Download The Pharmacology of Opioids

The Pharmacology
of Opioids
Chapter
9 Lisa Borg, MD
Michele Buonora, BS
Eduardo R. Butelman, PhD
Elizabeth Ducat, ANP
Brenda M. Ray, MS, MPH, FNP-BC
Mary Jeanne Kreek, MD
C h a p t e r
O u t l i n e
■■ Definition of Drugs in the Class
■■ Substances Included in the Class
■■ Epidemiology of Opioid Abuse and Addiction
■■ Pharmacokinetics of Specific Drugs
■■ Pharmacodynamics
■■ Tolerance Development
■■ Toxicity States and Their Medical
Management
■■ Medical Complications of Opioids
■■ Conclusions and Future Research
Directions
Definition of Drugs in the Class
Three distinct types of opioid receptors are found in the
nervous system: mu, kappa, and delta. Classic clinically
used opioid analgesics act primarily as agonists or partial agonists at mu receptors. Heroin or illicit prescription
opioids also act primarily as mu opioid receptor (MOP-r)
agonists. Compounds in this class include the natural
opiates (drugs derived from opium) and their man-made
congeners which are agonists or antagonists, as well as
the endogenous opioid neuropeptide agonists, products of
three separate genes (1). The genes for each of these three
receptors and each of these three classes of opioid peptides have been cloned from humans (2,3). These opioid
receptors are members of the Gi-protein–coupled, 7-transmembrane domain superfamily. The three main families of
endogenous opioid peptides—­
beta-endorphin, enkephalins, and dynorphins—have a degree of selectivity for the
three receptor types. For example, beta-endorphin and the
enkephalins have relatively high affinity at mu and delta
receptors and much lower at kappa. The dynorphins, by
contrast, have relative selectivity for kappa receptors over
the mu and delta. These receptors mediate a complex,
partially overlapping array of ­physiologic and neurobio-
logic functions (4). For the purposes of this chapter, we
will concentrate on the mu receptor as most of the clinically used opioids are active at this receptor. However, the
entire endogenous opioid system plays an important role
in responses to addictive opiates, including morphine,
codeine, and heroin, as well as to synthetic opioids (3).
Beta-endorphin is a product of proopiomelanocortin,
which is produced primarily in the anterior pituitary of
humans. It is also produced in the central nervous system
(CNS) and in the periphery. The mu receptors mediate
both the analgesic and rewarding effects of opioid compounds (be they heroin or prescription opioids) as well as
their effects on many systems in the body, such as in the
hypothalamic–pituitary–adrenal (HPA) axis, immune, gastrointestinal (GI), and pulmonary function.
The term “opioids” refers to all compounds, natural and
synthetic, functionally related to opium derived from poppies
and endogenous opioid neuropeptides. Opium is a naturally
occurring mixture directly derived from the juice of the opium
poppy (Papaver somniferum). Morphine (the prototypical
MOP-r agonist) is the main active alkaloid in opium, whereas
thebaine can be used as a starting point for production of
semisynthetic MOP-r ligands. This chapter reviews the pharmacology of several exogenous opioids that are significant in
the area of opioid addiction and its treatment, that is, heroin,
morphine, oxycodone, codeine, meperidine, pentazocine,
hydromorphone, and hydrocodone, as well as methadone,
levo-alpha-acetylmethadol (LAAM), and buprenorphine.
Substances Included in the Class
Heroin
Heroin is synthetically derived from the natural opioid
alkaloid morphine. Largely owing to its very rapid onset of
action and very short half-life, heroin is a popular drug of
abuse. Heroin is classified in Schedule I (i.e., not available
for any therapeutic use in the United States), although it
is available in a few countries as a medication for treatment of heroin addiction (5,6). Heroin is a prodrug that
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section 2 ■ Pharmacology
is not itself active. It is most effective when used intravenously, but increasingly is used intranasally and, sometimes, smoked in the free base form (7). Intranasal and
smoked routes may have increased in popularity because
of the wider availability of high-purity heroin in recent
years, and also as a means to reduce the risk of human
immunodeficiency virus (HIV-1) transmission from intravenous use. Heroin is rapidly deacetylated to 6-monoacetyl morphine and morphine, both of which are active at
the mu opioid receptor.
Morphine and Synthetic Compounds
Morphine is a natural product of the poppy plant, Papaver
somniferum. Chemically, morphine is an alkaloid that
belongs to the class of phenanthrenes. This class also
includes codeine and thebaine. Modifications of the latter result in synthetic compounds discussed below (4).
Morphine is prescribed primarily as a high-potency analgesic. Biotransformations or synthetic modifications of
the chemical structure of the morphine molecule at the 3,
6, and 17 positions produce other compounds, including
morphine-6-glucuronide (M6G), a major pharmacologically active metabolite of morphine in humans. Related
compounds include hydrocodone (Vicodin), oxycodone
(OxyContin), hydromorphone (Dilaudid), and heroin.
Synthetic compounds also include antagonists such as naloxone (Narcan), naltrexone (Trexan or ReVia or Vivitrol),
and nalmefene (Revix), as well as partial agonists such as
buprenorphine alone (Subutex) or, when combined with
naloxone, (Suboxone) (4).
Oxycodone
Oxycodone has been used clinically since the early 1900s.
It is combined with aspirin or acetaminophen for the treatment of moderate pain and is available orally without coanalgesic for severe pain (8). It is a popular drug of abuse,
especially in controlled-release (CR) formulations that
can be easily crushed and self-administered (intranasally
or IV) for a potentially toxic, rapid “high” (9). Oxycodone
is a semisynthetic compound derived from thebaine,
with agonist activity primarily at mu receptors. Although
structurally similar to codeine, it is pharmacodynamically
comparable to morphine and has a 1:2 equivalence with
morphine (10).
Codeine
French pharmacist Pierre-Jean Robiquet first discovered
several natural products including codeine (11). Codeine is
methyl morphine, with a methyl substitution on the phenolic hydroxyl group of morphine. It is more lipophilic than
morphine and thus crosses the blood–brain barrier faster.
It also has less first-pass metabolism in the liver, therefore,
greater oral bioavailability than morphine, although it is
less potent than morphine. A small part of codeine is metabolized to morphine via cytochrome 2D6 (4).
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Meperidine
Meperidine is a phenylpiperidine and has a number of congeners. It is mostly effective in the CNS and bowel; however, it is no longer used for treatment of chronic pain
owing to concerns regarding toxicity of its major metabolite
and should not be used for greater than 48 hours or at doses
greater than 600 mg/d. It has serotonergic activity when
combined with monoamine oxidase inhibitors, which can
produce serotonin toxicity (clonus, hyperreflexia, hyperthermia, and agitation) (12).
Pentazocine
Both parenteral and oral formulations of pentazocine were
approved for marketing in the late 1960s. It is one of the
initial “agonist–antagonist” medications. Pentazocine is a
weak antagonist or partial agonist (it has a “ceiling effect,”
plateau in maximal effect, contrasted with a full agonist) at
the mu receptor and is also a kappa receptor partial agonist.
In 1983, in order to block the euphorigenic effects of inappropriately injected pentazocine, pentazocine was manufactured in combination with naloxone (Talwin NX). Thus, if
injected, this formulation would actually precipitate withdrawal in those with opioid dependence. Some data from
the DAWN (Drug Abuse Warning Network) database indicated that abuse declined after this reformulation (13).
