Intoxicación opioides

8/17/2019 Intoxicación opioides

1/24

HISTORY AND INTRODUCTION

Opium, one of the oldest known pharmacologic agents,is derived from the poppy Papaver somniferum . TheSumerians first reported the psychotherapeutic benefits

of juice from immature poppy heads about 4000 BC.Opium solutions contained morphine, codeine, andnumerous other related alkaloids. In 1806, morphine

was isolated from opium by Sertürner. Other alkaloids were later isolated, including codeine in 1832 by Robiquet and papaverine in 1848 by Merck. Morphine

was soon recognized to be as addictive as opium. Attempts were made to increase morphine’s antinoci-ceptive and antidiarrheal properties while decreasingtolerance and dependence. The result was Dreser’ssynthesis of diacetylmorphine (heroin) in 1898.

The existence of specific opioid receptors wasdefinitively established in 1973 by Snyder and colleaguesin the United States and Terenius and colleagues in

Sweden. In 1975, Kosterlitz and Hughes identified twoendogenous pentapeptides with morphine-like activity—the leu-enkephalin and the met-enkephalin—openingthe door to the characterization of additional endoge-nous ligands. Work continues on opioid receptors

with the aim of improving our understanding of theirbiopharmacology and manipulating the beneficialeffects of opioids, while reducing their undesirableconsequences.

The term opiate specifically refers to all naturally occurring alkaloids derived from opium, including

morphine, 6-mono-acetyl-morphine, codeine, codethyline,and pholcodine. In contrast, the term opioid refers to alldrugs, natural or synthetic, with morphine-like actions oractions mediated through binding to opioid receptors.This chapter focuses on the clinical issues concerningthe acute and chronic toxicology of opioids andappropriate treatment relevant to current clinicalpractice.

EPIDEMIOLOGY

The dangers of opioid overdose have been recognizedfor as long as the use of opium itself. Overdose from

illicit opioid use has increased in many countries overthe past decade,1 as has the illicit production, trans-portation, and consumption of opioids, especially heroin. Higher production, increasing purity, and lowerprices have considerably contributed to the worldwideexpansion of opioid use. Higher heroin purity enablesusers to smoke or snort rather than inject it, contributingto widespread popularity, illustrated by a recently reported epidemic of heroin use.2 Changes in the routeof opioid administration over time may occur in relationto opioid tolerance or drug purity increase. Heroin vaporinhalation produced by heating heroin on aluminum foilis increasingly common. The majority of drug userscurrently entering treatment programs are noninjectors.

There is a trend toward multidrug use, with attendant drug-drug interactions and the risk of polyintoxication.In 2004, the Substance Abuse and Mental Health

Services Administration (SAMHSA) and the Drug Abuse Warning Network (DAWN) estimated that 19.1 million Americans ages 12 or older (about 7.9% of the popu-lation) were current illicit drug users.3 However, theprevalence of heroin use remains low in the generalpopulation when compared with alcohol, tobacco, orcannabis. Typically, less than 2% of the adult populationhas ever used heroin, and less than 1% is dependent onheroin. An estimated 300,000 persons in the UnitedStates suffer from heroin dependence or abuse (Fig.33-1), and 118,000 persons have used heroin for the first

time within the past 12 months with an average age of initiation at 24 years. The number of injectors has beenestimated to be about 5.3 million worldwide, whichappears to be constant. For 2003, the American Associ-ation of Poison Control Centers (AAPCC) reported22,600 opioid overdoses among the 270,000 exposures toanalgesics (around 8%), which resulted in 213 of 656deaths (around 35%) attributed to this pharmacologicalclass.4

The SAMHSA reported 709,000 hospital facility visitsin 2004 related to illicit drug use, versus 638,484 in 2001

33 Opioids LUKE YIP, MD ■ BRUNO MÉGARBANE, MD, PHD ■ STEPHEN W. BORRON, MD, MS

635

At a Glance…

■ Opioids elicit the same overall physiologic effects as morphinebut may demonstrate conspicuous differences following anoverdose.

■ The classic “opioid toxidrome” (mental status depression,respiratory depression, miosis, and decreased bowel motility)may not be apparent following a mixed overdose.

■ Purity and adulterants play a considerable role in the outcomeand complications of heroin use.

■ Inhalation of heated heroin vapors may result in a progressivespongiform leukoencephalopathy.

■ Acute lung injury may occur following opioid overdose ornaloxone therapy.

■ Higher doses of naloxone may be required to antagonize the

effects of high-potency opioids (e.g., fentanyl and its analogs,methadone, pentazocine, propoxyphene, and diphenoxylate).■ Naloxone has a short half-life, and the effects of most opioids

will significantly outlast several doses of naloxone.■ Judicious use of naloxone infusion may obviate the need for

endotracheal intubation.


2/24

and 323,100 in 1978.3 This increase does not necessarily reflect an elevation in the number of heroin users, but rather a greater number of individuals seeking help.Emergency department admissions for opioid overdose

were estimated in the United States at 93,000 per year in2002 versus 72,000 in 1995. In contrast, heroin use isdecreasing in western Europe, with a rise in the meanage, presumably in relation to the widespread intro-duction of opioid maintenance treatment programs andto the development of dependence on other illicit drugs(cannabis, cocaine, and amphetamines). In France, for

example, traditional opiate use has decreased since 1996, when both prescribed and diverted buprenorphineappeared on the scene.5 In other countries, variouslocally produced opioids are used, including “home-back” in Australia and New Zealand, prepared withcodeine and other opiates; “kompot” in Poland, madefrom poppy straw; and “black water opium” in Vietnam.

Opioids represent the most lethal illicit drug, withmost of the fatalities occurring in young males, resultingin 33,662 potential years of life lost and 42 years of lifelost per death.6 A dependent heroin injector has a 20 to30 times greater estimated risk for premature death thana similar-aged non–drug-using person. In 1995, opioidoverdose deaths accounted for 76% of all deaths due to

illicit drug use and 9% of deaths among young adults15 to 44 years of age in Australia.2 In Glasgow, nearly athird of all deaths among young adults 15 to 35 years of age were related to opioids.7 However, after a rise in thesecond half of the 1980s, the number of overdose deathshas generally stabilized or declined in the majority of

Western countries.1,5 Nearly two thirds of all long-termheroin users have self-overdosed on heroin at least once.8

Mortality for opioid users in maintenance treatment isreduced (about four times), in comparison to opioidusers involved in opioid-related emergencies.9 Substi-

tution therapy with methadone, levomethadyl acetate,or buprenorphine may result in a substantial reductionin consumption of illicit opiate and psychoactivesubstances.10-12 However, deaths have been attributed tomaintenance treatment as well, in relation to theiroverdose or misuse. Deaths have been reported in relationto buprenorphine “overdose.”13-16 Forensic studiesconcluded that these deaths were due to asphyxia, with

the underlying cause attributed to misuse and/orcoadministration of psychotropic substances. Buprenor-phine is injected by some users, despite the labeling forsublingual use.17-19 However, despite an estimated 90,000patients treated with high-dose buprenorphine (8 to16 mg/day) in France since 1996, the number of significant reported side effects has been limited.5,20

Interestingly, it appears that a strict limitation on thenumber of patients per prescribing physician forbuprenorphine substitution programs has been asso-ciated with very limited abuse of the product since itslaunch in the United States in 2002.21 Similarly, most lethal methadone intoxications are due to diverted orillegal methadone, in association with medications or

other illicit drugs.22,23 Recent increases in methadoneprescription under strict medical control have not increased the number of lethal methadone intoxicationsbut may have contributed to a large decrease in overalldrug intoxication deaths.24

PHARMACOLOGY

The Various Opioid Molecules

Morphine is still obtained from opium or extracted frompoppy straw. A number of natural alkaloids are derivedfrom Papaver somniferum, including phenanthrenes

(morphine, codeine, and thebaine) and benzylisoquino-lines (papaverine, noscapine). Codeine is methylmor-phine. Thebaine, the precursor of several compoundssuch as oxycodone and naloxone, differs from morphinein the methylation of its two hydroxyl groups and thepresence of double bonds in the ring. Heroin is adiacetylmorphine, in the 3 and 6 positions. Hydromor-phone, oxymorphone, hydrocodone, and oxycodone arealso made by modifying the morphine molecule.Synthetic opioids can be structurally divided into fiveclasses: morphinans, phenylpiperidines, benzomorphans,methadones, and propionanilides. Levorphanol is theonly commercially available opioid agonist from themorphinan series. The phenylpiperidine family includes

meperidine, diphenoxylate, loperamide, fentanyl,sufentanil, alfentanil, and remifentanil. Methadone andpropoxyphene are structurally related opioids. Somepartial opioid antagonists are clinically used, includingpentazocine (a benzomorphan derivative), nalbuphine(structurally related to naloxone and oxymorphone),buprenorphine (a semisynthetic opioid derived fromthebaine), and meptazinol. Minor changes in thechemical structure may convert an agonist into anantagonist opioid, like nalorphine (derived frommorphine) or naloxone and naltrexone (both derived

636 CENTRAL NERVOUS SYSTEM

Heroin

Cocaine

Marijuana

Sedatives

Stimulants

Pain relievers

Alcohol

Hallucinogens

Tranquilizers

Inhalants

67.8

27.8

17.6

17.4

16.1

12.3

11.9

11.6

11.3

10.3

0 10 20 30

Percent of users with dependence onor abuse of specific substance

40 50 60 70

FIGURE 33-1 Comparative incidence of dependence or abuse ofspecific substances among past users of substances in the UnitedStates in 2004. (Courtesy of the Substance Abuse and MentalHealth Services Administration, http://www.icpsr.umich.edu/SAMHDA.)


