# 40 - 467 Opioid-Related Disorders

### 467 Opioid-Related Disorders

cognitive behavioral techniques have also shown clinically significant 
improvements in abstinence and reduced cannabis use.

OTHER ADVERSE EFFECTS
■
■MENTAL ILLNESS
The association between marijuana use and increased risk of mental 
illnesses is an area of major concern. The risk of psychosis increases 
with the frequent consumption of high-THC-content cannabis (>10% 
THC). Even upon first exposure, high-potency cannabis can trigger 
acute psychotic episodes, which constitute one of the main causes for 
emergency department (ED) visits associated with cannabis use. Most 
of these psychotic episodes are transient but can become chronic with 
regular cannabis use. In those vulnerable, cannabis may trigger or exac­
erbate the presentation of schizophrenia. Many earlier studies (though 
not all) have linked adolescent cannabis use with higher risk and earlier 
onset of chronic psychosis, particularly for those using cannabis at 
higher frequency or with higher D9THC content. A large recent study 
showed a stronger association between cannabis use during adoles­
cence and risk of psychotic disorder than that documented in previous 
studies, consistent with the rise in cannabis potency. Concerns have 
also been raised regarding cannabis use during adolescence and a 
higher risk for depression and suicidality, though these associations 
have been much less studied.
PART 13
Neurologic Disorders
■
■ACCIDENTS
Cannabis use increases the risk of injuries when driving under its 
influence. D9THC impairs judgment, motor coordination, and reac­
tion time, all necessary for safe driving. Studies have found a direct 
relationship between blood D9THC levels and impaired driving ability.
■
■ACUTE AND CHRONIC TOXICITY
The increased availability of high-D9THC-content products over the 
past decade has been paralleled by increased marijuana-related ED vis­
its and hospital admissions. Such emergencies can be caused by acute 
toxicity and chronic use syndromes. Cannabis edibles are involved in 
a significant portion of acute cannabis toxicity events. Patients include 
children accidentally consuming sweet edibles and infrequent users 
such as “cannabis tourists” with limited experience of the consumed 
products or the longer onset time of edible products. Actual D9THC 
dose is difficult to envisage, for both edible or inhaled products, so 
naïve or infrequent users are at increased risk of overdosing. Can­
nabis toxicity is frequently manifested by severe anxiety, tachycardia, 
and even acute psychoses. Chronic high-dose cannabis use can also 
induce a cannabis hyperemesis syndrome (presenting as severe cycles 
of nausea, vomiting, and abdominal pain), a growing cause for ED and 
hospital admissions.
THERAPEUTIC POTENTIAL
Currently, no FDA-approved medications contain cannabis-derived 
THC, although synthetic D9THC (or dronabinol) is approved for 
treatment of chemotherapy-induced nausea and appetite stimulation. 
Several countries have approved the cannabis-derived D9THC:CBD 
formulation Sativex for treating chronic pain and multiple sclerosis 
(MS)-induced spasticity. However, evidence of Sativex efficacy in MS 
is largely based on patient reports. Chronic pain is one of the most 
frequent indications for which medical marijuana is used. A recent 
analysis of data from the New York prescription drug monitoring data­
base, from the years 2017-2019, revealed that chronic pain patients on 
long-term stable doses of opioid therapy (n >8000) who used medical 
marijuana for >8 months (compared to those who used medical marijuana 
for <30 days to 8 months) had a 30–50% reduction in opioid use.
■
■FURTHER READING
Albaugh MD et al: Association of cannabis use during adolescence 
with neurodevelopment. JAMA Psychiat 78:1, 2021.
Evanski JM et al: The first “hit” to the endocannabinoid system? 
Associations between prenatal cannabis exposure and frontolimbic 
white matter pathways in children. Biol Psychiatry Glob Open Sci 
4:11, 2024.