Hydromorphone
Hydromorphone is a more potent opioid analgesic than morphine. It is used for the treatment of moderate to severe pain
and is excreted, along with its metabolites, by the kidney. It
can be given intravenously, by infusion, orally, and per rectum, with low oral bioavailability. On a milligram basis, it
is five times more potent than morphine when given orally,
and 8.5 times as potent when given intravenously (14). A
minor pathway for the metabolism of morphine to hydromorphone has been identified (15).
Hydrocodone
Hydrocodone is a prescription drug frequently prescribed
for a relatively minor (such as dental) pain. It is often used
in combination with acetaminophen; thus, there can be
hepatotoxicity associated with its abuse (8).
Methadone
Methadone is a synthetic long-acting full mu opioid agonist, active by parenteral and oral routes. It was first synthesized as a potential analgesic in Germany in the late
1930s and first studied for human use in the 1950s in the
United States. It has been used primarily as a maintenance
treatment for heroin addiction since the first research done
in 1964 (16), and it was approved by the U.S. Food and
Drug Administration (FDA) in 1972. Methadone is also
used and is very effective in the treatment of chronic pain;
however, it should not be used in opioid-naïve patients,
due to the risk of respiratory depression. The l(R)-methadone enantiomer has up to 50 times more analgesic activity
and also the potential to produce more respiratory depression than the d(S)-enantiomer. Both enantiomers have
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Chapter 9 ■ The Pharmacology of Opioids
­modest N-­methyl-d-aspartate (NMDA) receptor antagonism. Methadone has a diphenylheptylamine chemical
structure and consists of a racemic mixture of d(S)- and
l(R)-methadone. Again, the l(R)-enantiomer is responsible
for the majority of opioid effects as it is up to 50 times more
potent than the d(S)-enantiomer (17).
Levo-alpha-acetylmethadol
LAAM is a synthetic, longer-acting (48-hour) congener
of methadone that is also orally effective. LAAM was first
studied in the 1970s for the treatment of heroin addiction
(18) and approved in 1993 by the FDA (19) after a large
multicenter safety trial. Postmarketing, after reports of prolonged QTc intervals on electrocardiogram, which can lead
to torsade de pointes that may have been caused by LAAM, a
black-box warning was added to the product label (20,21).
LAAM remains approved for humans in the United States.
However, no company is manufacturing LAAM at this time.
As the new drug application for LAAM has not been withdrawn, LAAM could once again be made available in the
United States (22).
Table 9-1 Formulations and their
Methods of Use/Abuse
Drug
Formulation
Method of Use/
Abuse
Heroin
Powder
Free base
IV, intranasal,
smoked, SC
Morphine
Oral, injectable
solution
Oral, SC, IV
Oxycodone
Tablet: can be
With aspirin or
With
acetaminophen
(potentially
hepatotoxic)
IR or CR
PO, abused when
crushed and
then snorted or
injected IV, SC
Codeine
Tablet
Pentazocine
Tablet
NX formulation:
combined with
naloxone
Clinical Uses
Clinically used opioids (i.e., primarily MOP-r agonists) are
used for pain control, and as maintenance medications for
opioid addiction (i.e., methadone and buprenorphine). For
minor pain, such as post–dental procedures, opioids such
as hydrocodone are used. For more chronic or severe pain,
opioids such as morphine may be used. There is the risk of
iatrogenic addiction, respiratory depression, and also diversion of these medications. As a result, they must be dispensed cautiously. This caution, however, must be carefully
balanced against the risk of undermedicating pain for each
individual patient. When there is addiction to opioids, the
approved long-acting opioid pharmacotherapies are available by prescription for detoxification and for maintenance,
the latter having a well-proven long-term beneficial effect
on patient health. Depot naltrexone (Vivitrol) was recently
(October 2010) approved as a monthly IM injection for
prevention of relapse following detoxification from opioid
addiction.
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Oral, SC, IV
Hydromorphone Oral
PO (low oral
bioavailability),
IV, PR (per rectum)
Hydrocodone
Tablet
With
acetaminophen
PO
Methadone
Tablet, liquid
PO, IV
LAAM
Tablet
PO
Buprenorphine
Tablet
With naloxone
Film (sublingual)
SL, IV, SC
Buprenorphine
Buprenorphine alone, and in combination with naloxone,
was approved in 2002 by the FDA as an office-based sublingual treatment for heroin and opioid addiction (23–25)
at the same time; buprenorphine was reclassified by the
Drug Enforcement Administration from a Schedule V to a
Schedule III drug (13). Buprenorphine alone, or when combined with naloxone, is a primarily MOP-r–directed partial
agonist and is also a kappa partial agonist. The structure of
buprenorphine is that of an oripavine with a C7 side chain,
which contains a tert-butyl group. Norbuprenorphine is a
major metabolite of buprenorphine in humans, with activity
at the MOP-r as well (25).
The formulations of specific drugs are shown in Table 9-1.
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Nonmedical Uses
Opioids are abused initially for their euphoria-inducing
effects. There are patients who are prescribed opioids for
pain treatment who go on to abuse and/or become dependent upon the medication, due to physiologic and/or psychological factors. Heroin, as mentioned, is not available for
medical indications in the United States. Methadone and
buprenorphine are sometimes diverted by those for whom
it is prescribed, generally not for euphoria-inducing effects,
but to prevent withdrawal.
Historical Features
Sumerian clay tablets (3000 bc.) refer to the poppy;
Sumerians named opium “gil” (“happiness”). The ancient
Egyptians also cultivated poppies. Opium use was initially restricted and later became widely used. “Thebaine”
is derived from the name for the Egyptian city “Thebes.”
“Opium” may be a Greek-derived word (“opion” = poppy
juice). Opium figures prominently in Greek mythology and
was also mentioned in Hippocrates’ writings (460–377 bc).
The ancient Roman author Pliny warned of the dangers of
addiction to opium. In 1804, a young German pharmacist,
Friedrich Sertürner, isolated morphine (which he named
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after Morpheus, the Greek god of dreams) (26). As a major
development in opioid use and abuse, the hypodermic needle was perfected in 1853, which allowed for rapid analgesia, but also greater abuse morbidity. Diacetylmorphine was
first synthesized as a semisynthetic analog in the 1870s by
the Bayer company and marketed under the name “heroin.”
Epidemiology of Opioid Abuse and
Addiction
The pharmacology of opioids is of particular relevance
to the treatment of addictive disorders, given reports of
increases in the abuse of illicit opioids, as well as illicit
use of prescribed opioid medications (27). More than
100,000 people aged 12 to 25 initiated use annually
between 1995 and 2002 (3). According to the Office of
National Drug Control Policy publication of January 2008,
more than 2.1 million teenagers in 2006 abused prescription drugs, and one-third of new abusers of prescription
drugs in 2006 were 12- to 17-year-olds. Among 12- to
13-year-olds, prescription drugs are the drug of choice
(28). According to the Substance Abuse and Mental Health
Services Administration (SAMHSA) Treatment Episode
Data Set, annual admissions to substance abuse treatment
for primary heroin abuse increased from 228,000 in 1995
to 254,000 in 2005, with the percentage of primary heroin
admissions remaining steady at about 14% to 15% of all
substance abuse treatment admissions (7).