3/24

CHAPTER 33 Opioids 637

PHARMACODYNAMICS

The clinically used opioids exert a common activity profile, mainly through opioid receptors. The centralanalgesic action of opioids is the most important property used in therapeutics.26 These antinociceptiveeffects are mediated through spinal and supraspinalopioid receptors. Analgesia occurs without loss of

consciousness. Given to patients in pain, opioids reducethe pain, while drowsiness commonly occurs andeuphoria may be experienced. Given to normal pain-free subjects, opioids may induce nausea, vomiting,drowsiness, apathy, or lessened physical activity.

Mood alterations including euphoria, tranquility, andrewarding properties may follow opioid administration.Their mechanism is still not clearly understood but seemsmediated by dopaminergic pathways, independently from those involved in physical dependence and analgesia.Pinpoint miosis is a near pathognomonic consequence of opioids on the parasympathetic innervation of pupils. Thecough reflex is depressed through a direct action on thecough center in the medulla. This antitussive action

represents the target effect of some opioid agents.Nausea and vomiting are caused by direct stimulation of the chemoreceptor trigger zone for emesis in the areapostrema of the medulla.

Opioids may be responsible for respiratory depres-sion, mainly by a direct effect on the brainstem respiratory centers. Opioids may also depress the pontine andmedullary centers involved in regulation of respiratory rhythmicity. With usual opioid doses, in the absence of underlying pulmonary or neurologic diseases, clinically significant respiratory depression is rare, unless otherpsychotropic or sedative medications are concomitantly used. Respiratory depression increases with the dose andis the incriminated mechanism of death following opioid

overdose. All phases of respiration may be depressed,including respiratory rate and tidal and minute volumes.Following an intravenous (IV) injection of morphine,maximal respiratory depression is obtained within 5 to10 minutes. High doses of certain opioids (fentanyl,alfentanil, remifentanil, and sufentanil) may produceacute muscular rigidity, involving the trunk and the chest

wall, sometimes compromising respiration. The mecha-nism for this is still debated and may involve basalganglia dopamine receptor blockade, 2-adrenergic or opioid receptor stimulation. In patients undergoinganesthesia, muscle rigidity may necessitate the adminis-tration of neuromuscular blocking agents to facilitatemechanical ventilation.

Endocrine effects have also been reported, includingthe inhibition of gonadotropin-releasing hormone andcorticotropin-releasing factor production, inducing adiminution in concentrations of luteinizing hormone,follicle-stimulating hormone, adrenocorticotropic hor-mone, and -endorphin circulating. Antidiuretic hormonerelease is also reduced. Opioids increase the musculartonus of the gastrointestinal (GI) tract and diminishperistaltic contractions. They also diminish biliary,pancreatic, and intestinal secretions, but increase analsphincter tone. Intestinal resting tone is increased and

from oxymorphone). These substitutions are critical indetermining agonist or antagonist properties, as well astheir interactions with the various opioid receptors.

A simple classification scheme including all opioids, whether clinically used or not, distinguishes naturalexogenous opioids, synthetic opioids, and endogenousopioids.

THE EXOGENOUS NATURAL OPIOIDSThis class includes opiates derived from Papaver somniferum , like morphine, as well as other animal-derived peptides, like deltorphines, extracted fromthe skin of South American frogs belonging to thePhyllomedusa genus and characterized by a high affinity to receptors.

THE SYNTHETIC OPIOIDSThis group may be subdivided into nonpeptide andpeptide-like molecules. The first subgroup includesmorphine derivatives, like heroin, buprenorphine,methadone, and etorphine (Fig. 33-2), as well as some selective agonists.

THE ENDOGENOUS OPIOIDSEndogenous opioids are naturally occurring peptides

with various types of opioid activity. They are producedafter the cleavage of high-molecular-weight precursors.This group includes endorphins, enkephalins, anddynorphins or neoendorphins. They are found at varioussites and in differing quantities throughout the centraland peripheral nervous system. Complex interactions

with multiple opioid receptors result in modulationof the response to painful stimuli. More recently, twotetrapeptides have been described and dubbed “endo-morphins” due to their high affinity to opioidreceptors, making them good candidates as endogenous

ligands of these receptors.25

Me

Me

MeO

HO

HO Prn

O

NMe

MeCOO

MeCOO

O

N

H

Me

MeO

HO

HO But

O

N Me

Me

Ph

Ph

Me

EtCO

N

Etorphin Heroin

MethadoneBuprenorphine

FIGURE 33-2 Chemical structures of the main opiate/opioidmolecules.


4/24

spasms may result. All these effects induce desiccationof the feces, leading to constipation and the therapeuticuse of some opioid compounds as antidiarrheic sub-stances. Opioids also increase bladder external sphinctertone, resulting in urinary retention, sometimes requiringbladder catheterization.

Opioid-related cardiovascular side effects are wellknown: mild reduction in blood pressure, risk for

orthostatic hypotension, or, uncommonly, bradycardia.Only propoxyphene is associated with significant cardio-

vascular toxicity due to sodium channel blockade.Opioids also induce peripheral vasodilatation at thera-peutic doses. The skin of the face, neck, and upper thoraxmay flush due to histamine liberation. The immunesystem also may be considered a potential therapeutictarget of opioids, including central immunomodulatory activity or direct effects on immune cells. This lattereffect is related to an activation of opioid receptorsexpressed on peripheral blood cells. Met-enkephalin and-endorphin may stimulate the chemotactic propertiesof neutrophils, monocytes, or lymphocytes. In contrast,morphine reduces the activity of natural killer lympho-

cytes and neutrophil activity. The latter immunosup-pressive effects appear to be mediated through receptors.27

Prolonged treatment with opioids may induce atolerance to their effect, characterized by the loss of theireffectiveness and the necessity to increase doses to obtainthe same effects. Dependence on opioids is responsiblefor the appearance of withdrawal when the opioidtherapy is abruptly stopped. Addiction results from analtered behavior with the compulsive use of opioids andan overwhelming need for their procurement and use.The molecular mechanisms of dependence and toleranceappear very complex, involving opioid and N -methyl-D-aspartate receptors. These pathways are physiologic

responses to opioid treatments and may be distinct fromthose involved in addiction.Morphine, tramadol, meperidine, fentanyl, and

related opioids are used primarily for their analgesicproperties. Codeine is used widely for its antitussiveaction. Given their dynamic and kinetic properties,methadone (with a long half-life) and buprenorphine(with partial agonist activity) are used as maintenancetherapies in heroin abusers. Naloxone, the therapeuticantagonist of reference, is used to reverse neurologicand respiratory depression induced by acute opioidpoisoning.

OPIOID RECEPTORSThe International Union on Receptor Nomenclaturehas recently recommended a nomenclature change fromthe historical Greek alphabet to one similar to otherneurotransmitter systems, the receptors , , and ,becoming OP1, OP2, and OP3, respectively.

28

1. The m opioid receptors (OP 3 ). The receptors were thefirst opioid binding sites described, in relation tomorphine agonist activity and high affinity.29

Morphine has a 50-times higher affinity for receptors in comparison with other opioids. Fentanyl

and other piperidyl agonists also have good affinity and selectivity for receptors (Table 33-1).

Naloxone is the only clinically used opioidreceptor antagonist, with a higher affinity for the than for the other receptors.30 Other antagonistsalso have good selectivity for receptors (Fig. 33-3).

Receptors are further classified into 1 and 2subclasses (Table 33-2). The 1 receptors found in

the periaqueductal gray matter, the nucleus raphemagnus, and the locus caeruleus are postulated tohave supraspinal analgesic properties. The 1receptors are responsible for almost all opioidanalgesic properties, and to some extent, their sideeffects. The 2 receptors, characterized by a loweraffinity for opioids than 1, are responsible for theuntoward side effects of opioids, including respi-ratory depression, delayed GI motility (nausea,

vomiting, and constipation), urinary retention, brady-cardia, miosis, euphoria, and physical dependence.

2. The k receptors (OP 2 ). The agonists produceanalgesia that is unaffected by tolerance orantagonists to receptors (see Table 33-2). The 1

receptors appear to be concentrated in the spinalcord, whereas 2 and 3 receptors appear to pre-dominate in the supraspinal region. They may evenoutnumber receptors in that region. Untowardeffects of stimulation include respiratory depres-sion (less than ), miosis, dysphoria, and psy-chotomimetic effects.

3. The receptors (OP1). The receptors mediatespinal analgesia, specifically via thermal nociception.Both enkephalins and -dynorphin bind to this class.The receptors also have a cortical distribution andmay have a role interacting with centrally located receptors. Untoward side effects include respiratory depression via decreased respiratory rate.29

All these opioid receptors have now been cloned andsequenced. They each consist of seven transmembranesegments (Fig. 33-4). The molecular conformations of the opioid receptors play an important role in theiractivity.31,32 All the opioid receptors belong to the G-protein–binding superfamily, with significant sequencehomology between their transmembrane regions. How-ever, important differences exist within their intra-cellular and extracellular segments, determining thedifferences in their binding properties (Table 33-3).Different mechanisms of cellular transduction are now described, depending not on the receptor type but on itslocalization. The G-protein structure contains threesubunits (, , ), from which the subunit is liberated

on the binding of the subunit to guanosinetriphosphate. The is then able to activate variouseffector systems, including phospholipase C, adenylatecyclase, other channels, or transport proteins (Fig. 33-5).The main postsynaptic signal trasduction mechanism isbased on the inhibition of the adenylate cyclase,mediated by inhibitory G proteins (Gi), associated with, , and opioid receptors.33,34 Opening of potassiumchannels may result from opioid receptor stimulation,

yielding membrane hyperpolarization and neuronalexcitability reduction.35,36 On the presynaptic membrane,the opioid receptor activation is associated with a closure



5/24

PHARMACOKINETICS

Opioids are available in numerous formulations, allowing various routes of administration, including oral, par-enteral, transdermal (fentanyl), transmucosal (morphine

of N-type calcium channels, resulting in a reduction of intracellular calcium concentration at the end of thesynapse and leading to the blockage of presynaptic

vesicle fusion with the terminal membrane and thereduction in neurotransmitter release.37