Hagler DJ Jr et al: Image processing and analysis methods for 
the Adolescent Brain Cognitive Development Study. Neuroimage 
202:116091, 2019.
Hiraoka D et al: Effects of prenatal cannabis exposure on devel­
opmental trajectory of cognitive ability and brain volumes in the 
Adolescent Brain Cognitive Development (ABCD) Study. Dev Cogn 
Neurosci 60:101209, 2023.
McDonald AJ et al: Age-dependent association of cannabis use with 
risk of psychotic disorder. Psychol Med 22:1, 2024.
National Survey on Drug Use and Health: Substance Use and Mental 
Health Services Administration, 2023. https://www.samhsa.gov/data/
release/2023-national-survey-drug-use-and-health-nsduh-releases.
Sarikahya MH et al: Prenatal THC exposure induces long-term, 
sex-dependent cognitive dysfunction associated with lipidomic and 
neuronal pathology in the prefrontal cortex-hippocampal network. 
Mol Psychiat 28:4234, 2023.
Schwabe AL et al: Uncomfortably high: Testing reveals inflated THC 
potency on retail cannabis labels. PLoS One 18:e0282396, 2023.
Volkow ND et al: Don’t worry, be happy: Endocannabinoids and can­
nabis at the intersection of stress and reward. Annu Rev Pharmacol 
Toxicol 57:285, 2017.
Wade NE et al: Cannabis use and neurocognitive performance at 
13-14 years-old: Optimizing assessment with hair toxicology in the 
Adolescent Brain Cognitive Development (ABCD) Study. Addict 
Behav 150:107930, 2024.
Thomas R. Kosten, Colin N. Haile

Opioid-Related Disorders
Opioid analgesics have been used since at least 300 b.c. Nepenthe 
(Greek for “free from sorrow”) helped the hero of the Odyssey, but 
widespread opium smoking in China and the Near East has caused 
harm for centuries. Since the first chemical isolation of opium and 
codeine 200 years ago, a wide range of synthetic opioids have been 
developed, and opioid receptors were cloned in the 1990s. Two of the 
most important adverse effects of all these agents are the development 
of opioid use disorder and overdose. Prescription opioids are primarily 
used for pain management, but due to ease of availability individuals 
procure and misuse these drugs with dire consequences. In 2022, for 
example, 8.9 million United States residents misused pain relievers and 
>76,000 overdose deaths involved opioids, nearly half combined with 
stimulants. These numbers continue to increase and have accelerated 
due to mixing of high-potency fentanyl derivatives with other opioids 
and stimulants. The accelerating death rates are partially because rever­
sal of fentanyl overdoses can require severalfold larger doses of nalox­
one than the doses in the intranasal devices used for nonmedical street 
resuscitations. Fentanyl-associated deaths also increased during the 
COVID-19 pandemic. The World Drug Report attributes the greatest 
global burden of morbidity and mortality to opioid misuse, including 
disease transmission, increased health care, crime, law enforcement, 
family distress, and lost productivity.
The terms dependence and addiction have been replaced with opioid 
use disorder, opioid intoxication, and opioid withdrawal. Opioid use 
disorder is defined in the Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5; 2022) as the repeated use of the opiate 
during a 12-month period while producing problems in two or more 
areas including tolerance, withdrawal, use of greater amounts of opioids 
than intended, craving, and use despite adverse consequences. This new 
definition reduces the diagnostic criteria from three problem areas to 
two, but this reduction has not changed the rates of these disorders 
because most opioid-using individuals meet more than three criteria.