The majority of persons in treatment for heroin addiction are in methadone maintenance treatment. Also, currently, there are approximately 24,000 US physicians eligible
to prescribe buprenorphine as office-based treatment to
patients for treatment of opioid dependence (personal communication, Reckitt-Colman Co.). Eligibility requirements
for physicians to use buprenorphine in treatment of addiction are as follows (as established by the SAMHSA DATA
2000; Drug Addiction Treatment Act 2000): completion of
an 8-hour continuing medical education course; notification of the government of the intent to use buprenorphine
for treatment of opioid-dependent patients; and having both
the capacity to provide or refer patients for ancillary services and, as of December 2006, being in agreement to treat
no more than 100 patients (increased from the original 30
maximum) at any one time in an individual or group practice (29,30).
Two cross-sectional studies conducted in New York City
from 2000 to 2004 found that among new admissions to
drug treatment, of those patients who had stopped injecting
heroin as of 6 months prior to the study, the most common
reasons for cessation included concerns about health and
preference for the intranasal route (31).
The recent and major problem of opioid abuse and
addiction is the illicit (nonprescription) use of prescription opioids, obtained illicitly or from family members or
friends. As of 2007, 8th, 10th, and 12th grade students
nationwide continued to show a decline in the proportions
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reporting illicit drug use. Less than 1% of ­students in these
grades reported any use of heroin in 2007. However, the
prevalence of other narcotic drug use reported for twelfth
graders was 9.2% (32). In a National Institutes of Health:
National Institute of Drug Abuse Research Report, published in 2001 and revised in 2005, it was reported that
benzodiazepines and opioid pain relievers were the two
most frequently reported prescription medications in
drug abuse–related cases (33). In 2005, 30.1% of persons
addicted to heroin sought treatment with methadone or
buprenorphine maintenance, whereas only 19.9% of those
addicted to illicitly used prescription opioids sought such
pharmacotherapy (7).
Neurobiology, Mechanisms of Action, and
Relationship to Abuse Liability
Abused opioids have primarily agonist effects at MOP-r receptors (encoded by the mu opioid receptor gene [OPRM1])
(17,34). MOP-r are members of the G-protein–coupled
7-transmembrane domain superfamily; they are coupled
to Gi and Go proteins, and thus MOP-r agonists typically
acutely result in a downstream decrease in adenylate cyclase
activity (35).
Distribution in CNS and mediation of different
functions
MOP-r are widely distributed in the CNS, and the constellation of their in vivo effects is mediated in different CNS
areas (36–38). Thus, therapeutically desirable analgesic
effects can be mediated in different sites including dorsal
spinal cord and thalamus, whereas undesirable effects, such
as respiratory depression, are thought to be mediated in
the brainstem (39). Other regions involved in the classic
processes of physiologic dependence/withdrawal to MOP-r
agonists are thought to include the locus ceruleus and
related centers (40,41). Classic rewarding effects of MOP-r
agonists, of relevance to abuse and addiction, are likely
mediated to a substantial degree in ventral and dorsal striatal areas and can depend (although not exclusively) (42)
on downstream activation of the dopaminergic mesocorticolimbic and nigrostriatal systems (43,44).
MOP-r Signaling Properties and Addiction/
Abuse Potential
A major underlying concept in the abuse potential of
MOP-r agonists is their pharmacodynamic efficacy (i.e.,
their relative ability to stimulate downstream second messenger systems). In general, compounds with progressively
greater efficacy (e.g., morphine or fentanyl-like compounds) have greater analgesic effects but also have greater
abuse potential than partial agonists such as buprenorphine
(35,45). Furthermore, other downstream effects of MOP-r
agonist exposure are now postulated to be of relevance to
the relative balance of therapeutic and undesirable effects
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Chapter 9 ■ The Pharmacology of Opioids
of MOP-r agonists, including propensity to cause tolerance,
or abuse potential. Major mechanisms of current interest
are the relative propensity of compounds to cause MOP-r
desensitization, and internalization, potentially related to
their ability to stimulate the β-arrestin signaling pathways
(46,47). For example, the main active heroin metabolite,
morphine, results in lesser desensitization and internalization of receptors, compared to the endogenous neuropeptide
ligands, or methadone (48). Thus, methadone maintenance
can be used effectively for extended periods without the
development of further tolerance (or progressively greater
methadone dose requirements) (49). By contrast, abused
heroin (through its main metabolite, morphine), or abused
prescription opioids, may result in progressive cycles of
dependence and tolerance, secondary to a lesser recruitment of endogenous MOP-r desensitization/internalization
mechanisms (50).
Pharmacokinetics of Specific Drugs
It is beyond the scope of this chapter to provide a comprehensive table of dosing equivalents. There are a number of
excellent reviews on this topic (4,8,51).
Heroin (Diacetylmorphine) Pharmacokinetics
Heroin is a very efficient prodrug that is more water soluble and more potent than morphine (52). It is synthesized
from morphine by acetylation at both the 3 and 6 positions
and metabolized in humans to active opioid compounds
first by deacetylation to the active 6-monoacetylmorphine
(6-MAM), and then by further deacetylation to morphine
(52). Well-designed studies of heroin pharmacokinetics
in humans have been performed (53–56). Heroin has an
average half-life in blood of 3 minutes after intravenous
administration; the half-life of 6-acetylmorphine in humans
appears to be 30 minutes (53).
The use of intranasal, intramuscular, and subcutaneous
heroin all produce peak blood levels of heroin or 6-acetylmorphine within 5 minutes; however, intranasal use has
about half the relative potency of parenteral routes (54).
Further research needs to be carried out on the role of
6-acetylmorphine (administered directly) in relation to the
pharmacokinetics of parenteral heroin, particularly its onset
of action and potency as compared with morphine. Most of
the enzymes involved in the metabolism of opioids are part
of the P450 microsomal enzyme system, though heroin and
morphine are also biotransformed outside this system.
Morphine Pharmacokinetics
Morphine is largely selective for MOP-r and is considered by
most physicians in the United States the drug of choice for
the treatment of cancer pain. Morphine is biotransformed
mainly by hepatic glucuronidation to the major but inactive
metabolite morphine-3-glucuronide (M3G) and the biologically active M6G compound (57).
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139
The pharmacokinetics of morphine and its metabolites
vary, depending on the route of administration. Its favorable
safety profile is due in large part to its pharmacokinetic profile. The oral bioavailability varies, from 35% to 75%, with
a plasma half-life ranging from 2 to 3.5 hours. The half-life
is less than the time course of analgesia, which is 4 to 6
hours, thus reducing accumulation. Morphine is metabolized mostly in the liver, with prolonged clearance because
of enterohepatic cycling with oral dosing (58). In the setting
of chronic liver disease, morphine oxidation is more affected
than is glucuronidation. Use of lower doses or longer dosing
intervals is recommended to minimize the risk of accumulation of morphine when chronic liver disease is present, particularly with repeated dosing. At 24 hours, more than 90%
of morphine has been excreted in urine. M6G elimination
seems to be closely tied to renal function, so accumulation
of metabolites can occur. With renal compromise, less than
10% of morphine and its metabolites are excreted in feces;
therefore, morphine should be used with great caution in
patients with renal disease (unlike methadone, which can
be given relatively safely in these patients: see Methadone
Pharmacokinetics). The higher sensitivity of older adults to
the analgesic properties of morphine may be related in part
to altered pharmacokinetics (59,60).
