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PK and Interactions of Opioids 1

PK and Interactions of Opioids 1

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Published by: Rachel Hannah on Jul 18, 2011
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Med-Psych Drug-Drug Interactions Update
Psychosomatics 44:2, March-April 2003 167
Pharmacokinetic Drug Interactions of Morphine, Codeine, andTheir Derivatives: Theory and Clinical Reality, Part I
C. A
, M.D.K
L. C
, M.D.
Pharmacokinetic drug-drug interactions with morphine, hydromorphone, and oxymorphone arereviewed in this column. Morphine is a naturally occurring opiate that is metabolized chieflythrough glucuronidation by uridine diphosphate glucuronosyl transferase (UGT) enzymes in theliver. These enzymes produce an active analgesic metabolite and a potentially toxic metabolite. Invivo 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 interactionscould change analgesic efficacy. Hydromorphone and oxymorphone, close synthetic derivatives of morphine, are also metabolized primarily by UGT enzymes. Hydromorphone may have a toxicmetabolite 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.
(Psychosomatics 2003; 44:167–171)
Dr. Armstrong is the Co-Medical Director, Center for Geriatric Psychia-try, Tuality Forest Grove Hospital, Forest Grove, Ore., and AssociateProfessor 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, Washing-ton, D.C., and Assistant Professor ofPsychiatry, UniformedServicesUni-versity of the Health Sciences, Bethesda, Md. Address correspondence toDr. Armstrong, Tuality Forest Grove Hospital, 1809 Maple St., ForestGrove, 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 official or as reflecting theviews of the Department of the Army or the Department of Defense.Copyright
2003 The Academy of Psychosomatic Medicine.
he narcotic analgesics can be categorized into threegroups. Two of the groups are synthetic chemicals:phenylpiperidines (e.g., meperidine [Demerol
] and fen-tanyl) and pseudopiperidines (e.g., methadone and pro-poxyphene [Darvon
]). The third group is related to thenaturally occurring alkaloids from the seeds of the poppyplant. These naturalopiumderivatives includeheroin,mor-phine, and codeine. Semi-synthetic derivatives from thisgroup include hydromorphone (Dilaudid
), oxymorphone(Numorphan
), hydrocodone (e.g., Vicodin
among oth-ers), oxycodone (e.g., OxyContin
and Percocet
), dihy-drocodeine, and buprenorphine (Buprenex
).This is the first of a two-part series. In this issue, thepharmacokinetic properties of morphine and its closely re-lated synthetic congeners, hydromorphone and oxymor-phone, will be reviewed. Emphasis in this report will beplaced on the enhancing or inhibiting of their metabolismby other drugs, which could potentially altertheiranalgesicefficacy. Part II, which will appear in an upcoming issue,will review codeine and related compounds (dihydroco-deine, hydrocodone, and oxycodone) and their pharmaco-kinetic drug-drug interaction profiles. Morphine and mor-phine derivatives also have the potential for pharmaco-dynamic drug interactions, but these interactions will not bediscussed in this series.The chemical structure ofmorphineis shown inFigure1. The 3 and 6 carbon atoms along with the 17 nitrogen(N) position are the three sites that have various substitu-tions of ester (
OCX2), hydroxyl (
OH), keto (
O),and methyl (
CH3) groups, creating other natural or syn-thetic opiate drugs. Morphine, as noted above, has hy-droxyl groups at the 3 and 6 carbons and a methyl groupat the 17 (N) position. Codeine simply adds a methylgroup
Med-Psych Drug-Drug Interactions Update
168 Psychosomatics 44:2, March-April 2003
FIGURE 1. Chemical Structure of Morphine
on the 3
position hydroxyl group of morphine (
OCH3attached to the 3-position carbon). Other synthetic narcot-ics have changes in the 3, 6, and 17 positions as well ashave a single bond between carbon 7 and 8.The 3, 6, and 17 positions are also the primary areasof oxidative (P450) metabolism. The 3 and 6 positions areoften referred to as the “O” site and “N” sites, respectively,in regards to oxidative P450 metabolism (based on theproximity of the 3 carbon to the oxygen atom and the 6carbon to the nitrogen atom of a separate ring). The liter-ature can be confusing, however, as the 17 position is alsoat times referred to as the “N” position. Whether or not theP450 enzymes are involved in the oxidative metabolism of a particular morphine derivative, the 3 and 6 positions arealso the main sites for conjugation with glucuronic acid byvarious phase 2 uridine diphosphate glucuronosyl transfer-ase (UGT) enzymes.MorphineMorphine is metabolized chiefly through glucuroni-dation. The P450 enzymes do not appear to be greatly in-volved in morphine’smetabolism.UGT2B7andUGT1A3are the major enzymes involved in the glucuronidation of morphine.
Although there is probably overlap, UGT2B7 primarily produces the6-conjugateandUGT1A3pro-duces the 3-conjugate. Both enzymes also create a com-bination 3/6 conjugate.The 3-conjugate (M3G) is usually made in moreabun-dance than the 6-conjugate(M6G) and isessentiallydevoidof any opioid analgesic activity.
Indeed, it may causeCNS neuroexcitatoryeffects,
andincreasingitsproductioncould lessen the overall desired analgesia. Chronic high-dose exposure to morphine has been shown to decreaseefficacy of morphine for pain, and Smith
hypothesizedthat increasing levels of M3G are to blame—even whendrug interactions are not suspected. Smith
supported theidea of rotating analgesics to avoid this problem (thiswould include rotating with non-morphine-like opiates,such as fentanyl, since even hydromorphone may alsohavethis problem).In contrast, M6G is more potent as an analgesic thanmorphine itself,