TABLE 33-1 Opioid Pharmacological Properties

a RECEPTOR, d RECEPTOR, m RECEPTOR,[3]HU-69,593 [3H]NALTRINDOL [3H]DAMGO

Nonselective Compounds

Dynorphin A 0.5 >1000 32Leu-enkephalin >1000 4.0 3.4

Met-enkephalin >1000 1.7 0.65-Endorphin 52 1.0 1.0Des-Tyr1--endorphin >1000 >1000 >1000(–)-Naloxone 2.3 17 0.93(+)-Naloxone >1000 >1000 >1000Levorphanol 6.5 5.0 0.086Dextrorphan >1000 >1000 >1000(±)-Bremazocine 0.089 2.3 0.75Ethylketocyclazocine 0.40 101 3.1Etorphine 0.13 1.4 0.23Pentazocine 7.2 31 5.7Diprenorphine 0.017 0.23 0.072-CNA 0.083 115 0.90-FNA 2.8 48 0.33Naltrexone 3.9 149 1.0Nalbuphine 3.9 >1000 11Nalorphine 1.1 148 0.97

m -Selective CompoundsCTOP >1000 >1000 0.18Dermorphin >1000 >1000 0.33Methadone >1000 >1000 0.72DAMGO >1000 >1000 2.0PLO17 >1000 >1000 30Morphiceptin >1000 >1000 56Codeine >1000 >1000 79Fentanyl 255 >1000 0.39Sufentanil 75 50 0.15Lofentanil 5.9 5.5 0.68Naloxonazine 11 8.6 0.054Morphine 538 >1000 14

k -Selective Compounds

Norbinaltorphimine 0.027 65 2.2Spiradoline 0.036 >1000 21

U-50,488 0.12 >1000 >1000U-69,593 0.59 >1000 >1000ICI 204,488 0.71 >1000 >1000

d -Selective Compounds

DPDPE >1000 14 >1000D-Ala2-deltorphin II >1000 3.3 >1000DSLET >1000 4.8 39BW 3734 17 0.013 26DADL >1000 0.74 16SIOM >1000 1.7 33Naltrindole 66 0.02 64NTB 13 0.013 12BNTX 55 0.66 18

Receptor affinity (Ki) were obtained using competition with [3H]naltrindol (), [3H]U69,593 (), and [3H]DAMGO () in the presence of the indicated

molecules.-CNA, -chlornaltrexamine;-FNA, -funaltrexamine; CTOP, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH 2; SIOM, 7-spiroindinooxymorphone.Data from Raynor K, Kong H, Chen Y, et al: Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors. Mol Pharmacol1994;45(2):330–334.


6/24

and hydromorphone), epidural, intrathecal, intranasal,and even intrapulmonary (by smoking) administration.In opioid overdoses, dosage, duration, and route of administration may influence symptoms and theirduration. Thus, considering opioid pharmacokineticproperties is useful in understanding their toxicologic

consequences and choosing the best methods of treatment.

Variable reduction in bioavailability results from first pass metabolism when absorbed through the GI tract.Morphine bioavailability by the oral route is only 25%, incontrast to codeine at 60%. Buprenorphine undergoes


K

HOO

OH

K K

HO

O

OO

N

N N

OH

OH

HO OH

N

NN

H K

O

K

HO

O

O

OH HH

HH

N N

O

HO

O

OH

HO

N

N

DAMGO

Morphine Fentanyl

TyrJDJAlaJGlyJN(Me)PheJGlyJoI TyrJProJtJMePheJDJProJNH2

PLO17

Naloxone

Naltrexone b-FNA

Naloxonazin

CH2CHKCH2 CH2CHKCH2

JCH2J

NHCO

CKC

CO2CH3

FIGURE 33-3 Selective opioid receptoragonists and antagonists.

TABLE 33-2 The Different Opioid Receptor Type and Subtypes

SPECIFIC REPORTED EFFECTS OF EACH RECEPTOR

RECEPTORS AGONISTS* ANTAGONISTS SUBTYPE

Morphine, methadone, DAMGO CTOP Sedation, euphoria1 Meptazinol Naloxonazin Supraspinal analgesia, peripheral analgesia,

euphoria, prolactin release2 Metkephamid Spinal analgesia, respiratory depression,

physical dependence, gastrointestinaleffects, bradycardia, puritis, dopamine, andgrowth hormone release

DSLET Naltrindol, NTB, BNTX Modulation of receptor function anddopaminergic neurons

1 DPDPE Spinal and supraspinal analgesia2 Deltorphin Supraspinal analgesia Dynorphin A, ethylketocyclazocine Nor-binaltorphimin (nor-BNI) Sedation, gastrointestinal effects1 U50,488H, spiradolin Spinal analgesia, diuresis, miosis2 Bremazocin Psychotomimesis, dysphoria3 Nalorphin Supraspinal analgesia

*Leverphanol and etorphin are nonspecific agonists of the three opioid receptor types, whereas naloxone and naltrexone are nonselective antagonistsof these three receptor types.


7/24

codeine to greater than 90% for methadone andbuprenorphine. Depression in albumin and other serumproteins (- or -globulin) resulting in decreasedbinding may produce higher levels of free opioid withpossible opioid toxicity. Changes in serum pH may alsoalter protein binding of opiates. Transport system

extensive first pass metabolism after oral administration,making the sublingual route mandatory for a bio-availability of 50%.38

Protein binding and any interaction that alters italso play a vital role in pharmacodynamics. The rangeof protein-bound opioid varies from a low of 7% for


MEPA

SAA G

AE

LL P

QP

P

FNA

SDAYPSACPSAGANASGPP

GA

R SA

S

S

S

S

SS

S

S S

S

S

SS

SS

L

L

L

L L

L

L

L L

L

L

L

L

L

L

L

L

L

L

L

L

L

L

L

L

L

L

LL

LL

L

L

A

A

A

AA

A

A A

A

A A

A

A

A

A

A

A

A

A

A

AAA

AA

AA

A

A

A

LA

I

T

T T

T

T

T

T

T

T T

T

T

T

T

T

T

T

TTT

V

I

I

I

I

I

II

I

I

I I

I

I

I

I

I

IIY

V

V

C

V G

G

GG

G

G

G

G

GGG

G

NV L

M F

GV

RY

K M

M

MM

K

K

N YIFN

N

D

A

S L P

FQS

KY

M

E

W P F

F

F

EL

CK

V LS

S

S

ID

DD

D

D

D D

D

D

D

D

Y

Y

RY

V CH P V K

DF

R

PAK

K

N

CWV

GVG

G

VP

M V M

M

M M

V

V V

V

V

V

V

V

V

V VVV

V V

VV

V VV

V

R

R

R

R

R

RR

R

R R

R

R

R

R

RRRR

P

C

C

C

C

C

C

C

C

C

Q F

FF

FF F

F

F

F

F

PP

P

R

P

P

P

PP

P

PP

W W

W

W

K

K K

K

Y

Y

Y

Y

E E

R

E

E

Q

H

H

N

N

A

S

V

F

N

TMH 5 TMH 6

TMH 4

TMH 3

Phe5.43

Phe6.44

Phe5.47

Tyr3.33

Trp

4.50

Trp6.48

His

6.52

A

BFIGURE 33-4 A, Molecular representation of opioid receptors. All receptors exhibit seven transmembrane segments with differencesdetermining specific binding properties. B, As an example, we represented the aromatic and polar residues of the receptors, which arespecific for its binding sites.


8/24

proteins, such as P-glycoproteins, may also influencetissue distribution. Crossing the blood-brain barrier isdependent on lipid solubility and polarity and influencesclinical effects. Heroin (diacetylmorphine) enters thebrain more readily than both of its metabolites, 6-monoacetylmorphine (6-MAM) and morphine, explainingits greater addictive potential.

Opioids generally undergo hepatic metabolism withsome form of conjugation, hydrolysis, oxidation, ordealkylation. Some of the resulting metabolites havebeen implicated in the activity or recognized toxic sideeffects of various opioids. Examples of this include themetabolism of codeine to morphine, morphine to the

more active morphine-6-glucuronide, buprenorphineto norbuprenorphine, meperidine to the potentially neurotoxic normeperidine, and propoxyphene to thepotentially cardiotoxic norpropoxyphene. Figure 33-6illustrates the metabolism of buprenorphine, whichundergoes extensive cytochrome P-450 3A4-mediatedN -dealkylation to norbuprenorphine and then glu-curonidation.39 Cytochrome genotype appears to be animportant parameter in opioid efficacy or toxicity. Smalldoses of codeine, which is bioactivated into morphine by cytochrome P-450 2D6, may be responsible for life-threatening intoxication in patients with allele patternsinducing ultrarapid metabolism, in combination withinhibition of cytochrome P-450 3A4 activity and a

transient reduction in renal function.40

Excretion of opiates occurs primarily via the renalroute, with about 90% of the opioid metaboliteseventually being excreted in the urine, usually viaglomerular filtration. A small amount may end up in theGI tract via enterohepatic circulation. The urinary detection of opioids or metabolites is a routinely useddiagnostic test. The presence of 6-MAM in the urine is areliable marker of recent heroin consumption, becausehumans cannot acetylate morphine but only deacetylateheroin. Renal failure leads to toxic effects via accu-mulated drug or active metabolites (morphine-6-

glucuronide or normeperidine). Hepatic dysfunctionresults in delayed liver metabolism of certain opioids(meperidine, pentazocine, and propoxyphene), leadingto accumulation and development of central nervoussystem (CNS) or respiratory depression.