Oxycodone Pharmacokinetics
The onset of action of oxycodone begins after 1 hour of
PO (oral) administration, and in the CR form lasts for
approximately 12 hours, with a plasma half-life of 3 to 4
hours for the immediate release (IR). Stable plasma levels
are achieved within 24 hours. Oral bioavailability ranges
from 60% to 87%, with 45% protein bound. Oxycodone
is mostly metabolized in the liver, with the remainder as
well as the metabolites metabolized in the kidneys. The two
main metabolites are oxymorphone, which is also a potent
analgesic, and the weaker analgesic noroxycodone, which
is its major metabolite (10,61). In terms of protein binding
and lipophilicity, oxycodone is similar to morphine, with
slightly longer half-life and greater bioavailability. Unlike
morphine, oxycodone is metabolized mostly by the cytochrome enzyme CYP2D6, while morphine in humans is primarily glucuronidated (62).
Codeine Pharmacokinetics
Codeine has a high oral–parenteral effect, owing to low
first-pass metabolism in the liver. Metabolites are mostly
inactive and excreted in the urine, with about 10% demethylated via CYP2D6 to morphine, which is mostly responsible for the analgesic effect of codeine, as codeine itself has
very low affinity for opioid receptors. Genetic variations
in this enzyme system may result in lower production of
M6G. The allelic variants have different frequency in different ethnic groups, and can affect the depth of analgesia.
Repeated doses of codeine may result in the accumulation
of the active metabolite M6G in patients with renal disease.
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section 2 ■ Pharmacology
Meperidine Pharmacokinetics
Onset of analgesia begins with the oral route after 15 minutes, with peak in 1 to 2 hours, which is close to peak level
in plasma, with duration of about 1.5 to 3 hours (4). It is
absorbed by all routes, but intramuscular administration
results in a less reliable peak plasma level after 45 minutes, with wide range of plasma concentrations. After oral
administration, about 50% of meperidine enters circulation
without first-pass metabolism, with peak at 1 to 2 hours.
Meperidine is mostly metabolized in the liver, with half-life
of about 3 hours. Cirrhosis leads to increased bioavailability
and half-life of both meperidine and normeperidine. Sixty
percent of meperidine is protein bound and little is excreted
unmetabolized (12).
Pentazocine Pharmacokinetics
Pentazocine is a mixed agonist–antagonist (with intermediate efficacy effects at both MOP-r and KOP-r) that can be
given intramuscularly or orally, but is not currently available
in the oral formulation. It can cause psychotomimetic effects
(likely due to its KOP-r actions) and therefore has a very
limited role in the treatment of chronic pain. Its duration of
action is 3 to 6 hours. Its peak effect is at 0.5 to 1 hour when
given intramuscularly and 1 to 2 hours when given orally (8).
Sixty percent of the drug is bound to protein. Pentazocine is
metabolized by the liver via oxidative and glucuronide conjugation with an extensive first-pass effect. When administered
orally, the bioavailability of pentazocine is about 10%, except
in patients with cirrhosis, which increases bioavailability to
60% to 70%. The drug half-life is 2 to 3 hours. Small amounts
of unchanged pentazocine are excreted with urine (8).
Hydromorphone Pharmacokinetics
Hydromorphone is shorter acting than morphine. It is
derived from morphine, although it may also be produced
in the body in small amounts by N-demethylation of hydrocodone. It has an oral bioavailability of 30% to 40%, with an
analgesic onset after 10 to 20 minutes, which peaks at about
30 to 60 minutes and persists for about 3 to 5 hours. The
oral–parenteral ratio is about 5:1, with an equivalency of
1.5 mg of hydrocodone to 10 mg morphine (63).
Hydrocodone Pharmacokinetics
Hydrocodone has a half-life of 2 to 4 hours, with a peak
effect at 0.5 to 1 hour. Its duration of action is 3 to 4 hours
(8). Codeine may show up as trace quantities of hydrocodone in urine testing as up to 11% of codeine is metabolized to hydrocodone (64), which could be misinterpreted
as hydrocodone abuse.
Methadone Pharmacokinetics
Methadone, as used in the United States, is a racemic compound; the l(R)-enantiomer is the active enantiomer and
the other d(S)-enantiomer is the inactive enantiomer. Both
0002052880.INDD 140
enantiomers are weak NMDA receptor antagonists; therefore, racemic methadone, retards and attenuates the development of opioid tolerance (65). Methadone meets the
two important criteria for a medication for the treatment
of addiction: high systemic bioavailability (>90%) with
oral administration and long apparent half-life with longterm administration in humans (66). The medical safety of
long-term methadone maintenance treatment has been well
­studied (67).
Oral methadone has a rapid absorption but a delayed
onset of action, with peak plasma levels achieved by
2 to 4 hours and sustained over a 24-hour dosing period
(36,66,68,69). Moreover, the mean plasma apparent terminal half-life of racemic d,l-methadone in human subjects
is around 24 hours (66). The l-enantiomer has a half-life
of 36 hours (65,70,71). Biotransformation of methadone
is accelerated in the third trimester; therefore, methadone
dose may need to be increased in the final stages of pregnancy (72).
When taken on a chronic basis, methadone is stored
and accumulated mostly in the liver (68,73). Methadone
plasma levels are relatively constant because of slow release
of unmetabolized methadone into the blood, which extends
the apparent terminal half-life. Methadone is more than
90% plasma protein bound both to albumin and globulins
(72,74). These properties help explain why methadone
maintenance treatment is effective as a once-daily, orally
administered pharmacotherapy for heroin addiction (16),
unlike heroin and morphine, both of which have a relatively
rapid onset and offset of effect and short duration of action.
Owing to the long half-life of methadone, when beginning long-term methadone maintenance treatment (usually
starting with a 20- to 40-mg daily dose), escalation of dose
exceeding the rate of development of tolerance can result in
accumulation, with sedation and even respiratory depression. Thus, dosages must be increased slowly, usually by 10
mg every 4 to 7 days. In some patients, doses in the appropriate range (e.g., 80 to 150 mg/d) do not result in either
clinical improvement or in apparent therapeutic plasma
levels of 250 to 400 ng/mL, and this may be due to “rapid
metabolism” related to individual genetic differences of the
cytochrome P450– enzyme or p-glycoprotein–related transporter systems (69,75,76), the latter also potentially related
to blood–brain barrier passage of methadone. Methadone
levels in the cerebrospinal fluid peak 3 to 8 hours after
methadone ­dosing (77,78).
Methadone is biotransformed in the liver by the cytochrome P450–related enzymes (primarily by the CYP3A4
and, to a lesser extent, the CYP2B6, CYP2D6, and CYP1A2
systems) to two N-demethylated biologically inactive
metabolites, which undergo additional oxidative metabolism (17,65). Methadone and its metabolites are excreted
in nearly equal amounts in urine and in feces (78–82).
In patients with renal disease, methadone can be cleared
almost entirely by the GI tract, reducing potential toxicity
by preventing accumulation (80–82). Patients with severe
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Chapter 9 ■ The Pharmacology of Opioids
long-standing liver disease have decreased methadone
metabolism and thus slower metabolic clearance of methadone, yet lower than expected plasma methadone levels as
a result of lower hepatic reservoirs of methadone because
of reduced liver size. Methadone disposition is relatively
normal in patients with mild to moderate liver impairment
(78,83,84).
