Med-Psych Drug-Drug Interactions Update Pharmacokinetic Drug Interactions of Morphine, Codeine, and Their Derivatives: Theory and Clinical

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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on the 3 position hydroxyl group of morphine ( OCH3 attached to the 3-position carbon). Other synthetic narcotics have changes in the 3, 6, and 17 positions as well as have a single bond between carbon 7 and 8. The 3, 6, and 17 positions are also the primary areas of oxidative (P450) metabolism. The 3 and 6 positions are often referred to as the O site and N sites, respectively, in regards to oxidative P450 metabolism (based on the proximity of the 3 carbon to the oxygen atom and the 6 carbon to the nitrogen atom of a separate ring). The literature can be confusing, however, as the 17 position is also at times referred to as the N position. Whether or not the P450 enzymes are involved in the oxidative metabolism of a particular morphine derivative, the 3 and 6 positions are also the main sites for conjugation with glucuronic acid by various phase 2 uridine diphosphate glucuronosyl transferase (UGT) enzymes. Morphine Morphine is metabolized chiey through glucuronidation. The P450 enzymes do not appear to be greatly involved in morphines metabolism. UGT 2B7 and UGT 1A3 are the major enzymes involved in the glucuronidation of morphine.13 Although there is probably overlap, UGT 2B7 primarily produces the 6-conjugate and UGT 1A3 produces the 3-conjugate. Both enzymes also create a combination 3/6 conjugate. The 3-conjugate (M3G) is usually made in more abundance than the 6-conjugate (M6G) and is essentially devoid of any opioid analgesic activity.4,5 Indeed, it may cause CNS neuroexcitatory effects,6 and increasing its production could lessen the overall desired analgesia. Chronic highdose exposure to morphine has been shown to decrease
FIGURE 1. Chemical Structure of Morphine

HO (3)

(17) NCH3 (14) O (8) (6) HO (7)

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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cal evidence for the consequences of these interactions are far from clear. Table 1 provides a summary of the only in vivo human studies of morphine used concomitantly with other known inhibitors/inducers. The results are interesting, but we do not believe they give the clinician at this time a rm ability to predict or generalize other potential drug-drug interactions. Since the UGT enzymes are induced by phenobarbital, one might conceive of an in vivo study trying to correlate morphine and metabolite levels with analgesic efcacy. However, such a study would be complicated by the overwhelming pharmacodynamic CNS interaction of morphine and phenobarbital, making any conclusions difcult. In vitro studies suggest that morphines metabolism can be altered through drugs that inhibit UGT enzymes. Wahlstrom et al.19 demonstrated that amitriptyline, nortriptyline, and clomipramine all inhibit UGT enzymes and decrease the formation of M3G and M6G. Chloramphenicol and diazepam may also inhibit morphines glucuronidation.20,21 Similarly, morphine itself may competitively inhibit UGT 2B7. Finally, it has been hypothesized that morphine is a Pglycoprotein (P-gp) substrate22 and that pharmacokinetic P-gp inhibition could enhance analgesic effects by allowing more morphine through the blood-brain barrier.23 The only study to date looking at this possible potentiation was done by Drewe et al.24 who used the P-gp inhibitor valspodar in 18 healthy comparison subjects concomitantly using morphine. The result revealed only slight and probably clinically insignicant changes in CNS morphine ef-

TABLE 1. Authors Fromm et al.

Summary of In Vivo Studies of Drug-Drug Interactions With Morphine Drug Used With Morphine
16

Study Design

Results

Comments

Rifampin

Aasmundstad and Storset17

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

Morphine Hydromorphonea (Dilaudid ) Oxymorphonec (Numorphan )

a

P450 2D6 product of hydrocodone. Possible, but more research necessary to conrm. c P450 2D6 product of oxycodone.
b