Drug interactions may occur at various sites affectingthe absorption, metabolism (induction of hepaticenzymes), and elimination of opioids (competition forrenal excretion) contributing to the potentiation orreduction of their effects. Acceleration of metabolism inthe liver, which results from phenytoin induction, may result in diminished activity (methadone) or an increasein potentially toxic metabolites (normeperidine). The

discontinuation of an interacting drug may play just asimportant a role as the addition of one in changing thebioavailability and activity of opioids. These interactionsmay lead to the onset of overdose or withdrawal symptoms.Interaction between buprenorphine and benzodiazepines,

which is suspected to be one of the mechanisms of buprenorphine-related toxicity or fatality,41 has beenattributed to a pharmacodynamic mechanism.42

TOXICOLOGY

In general, a drug classified as an opiate or opioid elicitsthe same overall physiologic effects as morphine, the

prototype of this group. However, there are conspicuousdifferences among these agents, which will be specifically addressed. Varying degrees of the classic “opiatetoxidrome” (i.e., mental status depression, respiratory depression, miosis, and decreased bowel motility) may manifest in patients administered opioids.

Central Nervous System Effects

A dose of 5 to 10 mg of morphine usually producesanalgesia without altering mood or mental status in apatient. Sometimes dysphoria rather than euphoria may


TABLE 33-3 Selective Activity of the Main Opiate/Opioid on the Different Opioid Receptors

MOLECULES ACTIVITY RECEPTOR RECEPTOR RECEPTOR

Morphine Agonist +++ +Methadone Agonist +++Etorphin Agonist +++ +++ +++Fentanyl Agonist +++Sufentanyl Agonist +++ + +Buprenorphine Agonist–antagonist P ? – –Nalorphin Agonist–antagonist – – – +Pentazocin Agonist–antagonist P ++Naloxone Antagonist – – – – – –Naltrexone Antagonist – – – – – – –

Endogenous Peptides*

Met- et Leu-enkephalins Agonist ++ +++-endorphin Agonist +++ +++Dynorphin A Agonist ++ +++Dynorphin B Agonist + + +++-neoendorphin Agonist + + +++

*Enkephalins and endorphins are considered the endogenous ligands of and receptors; dynorphin A activity is related to receptors.+, agonist; –, antagonist; P, partial agonist; ?, not determined.


9/24


Ca2; Ca2;

Ca2; Ca2;

Ca2;

K;

;

;

;;

;;

:

:

ATP AMPc

PLC

PIP2IP3

AC

bg aq

ai

MAPK

ai

FIGURE 33-5 Regulation of thedifferent cellular effectors by theopioid receptors MAPK (mitogen-activated protein kinases), AC(adenylate cyclase), PLC (phos-pholipase C), IP3 (inositol 1,4,5triphosphate), and PIP2 (phos-phatidylinositol 4,5 biphosphate).

HO

O

HO

H3CO

CH3

CH3CH3

CH3

NJ

C

HO

O

HO

H3CO

CH3

CH3

CH3CH3

NJ

C

HO

O

HO

H3CO

CH3

CH3CH2OH

CH3

NJ

C

HO

O

HO

H3CO

CH3

CH3CH3

CH3

C

HO

O

HO

H3CO

CH3

CH3CH2OH

CH3

NHNH

C

OH

HO

O

HO

H3CO

CH3

CH3CH3

CH3

C

OH

NH

Hydroxylation

Hydroxylation

Hydroxylation

N -dealkylation

N -dealkylation

N-dealkylation

CYP3A5,3A4,3A7,2C8

CYP3A5,3A4,3A7,2C8 CYP3A4,3A5

M1

Norbup M3Bup

M2 M4 (or M5)

FIGURE 33-6 Liver metabolism of buprenorphine (Bup), as demonstrated in vitro, using liver microsomes. Various cytochromes P-450(CYP) are involved, resulting in the production of a predominant active metabolite, the norbuprenorphine (Norbup). Other metabolites(M1 to M5) are also produced, but their role and importance in vivo are unknown. (From Chang Y, Moody DE, McCance-Katz EF: Novelmetabolites of buprenorphine detected in human liver microsomes and human urine. Drug Metab Dispos 2006;34(3):440–448.


10/24

manifest, resulting in mild anxiety or a fear reaction.Nausea is frequently reported, whereas vomiting isoccasionally observed. The clinical effects of morphineare accentuated with increasing doses (e.g., analgesia isstronger, lethargy and drowsiness progress to sleepinessand coma). Slurred speech and significant motorincoordination are usually absent.

Morphine and most of its congeners cause pupillary

constriction. This effect is predominantly a central effect and is accentuated following an overdose. Not allpatients taking opioids present with miosis. Patientstaking meperidine or propoxyphene regularly maintainnormal pupillary size, and patients taking pentazocinemay not develop miosis.43 Mydriasis may occur in severely poisoned patients secondary to hypoxic or anoxicbrain injury. Combination drug use such as cocaine andheroin (“speedball”), scopolamine-adulterated heroin,and Lomotil (diphenoxylate hydrochloride and atropinesulfate; Pfizer, New York, NY) or the presence of adulterants may produce variable pupil size dependingon the relative contribution by each agent.

Cerebral circulation does not appear to be altered

by therapeutic doses of morphine, unless respiratory depression and carbon dioxide retention result incerebral vasodilation.44 Seizures are rare adverse drugevents associated with most therapeutic opioid dosing.In an acute opioid overdose, seizures are most likely tobe caused by hypoxia. Morphine-induced seizures haveonly been reported in neonates,45 and seizures should beanticipated in patients with meperidine, propoxyphene,or tramadol toxicity.

Respiratory Effects

Respiratory failure is the most serious consequence fromopioid overdose. Opioids reduce ventilation by diminishingthe sensitivity of the medullary chemoreceptors in therespiratory centers to an increase in carbon dioxidetension (PaCO2) and depress the ventilatory response tohypoxia.46 The combined diminution in hypercapnicand hypoxic drive leaves virtually no stimulus to breathe,and apnea ensues. Even small doses of morphine depressrespiration by directly affecting the brainstem respiratory centers. Morphine-induced respiratory depressioninitially relates more closely to changes in tidal volumeand a reduction of respiratory rate with escalatingdoses.30,44 The peak respiratory depressant effect isusually noted within 7 minutes of IV morphine admin-istration, and may be delayed for up to 30 minutes if thedrug is administered intramuscularly. Normal carbondioxide sensitivity usually returns within 2 to 3 hours,

while minute volume may remain below normal for up to5 hours following a therapeutic dose.47

Cardiovascular Effects

Therapeutic opioid doses cause arteriolar and venousdilation and may result in a mild decrease in bloodpressure.48 This change in blood pressure is clinically insignificant while the patient is supine, but significant orthostatic changes are common.49 Hypotension appears tobe mediated by histamine release50 and may be related tothe nonspecific ability of certain opioids to activate mast cell

G protein,51 which induces degranulation of histamine-containing vesicles. The combination of H1 and H2antagonists appears to be effective in ameliorating thehemodynamic effects of opioids.52 Not all opioids areequivalent in their ability to release histamine. In one study,meperidine produced the most, and fentanyl the least,hypotension and elevation of plasma histamine levels.53

Bradycardia is unusual, but a reduction in heart rate is

common as a result of the associated reduction in CNSstimulation. Myocardial damage (necrotizing angiitis) inopiate overdose associated with prolonged hypoxic comamay be mediated by cellular components released duringrhabdomyolysis, direct toxic effects, or hypersensitivity tothe opioids or adulterants.54

Gastrointestinal Effects

Therapeutic use of opioids, morphine in particular,produces significant nausea and vomiting.55 It is mediatedthrough agonism at dopamine-2 receptor subtypes

within the chemoreceptor trigger zone of the medulla.Opioid-induced constipation is an adverse drug event of

both the therapeutic and recreational use of opioids. It ismediated by 2 receptors within the smooth muscle of the intestinal wall. Morphine and related drugs may cause a delay in the passage of gastric contents throughthe pylorus up to 12 hours and marked decrease inintestinal peristalsis.

SPECIFIC OPIOIDS

Heroin

Heroin has two to five times the analgesic potency of morphine, with similar effects on the CNS.56 Virtually

all street heroin in the United States is produced inclandestine laboratories and is adulterated prior todistribution. The purity of street heroin is between 5%and 90%, and is usually less than 50%.57 Adulterants may include noscapine, caffeine, procaine, various sugars,phenobarbital, methaqualone, quinine, and acetamino-phen in combination with caffeine.58,59 Heroin isgenerally bought by the “bag” (25 mg) or quarter gramand may also be mixed with other drugs of abuse (e.g.,“speed ball”). Purity and adulterants may play aconsiderable role in the outcome and complications of heroin use. Interindividual variation in sensitivity andtolerance makes correlation of serum heroin levels withclinical symptoms difficult.