Other drugs can interact with methadone because of their
effects on hepatic enzymes in the cytochrome P450–related
enzyme system (74): see chart. The drug–drug interactions
with methadone are complex and must be considered on a
case-by-case basis in individual patients (74). The major
categories of drugs potentially interacting with methadone
include both inducers and inhibitors of CYP3A4, (as well
as inhibitors of CYP2D6, such as paroxetine) (84). CYP3A4
inducers include rifampin (85), rifabutin (86), carbamazepine (87), phenytoin (88), and phenobarbital (63), some of
which have been shown to have a documented effect (85),
(87), (88). Although CYP3A4 inhibitors, which include
fluconazole (89), fluvoxamine (90), fluoxetine (91), paroxetine (84), and possibly erythromycin and ketoconazole,
have been hypothesized to result in significant drug interactions (17,65,74), very few of these medications have
been shown to have a documented effect, either pharmacokinetic or pharmacodynamic, in humans at the doses
used in methadone treatment, and some have been shown
to have little or no effect, such as rifabutin (86) and fluoxetine (91).
A number of studies have examined specific antiretroviral medications used in the treatment of HIV-1 and their
interaction with methadone. There are reported pharmacokinetic interactions, usually through the CYP3A4 system,
affecting either methadone or the antiretroviral medication,
which sometimes have clinical manifestations (92,93).
Methadone levels are significantly affected by the regular consumption of more than four alcoholic drinks per day
(94). Lowered methadone biotransformation secondary to
hepatic enzyme competition occurs during excessive ethanol use, with resultant increases in levels of methadone
(95). When chronic use of alcohol is no longer present, the
metabolism may be accelerated owing to the enhancement
of the P450 enzymes (95), resulting in lower than expected
plasma methadone levels.
St. John’s wort (a dietary supplement sometimes selfadministered by patients for depression) and grapefruit
juice (via the CYP3A4 isoenzyme system) may affect the
plasma concentration of methadone (96,97) and are not
recommended during methadone maintenance treatment
(97).
Levo-alpha-acetylmethadol Pharmacokinetics
LAAM, a congener of methadone, shares with methadone
the properties of long duration of effect (48 vs. 24 hours
for methadone, in part owing to its active metabolites norLAAM and dinorLAAM, as well as its steady-state perfusion
0002052880.INDD 141
141
of mu opioid receptors), oral effectiveness (18), and function as a pure opioid agonist, active mostly at the mu opioid receptor. NorLAAM and dinorLAAM accumulate with
chronic administration. In addition, LAAM and its metabolites bind to tissue proteins (18).
The clearance of norLAAM and LAAM is similar, whereas
the clearance of dinorLAAM is more prolonged than that of
its parent compound (18). The peak pharmacologic effect
of LAAM as measured by amount of pupillary constriction
occurred at 8 hours and then diminished at a rate most like
that of norLAAM metabolism (18).
Because of the metabolism of LAAM by the cytochrome
P450 3A4 system–related microsomal enzymes to norLAAM
and dinorLAAM, drug interactions can occur (e.g., rifampin
and long-term alcohol abuse tend to induce this enzyme
system). In their presence, increased biotransformation of
LAAM could accelerate the production of norLAAM and
dinorLAAM. LAAM metabolism theoretically could be
retarded if hepatic drug metabolism is diminished, as occurs
in the presence of very large quantities of either ethanol, or
perhaps with large doses of benzodiazepines, or with intake
of cimetidine (18).
Buprenorphine Pharmacokinetics
Buprenorphine is metabolized to norbuprenorphine, due to
dealkylation in the cytochrome P450–related enzyme 3A4
system, of which buprenorphine itself is a weak inhibitor
(98). Buprenorphine undergoes extensive first pass in the
liver; thus, it is administered sublingually with 50% to 60%
bioavailability. Despite the ceiling effect of buprenorphine as
previously described, there have been a number of reported
cases of deaths in Europe with concurrent benzodiazepine
abuse (99). There have been many reports of the intravenous abuse of the sublingual preparation of buprenorphine
in many countries. A second formulation of sublingual
buprenorphine (combined with naloxone), was developed
in 1984, and modeled after our early well-studied formulation of methadone/naloxone, is now increasingly used in
the United States and worldwide (67). In this formulation,
naloxone will not precipitate withdrawal when taken sublingually because of its limited oral bioavailability; however,
it may block the initial euphoric effects of buprenorphine
if abused by the intravenous route and may also then precipitate acute opioid withdrawal (100,101). However, naloxone apparently cannot effectively displace buprenorphine in
overdose situations, particularly when benzodiazepines are
present. With acute buprenorphine intoxication, there may
be mild mental status changes, mild to minimal respiratory
effects, small but not pinpoint pupils, and essentially stable
vital signs. In some situations, naloxone apparently can
improve the respiratory depression but with limited effect
on the other symptoms (101). Patients should be observed
for 24 to 48 hours.
Initially developed as an analgesic, buprenorphine has
been shown in most studies to be as effective as morphine
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in many situations. Buprenorphine has some modest kappa
opioid receptor (KOP-r) activity, as a partial agonist (102).
Owing to its ceiling effect, increasing buprenorphine doses
in humans beyond 32 mg sublingually has no greater
MOP-r agonist effect (103). Sixteen milligrams sublingual
buprenorphine is the most commonly used dose in the
treatment of opioid addiction, which is similar in efficacy to
around 60 mg of methadone (104).
Buprenorphine has a long duration of action (24 to 48
hours) when administered on a chronic basis, not because
of its pharmacokinetic profile, but because of its very slow
dissociation from MOP-r. Two important properties of
buprenorphine are (a) its apparent lower severity of withdrawal signs and symptoms on cessation, compared with
heroin, and, possibly, with methadone and LAAM and (b)
its reduced potential to produce lethal overdose when used
alone in opiate-naïve or nontolerant persons, because of its
partial agonist properties. Given intravenously, buprenorphine has an apparent beta-terminal plasma half-life of
about 3 to 5 hours. When given orally, it is relatively ineffective because of its first-pass metabolism (18), that is, rapid
biotransformation, probably by the intestinal mucosa and,
especially, by the liver. Sublingual preparations of buprenorphine can be liquid or tablet, both of which require about
120 minutes for time to peak. However, peak plasma concentrations of the sublingual tablet and mean area under the
plasma concentration time curve are lower than that of the
liquid at equivalent doses (103,105–107).
In two positron emission tomography (PET) studies
of MOP-r with buprenorphine, studies initiated in volunteers (13 initiated, 5 completing), who were treated with
buprenorphine for up to 10 weeks maximum, at dosages
of 2 mg, 16 mg, and 32 mg sublingually, it was found that
buprenorphine induced dose-dependent reductions in
MOP-r availability occupation far greater than that seen
during moderate to high dose methadone maintenance
treatment (36,108,109). This is consistent with high receptor occupancy by buprenorphine as a partial agonist, at
therapeutic doses.
The mechanism by which buprenorphine blocks the
effects of heroin or morphine is probably similar to those
observed with methadone in maintenance treatment, which
blocks moderate to high doses of heroin or morphine, principally by tolerance and cross-tolerance (16). This may be
in addition to relative blockade due to buprenorphine’s partial agonist profile.
Pharmacodynamics
The pharmacodynamics of the clinically important MOP-r
agonists are wide ranging, with the most pronounced effects
produced in the CNS and GI tract.
The mechanism of action for all of the clinically relevant
opioids described here is at the MOP-r, in which they act
preferentially as agonists, except for buprenorphine, which
is a partial mu opioid agonist (109), and a low efficacy
0002052880.INDD 142
ligand (antagonist or partial agonist) at kappa receptors
(102).