A striking recent aspect of illicit opioid use has been its marked 
increase as the gateway to illicit drugs in the United States. Since 2007, 
prescription opiates have surpassed marijuana as the most common 
illicit drug that adolescents initially use, although overall rates of opi­
oid use are far lower than marijuana. The most used opioids had been 
diverted prescriptions for oxycodone and hydrocodone until about 2015, 
when fentanyl misuse and lethal overdose rose exponentially. Two opi­
oid maintenance treatment agents—methadone and buprenorphine—
are also misused, but at substantially lower rates, and the partial opioid 
agonists such as butorphanol, tramadol, and pentazocine are misused 
even less frequently. Because the chemistry and general pharmacology 
of these agents are covered in major pharmacology texts, this chapter 
focuses on neurobiology and pharmacology relevant to opioid use disor­
der and its treatments. Although the neurobiology of misuse involves all 
four of the known opioid receptors—mu, kappa, delta, and nociceptin/
orphanin—the mu receptor is the most clinically related to opioids.
■
■NEUROBIOLOGY
After binding to mu opioid receptors, opioids downregulate intracel­
lular messenger systems and activate potassium ion channels, as sum­
marized in Table 467-1. All opioid receptors are G protein–linked and 
coupled to the cyclic adenosine monophosphate (cAMP) second mes­
senger system and to G protein–coupled inwardly rectifying potassium 
channels (GIRKs). The GIRKs increase permeability to potassium ions, 
causing hyperpolarization and inhibiting action potential production. 
Thus, opioids inhibit the activity of all neurons with opioid receptors 
and induce analgesia, sedation, and drug reinforcement through vari­
ous brain pathways.
Relevant pathways for the reinforcing euphoric effects of opioids 
include the mesolimbic dopaminergic pathway from the ventral teg­
mental area (VTA) to the nucleus accumbens (NAc), where opioids 
indirectly increase synaptic levels of dopamine through inhibition 
of GABAergic neurons that inhibit both the VTA and the NAc. The 
positive subjective effects of opioid drugs also include mu receptor 
desensitization and internalization, potentially related to stimulation of 
β-arrestin signaling pathways. However, the “high” only occurs when 
the rate of change in dopamine is fast. Large, rapidly administered 
doses of opioids block γ-aminobutyric acid (GABA) inhibition and 
produce a burst of VTA dopamine neuron activity that is associated 
with a “high” in commonly misused substances. Therefore, routes of 
administration that slowly increase opioid blood and brain levels, such 
as oral and transdermal routes, are effective for analgesia and sedation 
but do not produce an opioid “high” that follows smoking and intra­
venous routes. Other acute effects such as analgesia and respiratory 
β-endorphin
enkephalins
K+
µ
µ
Na+
Na+
Gi/o
Gi/o
AC
Nucleus
Nucleus
PKA
PKA
BDNF
BDNF
TH
TH
cAMP
cAMP
CREB
CREB
A
B
FIGURE 467-1  Normal mu-receptor activation by endogenous opioids inhibits the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP responseelement binding protein (CREB) cascade in noradrenergic neurons within the locus coeruleus (A) through inhibitory Gi/o protein influence on adenylyl cyclase (AC). 
Similarly, acute exposure to opioids (e.g., morphine) inhibits this system, whereas chronic exposure to opiates (B) leads to upregulation of the cAMP pathway in an attempt 
to oppose opioid-induced inhibitory influence. Upregulation of this system is involved in opioid tolerance, and when the opioid is removed, unopposed noradrenergic 
neurotransmission is involved in opioid withdrawal. Upregulated PKA phosphorylates CREB, initiating the expression of various genes such as tyrosine hydroxylase (TH) 
and brain-derived neurotrophic factor (BDNF). BDNF is implicated in long-term neuroplastic changes in response to chronic opioids.