Heroin is available as either a hydrochloride salt or abase, with the base being the prevalent form in most regions of the world. The hydrochloride salt form istypically a white or beige powder and is highly watersoluble, which allows simple IV administration. Heroinbase is often brown or black in color, and “black tarheroin” is one designation referring to an impure formavailable in the United States. Heroin base is virtually insoluble in water, and requires heating until it liquefiesprior to IV administration. This process involves heatingthe powder in a spoon or bottle cap until it is dissolved,passing the heroin through cotton or a cigarette filter



11/24

speech, disturbed cerebellar speech, and ataxia. After2 to 4 weeks some patients developed rapid worseningof the cerebellar symptoms (e.g., gait disturbance).Hyperactive deep tendon reflexes and pathologicreflexes with hypertonic hemiplegia or tetraplegiadeveloped. Some patients developed tremor of the headand shoulders, and others developed myoclonic jerks orchoreoathetoid movements. In most cases palmomental,

snout, and oculomandibular reflexes became evident.Patients who did not deteriorate remained stable withsubsequent partial improvement. Within the next 2 to4 weeks some patients further progressed in their clinicalcourse and developed stretching spasms, profuseperspiration, central pyrexia, and blindness. The spasticparesis became hypotonic and resulted in areflexia.Some patients developed akinetic mutism. All patients

who had progress to this stage died, most because of res-piratory difficulties. The mortality rate was 25%. Survivorshave stabilized with severe deficits or shown modest degrees of improvement.81,82

Heroin toxicity may be associated with cardiacconduction abnormalities and dysrhythmias,83-85 which

may be the result of metabolic derangements associated with hypoxia, a direct effect of heroin or its metabolitesor of adulterants.54,86,87 Quinine-adulterated heroin hasbeen associated with dysrhythmias,88,89 amblyopia,90 andthrombocytopenia.91 Patients exposed to heroin that hasbeen adulterated with scopolamine may present in acuteanticholinergic crisis.92 Surreptitious addition of cocaineto heroin may cause significant myocardial ischemiaor infarction.93 Other reported adulterants includethallium,94 lead,95 amphetamines,96 chloroquine,97 andstrychnine.98

Codeine

Codeine (methylmorphine) is available as a sole ingre-dient and in combination with aspirin or acetamino-phen. Codeine is rapidly absorbed by the oral route,producing a peak plasma level within 1 hour of atherapeutic dose.99 Ten percent of codeine is metabolizedto morphine.100 Both codeine and morphine appear inthe urine within 24 to 72 hours, with only morphinebeing detected in the urine at 96 hours.99 The effect of codeine on the CNS is comparable but less pronouncedthan that of morphine. An IV codeine phosphate dose of 750 to 900 mg produces symptoms similar to those seen

with acute heroin overdose.101 Fatal ingestions withcodeine alone are rare. The estimated lethal dose in anonabuser is 800 mg, with a serum codeine concen-

tration of 0.14 to 4.8 mg/dL.102,103

Fentanyl

Fentanyl is a synthetic opioid with rapid onset of actionand short duration of action, and has a potency 100times that of morphine. It is highly lipid soluble and hasa volume of distribution of 60 to 300 L.104 Legitimatefentanyl use is limited to anesthesia and conscioussedation, and it has been abused mostly by medical andparamedical personnel because of limited access since it

was first introduced. Numerous fentanyl analogs (e.g., -

into a syringe, and boiling the cotton or filters to extract additional drug. The filtered heroin and the extract areinjected IV or subcutaneously (“skin popping”). Somedrug users may become acutely ill with a benign febrile,leukocytic syndrome following an IV injection. Thiscondition is known as “cotton fever,” and its etiology hasbeen attributed to bacteremia following injection of Enterobacter agglomerans that has colonized in the cotton

or cigarette filters.60Heroin may also be taken intranasally (snorted) and

by inhalation of heated vapors. Inhalation of heated vapors is known as “chasing the dragon,” “Chinesing,” or“Chinese blowing,” and involves placing heroin base onaluminum foil, heating it from below with a flame, andinhaling the thick white pyrolysate through a straw. Thebioavailability of heroin administered by this route iscomparable with that of heroin administered by otherroutes, and the clinical and toxicological effects are dosedependent.61,62

Physiologically, the effects of heroin are identical tothose described for morphine.63,64 The plasma half-life of heroin is 5 to 15 minutes. Heroin is initially deacetylated

in the liver and plasma and then is renally excretedas a conjugate, with small amounts of morphine, diacetyl-morphine, and 6-MAM.65 The initial heroin rush isprobably due to its high lipid solubility and rapidpenetration into the CNS.56 The majority of its lastingeffects are attributable to its metabolites 6-MAM andmorphine.49 Fatal overdoses with heroin have beenreported with serum morphine concentrations of 0.1 to1.8 g/mL.66

Acute lung injury (noncardiogenic pulmonary edema)as a complication of heroin overdose was first describedby William Osler during an autopsy.67 Its presentationand clinical course following nonfatal heroin overdoses

were first described in 1953,68 and later in case series and

reports.69

Patients with acute lung injury may present early on in their course; within 2 hours of parenteralheroin use and up to 4 hours following intranasal heroinuse.66,69,70 Typically, the patient awakens from an opioidcoma, either spontaneously or following an opioidantagonist, and over the subsequent several minutes tohours develops hypoxemia and pulmonary rales. Classicfrothy, pink sputum is occasionally observed in thepatient’s airway. Acute lung injury was reported in48% of hospitalized heroin overdose patients71 and wasnoted in 50% to 90% of heroin overdose patients at postmortem examinations, many of whom died in aprehospital setting.72,73 Postmortem studies of patients

who succumbed to heroin-induced acute lung injury

showed no gross cardiac pathology.74

The mechanism foracute lung injury may be multifactorial and includes pro-found hypoxemia, hypersensitivity reactions, immunecomplex deposition in the alveolar capillary membrane,histamine-induced capillary leakage, neurogenic sympa-thetic discharge, and transient lymphatic pumpingirregularities.70-72,75-79

A consequence of “chasing the dragon” is a pro-gressive spongiform leukoencephalopathy and was first reported from the Netherlands.80 The initial symptomsinclude pronounced motor restlessness (e.g., compulsionto move), apathy, bradyphrenia, soft (pseudobulbar)



12/24

methylfentanyl [“China White”], 3-methylfentanyl, -methyl-acetyl-fentanyl, -methyl-fentanyl acrylate, andbenzyl fentanyl) have been illicitly synthesized anddistributed on the street as heroin substitutes.105-109 They can be 200 to 6000 times more potent than morphine.Toxic effects may be experienced with very smallamounts. Typically, the patients present comatose andapneic. In such cases, unsuspecting users administer their

usual “dose” of heroin, which surreptitiously contains variable amounts of an illicit fentanyl analog. A numberof “heroin-related” deaths have been attributed to theseagents secondary to marked increased potency compared with heroin.106-108

Rapid IV injection of certain high-potency opioids(e.g., fentanyl) may result in acute muscular rigidity primarily involving the trunk, and may impair chest wallmovement and exacerbate hypoventilation. Similareffects contribute to lethality during epidemics of fentanyl-adulterated heroin.107 Although motor activity resembling seizures has been associated with fentanyluse,110-112 simultaneous electroencephalogram recordingduring fentanyl induction of general anesthesia did not

show epileptiform activity.113-116 This suggests a myoclonicrather than epileptic nature of the observed muscleactivity.115

Fentanyl is available as a patch; a transdermal delivery system establishes a depot of drug in the upper skinlayers, where it is available for systemic absorption. Afterremoval of the patch, drug absorption from the dermalreservoir continues and the effective fentanyl half-life is17 hours, versus 2 to 4 hours associated with the IV route(Duragesic [fentanyl], Janssen Pharmaceutica, Piscataway,NJ). The availability of a transdermal fentanyl delivery system provides a widening pool of individuals withaccess. Prescribed transdermal fentanyl patches can besold or stolen. Disabling myoclonus has been reported

after several days of fentanyl therapy by the transdermaldelivery system.117 Misuse and abuse of the fentanylpatch has been reported in the form of simultaneousapplication of multiple patches, ingestion, inhalation,and IV injection of the transdermal fentanyl patchcontents, which has resulted in respiratory arrest anddeath.118-124

Meperidine

Meperidine is a synthetic opioid and is chemically different from the traditional opiates. Althoughconsidered to possess strong analgesic properties when

given by the parenteral route, it is less than half aseffective if given by the oral route.125 It appears to be acommon drug of abuse among medical personnel, withfew reports of meperidine poisoning or fatalities.126-128

Meperidine is metabolized in the liver primarily by N -demethylation to normeperidine, an active metabolite

with half the analgesic and euphoric potency of meperidine, and twice the neurotoxic properties.129,130

Excretion is primarily through the kidneys as conjugatedmetabolites.131 Meperidine and normeperidine may bedetected in either urine or serum.131 Meperidine toxicity

has been attributed to the accumulation of normeperi-dine in patients with renal impairment, which has anelimination half-life of 14 to 24 hours.132-134 However,

when meperidine is used in large doses and at frequent dosing intervals, seizures may occur in patients withnormal renal function.135-138

Meperidine also interacts with serotonin receptors by blocking presynaptic reuptake of serotonin. A potentially

fatal form of serotonin syndrome may occur in patientson monoamine oxidase inhibitors (MAOIs) and istreated with meperidine.139

Meperidine is the prototype for a series of homologsthat are used as heroin substitutes. In a process tosynthesize a meperidine analog, 1-methyl-4-phenyl-propionoxypiperidine (MPPP), as a heroin substitute, aclandestine drug laboratory inadvertently introduced1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by incorrect heating of the synthetic mixture. WhenMPTP is introduced into the body, monoamine oxidase-B in glial cells metabolizes MPTP to MPP+, whichselectively destroys dopamine-containing cells in thesubstantia nigra by inhibiting mitochondrial oxidative

phosphorylation.140,141 MPTP contaminant led to anepidemic of severe parkinsonism among IV drug abusers(“frozen addicts”) within days of repeated injections.142-144

Diphenoxylate and Loperamide

Diphenoxylate is structurally similar to meperidine, withlimited absorption from the GI tract that contributes toits strong local constipating effects, and is used in themanagement of diarrhea. Diphenoxylate (2.5 mg) isformulated with 0.025 mg of atropine sulfate (Lomotil).In therapeutic doses, the drug has no significant CNSeffects. However, the standard adult formulation may

result in significant systemic absorption and toxicity inchildren. One half tablet of Lomotil has been reportedto cause serious toxicity in children.145-147 Signs andsymptoms arising from a toxic ingestion may be delayed,prolonged, or recurrent.147 This is related to the delayedgastric emptying effects inherent to both opioids andanticholinergics, and more important, the accumulationof the hepatic metabolite difenoxin, which is a signifi-cantly more potent opioid than diphenoxylate andpossesses a longer serum half-life.148,149

Loperamide, an over-the-counter antidiarrheal agent,is another meperidine analog with limited absorptionfrom the GI tract, and appears to have a high safety profile.150

Methadone

Methadone is a synthetic opioid commonly used in thetreatment of chronic pain or detoxification, or as amaintenance substitute for opioid addiction, and is alsosold on the streets.151,152 Methadone is well absorbedfrom the GI tract, resulting in a peak plasma level within2 to 4 hours, with peak effect occurring within 2 hours.153

It has an average half-life of 25 hours and may be



13/24

rates.5 In the United States, restricted conditions fordrug prescription (no more than 30 patients perqualifying certified physician) have resulted in littleabuse since its launch.21

As with other opioids, buprenorphine intoxicationincludes coma, respiratory depression, and pinpoint pupils. Several deaths have been associated with bupren-orphine misuse or psychotropic drug coingestion,including benzodiazepines.14 However, forensic deter-mination of the exact role of buprenorphine in thedeath process appears difficult, because other factorsmay be involved (and potentially unknown), includingsubstitution modality and concomitant intake of otherdrugs.20 Moreover, the exact mechanism of interactionbetween buprenorphine and benzodiazepines (oftenimplicated in buprenorphine deaths) is unknown.165

The clinical role of drugs that interact with CYP3A4and that may modify production of norbuprenorphine(an active metabolite with more potent respiratory depressant effects) is unknown.

