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`Library of Congress Cataloging-in-Publication Data
`
`Karch, Steven B.
`Karch’s pathology of drug abuse / StevenB. Karch. -- 4th ed.
`p.;em.
`Includes bibliographical references and index.
`ISBN 978-0-8493-7880-5 (hardcover : alk. paper)
`1. Drug abuse--Pathophysiology. 2, Drugs of abuse--Toxicology.
`abuse.
`
`I. Title. I. Title: Pathology of drug
`
`(DNLM: 1. Substance-Related Disorders--physiopathology. 2. Anabolic Agents--adverse effects.
`3. Cocaine--adverse effects. 4. Designer Drugs--adverse effects. 5. Narcotics--adverse effects. 6.
`Substance-Related Disorders--history. WM 270 K18k 2009]
`RM316.K37 2009
`615'.78--de22
`
`2008039584
`
`Visit the Taylor & Francis Website at
`http://www.taylorandfrancis.com
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`http://www.crepress.com
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`This material may be protected by Copyrightlaw (Title 17 U.S. Code)
`
`436
`
`Karch’s Pathology of Drug Abuse
`
`French law was changed in 1996 to allow generalpractitioners to prescribe buprenor-
`phineto heroin addicts. As in the U.S., French law limits methadoneprescribingto special
`government-controlled centers. When the law wasfirst changed, there were concerns that
`toxicity and lethal outcomes mightbe more frequent with buprenorphine than methadone.
`The results of recent studies indicate, however, that death rates with methadonereplace-
`menttherapyare nearly three times higher than with buprenorphine (Auriacombeetal.,
`2001).
`
`5.9.1.2 Pharmacology
`Like morphine,but unlike mostother opioids, the major metabolic pathway for buprenor-
`phineis glucuronidation, not oxidation. Microsomal oxidation does occur (CYP3A), but
`only modest amounts of norbuprenorphine are produced (Coneet al., 1984). Except in
`the presence of end-stage liver disease, glucuronidation is generally not impaired byliver
`disorders, which means that buprenorphine pharmacokinetics are not affected either
`(Tegederet al., 1999), and that it can be given to patients with renal failure (Boger, 2006).
`Free buprenorphineis not detected in urine, although the glucuronides can be detected
`in the urine for up to four days, and both of the glucuronides can be detected in feces,
`after either oral or sublingual administration,for as long as a weekafter ingestion.Thisis
`because of extensive enterohepatic circulation (Coneet al., 1984).
`Buprenorphinecanbegiven by anyroute,but because there is very great inter-individ-
`ual variability in bioavailability, resultant peak plasma concentrations may vary widelyas
`well (51.4 and 27.8% for sublingual and buccalroutes, respectively) (Kuhlman etal., 1996).
`Studies in humansare lacking, but measurements in animals showthat after nasal admin-
`istration bioavailability is very high, and maximal plasma concentrations occur almostas
`rapidly as after parenteral administration (Lindhardtet al., 2000). This observation raises
`the possibility that buprenorphine could be abused by“snorting.”
`Plasma concentrationsof0.5 ng/mLaresufficient to produce surgical analgesia (Amani
`et al., 1997). In three studies, opioid naive healthy male subjects received Subutex® tablets
`(buprenorphine 2 and 8 mg [n = 27] or 12 and 16 mg [n = 27]) or Suboxone® (two for-
`mulations) tablets (buprenorphine 8 mg/naloxone 2 mg [n = 36]) sublingually, under a
`naltrexone block for assessment of buprenorphine pharmacokinetics andtablet disintegra-
`tion times. Maximum plasmavalues ranged from 1.6 to 6.4 ng/mL andT,,,, from 0.5 to
`3 hours. Largefluctuations in plasmalevels after eating were observed, strongly support-
`ing the role of enterohepatic recirculation in buprenorphine users. The terminalhalf-life
`in these studies was approximately 26 hours (range 9-69). The results of earlier work had
`suggested that, during daily buprenorphine maintenancetherapy, plasma concentrations
`neededto be greater than 0.7 ng/mLto beeffective. More recent studies suggest that the
`number maybesignificantly lower.