TABLE 467-1  Actions of Opioid Receptors
RECEPTOR TYPE
ACTIONS
Mu (μ) (e.g., morphine, 
buprenorphine)
Analgesia, reinforcement euphoria, cough and appetite 
suppression, decreased respirations, decreased GI 
motility, sedation, hormone changes, dopamine and 
acetylcholine release
Dysphoria, decreased GI motility, decreased appetite, 
decreased respiration, psychotic symptoms, sedation, 
diuresis, analgesia
Kappa (κ) (e.g., 
butorphanol)
Analgesia, euphoria, physical dependence, hormone 
changes, appetite suppression, dopamine release
Delta (δ) (e.g., 
etorphine)
Nociceptin/orphanin 
(e.g., buprenorphine)
Analgesia, appetite, anxiety, tolerance to opioids, 
hypotension, decreased GI motility, 5-HT and NE 
release
Abbreviations: GI, gastrointestinal; 5-HT, serotonin; NE, norepinephrine.
CHAPTER 467
depression involve opioid receptors located in other brain areas such as 
the periaqueductal grey for pain and medulla oblongata for respiration.
Opioid tolerance and withdrawal are related to genetic polymor­
phisms that impact several proteins and that after chronic opioid dos­
ing affect the functioning of the cAMP–protein kinase A (PKA)–cAMP 
response-element binding protein (CREB) intracellular cascade within 
the locus coeruleus (LC) (Fig. 467-1). Up to 50% of the risk for with­
drawal is related to specific functional polymorphisms including one 
in the mu opioid receptor gene producing a threefold increase in this 
receptor’s affinity for opioids and the endogenous ligand β-endorphin. 
Epigenetic DNA methylation changes in the mu receptor gene also 
appear to act as compensation by inhibiting gene transcription and 
reducing the number of mu receptors.
Opioid-Related Disorders
After chronic opioid dosing and its sustained inhibition of the 
cAMP molecular cascade as shown in Fig. 467-1, a compensation 
occurs in this cascade within the LC neurons that mediate opioid toler­
ance and withdrawal. Noradrenergic (NE) neurons in the LC activate 
the cerebral cortex. When large opioid doses saturate and activate all of 
the LC’s mu receptors, action potentials cease. When this direct inhibi­
tory effect is sustained over weeks and months of opioid use, a second­
ary set of adaptive changes occur to upregulate cyclic AMP enzyme 
activity. When the inhibiting opioid is abruptly discontinued, overac­
tivity occurs in NE neurons of the LC that contribute to withdrawal 
symptoms (Fig. 467-1). This molecular model of NE neuronal activa­
tion during withdrawal has had important treatment implications, such 
as the use of the presynaptic α2-agonists clonidine and lofexidine to 
treat opioid withdrawal by again suppressing NE neuronal activation 
Morphine
HO
H
H
O
N
CH3
K+
HO
Modified gene
expression,
neuroplasticity,
genetic effects
AC

through feedback inhibition of this neuronal activity. Other contribu­
tors to withdrawal include deficits within the dopamine reward system 
and overactive neurotransmission within the glutamatergic system.

