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Psychosomatics 44:167-171, April 2003
© 2003 The Academy of Psychosomatic Medicine

Pharmacokinetic Drug Interactions of Morphine, Codeine, and Their Derivatives: Theory and Clinical Reality, Part I

Scott C. Armstrong, M.D., and Kelly L. Cozza, M.D.

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{at}tuality.org (e-mail).
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.

ABSTRACT

Pharmacokinetic drug-drug interactions with morphine, hydromorphone, and oxymorphone are reviewed in this column. Morphine is a naturally occurring opiate that is metabolized chiefly 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 efficacy. 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 difficult to make conclusions with these drugs.

Key Words: Drug-Drug Interactions

The 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 first 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 efficacy. 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 profiles. Morphine and morphine 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 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.



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FIGURE 1. Chemical Structure of Morphine


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 chiefly through glucuronidation. The P450 enzymes do not appear to be greatly involved in morphine's metabolism. UGT 2B7 and UGT 1A3 are the major enzymes involved in the glucuronidation of morphine.1–3 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 high-dose exposure to morphine has been shown to decrease efficacy of morphine for pain, and Smith6 hypothesized that increasing levels of M3G are to blame—even 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 significant analgesic efficacy 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 bio-availability11 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 efficacy of patient response to analgesia from morphine.13,14

Because morphine's 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 M6G—thus changing its analgesic efficacy or side effect profile. 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 morphine's pharmacokinetic drug-drug interaction profile 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 morphine's efficacy, since M6G levels would be decreased. Another possible outcome would be that UGT 2B7 inhibition would increase morphine's efficacy because of an increase in parent drug levels. Inducing the enzyme might increase morphine's efficacy by increasing production of M6G or decrease the efficacy by reducing the levels of the parent drug. To complicate matters, induction could increase M3G levels, which could lead to a decrease in efficacy by increasing the levels of the toxic M3G. In other words, any scenario seems possible! As expected, the clinical 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 firm ability to predict or generalize other potential drug-drug interactions.


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TABLE 1. Summary of In Vivo Studies of Drug-Drug Interactions With Morphine



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 efficacy. However, such a study would be complicated by the overwhelming pharmacodynamic CNS interaction of morphine and phenobarbital, making any conclusions difficult.

In vitro studies suggest that morphine's 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 morphine's glucuronidation.20,21 Similarly, morphine itself may competitively inhibit UGT 2B7.

Finally, it has been hypothesized that morphine is a P-glycoprotein (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 insignificant changes in CNS morphine effects. 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 5–8 times more potent than morphine.28 The reasons for these differences are unclear, but hydromorphone's 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 efficacy 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 metabolite's effects on the human CNS would be important to know—unfortunately, 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 hydromorphone's efficacy 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, efficacy 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 unidentified enzyme (see hydromorphone's 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 oxycodone's efficacy.

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 unidentified 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 efficacy. These studies are few, however, and are not always consistent with theory. Studies with hydromorphone and oxymorphone drug-drug interactions are scant; however, hydromorphone-3-gluconate (H3G), hydromorphone's main UGT metabolite, may also be toxic to the CNS and ultimately decrease efficacy of hydromorphone with chronic use.


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TABLE 2. Morphine, Hydromorphone, and Oxymorphone Metabolism