PropoxyphenePropoxyphene is structurally related to methadone, andtoxicity has resulted in significant morbidity andmortality.166-168 It is available alone or in combination

with aspirin or acetaminophen. Oral administration isfollowed by rapid absorption, with peak serum levelsoccurring within 1 hour.169 The plasma half-lives of propoxyphene and its main active hepatic metabolitenorpropoxyphene are 6 to 12 hours and 37 hours,respectively. Norpropoxyphene is also the primary metabolite excreted in the urine and is believe to playa role in the prolonged clinical course following anoverdose.170,171 Prominent cardiovascular effects may occur with propoxyphene toxicity and manifest by wide-complex dysrhythmias and negative contractility throughsodium channel antagonism similar to that of type IA antidysrhythmic agents. Propoxyphene appears to beresponsible for both CNS (e.g., respiratory depressionand seizures) and cardiac toxicity (e.g., QRS prolonga-tion, negative inotropy, and dysrhythmias), whereas nor-propoxyphene contributed only to the cardiotoxicity.172

The clinical course following an overdose may besevere and rapidly progressive, with cardiac dysrhythmias,circulatory collapse, seizures, and respiratory arrest developing within 1 hour.173-178 Propoxyphene toxicity may result in focal and generalized seizures.176,178 Theminimum toxic dose reported is 10 mg/kg, and20 mg/kg is considered potentially fatal,179 but tolerance

develops with chronic use. Doses of 1000 to 2000 mgmay be ingested or injected with minimal signs of intoxication in chronic propoxyphene abusers andheroin addicts.178,180-182 Blood levels in fatal overdosecases range from 0.1 to 2.5 mg/dL.167,168

Pentazocine

Pentazocine is a synthetic analgesic class with bothagonist and weak antagonist activity at the opioid

as long as 52 hours during long-term maintenancetherapy.154 Methadone and its inactive metabolite, anN -demethylated pyrolidine, may be detected in eitherurine or plasma.155 Its analgesic, sedative, euphoric, andrespiratory depressive effects are comparable with thoseseen with analogous doses of morphine.156,157 In anontolerant person, a 40- to 50-mg dose may producecoma and respiratory depression.155,158 Rapid escalation

of methadone doses have been associated with choreo-athetoid movements and may be due to enhanced striataldopamine release.159 Unintentional pediatric poisoning

with fatal consequences has occurred in situations in which parents on methadone maintenance treatment had improperly stored their methadone at home.160

A protracted clinical course is expected followingan overdose. There is a possible association betweenpatients on very high doses of methadone and havingtorsades de pointes, particularly in a setting of additionaldysrhythmia risk factors (e.g., hypokalemia).161 In thesepatients the mean daily methadone dose was 397 ± 283mg and their mean QTc interval was 615 ± 77 msec.

Buprenorphine

Buprenorphine is a semisynthetic, highly lipophilicopioid, with 25 to 50 times more potent analgesicactivity than morphine.162 Sublingual buprenorphineis well absorbed, with 60% to 70% of the bioavailabilityof the IV route. Buprenorphine is mainly metabolizedin the liver by CYP3A4 to an active dealkylated meta-bolite, norbuprenorphine. There is no direct relation of buprenorphine’s clinical effects with plasma concen-trations.

Buprenorphine is a partial receptor agonist and a weak receptor antagonist, with ceiling effects. Dose-

effect relationships, both in animals and humans, suggest a plateau of respiratory effects.163 Buprenorphine shows a very slow dissociation from opioid receptors, and con-sequently, has a long duration of action. These pharma-cologic properties appear to be of utmost importanceregarding its safety for use in substitution treatment.They confer a low level of physical dependence and mild

withdrawal symptoms on cessation after prolongedadministration. Although respiratory depression canbe prevented by prior administration of naloxone,buprenorphine is weakly antagonized by naloxone givenafter buprenorphine.164

Buprenorphine 8 to 16 mg/day has been used inFrance as a maintenance treatment for opioid-dependent

patients since 1996. In 2002, buprenorphine wasapproved by the Food and Drug Administration for thetreatment of opioid addiction in certified physicians’offices. A mixture of buprenorphine and naloxonenamed Suboxone (Reckitt Benckiser Healthcare, Ltd.,Hull, UK) is also available, designed to discourage IV use. Since the advent of office-based availability,buprenorphine has been successfully used for opioiddetoxification, with a good safety profile.10,11 In France,the introduction of high-dose buprenorphine coincided

with a decrease in opiate/opioid poisoning mortality



14/24

receptors.183 The physiologic effects of pentazocine aresimilar to morphine, and with one third of its analgesicpotency.183 When administered by the oral route, peakplasma pentazocine levels occur within 1 hour.184

Pentazocine is extensively metabolized in the liver,183,184

with the parent compound and metabolites detectable ineither urine or plasma.183 Anxiety, dysphoria, andhallucinations may be more common with pentazocine

than with other opiate derivatives.183Pentazocine (Talwin, Sandoz, Princeton, NJ) is asso-

ciated with a fairly specific scenario of parenteral abuse when used in combination with the antihistamine tri-pelennamine (Pyribenzamine, Novartis, Basel, Switzer-land), a blue capsule. This combination forms a street product known as “T’s and blues” and, once solubilizedand injected, was used as a heroin substitute that waspreviously popular among addicts because of its heroin-like “rush” and lower cost.185-187 Newer combination street products, such as pentazocine with methylphenidate,have been reported.188 Acute toxicity results in thetypical opiate intoxication syndrome, as well as dyspnea,hyperirritability, hypertension, and seizures. It is believed

that these effects may be directly related to thetripelennamine dose.186,189,190

In an effort to curtail IV pentazocine abuse, the oralpreparation was reformulated to contain 0.5 mg of naloxone (Talwin-NX, Sandoz, Princeton, NJ).191 Thenaloxone component is inactivated when taken orally,and avoids withdrawal symptoms. However, when Talwin-NX is parenterally administered, pentazocine’s effectsare antagonized by naloxone, which causes withdrawal inopiate-dependent individuals. Because pentazocine’sduration of action exceeds that of naloxone, delayedrespiratory depression may occur.

Dextromethorphan

Dextromethorphan, an analog of codeine and the opticalisomer of levorphanol (a potent opioid analgesic), isfound in a large number of nonprescription coughand cold remedies. Within the therapeutic dose, dex-tromethorphan lacks analgesic, euphoriant, and physicaldependence properties.192 Dextromethorphan is formu-lated as the hydrobromide salt. It is available as a singleingredient or in combination with decongestants(sympathomimetics) and antihistamines. Dextrometho-rphan is well absorbed from the GI tract, with peakplasma levels occurring 2.5 and 6 hours after ingestion of regular and sustained-release preparations, respectively.The therapeutic effect lasts 3 to 6 hours, with a

corresponding plasma half-life of 2 to 4 hours. Thepredominant antitussive effect is attributed to the activemetabolite dextrorphan.193

Over-the-counter access appears to be the primary reason for its popularity in abuse, although its abusepattern seems to be self-limiting due to adverse drugevents, such as lethargy, somnambulism, and ataxia, aftera few weeks of abuse.194 Dextromethorphan abuseappears to be associated with a psychological rather thana physiologic dependence syndrome.192 Recreationdextromethorphan abusers report increased perceptualawareness, altered time perception, euphoria, and visual

hallucinations.194-196 Long-term dextromethorphan usemay result in bromide toxicity.197 Since dextromethor-phan frequently appears in combination products, thecontribution of these co-ingestants should be consideredin assessing overdose or abuse cases.