Opioids in general affect heat regulation mechanisms
in the hypothalamus. Body temperature decreases slightly,
except with chronic high doses where temperature may
be increased (4). Opioids also act in the hypothalamus to
inhibit the release of gonadotropin-releasing hormone and
corticotropin-releasing hormone, producing a reduction in
luteinizing hormone, follicle-stimulating hormone, adrenocorticotropin hormone (ACTH), and beta-endorphin (110).
With decrease in these hormones, plasma concentrations of
testosterone and cortisol are lowered. Mu agonists increase
the amount of prolactin in plasma by decreasing dopaminergic inhibition. Given chronically, there is tolerance to the
effects of morphine on the neuroendocrine system. Mu opioid agonists also tend to have antidiuretic effects (111–114).
Morphine also causes constriction of the pupil (4).
Opioids can cause seizures at doses much higher than used
for analgesia. Naloxone is less potent in antagonizing seizures due to meperidine versus other opioids such as morphine or methadone, possibly due to convulsant metabolites
(normeperidine). Therefore, meperidine is no longer used
for chronic pain, and is not to be used for greater than 48
hours or greater than 600 mg/d dose (12).
All opioids must be used cautiously in patients with
impaired respiratory function. Also, opioids have the potential to elevate intracranial pressure (115) (e.g., in the setting
of head injury, they can produce an exaggerated respiratory
depression, as well as mental status changes that can confuse the clinical picture). Typical side effects of all opioids
include drowsiness, nausea, and constipation, while vomiting, pruritus, and dizziness are less common; however, all of
these tend to lessen in intensity over time.
Codeine is commonly used to suppress cough at doses
lower than used for analgesia (starting with 10 to 20 mg given
orally) and can increase to higher doses for chronic (lower airway) cough. Codeine reduces cough via a central mechanism,
with doses greater than 65 mg not indicated, owing to little
increased therapeutic effect with increasing side effects (4).
Pentazocine as a mixed agonist–antagonist drug has
a “ceiling effect,” like buprenorphine, which limits the
degree of analgesia. Pentazocine can lead to the development of psychotomimetic side effects, not reversible with
naloxone; therefore, these may not be mediated through
MOPr. Pentazocine has affinity for kappa receptors (116).
Pentazocine can also produce withdrawal in opioid-tolerant
patients, due to its weak antagonist effects.
Methadone, like all mu opioid agonists, affects multiple
organ systems, with tolerance developing at different rates
to each effect. In the treatment of illicit opioid dependence
or pain with prescribed opiates, proper dosing (titrated to
the tolerance of the individual patient) is essential to avoid
CNS depression. The precise neuronal and molecular mechanisms of physical tolerance have not been fully elucidated
(112). However, it has been shown in studies of the d(R)enantiomer of methadone (which is relatively inactive at
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Chapter 9 ■ The Pharmacology of Opioids
the MOP-r) that this isomer has modest NMDA antagonist
activity, which attenuates the development of morphine
tolerance in rodents, but does not affect physical dependence (117). Tolerance to the different effects of methadone
occurs at different time points, with persistence (after at
least 3 years of chronic treatment) of increased sweating and
constipation (67) as well as a persistence of the pulsatile
increase in prolactin entrained to the peak level of methadone, which occurs approximately 2 to 4 hours after daily
administration (110,113,114).
With the use of oral methadone, analgesia occurs at 30
to 60 minutes. The analgesic effect of a single methadone
dose given intramuscularly is equivalent to morphine, but
its cumulative effects occur over time (8). It is recommended
that methadone not be used for analgesia in mu agonist–naïve
patients due to the risk of accumulation. Rather, it should be
used only in patients who have already been exposed to mu
agonists and have gained a degree of tolerance.
Any euphoria produced by any opioid agonist, primarily
short-acting opioids, apparently is mediated in part by the
ventral tegmentum, where opioid agonist–mediated inhibition of GABAergic neurons results in disinhibition and thus
activation of dopamine neurons extending to the nucleus
accumbens. Norepinephrine-secreting cells in the locus
ceruleus appear to play an important role in opioid withdrawal, whereas both serotonin and dopamine exert effects
on dependence and craving (112,114).
Chronic administration of long-acting opioids (such
as methadone) leads to the gradual development of tolerance to the effects on hypothalamic-releasing factors, with
resumption of normal menses and return of plasma levels
of testosterone to normal within 1 year as well as return
to normal levels and activity of anterior pituitary-derived
ACTH and beta-endorphin and normal ACTH stimulation
in approximately 3 months (67,110). In humans, prolactin release is under tonic inhibition by tuberoinfundibular
dopaminergic tone. With the use of short-acting opiates,
there is a prompt increase in the release of prolactin because
of an abrupt lowering of dopamine levels in the tuberoinfundibular dopaminergic system. With chronic methadone
treatment, there is partial, but not complete, tolerance to
this response (see below) (67,110,113,118,119).
The metyrapone test blocks 11-beta-hydroxylation of
cortisol in the adrenal cortex. Heroin reduces the normal
stress response to this test. However, a normal response is
restored during chronic methadone maintenance treatment
(67,110,120,121). With heroin use, thyroid levels may be
elevated because of raised thyroid-binding globulin; thus,
there are increased measures without abnormal function
(67,110). The hypothalamic and pituitary effects of opioids
can produce antidiuretic effects by the release of vasopressin (4,110).
Acutely, short-acting opiates can cause many effects.
During chronic methadone maintenance treatment, many of
these effects may diminish or present with a different time
course. In the cardiovascular system, acute administration
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143
of opioids may cause peripheral vasodilatation, decreased
peripheral resistance, reduced baroreceptor reflexes, histamine release, and decreased reflex vasoconstriction caused
by raised PCO2 (4). In the stomach, hydrochloric acid
secretion may be inhibited, and somatostatin release from
the pancreas may be elevated (4). Acetylcholine release
from the GI tract is inhibited, and motility is slowed, as is
absorption of drugs. The presence of increased appetite has
also been noted. Biliary, pancreatic, and intestinal secretions may be reduced and digestion in the small intestine
slowed. In the large intestine, there are reduced propulsion
and higher tone (4,67,110,111). Tolerance develops to each
of these effects. The short-acting opioids such as heroin
or morphine, administered on an acute or chronic basis,
reduce rosettes formed by human T lymphocytes (110,111).
Morphine reduces cytotoxic activity of natural killer cells
and increases growth of implanted tumors in experimental
models (110,111). In contrast, with the chronic use of the
long-acting opioid methadone, absolute numbers of T cells,
T-cell subsets, B cells, and quantitative immunoglobulins
are gradually restored to normal over 3 to 10 years, along
with restoration of normal natural killer cell activity (122).
During the chronic use of short-acting narcotics, these
immunologic indices are abnormal (e.g., with the use of
heroin), possibly in part by mediation through the neuroendocrine system, since cortisol suppresses many parameters
of immune function and cortisol levels increase in opioid
withdrawal. Normalization of most of these immunologic
indices may gradually occur with methadone maintenance
treatment (67,110,111). Thus, during methadone maintenance treatment, no daily withdrawal episodes occur.