■
■PHARMACOLOGY
Tolerance and withdrawal commonly occur with chronic daily use, 
developing as quickly as 6–8 weeks depending on dose concentration 
and dosing frequency. Tolerance is primarily pharmacodynamic with 
relatively limited induction of cytochrome P450 2D6 and 3A4 or other 
liver enzymes. Metabolism then includes conjugation to glucuronic 
acid and excretion of small amounts in feces. The plasma half-lives 
generally range from 2.5 to 3 h for morphine and >22 h for methadone. 
The shortest half-lives of several minutes are for fentanyl-related opi­
oids, and the longest are for buprenorphine and its active metabolites, 
which can block opioid withdrawal for up to 3 days after a single dose. 
Tolerance to opioids leads to the need for increasing amounts of drugs 
to sustain the desired euphoric effects—as well as to avoid the discom­
fort of withdrawal. This combination has the expected consequence 
of strongly reinforcing misuse once it has started. Methadone taken 
chronically at maintenance doses is stored in the liver, which may 
reduce the occurrence of withdrawal between daily doses. The role of 
endogenous opioid peptides in tolerance and withdrawal is uncertain.
PART 13
Neurologic Disorders
The clinical features of opioid misuse are tied to the route of admin­
istration and rapidity of the drug reaching the brain. Intravenous and 
smoked administration rapidly produces high drug concentrations in 
the brain. This produces a “rush,” followed by euphoria, a feeling of 
tranquility, and sleepiness (“the nod”). Heroin produces effects that last 
3–5 h, and several doses a day are required to forestall manifestations 
of withdrawal in chronic users. Symptoms of opioid withdrawal begin 
8–10 h after the last dose; lacrimation, rhinorrhea, yawning, and sweat­
ing appear first. Restless sleep followed by weakness, chills, gooseflesh 
(“cold turkey”), nausea and vomiting, muscle aches, involuntary move­
ments (“kicking the habit”), hyperpnea, hyperthermia, and hyperten­
sion occur in later stages of the withdrawal syndrome. The acute course 
of withdrawal may last 7–10 days. A secondary phase of protracted 
abstinence lasts for 26–30 weeks and is characterized by hypotension, 
bradycardia, hypothermia, mydriasis, and decreased responsiveness of 
the respiratory center to carbon dioxide.
Besides the brain effects of opioids on sedation and euphoria and the 
combined brain and peripheral nervous system effects on analgesia, a 
wide range of other organs can be affected. The release of several pitu­
itary hormones is inhibited, including corticotropin-releasing factor 
(CRF) and luteinizing hormone, which reduces levels of cortisol and 
sex hormones and can lead to impaired stress responses and reduced 
libido. An increase in prolactin also contributes to the reduced sex 
drive in males. Two other hormones affected are thyrotropin, which is 
reduced, and growth hormone, which is increased. Respiratory depres­
sion results from opioid-induced insensitivity of brainstem neurons to 
increases in carbon dioxide, and in patients with pulmonary disease, 
this can result in clinically significant complications. In overdoses, 
aspiration pneumonia is common due to loss of the gag reflex. Opioids 
reduce gut motility, which is helpful for treating diarrhea but can lead 
to nausea, constipation, and anorexia with weight loss. Deaths occurred 
in early methadone maintenance programs due to severe constipa­
tion and toxic megacolon. Opioids such as methadone may prolong 
QT intervals and lead to sudden death in some patients. Orthostatic 
hypotension may occur due to histamine release and peripheral blood 
vessel dilation, which is an opioid effect usefully applied to managing 
acute myocardial infarction. During opioid maintenance, interactions 
with other medications are of concern; these include inducers of the 
cytochrome P450 system (usually CYP3A4) such as rifampin and 
carbamazepine.
Heroin users, in particular, tend to use opioids intravenously and are 
likely to be polydrug users, also using alcohol, sedatives, cannabinoids, 
and stimulants. None of these other drugs are substitutes for opioids, 
but they have desired additive effects. Therefore, one needs to be sure 
that the person undergoing a withdrawal reaction is not also withdraw­
ing from alcohol or sedatives, which might be more dangerous and 
more difficult to manage.