Dextromethorphan blocks presynaptic serotoninreuptake and may elicit the serotonin syndrome inpatients on MAOI therapy.198,199 Interaction between

dextrorphan and the “ receptor” produces aphencyclidine-like dysphoria.200 The metabolism of dextromethorphan to dextrorphan is dependent onCYP2D6 activity, an enzyme with a significant geneticpolymorphism. Patients who express extensive metab-olizer polymorphism appear to experience more drug-related psychoactive effects, whereas patients with poormetabolizers experience more adverse effects related tothe parent compound.201 Occasionally, a patient may experience choreoathetoid or dystonia-like movements

while on dextromethorphan.202

Tramadol

Tramadol is structurally similar to morphine and hasboth opioid and nonopioid mechanisms responsible forits clinical effects. It is a centrally acting analgesic withmoderate affinity for opioid receptors. However, themetabolite O -demethyl tramadol appears to have ahigher affinity than the parent compound for the samereceptors. In therapeutic doses, tramadol does not appear to produce significant respiratory depression orhave significant cardiovascular effects. Most of theanalgesic effects are attributed to the nonopioidproperties of the drug. Tramadol may exert its analgesiceffect by blocking the reuptake of biogenic amines (e.g.,norepinephrine and serotonin) at synapses in thedescending neural pathways, which inhibits pain

responses in the spinal cord.203

Serotonin syndrome may develop in patients concurrently taking tramadol andserotonin reuptake inhibitor medication.204,205 Seizuresmay occur during therapeutic dosing.206

BODY PACKERS

The transportation of illicit drugs by internal conceal-ment is an important means of international smuggling,

with accounts of body packing worldwide. Body packersare sometimes called “mules,” “swallowers,” “internalcarriers,” or “couriers.” These are people who transport large numbers of meticulously prepared illicit drugpackets in their GI tracts across borders with the intent to

sell or receive compensation for transporting the drug.Typically, the packets contain either concentratedcocaine or heroin. If one of these packets ruptures, theamount of drug released may cause life-threateningtoxicity.207,208

CLINICAL MANIFESTATIONS

Mental status depression, respiratory depression, miosis,and decreased bowel motility are the hallmarks of opiateintoxication, with the magnitude and duration of toxicity



15/24

Meperidine- and propoxyphene-related seizures may bemore frequent in chronic drug abusers with renaldysfunction.

Hypotension may occur following opiate overdose,although pentazocine intoxication may result inhypertension.186 Heroin and propoxyphene toxicity may be associated with nonspecific ST-segment and T-wavechanges, first-degree atrioventricular block, atrial

fibrillation, prolonged QTc intervals, and ventriculardysrhythmias.83-85,173-175 Cardiovascular findings may beexacerbated by electrolyte abnormalities, metabolicderangements associated with hypoxia, or adulterants(e.g., quinine) in street drugs.

The anticholinergic and opioid effects may besignificantly delayed, prolonged, or recurrent following aLomotil overdose.147,243 The relevance of delayed toxicity is highlighted by a patient with an asymptomaticpresentation 8 hours postingestion who was observed forseveral hours and discharged. This patient returned tothe emergency department 18 hours postingestion withsevere atropinism.243 Toxicity may manifest as a biphasicclinical syndrome, and patients may manifest anti-

cholinergic toxicity (CNS excitement, hypertension,fever, flushed dry skin) before, during, or after opioideffects. However, opioid effects (CNS and respiratory depression with miosis) may predominate or occur with-out any signs of atropinism. Cardiopulmonary arresthas been reported to occur 12 hours after Lomotilingestion.244

Patients presenting after a tramadol overdose may exhibit lethargy, nausea, tachycardia, agitation, seizures,coma, hypertension, and respiratory depression.240

Tramadol-associated seizures are brief, and significant respiratory depression is uncommon.

Interaction between meperidine and MAOIs, dex-tromethorphan and MAOIs, and tramadol and selective

serotonin reuptake inhibitors may result in the serotoninsyndrome.245-246 Patients with severe serotonin syndromeexhibit rapid onset of altered mental status, musclerigidity, hyperthermia, autonomic dysfunction, coma,seizures, and death.

Rhabdomyolysis, hyperkalemia, myoglobinuria, andrenal failure may complicate the clinical course of anacute opioid overdose or opioid dependence.86,247,248

Rhabdomyolysis has been reported following IV,inhalational, and intranasal heroin abuse.249 Acute renalfailure may be due to direct insult by the abusedsubstance, adulterants in the street drugs, and prolongedcoma.86,247,248 Chronic parental drug use may result inglomerulonephritis and renal amyloidosis and has been

associated with concurrent bacterial infections.250-253

Body packers are typically asymptomatic, but are at risk for delayed and prolonged toxicity from packet rupture.254 Symptomatic patients will exhibit the typicalsigns and symptoms of opiate intoxication. Body packersmay also present with or develop signs and symptomsof intestinal obstruction, and occasionally intestinalperforation and peritonitis.255

Clandestine laboratories have produced exceedingly potent and toxic drugs as new manufacturing methodshave been developed to circumvent the use of controlledor unavailable precursor compounds. As government

dependent on the dose and individual degree of tolerance. The clinical effects of an overdose with any one of the agents in this class are similar. However, asdiscussed, there are important differences betweencertain drugs. Overdoses resulting in toxicity often havea prolonged clinical course, partially due to an opioid-induced decrease in GI motility and prolonged half-lifeof the drug or its active metabolites.

Miosis is considered a consistent finding in opioidpoisoning, with the exception of meperidine, por-poxyphene, petazocin, dextromethorphan use, in case of a mixed overdose with an anticholinergic or sympath-omimetic drug, or when severe acidemia, hypoxemia,hypotension, or a CNS structural disorder is present.

Patients presenting with CNS depression following anopioid overdose represent the most seriously intoxicatedpatients. However, codeine, meperidine, and dextro-methorphan intoxications are remarkable for CNShyperirritability, resulting in a mixed syndrome of stuporand delirium. In addition, patients with meperidinetoxicity may also have tachypnea, dysphoric and hallucino-genic episodes, tremors, muscular twitching, and spasti-

city,126,132,133,135 whereas patients with dextromethorphantoxicity may also manifest restlessness and clonus.196,209-212

Acute lung injury after heroin overdose may not beunique. It has been reported with overdoses of opioidsthat include methadone, propoxyphene, codeine,buprenorphine, and nalbuphine.76,102,103,189,213-222 Acutelung injury may not develop until 24 hours followingmethadone overdose.70,71,223,224

Patients with heroin-induced acute lung injury typically have normal capillary wedge pressures andelevated pulmonary arterial pressures.224,225 In contrast,elevated systemic, pulmonary arterial, and pulmonary capillary wedge pressures and total systemic vascularresistance are seen with pentazocine intoxication.226

These effects are believed to result from transient endo-genous catecholamine release.227 Signs and symptoms of heroin-induced acute lung injury usually resolve within24 to 36 hours.69,228,229 Persistent pulmonary symptomsbeyond 24 to 48 hours may indicate aspiration or bacterialpneumonitis, with atelectasis, fibrosis, bronchiectasis,granulomatous disease, or pneumomediastinum.230

Adulterants in street drugs are potential pulmonary toxicants.231 The injection of adulterants such as talc(magnesium trisilicate) has produced granulomatosisin small pulmonary arteries, resulting in pulmonary thrombosis, pulmonary hypertension, and acute corpulmonale.189,190,230,232 Other potential pulmonary complications associated with IV opioid use include

pulmonary arteritis, septic emboli, lung abscess, bacterialpneumonia, aspiration pneumonitis, pulmonary edema,and respiratory arrest.

Seizures and focal neurologic signs are usually absent following opiate intoxication233 unless precipitated by severe hypoxia, dysrhythmia and hypotension, an intra-cranial process (e.g., brain abscess and subarachnoidhemorrhage), hypersensitive immune vascular injuryor vasculitis, proconvulsive adulterants, meperidine,propoxyphene, pentazocine (T’s and blues), or tramadoluse.176,178,186,234-242 Normeperidine neurotoxicity may manifest as delirium, tremor, myoclonus, or seizures.



16/24

authorities stringently regulate these products and theirprecursors, new drugs and methods are designed to taketheir place.105 Since these drugs may contain a wide

variety of active ingredients, adulterants, and contami-nants, the clinical syndromes seen in the abuser may beonly partly related to the opioid component.

DIAGNOSIS

Laboratory Studies

Laboratory studies such as complete blood count, serumelectrolytes, blood urea nitrogen, creatinine, creatinephosphokinase, urinalysis, arterial blood gas, electrocar-diography, imaging studies, and lumbar puncture shouldbe obtained as clinically indicated. Laboratory investi-gations should also include infections associated withIV drug abuse (e.g., endocarditis, aspergillosis, bacter-ial meningitis, cutaneous abscess, mycotic aneurism,intracranial abscess, epidural abscess, transverse myelitis,

viral hepatitis, wound botulism, tetanus, osteomyelitis,and acquired immunodeficiency syndrome).

MANAGEMENT

Opioid toxicity should be part of the differentialdiagnosis in all comatose patients. However, the classic“opioid toxidrome” may not be apparent following amixed overdose. Respiratory support is paramount in themanagement of patients with opioid toxicity; and thepatient should be managed according to current advanced cardiac life support guidelines. Prioritiesinclude assessment and establishment of effective

ventilation and oxygenation, followed by ensuringadequate hemodynamic support. Initial support with a

bag-valve-mask (BVM) device is appropriate, along with100% oxygen supplementation. Oral or nasal airway placement may be helpful, and caution is advised withtheir use given the potential for vomiting and/oraspiration. A suction apparatus should be available forimmediate use at the patient’s bedside. Ventilatory support can usually be safely provided with a BVM device

while awaiting the reversal of respiratory depression by an opioid antagonist. Endotracheal intubation isindicated in severely compromised patients in whom thereis a real risk for aspiration or in patients who do not satisfactorily respond to opioid antagonists.

GI decontamination should be considered after vitalsigns have been stabilized. Opioids may cause decreased

GI motility, and this suggests there may be some benefit to GI decontamination several hours postingestion.Gastric lavage may be of benefit in patients who arecritically ill, do not respond to naloxone, are suspect of polypharmacy overdose, or have overdosed on Lomotil;retrieval of Lomotil pills as late as 27 hours postingestionhas been reported.147 In the obtunded patient,endotracheal intubation should be performed prior tothe placement of the orogastric tube to minimize the riskof aspiration. Early administration of activated charcoalhas been advocated as the sole GI decontaminationprocedure. Although the clinical benefits of multiple

oral doses of activated charcoal remain to be established,it has potential benefit because of the prolongedabsorption phase typically encountered with opioidoverdoses. Patients should be closely monitored for thepresence of bowel sounds and passing of charcoal-ladenstool. Repeat charcoal doses should not be used in theabsence of active bowel sounds or in the presence of anileus. Ipecac-induced emesis in patients with opioid

overdose is not recommended given the potential forrapid deterioration and the risk for aspiration.