Tolerance Development
Tolerance may be defined as a loss of any effect after
repeated use, leading to the need for higher doses to get the
desired equivalent effect (112,123). Physical dependence is
now known to be molecularly and clinically different from
tolerance (112,123). All opiate and opioid medications
lead to development of tolerance and physical dependence,
though the rate of development of tolerance varies from one
medication to another. Tolerance may develop at different
rates for any side effects of any opioid medication and can
occur over days, weeks, or years. Development of tolerance
to opiates and opioids does not involve drug disposition
and metabolism. There appears to be a complex interplay at
both the single-cell and neuronal system levels (112).
Two unique characteristics distinguish methadone from
almost all other therapeutic opiates and opioids. First, after
binding to MOP-r, the methadone–opioid receptor complex
undergoes rapid endocytosis, exactly like endogenous opioids (e.g., beta-endorphin or met-enkephalin) (112,123).
Second, it has been shown that both enantiomers of methadone, present in equal amounts in a racemic mixture, have
modest NMDA antagonist action and that NMDA antagonism attenuates or prevents tolerance to opiates and opioids
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(57,112). Thus, this modest NMDA antagonist activity may
contribute to the slow rate of development of tolerance to
methadone (117).
Patients maintained on methadone rapidly develop partial or full tolerance to most of methadone’s side effects (e.g.,
nausea and vomiting, miosis, sedation). However, tolerance
develops at a slower rate to the neuroendocrine effects of the
HPA and hypothalamic–pituitary–gonadal axes. Tolerance
develops even more slowly to the constipating effects of opioids (67). The only side effect to which tolerance does not
develop is sweating (67), which is not excessive and does
not interfere with extreme physical activities in heat or in
sunlight. Tolerance develops more rapidly to the “on–off”
effects of short-acting narcotics (e.g., heroin, morphine, and
even extended-release preparations of short-acting narcotics, such as oxycodone [OxyContin]). Therefore, the GI and
neuroendocrine side effects of short-acting opioids tend to
persist (66).
Toxicity States and Their Medical
Management
Acute opioid overdose is characterized by the triad of stupor or coma, respiratory depression, and “pinpoint” pupils.
Needle marks may be noted.
Individualized dosing and reliance on regular clinical assessments are important, as diminished respiration
occurs with opioids until tolerance develops. When any
opioid is used beyond the degree of tolerance that is developed, reduced response to carbon dioxide centers in the
pons and medulla can lead to CO2 retention. Initially there
is depressed cough (which is mediated by the medulla)
as well as nausea and vomiting, which may be mediated
by the area postrema of the medulla, and which disappear
rapidly with the development of tolerance. Constriction
of the pupil is the result of parasympathetic nerve excitation. In opioid overdose, convulsions have been reported,
probably because of inhibition of the release of GABA in
the CNS (4).
Mydriasis or normal pupils may be observed in patients
with an overdose of meperidine, propoxyphene, dextromethorphan, pentazocine, and diphenoxylate with atropine
(i.e., Lomotil) (4,124,125).
A full opioid overdose can be effectively treated with an
opioid antagonist. However, the pharmacokinetic profile of
the opioid must be considered. Since naloxone has a half-life
of only 30 minutes, more than one dose may be needed for
management of any opioid overdose. When overdose occurs
owing to excessive use of methadone in an opioid-naive or
weakly tolerant person, repeated intravenous doses or intravenous constant infusion of naloxone may be needed for
up to 24 hours or longer. Most opioids have a half-life of 4
hours or longer; therefore, repeated naloxone administration is usually needed. Otherwise, the overdose may be only
transiently reversed, and the patient may lapse back into the
comatose overdose situation (94).
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Medical Complications of Opioids
Central Nervous System
Effects of opioids on the CNS are minimal in therapeutic doses. The two main effects of opioid overdose on the
CNS are depression of the mental status and depression of
respiratory activity. Depending on the dose ingested, mental status may vary from mild sedation to stupor and coma.
Significant depression of mental status is accompanied by
a suppressed gag reflex, which predisposes the patient to
aspiration of gastric contents into the lungs in the setting of
centrally mediated nausea and vomiting. A few opioids may
cause generalized seizures (e.g., high-dose meperidine).
Respiratory depression manifests itself as low respiratory
rate, hypoxia, and hypercarbia; it is the most frequent cause
of death owing to opioid overdose (4).
Pulmonary
Effects of opioids on the pulmonary system are minimal in
therapeutic doses. In addition to causing centrally mediated respiratory depression, overdose of opioids may affect
the respiratory system directly by causing noncardiogenic
pulmonary edema (NCPE) and bronchospasm. NCPE typically presents with frothy, pink bronchial secretions, cyanosis, and rales accompanying respiratory depression in a
stuporous or comatose patient. NCPE is particularly associated with intravenous and inhalational use of heroin and
occurs in 48% to 80% of patients hospitalized with heroin
overdose. Heroin may also induce acute bronchospasm (4).
Cardiovascular
Effects of opioids on the cardiovascular system are minimal
in therapeutic doses. In overdose, cardiovascular dysfunction occurs mostly owing to hypoxia caused by respiratory depression. Opioids may cause a release of histamine
leading to vasodilatation that, in turn, results in orthostatic
hypotension. Morphine directly reduces peripheral vascular tone, an effect that is used therapeutically in pulmonary
edema and myocardial infarction.
The effect of opioids on heart rate is variable: Nausea and
vomiting may stimulate vasovagal tone, leading to brachycardia; however, orthostatic hypotension may reflexively cause
mild tachycardia. Overdose of propoxyphene may lead to direct
myocardial toxicity. Cardiovascular problems associated with
an intravenous route of opioid abuse include bacterial endocarditis, venous thrombosis, septic pulmonary emboli, emboli of
cornstarch and talc (additives) to the retina, lungs, kidney, and
liver, pseudoaneurysms, and mycotic aneurysms (125).
High (>300 mg/d) doses of methadone have been associated with prolongation of QTc interval and with torsades
de pointes (126). Many patients receiving high doses of
methadone were receiving other medications as well, such
as antiretrovirals, which are known to prolong QTc (127).
Chlorobutanol, the preservative used in the only commercial formulation of parenteral methadone, potentiates
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Chapter 9 ■ The Pharmacology of Opioids
­ ethadone’s ability to block ionic current through cardiac
m
potassium channels, thus contributing to QTc prolongation
(128). A prospective cohort study (129) of methadone treatment showed a statistically significant (mean of 10.8 ms)
prolongation of QTc interval regardless of methadone dose
during the first 2 months of methadone treatment; however,
this prolongation did not appear to be clinically significant.
The mean QTc value in this study was 428 ms; a QTc value of
greater than 500 ms is considered to be a potential risk for
torsades de pointes (129). The degree of QTc prolongation
correlates with both the trough and peak serum methadone
concentrations (130). In 2005, another study showed that
methadone modestly increased both QTc (by 14.1 ms) and QTc
dispersion (from 32.9 ± 12 to 42.4 ± 15 ms) after 6 months of
therapy. The effect was not thought to be clinically significant
(131). A 2006 cross-sectional study in Tel Aviv, Israel, showed
that methadone maintenance therapy was safe, but that QTc
interval must be measured before and during therapy with
high doses (>120 mg/d) of methadone (132).
Gastrointestinal
In addition to causing nausea and vomiting, short-acting
opioids (and also early maintenance treatment with longacting opioids) slows GI motility, leading to constipation
and possible fecal impaction. This centrally and peripherally
mediated effect may lead to changes in intestinal absorption.