Intravenous opioid use carries with it the risk of serious compli­
cations. The common sharing of hypodermic syringes can lead to 
infections with hepatitis B and HIV/AIDS, among others. Bacte­
rial infections can lead to septic complications such as meningitis, 
osteomyelitis, and abscesses in various organs. Off-target effects or 
additions of other agents to opioids synthesized in illicit drug labs can 
lead to serious toxicity. For example, attempts to illicitly manufacture 
meperidine in the 1980s produced a parkinsonism-inducing neuro­
toxin, MPTP (Chap. 446). More recently, adding xylazine to illicit 
fentanyl markedly increased fentanyl’s respiratory suppression, leading 
to overdose deaths. Individuals who inject fentanyl and xylazine also 
can develop necrosis and have an increased risk of limb amputation.
TREATMENT
Opioid Overdose
The acute treatment of opioid overdose with naloxone or nalmefene 
is a medical emergency, and after reversal of that life-threatening 
complication, clinicians have two general treatment options: opioid 
maintenance or detoxification. Opioid agonist and partial agonist 
medications are commonly used for both maintenance and detoxi­
fication purposes. α2-Adrenergic agonists are primarily used for 
detoxification. Antagonists are used to accelerate detoxification 
and then continued after detoxification to prevent relapse. The 
residential medication-free programs have had some success but 
generally less than the medication-based programs. Success of the 
various treatment approaches is assessed as retention in treatment 
and reduced opioid and other drug use; secondary outcomes, such 
as reduced HIV risk behaviors, crime, psychiatric symptoms, medi­
cal comorbidity, and overdoses, also indicate successful treatment.
Potentially lethal overdoses require rapid recognition and treat­
ment with naloxone or nalmefene, two highly specific reversal 
agents that are relatively free of complications. The diagnosis is 
based on recognition of characteristic signs and symptoms, includ­
ing shallow and slow respirations, pupillary miosis (mydriasis does 
not occur until significant brain anoxia supervenes), bradycardia, 
hypothermia, and stupor or coma. Blood or urine toxicology stud­
ies can confirm a suspected diagnosis, but immediate management 
must be based on clinical criteria. If naloxone is not administered, 
progression to respiratory and cardiovascular collapse leading to 
death occurs. With fentanyl overdoses, the naloxone dose may be 
twice that needed for other opioids, and recent rescue preparations 
contain twice the traditional dosing. Additionally, nalmefene has 
recently become available for treatment of overdose and has higher 
potency and lasts longer than naloxone. Opioids generally do not 
produce seizures except for unusual cases of polydrug use with the 
opioid meperidine, with high doses of tramadol, or in the newborn.
In addition to naloxone, management of overdose requires sup­
port of vital functions, including intubation if needed (Table 467-2). 
If the overdose is due to buprenorphine or fentanyl, then naloxone 
might be required at total doses of 10 mg or greater, but primary 
buprenorphine overdose is nearly impossible because this agent is 
a partial opioid agonist, meaning that as the dose of buprenorphine 
is increased, it has greater opioid antagonist than agonist activity. 
Thus, a 0.2-mg buprenorphine dose leads to analgesia and seda­
tion, while a hundred times greater 20-mg dose produces profound 
TABLE 467-2  Management of Opioid Overdose
Establish airway. Intubation and mechanical ventilation may be necessary.
Naloxone 0.4–2.0 mg (IV, IM, or endotracheal tube). Onset of action with IV is 
~1–2 min.
Repeat doses of naloxone if needed to restore adequate respiration or a 
continuous infusion of naloxone can be used.
One-half to two-thirds of the initial naloxone dose that reversed the respiratory 
depression is administered on an hourly basis (note: naloxone dosing is not 
necessary if the patient has been intubated).