Naloxone is a pure competitive opioid antagonist at the , , and receptors, and has a greater affinity forthe receptor than for the or receptors. It canreverse the analgesia, respiratory depression, miosis,hyporeflexia, and cardiovascular effects of opiatetoxicity 256,257 and is effective in terminating opioid-induced vomiting. The goal of naloxone therapy is toreestablish adequate spontaneous ventilation andmaintain adequate airway reflexes without precipitatingan acute withdrawal syndrome.258 Naloxone is relatively contraindicated in the pregnant patient, in whomprecipitation of acute narcotic withdrawal may induce

premature labor or miscarriage. However, this does not preclude judicious naloxone use in pregnant patients

with severe respiratory depression. A judicious startingdose for IV naloxone may be 0.05 to 0.1 mg if the patient is possibly opioid dependent. Otherwise, an initial 2-mgdose can be administered. The recommended pediatricnaloxone dose is 0.1 mg/kg, up to 2 mg. For high-potency opioids (e.g., fentanyl and its analogs) or opioids with agreater affinity for the or receptor (e.g., pentazocine,propoxyphene) a larger than usual dose of naloxonemay be needed to successfully antagonize the opioideffects.259 Repeat IV naloxone boluses up to 10 to 20 mgshould be considered if there is a history of opioidexposure, a strong clinical suspicion based on presenting

signs and symptoms, or a partial response to the initialnaloxone dose. Submental, intranasal, intralingual,endotracheal, intraosseous, intramuscular, and sub-cutaneous routes of naloxone administration are accept-able alternatives when vascular access is not readily available.260-264 However, intramuscular and subcuta-neous injections are less desirable in the emergent situation. Repeat naloxone boluses may be requiredevery 20 to 60 minutes because of its short eliminationhalf-life (60 to 90 minutes) compared with that of most opioids.265 A continuous naloxone infusion may beconsidered in patients who have a positive response andrequire repeated bolus doses because of recurrent respiratory depression.266-268 A therapeutic naloxone

infusion may be made up by multiplying the effectivenaloxone bolus dose by 6.6, adding that quantity to1000 mL normal saline, and infusing the solution at100 mL/hr. The infusion is titrated to maintain adequatespontaneous ventilation without precipitating acuteopioid withdrawal and is empirically continued for 12 to24 hours. The patient should be admitted to an intensivecare setting where the patient will be frequently assessedduring this time. After discontinuing the naloxonetherapy, the patient should be carefully observed for 2 to4 hours for recurrent respiratory depression. In theevent of acute iatrogenic opioid withdrawal, allow the



17/24

dysrhythmias should be managed according to current advance cardiac life support guidelines. Sodium bicar-bonate may be useful in treating cardiotoxicity fromdrugs with “quinidine-like effects” (type IA antidys-rhythmics) that impair sodium channel functioning,manifested by widened QRS complexes, dysrhythmias,and hypotension. Sodium bicarbonate has beenreported to be effective in narrowing the QRS complex

in the setting of propoxyphene-induced wide complexdysrhythmias.291 Sodium bicarbonate (1 to 2 mEq/kg)may be administered as an IV bolus over a period of 1 to2 minutes. Greater amounts may be required to treat unstable ventricular dysrhythmias. Sodium bicarbonateboluses can then be repeated as needed with the endpoint of stabilizing or narrowing the QRS interval.Excessive alkalemia (pH greater than 7.55) andhypernatremia should be avoided.

Management of seizures should follow current treat-ment guidelines and should include benzodiazepines orbarbiturates. Adjunct naloxone therapy may be effectivein propoxyphene-292 but not meperidine- or tramadol-related seizures. Experimental evidence suggests naloxone

may potentiate normeperidine-induced seizures by inhibiting an anticonvulsant effect of meperidine.293

Naloxone appears to potentiate the anticonvulsant effects of benzodiazepines and barbiturates, and may antagonize the effects of phenytoin.294 Seizure has beenreported immediately following naloxone administrationfor tramadol overdose.240,295 The tramadol package insert cautions against naloxone use in overdose situations.

The management of serotonin syndrome is primarily supportive. Sedation, paralysis, intubation and ventilation,anticonvulsants, antihypertensives, and aggressive rapidcooling may all be necessary. There has been somesuccess with nonspecific serotonin antagonist cyprohep-tadine (4 to 8 mg every 8 hours orally).296

The occurrence of acute lung injury appears to beclinically unpredictable,70,71,76,297 and it has beensuggested that a man in his late thirties who is a relatively inexperienced heroin user and has a Glasgow ComaScale score of 4 to 5, has a respiratory rate of 6, andrequires naloxone to maintain his respiratory drive inthe prehospital setting would have a high likelihoodof developing acute lung injury.298 It has been recom-mended to observe all patients for at least 24 hoursfollowing emergence from an opioid overdose. However,some clinicians suggest that 4 hours patient observationmay be sufficient following a pure IV heroin or short-acting opioid overdose.69,299 An even shorter observationof at least 1 hour in an emergency department has been

investigated and may be acceptable, and remains to be validated.300 This study suggests that patients withpresumed opioid overdose can be safely discharged1 hour after naloxone administration if they (1) canmobilize as usual, (2) have oxygen saturation on roomair greater than 92%, (3) have a respiratory rate between10 and 20 breaths per minute, (4) have a temperaturebetween 35.0° C and 37.5° C, (5) have a heart ratebetween 50 and 100 beats per minute, and (6) have aGlasgow Coma Scale score of 15.

The management of acute lung injury should includeadequate ventilation, oxygenation, and positive-pressure

effect of naloxone to abate and avoid administeringadditional opioids.

Clinical experience has demonstrated naloxone to bean extremely safe drug. It has been administered at abolus dose of 5.4 mg/kg followed by infusion at4 mg/kg/hr for 23 hours in the treatment of acute spinalcord injury.269 Although naloxone is ordinarily a safedrug, there have been reports ascribing acute lung

injury,222,270-275 hypertension, cardiac dysrhythmias, anddeath to naloxone therapy.276-279 Typically, the patient hasa depressed consciousness and respiration. Afternaloxone administration, the patient awakens and overminutes to hours is noted to become hypoxic with anadequate respiratory rate and to develop pulmonary edema. Pink, frothy sputum may be evident in thenasopharyngeal area. Acute naloxone-induced withdrawalhas been associated with massive CNS sympatheticdischarge, which may be a precipitating factor in thedevelopment of “neurogenic” pulmonary edema.280-282 It appears that the pulmonary injury is at the alveolar-capillary membrane, resulting in manifestations con-sistent with acute respiratory distress syndrome.77,218

Abrupt heroin withdrawal precipitated by naloxone may contribute to the development of acute lung injury.However, it cannot be the only effect. Naloxone does not appear to directly alter the vascular permeability of thelung.283 Pulmonary edema was reported in 50% to 90%of the autopsies performed on heroin overdose patients,many of whom were declared dead in the prehospitalsetting and never received naloxone.72,73 In addition,opioid antagonist was unavailable when the initial casesof pulmonary edema were reported. A mechanical effect in which negative intrathoracic pressure generated by attempted inspiration against a closed glottis creates alarge pressure gradient across the alveolar membraneand draws fluid into the alveolar space may be

responsible for the observed association betweennaloxone administration and acute lung injury, similar to ventilator-associated pulmonary edema (Müller man-euver) prior to the advent of demand ventilators andneuromuscular blockers.284 Opioid poisoning may result in glottic laxity, prevent adequate air entry during inspi-ration, and may be especially prominent at the time of naloxone administration. This may result in breathingbeing reinstituted prior to the return of adequate upperairway function.

Naloxone is effective in reversing diphenoxylate(Lomotil)-induced opioid toxicity, but recurrence of respiratory and CNS depression is common.243 Allpatients with significant diphenoxylate overdose should

be admitted for monitored observation in the hospitalfor at least 24 hours.147 Naloxone has been reportedto reverse, though inconsistently, the CNS effects of ethanol, benzodiazepines, clonidine, chlorpromazine,and valproic acid following an overdose.285-288

Naloxone administration may “unmask” cocaine toxic-ity in patients using “speedballs”289 or anticholinergictoxicity in patients using heroin and scopolamine.290

Hypotension may respond to naloxone therapy, but may require fluid resuscitation and vasopressors.Overzealous fluid resuscitation should be avoidedbecause of the risk for pulmonary edema. Cardiac



18/24

ventilation as needed. Inotropic and chronotorpicagents and preload- and afterload-reducing agentsappear to be of little value. In one case series, themajority of patients only required supplemental oxygen,and 33% of patients required mechanical ventilation.69

Asymptomatic body packers may be managed conser- vatively by the prograde route provided the condition of packaging does not appear to be compromised. Some

clinicians suggest whole bowel irrigation with polyeth- ylene glycol electrolyte lavage solution based onretrospective case series and case reports.207,301-303 A proposed method, based on more than 100 cases of cocaine body packers, together with more than 10 years’experience, suggests a safe and efficient method for themedical management of asymptomatic body packers.This same method may be applied to heroin body packers and involves the oral administration of a water-soluble contrast solution followed by serial abdominalradiographs (Box 33-1).304,305

Body packers who develop opiate toxicity can often bemanaged with continuous naloxone infusion, activatedcharcoal, and whole bowel irrigation. Surgical

intervention is indicated for patients with intestinalobstruction or perforation, and may be indicated whenpackets fail to progress through the GI tract afterconservative management. Endoscopic retrieval of a few packets that are retained in the stomach may beconsidered, and should be performed by an experiencedendoscopist.

Pruritis is a common opioid adverse drug event. It may be localized or general and range from mild to severe.

Antihistamines are usually ineffective, but naloxone hasfrequently been found to offer relief. Ondansetron hasbeen reported to provide relief in ref

Documents

Intoxicación opioides