Morphine may cause spasms of the sphincter of Oddi; hence,
it should not be used in biliary colic. However, clinical studies have not shown a significant difference between sphincter
effects of morphine and meperidine, which are often recommended for biliary colic. Prospective studies determined that
tolerance to the constipating effect of chronic methadone
maintenance treatment develops within 3 years (67).
Renal
Heroin, illicit methadone, and propoxyphene have been
rarely associated with rhabdomyolysis, which may cause
renal failure. However, there is considerable evidence that
this is owing to admixtures of other chemicals with illicit
drugs. Rhabdomyolysis has never been seen in methadone
treatment. Heroin, morphine, and pentazocine may cause
nephropathy when used intravenously, leading to glomerulonephritis (125).
Musculoskeletal
Very high doses of opioids may induce centrally mediated muscle rigidity of the chest and abdominal wall.
Intravenously abused opioids may cause osteomyelitis, septic arthritis, polymyositis, and fibrous myopathy (4).
Infectious Diseases
Injection routes (intravenous, subcutaneous) of opioid
abuse, due to the use of shared unclean needles, may lead to
transmission of HIV-1 infection, hepatitis B, hepatitis C, as
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145
well as bacteria causing cellulitis, skin and neck abscesses,
endocarditis, and botulism (125).
Conclusions and Future Research
Directions
The specific neuronal and molecular basis of opioid tolerance and dependence, which may differ between different
end points (e.g., analgesia, vs. respiratory depression, vs.
mediation of reward), has not been fully elucidated.
Physiogenetics and Pharmacogenetics of MOP-r
Function
Five single nucleotide polymorphisms have been identified
in the coding region of the human OPRM1 (132). Three of
these five single nucleotide polymorphisms lead to amino
acid changes, and two (the A118G and the C17T variants)
have high allelic frequencies: 2% to more than 40%, in different cultural and ethnic groups. The C17T variant may have
some association with opiate dependence (132). Binding
studies have shown that exogenous ligands, including
methadone and morphine, bind similarly to the A118G variant and to the prototype receptor; however, the endogenous
opioid beta-endorphin has greater affinity and potency in
activating the receptor, in certain constructs (132). Genetic
factors, such as the presence of this functional A118G variant, which regulates pharmacodynamics, may contribute to
intersubject variability with response to opioid ligands, or
especially the opioid antagonists (132–134).
Stress Responsivity
Atypical response to stress and stressors, as demonstrated
by changes in HPA axis function, has been shown in heroin
addicts. These responses tend to normalize after stabilization
on a steady dose of methadone. During cycles of heroin addiction, abstinence, and relapse, there is a flattened circadian
rhythm of glucocorticoid levels, with increased levels during
opiate withdrawal. With steady-state methadone treatment,
both circadian rhythms and plasma levels of the HPA axis normalize, as do responses of the HPA axis to chemically induced
stress (120). One imaging study using PET showed only 19%
to 32% greater occupancy of opioid receptors in specific brain
areas related to pain and analgesia, as well as addiction (caudate, putamen, amygdala, anterior cingulate cortex, and thalamus) during steady-dose methadone maintenance volunteers
compared with normal volunteers (36). The presence of these
unoccupied receptors may be followed up as a research direction, to potentially explain how physiologic systems disrupted
during cycles of heroin abuse, can become normalized during
methadone maintenance treatment.
The effects of another MOP-r partial agonist widely used
in the treatment of opioid addiction, buprenorphine (or
buprenorphine/naloxone), on specific indices of neuroendocrine function have not been extensively studied. The
effects of buprenorphine on other aspects of ­physiology
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known to be disrupted during cycles of opiate addiction
have also not been studied extensively. In the area of opioid
agonist treatment pharmacology, more rigorous studies of
complex drug interactions with methadone and other medications are needed, including studies of medications for
patients with comorbid conditions, such as HIV-1, hepatitis
C virus, and psychiatric illnesses. From a broader perspective, basic science information at the molecular and animal
level should be integrated with clinical research and observation (3). This research should include further elucidation
of the differences in the stress-responsive HPA axis in persons maintained on other long-acting opioid agonist pharmacotherapy, such as buprenorphine versus methadone,
including possible gender differences.
Evolutions in Medical Maintenance
Studies conducted since the mid-1980s have demonstrated
the effectiveness of “medical maintenance,” which involves
transferring patients in a conventional methadone maintenance treatment program to a monthly office-based treatment with methadone. In order to qualify in the early
studies, methadone-maintained patients have to be abstinent from illicit substances for months to years, employed,
and adhere to conventional treatment before they can be
admitted to office-based methadone treatment (135–137).
Federal Guidelines governing methadone maintenance
treatment were rigorously reanalyzed by all three branches
of the government, and the new interpretations of the guidelines published in the Federal Register, and were finally
approved in early 2001 (21). Now, in accordance with
Federal Guidelines, any patient may be transferred from a
methadone maintenance clinic, constituted according to
the old and new guidelines, to an individual physician’s
office-based practice at any time, based solely on the clinical assessment of the medical staff of the clinic and the physician who is accepting the patient. There is no constraint
on length of time in a methadone clinic before moving to
an office-based practice, dose of methadone being used, or
length of time of abstinence from illicit use of substances
(21). There are no further requirements other than the fact
that the physicians offering office-based treatment will refer
the patient back to the original methadone clinic or another
methadone clinic with which a referral has been arranged, if
any significant problems ensue. However, individual states
may impose more rigid regulations.
The guidelines governing entrance into methadone
maintenance treatment remain very strict and far beyond
the establishment of a Diagnostic and Statistical Manual
of Mental Disorders, Fourth Edition (DSM-IV) diagnosis
of opiate addiction. Requirements include multiple daily
self-administrations of heroin or any short-acting opiate for
1 year or more. To appropriately conduct a study of officebased induction to methadone maintenance treatment,
the individual physicians involved each create a setting to
adhere to the guidelines of a “methadone clinic.” One study
reported outstanding success in office-based induction into
methadone maintenance treatment (138).
To enter buprenorphine or buprenorphine/naloxone
treatment, it is necessary only that a patient meet the
DSM-IV criteria for “opioid dependence” (i.e., opioid addiction). Each physician administering buprenorphine (or
buprenorphine/naloxone) maintenance treatment must
take an 8-hour training course and should offer access to
behavioral therapy. Office-based buprenorphine treatment
has been found to be effective in many patients (139,140).
Patients with high levels of tolerance to an opioid may
not be able to be effectively treated with the partial agonist
buprenorphine or with buprenorphine/naloxone, since the
maximal effective dose of buprenorphine is around 24 or
32 mg sublingually, approximately equivalent to 60 or 70
mg of methadone (relatively low doses) (141). Patients may
be transferred with ease from buprenorphine to methadone
maintenance treatment. The converse is not as simple, as
the addition of buprenorphine will produce opioid withdrawal in patients who are being maintained on usual doses
of methadone. Thus, significant dose reduction of methadone to suboptimal treatment levels (e.g., 30 to 40 mg/d)
must be used prior to starting buprenorphine treatment.
Acknowledgments
Support for this chapter has been provided by grants from the
National Institutes of Health (NIH): National Institute of Drug
Abuse (NIDA) Grant P60-DA05130. We also thank Ann Ho,
PhD; and Charles Inturrisi, PhD, for assistance in preparation
of the manuscript. We are especially grateful to Susan Russo,
who helped in preparation of the manuscript.
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