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fects. This interaction is still open to research, but many drugs are P-gp inhibitors and therefore may enhance CNS morphine effects, such as cyclosporine, diltiazem, and itraconazole.25 Hydromorphone and Oxymorphone Both of these semi-synthetic morphine analogs are structurally very similar to morphine. Hydromorphone (Dilaudid and others) has a keto ( O) group at the 6-position carbon and a single bond between carbons 7 and 8. Oxymorphone (Numorphan ) is similar to hydromorphone except that it adds a hydroxyl ( OH) group to the 14-carbon position. Hydromorphone is a potent semi-synthetic opiate. Although it is available as a stand-alone agent, it is the P450 2D6 metabolite of hydrocodone.26 Hydromorphone, when used in patient-controlled analgesia (PCA) models, has been measured to be three times more potent than morphine.27 This result differs from single-dose studies, which would imply that hydromorphone is 58 times more potent than morphine.28 The reasons for these differences are unclear, but hydromorphones metabolism over time in PCA use may account for the discrepancy. Similar to morphine, hydromorphone is minimally metabolized by P450 enzymes. However, there is some reduction by an enzyme (currently named by its function, dihydromorphinone ketone reductase) at the 6-carbon position to form dihydromorphone and its isomer, dihydroisomorphone. Neither compound is active an as analgesic in humans. Most hydromorphone is glucuronidated at the 3-carbon to form hydromorphone-3-glucuronide (H3G) via the UGT enzymes 1A3 and 2B7.2,29,30 Other UGT enzymes may be involved. The pharmacological activity of H3G in humans has not been established, but in rats it has been shown to be excitatory and can lead to seizures.31 Smith6 postulated that the observation in chronic pain patients of a decreased efcacy with hydromorphone is because of increasing H3G levels and proposed alternating hydromorphone with other non-morphine-like analgesics to avoid this problem. H3G/hydromorphone ratios in cancer patients have been measured to average 27:1 in steady state,32 so knowledge of this metabolites effects on the human CNS would be important to knowunfortunately, little is actually known. No evidence to date indicates that hydromorphone inhibits or induces any enzymes. In addition, there is very little literature to indicate what occurs to hydromorphones efcacy when UGT enzymes are inhibited or induced by other drugs. However, there is some evidence that hydrocodone is a weaker analgesic than hydromorphone, and, therefore, efcacy of hydrocodone may be dependent on P450 2D6 activity (converting it to hydromorphone), since little glucuronidation occurs with hydrocodone.33 Oxymorphone is metabolized in a similar way as hydromorphone, with UGT 2B7 being the primary one creating the 6-glucuronide and reduction of the 6-carbon keto group by an unidentied enzyme (see hydromorphones metabolism above).29,34 It is only a parenteral medication, unlike morphine and hydromorphone. Very little has been published about the potential for pharmacokinetic drug interactions with oxymorphone. Oxymorphone is the P450 2D6 metabolite product of oxycodone. However, unlike the problem with hydrocodone/hydromorphone, oxycodone is a potent analgesic itself, so decreasing P450 2D6 activity should not reduce oxycodones efcacy. Summary Morphine, hydromorphone, and oxymorphone are not oxidatively metabolized by P450 enzymes. Therefore, inhibition/induction or genetic polymorphisms of P450 enzymes should have little to no effect on the metabolism/ clearance of these drugs. Hydromorphone and oxymorphone are reduced by an unidentied enzyme(s). Drug interactions with this enzyme(s) are unknown. Morphine, hydromorphone, and oxymorphone are principally metabolized by UGT enzymes, which add a glucuronic acid moiety to the drugs. UGT enzymes typically inactivate drugs. Morphine is an exception. Morphine is converted to morphine-6-gluconate (M6G) in small quantities, but M6G is up to 50 times more potent than morphine. In addition, another metabolite, created in greater quantities than M6G, morphine-3-gluconate (M3G), has no analgesic properties but may have CNS toxicity that includes irritability. Studies have shown that other drugs that alter UGT activity by inhibition or induction can change morphine, M3G, and M6G levels and alter analgesic efcacy. These studies are few, however, and are not always consistent with theory. Studies with hydromorphone and oxymorphone drug-drug interactions are scant; however, hydromorphone3-gluconate (H3G), hydromorphones main UGT metabolite, may also be toxic to the CNS and ultimately decrease efcacy of hydromorphone with chronic use.

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