`Interaction with HIV medications is possible. N-dealkylation of buprenorphine
`is mediated by P-450 CYP3A4 (Cowan, 2003). With each year it becomes increasingly
`clear that interactions do occur andthat antiretrovirals and buprenorphine competefor
`the same enzyme. In vitro buprenorphine inhibits CYP3A4 and other CYP enzymesas
`well. The concurrent administration of buprenorphine with some protease inhibitors
`can lowerlevels of buprenorphine(Iribarneet al., 1998a; Bruce and Altice, 2006). Indi-
`navir can prevent > 85% of buprenorphine’s dealkylation (Iribarne et al., 1998a). As a
`consequence, concentrations of buprenorphine maybe greatly increased whenitis given
`with an antiretroviral. Ketoconazole and other imidazole derivatives are well known
`0003
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`

`Opiates and Opioids
`
`437
`
`inhibitors of buprenorphine dealkylation (Iribarneet al., 1997), as are some antidepres-
`sants, especially SSRIs such as fluoxetine and fluvoxamine(Regieretal., 1990; Iribarne
`et al., 1998b). There have been reportsoffatal interactions between buprenorphine and
`some benzodiazepines (Reynaudet al., 1998; Tracquiet al., 1998a; Gaulier et al., 2000),
`especially diazepam andflunitrazepam.It is believed that whenopiate users take both
`together they enhance the possibility of respiratory depression, though this mechanism
`has never been proven.
`The clinical effectiveness of any opioid maintenance regimen for heroin dependence
`is believed to result from a medication’s ability to decrease [1-opioid receptor availability,
`preventing heroin (or other opioids) from binding to them, and preventing,or atleast
`attenuating, withdrawal symptoms These findings suggest that high-dose buprenor-
`phine maintenance produces near-maximal pL receptor occupation, and pt receptoravail-
`ability correlates well with plasma levels; buprenorphine-related opioid symptoms and
`antagonist blockade exhibit concentration-effect relationships. Other studies have shown
`that buprenorphine, unlike morphine, does not depress immuneresponsesoractivate the
`hypothalamic-pituitary-adrenal axis (Gomez-Flores and Weber, 2000).
`In animalstudies, buprenorphine treatmentcausesa statistically significant butclini-
`cally insignificant change in pulse and blood pressure (Martinezetal., 1997). In patients
`undergoing open-heart procedures with cold cardioplegia, pretreatment with buprenor-
`phineis cardioprotective; postoperatively there is improved metabolism and higher car-
`diac output. The protective effect is in some wayrelatedto activation of 1 opiate receptors
`(Boachie-Ansahet al., 1989), and thereis interest in the use of this drug as an adjunct
`during heart surgery.
`
`§.9.1.3. Detection
`Buprenorphine is quickly cleared from the urine andit is many times more potent than
`morphine, which meansthat detection could be problematic. Earlier methodologiesusing
`radioimmunoassays could not separate parent from metabolite and were unreliable. A
`numberof reagent makers now produce ELISA kits, though these kits are expensive, and
`tandem mass spectrometry would seem to offer a better alternative. Buprenorphine can
`usually, but not always, be detected in hair samples, at concentrations ranging from 6 to
`597 ng/g (mean, 137 ng/g) (Tracqui et al., 1998a). It is very stable in refrigerated blood
`samples, with recovery rates of more than 70% after 6 months of storage (Hadidi and
`Oliver, 1998).
`
`5.9.1.4 Drug Concentrations
`When measured in postmortem blood,concentrations of buprenorphine andits primary
`metabolite norbuprenorphine range from 1.1 to 29.0 ng/mL (mean,8.4 ng/mL) and0.2
`to 12.6 ng/mL (mean,2.6 ng/mL), respectively. As is true for morphine and heroin, these
`concentrations overlap those that have been reported in clinical settings, where there is
`no evidenceof toxicity. Somewhat surprisingly, given the high degree of buprenorphine
`protein binding, extensive tissue distribution occurs. Buprenorphine accumulatesin bile,
`where concentrations may reach values of more than 75 mg/L. Norbuprenorphine seems
`to have the same pattern of distribution as the parent compound, although measured
`concentrationsare generally very much lower than thoseof the parent compound.
`0004
`
`0004
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`