50 times
more potent.
M6G hasbeen proposed as a possible future parenteral analgesic,
and several studies have found significant analgesic effi-cacy with M6G through the intravenous route.
Nebu-lized M6G is poorly absorbed and is therefore a poor routefor delivery of M6G. The oral route of M6G has poor bio-availability
and is metabolized in the gut back to mor-phine, which is subsequently re-conjugated again by UGT2B7. Hence, the oral route of M6G may not offer any ad-vantage to oral morphine. Similarly, when oral/parenteralmorphine is metabolized to M6G in the liver, it undergoesenterohepatic circulation/recycling,
which can slow theeffective clearance of the drug as it recycles itself frommorphine to M6G back to morphine.Although there is genetic variability (polymorphisms)of the UGT enzymes 2B7 and 1A3, this variability has notyet clearly been shown to alter levels of production of M3G/M6G or to change the efficacy of patient response toanalgesia from morphine.
Because morphine’s clearance is dependent on UGTenzymes, it should not be a surprise that other drugs thatinhibit or induce UGT enzymes could affect the levels of morphine, M3G, or M6G—thus changing its analgesic ef-ficacy or side effect profile. However, the UGT enzymesare not as well understood as are the P450 enzymes,
andwell-designed in vivo studies that have looked into mor-phine’s pharmacokinetic drug-drug interaction profile arefew. A list of potential drugs that can inhibit/induceUGTs can be found at www.mhc.com//Cytochromes// UGT//index.html.Theoretically, inhibiting UGT 2B7 could decreasemorphine’s efficacy, since M6G levels would bedecreased.Another possible outcome would be that UGT 2B7 inhi-bition would increase morphine’s efficacy because of anincrease in parent drug levels. Inducing the enzyme mightincrease morphine’s efficacy by increasing production of M6G or decrease the efficacy by reducing the levels of theparent drug. To complicate matters, induction could in-crease M3G levels, which could lead to a decrease in ef-ficacy by increasing the levels of the toxic M3G. In otherwords, any scenario seems possible!As expected,theclini-
Med-Psych Drug-Drug Interactions Update
Psychosomatics 44:2, March-April 2003 169
TABLE 2. Morphine, Hydromorphone, and Oxymorphone MetabolismDrugP450 EnzymeMetabolismUGT and Other EnzymeMetabolismUGT 2B7 Inhibitionor InductionToxicMetabolitesActiveMetabolites
Morphine Negligible 1A3 and 2B7 Moderate inhibition M3G M6GHydromorphone
)1A3, 2B7, and reduced bydihydromorphinone ketonereductaseH3G
)2B7, other UGTs, and byunspecified reductase
P450 2D6 product of hydrocodone.
Possible, but more research necessary to confirm.
P450 2D6 product of oxycodone.
TABLE 1. Summary of In Vivo Studies of Drug-Drug Interactions With MorphineAuthorsDrug Used WithMorphine Study Design Results Comments
Fromm et al.
Rifampin Ten healthy volunteers; double-blind, placebo-controlled,crossover design; morphine,10 mg, given alone and thenafter 13 days of exposure torifampin, 600 mg/day; painthresholds and drugpharmacokinetics measuredAfter rifampin exposure, AUCof morphine, M3G, and M6Gdecreased; pain thresholdsbecame similar to placeboAlthough rifampin did decreaseefficacy of morphine, thedecrease in AUC of UGTmetabolites M3G and M6Gsuggests possible mechanismsother than induction of UGTenzymesAasmundstad andStorset
Ranitidine Eight healthy volunteers; double-blind, placebo-controlled,crossover design; ranitidine—potential inhibitor of UGT—added to morphine andpharmacokinetics measuredRanitidine decreased serumM3G/M6G ratio and increasedAUC of morphinePossible evidence of ranitidineinhibiting UGT 2B7 and 1A3Tighe et al.
Diclofenac A single 100-mg dose of diclofenac, a potential UGTinhibitor, was given to sevenpost-op patients controllingtheir own morphineadministrationMorphine consumptiondecreased by 20%, but levelsof M6G were unchangedUnknown mechanism—perhapsinhibition of renal clearance of M6G rather than UGTinhibition
cal evidence for the consequences of these interactions arefar from clear. Table 1 provides a summary of the only invivo human studies of morphine used concomitantly withother known inhibitors/inducers. The results are interest-ing, but we do not believe they give the clinician at thistime a firm ability to predict or generalize other potentialdrug-drug interactions.Since the UGT enzymes are induced by phenobarbital,one might conceive of an in vivo study trying to correlatemorphine and metabolite levels with analgesic efficacy.However, such a study would be complicated by the over-whelming pharmacodynamic CNS interaction of morphineand phenobarbital, making any conclusions difficult.In vitro studies suggest that morphine’s metabolismcan be altered through drugs that inhibit UGT enzymes.Wahlstrom et al.
demonstrated that amitriptyline,nortrip-tyline, and clomipramine all inhibit UGT enzymes and de-crease the formation of M3G and M6G. Chloramphenicoland diazepam may also inhibit morphines glucuronida-tion.
Similarly, morphine itself may competitively in-hibit UGT 2B7.Finally, it has been hypothesized that morphine is a P-glycoprotein (P-gp) substrate
and that pharmacokineticP-gp inhibition could enhance analgesic effects by allow-ing more morphine through the blood-brain barrier.
Theonly study to date looking at this possible potentiation wasdone by Drewe et al.
who used the P-gp inhibitor val-spodar in 18 healthy comparison subjects concomitantlyusing morphine. The result revealed only slight and prob-ably clinically insignificant changes in CNS morphine ef-

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