Associate Professor of Psychiatry, Oregon Health Sciences University, Portland, Ore. Dr. Cozza is the staff psychiatrist for the Infectious Disease Service, Department of Medicine, Walter Reed Army Medical Center, Washington, D.C., and Assistant Professor of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, Md. Address correspondence to Dr. Armstrong, Tuality Forest Grove Hospital, 1809 Maple St., Forest Grove, OR 97116; scott.armstrong@tuality.org (e-mail). The opinions or assertions contained herein are the private views of the authors and are not to be construed as ofcial or as reecting the views of the Department of the Army or the Department of Defense. Copyright 2003 The Academy of Psychosomatic Medicine.
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efcacy of morphine for pain, and Smith6 hypothesized that increasing levels of M3G are to blameeven when drug interactions are not suspected. Smith6 supported the idea of rotating analgesics to avoid this problem (this would include rotating with non-morphine-like opiates, such as fentanyl, since even hydromorphone may also have this problem). In contrast, M6G is more potent as an analgesic than morphine itself,7 possibly 50 times more potent.8 M6G has been proposed as a possible future parenteral analgesic,7 and several studies have found signicant analgesic efcacy with M6G through the intravenous route.9,10 Nebulized M6G is poorly absorbed and is therefore a poor route for delivery of M6G. The oral route of M6G has poor bioavailability11 and is metabolized in the gut back to morphine, which is subsequently re-conjugated again by UGT 2B7. Hence, the oral route of M6G may not offer any advantage to oral morphine. Similarly, when oral/parenteral morphine is metabolized to M6G in the liver, it undergoes enterohepatic circulation/recycling,12 which can slow the effective clearance of the drug as it recycles itself from morphine to M6G back to morphine. Although there is genetic variability (polymorphisms) of the UGT enzymes 2B7 and 1A3, this variability has not yet clearly been shown to alter levels of production of M3G/M6G or to change the efcacy of patient response to analgesia from morphine.13,14 Because morphines clearance is dependent on UGT enzymes, it should not be a surprise that other drugs that inhibit or induce UGT enzymes could affect the levels of morphine, M3G, or M6Gthus changing its analgesic efcacy or side effect prole. However, the UGT enzymes are not as well understood as are the P450 enzymes,15 and well-designed in vivo studies that have looked into morphines pharmacokinetic drug-drug interaction prole are few. A list of potential drugs that can inhibit/induce UGTs can be found at www.mhc.com//Cytochromes// UGT//index.html. Theoretically, inhibiting UGT 2B7 could decrease morphines efcacy, since M6G levels would be decreased. Another possible outcome would be that UGT 2B7 inhibition would increase morphines efcacy because of an increase in parent drug levels. Inducing the enzyme might increase morphines efcacy by increasing production of M6G or decrease the efcacy by reducing the levels of the parent drug. To complicate matters, induction could increase M3G levels, which could lead to a decrease in efcacy by increasing the levels of the toxic M3G. In other words, any scenario seems possible! As expected, the cliniPsychosomatics 44:2, March-April 2003
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Summary of In Vivo Studies of Drug-Drug Interactions With Morphine Drug Used With Morphine
16
Study Design
Results
Comments
Rifampin
Ranitidine
Tighe et al.18
Diclofenac
Ten healthy volunteers; double- After rifampin exposure, AUC Although rifampin did decrease blind, placebo-controlled, of morphine, M3G, and M6G efcacy of morphine, the crossover design; morphine, decreased; pain thresholds decrease in AUC of UGT 10 mg, given alone and then became similar to placebo metabolites M3G and M6G after 13 days of exposure to suggests possible mechanisms rifampin, 600 mg/day; pain other than induction of UGT thresholds and drug enzymes pharmacokinetics measured Eight healthy volunteers; double- Ranitidine decreased serum Possible evidence of ranitidine blind, placebo-controlled, M3G/M6G ratio and increased inhibiting UGT 2B7 and 1A3 crossover design; ranitidine AUC of morphine potential inhibitor of UGT added to morphine and pharmacokinetics measured A single 100-mg dose of Morphine consumption Unknown mechanismperhaps diclofenac, a potential UGT decreased by 20%, but levels inhibition of renal clearance of inhibitor, was given to seven of M6G were unchanged M6G rather than UGT post-op patients controlling inhibition their own morphine administration
TABLE 2. Drug
Morphine, Hydromorphone, and Oxymorphone Metabolism P450 Enzyme Metabolism Negligible UGT and Other Enzyme Metabolism 1A3 and 2B7 1A3, 2B7, and reduced by dihydromorphinone ketone reductase 2B7, other UGTs, and by unspecied reductase UGT 2B7 Inhibition or Induction Moderate inhibition Toxic Metabolites M3G H3Gb Active Metabolites M6G
P450 2D6 product of hydrocodone. Possible, but more research necessary to conrm. c P450 2D6 product of oxycodone.
b
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References
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