REFERENCES

  1. Coffman BL, Rios GR, King CD, Tephly TR: Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos 1997; 25:1-4[Abstract/Free Full Text]
  2. Green MD, King CD, Mojarrabi B, Mackenzie PI, Tephly TR: Glucuronidation of amines and other xenobiotics catalyzed by expressed human UDP-glucuronosyltransferease 1A3. Drug Metab Dispos 1998; 26:507-512[Abstract/Free Full Text]
  3. Donnelly S, Davis MP, Walsh D, Naughton M: Morphine in cancer pain management: a practical guide. Support Care Cancer 2002; 10:13-35[CrossRef][Medline]
  4. Penson RT, Joel JP, Bakhshi K, Clark SJ, Langford RM, Slevin ML: Randomized placebo-controlled trial of the activity of the morphine glucuronides. Clin Pharmacol Ther 2000; 68:667-676[CrossRef][Medline]
  5. Penson RT, Joel SP, Clark S, Gloyne A, Slevin ML: Limited phase I study of morphine-3-glucuronide. J Pharm Sci 2001; 90:1810-1816[CrossRef][Medline]
  6. Smith MT: Neurotoxicity effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites. Clin Exp Pharmacol Physiol 2000; 27:524-528[CrossRef][Medline]
  7. Lotsch J, Geisslinger G: Morphine-6-glucuronide: an analgesic of the future? Clin Pharmacokinet 2001; 40:485-499[CrossRef][Medline]
  8. Christrup LL: Morphine metabolites. Acta Anaesthesiol Scand 1997; 41(1, part 2):116-122
  9. Buetler TM, Wilder-Smith OH, Wilder-Smith CH, Aebi S, Cerny T, Brenneisen R: Analgesic action of i.v. morphine-6-glucuronide in healthy volunteers. Br J Anaesth 2000; 84:97-99[Abstract/Free Full Text]
  10. Murthy BR, Pollack GM, Brouwer KL: Contribution of morphine-6-glucuronide to antinociception following intravenous administration of morphine to healthy volunteers. J Clin Pharmacol 2002; 42:569-576[Abstract]
  11. Penson RT, Joel SP, Roberts M, Gloyne A, Beckwith S, Slevin ML: The bioavailability and pharmacokinetics of subcutaneous, nebulized, and oral morphine-6-glucuronide. Br J Clin Pharmacol 2002; 53:347-354[CrossRef][Medline]
  12. Hasselstrom J, Sawe J: Morphine pharmacokinetics and metabolism in humans. Enterohepatic cycling and relative contribution of metabolites to active opioid concentrations. Clin Pharmacokinet 1993; 24:344-354[Medline]
  13. Coffman BL, King CD, Rios GR, Tephly TR: The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268). Drug Metab Dispos 1998; 26:73-77[Abstract/Free Full Text]
  14. Holthe M, Klepstad P, Zahlsen K, Borchgrevink PC, Hagen L, Dale O, Kaasa S, Krokan HE, Skorpen F: Morphine glucuronide-to-morphine plasma ratios are unaffected by the UGT2B7 H268Y and UGT1A1*28 polymorphisms in cancer patients on chronic morphine therapy. Eur J Clin Pharmacol 2002; 58:353-356[CrossRef][Medline]
  15. Armstrong SC, Cozza KL, Oesterheld JR: Med-Psych Drug-Drug Interactions Update. Psychosomatics 2002; 43:77-81[Free Full Text]
  16. Fromm MF, Eckhardt K, Li S, Schanzle G, Hofmann U, Mikus G, Eichelbaum M: Loss of analgesic effect of morphine due to coadministration of rifampin. Pain 1997; 72(1-2):261-267
  17. Aasmundstad TA, Storset P: Influence of ranitidine on the morphine-3-glucuronide to morphine-6-glucuronide ratio after oral administration of morphine in humans. Hum Exp Toxical 1998; 17:347-352[CrossRef]
  18. Tighe KE, Webb AM, Hobbs GJ: Persistently high plasma morphine-6-glucuronide levels despite decreased hourly patient-controlled analgesia morphine use after single-dose diclofenac: potential for opioid-related toxicity. Anesth Analg 1999; 88:1137-1142[Abstract/Free Full Text]
  19. Wahlstrom A, Lenhammar L, Ask B, Rane A: Tricyclic antidepressants inhibit opioid receptor binding in human brain and hepatic morphine glucuronidation. Pharmacol Toxicol 1994; 75:23-27[Medline]
  20. Yue Q, von Bahr C, Odar-Cederlof I, Sawe J: Glucuronidation of codeine and morphine in human liver and kidney microsomes: effect of inhibitors. Pharmacol Toxicol 1990; 66:221-226[Medline]
  21. Grancharov K, Naydenova Z, Lozeva S, Golovinsky E: Natural and synthetic inhibitors of UDP-glucuronosyltranferase. Pharmacol Ther 2001; 89:171-186[CrossRef][Medline]
  22. Crowe A: The influence of P-glycoprotein on morphine transport in Coca-2 cells. Comparison with paclitaxel. Eur J Pharmacol 2002; 440:7-16[CrossRef][Medline]
  23. Armstrong SC, Cozza KL: Consultation-Liaison Psychiatry Drug-Drug Interactions Update. Psychosomatics 2001; 42:269-272[Free Full Text]
  24. Drewe J, Ball HA, Beglinger C, Peng B, Kemmler A, Schachinger H, Haefeli WE: Effect of P-glycoprotein modulation on the clinical pharmacokinetics and adverse effects of morphine. Br J Clin Pharmacol 2000; 50:237-246[CrossRef][Medline]
  25. Yu DK: The contribution of P-glycoprotein to pharmacokinetic drug-drug interactions. J Clin Pharmacol 1999; 39:1203-1211[Abstract]
  26. Otton SV, Schadel M, Cheung SW, Kaplan HL, Busto UE, Sellers EM: CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone. Clin Pharmacol Ther 1993; 54:463-472[Medline]
  27. Dunbar PJ, Chapman CR, Buckley FP, Gavrin JR: Clinical analgesic equivalence for morphine and hydromorphone with prolonged PCA. Pain 1996; 68(2-3):265-270
  28. Sarhill N, Walsh D, Nelson KA: Hydromorphone: pharmacology and clinical applications in cancer patients. Support Care Cancer 2001; 9(20):84-96
  29. Radominska-Pandya A, Czernik PJ, Little JM, Battaglia E, Mackenzie PI: Structural and functional studies of UDP-glucuronosyltransferases. Drug Metab Rev 1999; 31:817-899[CrossRef][Medline]
  30. Dilaudid® (Hydromorphone hydrochloride), Abbott Laboratories N. Chicago, IL December, 2001
  31. Wright AW, Nocente ML, Smith MT: Hydromorphone-3-glucuronide; biosynthesis and preliminary pharmacological evaluation. Life Sci 1998; 63:401-411[CrossRef][Medline]
  32. Hagen N, Thirlwell MP, Dhaliwal HS, Babul N, Harsanyi Z, Darke AC: Steady-state pharmacokinetics of hydromorphone and hydromorphone-3-glucuronide in cancer patients after immediate and controlled-release hydromorphone. J Clin Pharmacol 1995; 35:37-44[Abstract]
  33. Cone EJ, Darwin WD, Gorodetzky CW, Tan T: Comparative metabolism of hydrocodone in man, rat, guinea pig, rabbit, and dog. Drug Metab Dispos 1978; 6:488-493[Abstract]
  34. Numorphan® (Oxymorphone hydrochloride), Endo Pharmaceuticals Inc., September 1999



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