opioid antagonism, precipitating opioid withdrawal in a person 
who had opioid use disorder from morphine or methadone. It is 
important to recognize that the goal is to reverse respiratory depres­
sion and not to administer so much naloxone that it precipitates 
opiate withdrawal. Because naloxone only lasts a few hours and 
most opioids last considerably longer, an IV naloxone drip with 
close monitoring is frequently employed to provide a continuous 
level of antagonism for 24–72 h depending on the opioid used in 
the overdose (e.g., morphine vs methadone). Whenever nalox­
one has only a limited effect, other sedative drugs that produce 
significant overdoses must be considered. The most common are 
benzodiazepines, which have produced overdoses and deaths in 
combination with buprenorphine. A specific antagonist for benzo­
diazepines, flumazenil at 0.2 mg/min can rapidly reverse overdoses, 
but it may precipitate seizures and increase intracranial pressure. 
Like naloxone, administration for a prolonged period is usually 
required because most benzodiazepines remain active for consider­
ably longer than flumazenil. Support of vital functions may include 
oxygen and positive-pressure breathing, IV fluids, pressor agents 
for hypotension, and cardiac monitoring to detect QT prolongation, 
which might require specific treatment. Activated charcoal and gas­
tric lavage may be helpful for oral ingestions, but intubation will be 
needed if the patient is stuporous.
OPIOID WITHDRAWAL
The principles of detoxification are the same for all drugs: to sub­
stitute a longer-acting, orally active, pharmacologically equivalent 
medication for the substance being used, stabilize the patient 
on that medication, and then gradually withdraw the substituted 
medication. Methadone and buprenorphine are the two principal 
medications used to treat opioid use disorder. Clonidine, a centrally 
acting sympatholytic agent, has also been used for detoxification 
in the United States. By reducing central sympathetic outflow, 
clonidine mitigates many of the signs of sympathetic overactivity 
but typically requires augmentation with other agents. Clonidine 
has no narcotic action and is not addictive. Lofexidine, a clonidine 
analogue with fewer hypotensive effects, was approved for use in 
the United States in 2018 for management of opioid withdrawal 
symptomology.
Methadone for Detoxification  Dose-tapering regimens for detox­
ification using methadone range from 2–3 weeks to as long as 
180 days, but this approach is controversial given the relative 
effectiveness of methadone maintenance and the low success rates 
of detoxification. Unfortunately, most patients tend to relapse to 
heroin or other opioids during or after the detoxification period, 
indicative of the chronic and relapsing nature of opioid use disorder.
Buprenorphine for Detoxification  Buprenorphine does not appear 
to lead to better outcomes than methadone but is superior to cloni­
dine in reducing symptoms of withdrawal, in retaining patients in 
a withdrawal protocol, and in completing treatment, although it 
can precipitate withdrawal in patients dependent on fentanyl or on 
maintenance doses of methadone (>80 mg daily).
`2-Adrenergic Agonists for Detoxification  Several α2-adrenergic 
agonists have relieved opioid withdrawal by suppressing brain NE 
hyperactivity. Clonidine relieves some signs and symptoms of opi­
oid withdrawal such as lacrimation, rhinorrhea, muscle pain, joint 
pain, restlessness, and gastrointestinal symptoms. Related agents 
are lofexidine, guanfacine, and guanabenz acetate. Lofexidine can 
be dosed up to ~2 mg/d and appears to be associated with fewer 
adverse effects. Clonidine or lofexidine is typically administered 
orally, in three or four doses per day, with dizziness, sedation, leth­
argy, and dry mouth as the primary adverse side effects. Outpatientmanaged withdrawal regimens require close follow-up, often with 
naltrexone maintenance to prevent relapse.
Rapid and Ultrarapid Opioid Detoxification  The opioid antago­
nist naltrexone, typically combined with an α2-adrenergic agonist, 
has been purported to shorten the duration of withdrawal without 

significantly increasing patient discomfort. Completion rates using 
naltrexone and clonidine range from 75 to 81% compared to 40 to 
65% for methadone or clonidine alone. Ultrarapid opioid detoxi­
fication is an extension of this approach using anesthetics but is 
highly controversial due to the medical risks and mortality associ­
ated with it.

Medications for Preventing Relapse to Illicit Opioids 

Stopping opioid use is much easier than preventing relapse. Long-term 
relapse prevention for individuals with opioid use disorder requires 
combined pharmacologic and psychosocial approaches. Chronic users 
tend to prefer pharmacologic approaches; those with shorter histories 
of drug use are more amenable to detoxification and psychosocial 
interventions.
Methadone maintenance substitutes a once-daily oral opioid dose 
for three to four times daily heroin. Methadone saturates the opioid 
receptors and, by inducing a high level of opioid tolerance, blocks the 
euphoria from additional opioids. Buprenorphine, a partial opioid 
agonist, also can be given once daily at sublingual doses of 4–32 mg 
daily, and in contrast to methadone, it can be given in an office-based 
primary care setting.
CHAPTER 467
Opioid-Related Disorders
METHADONE MAINTENANCE  Methadone’s slow onset of action when 
taken orally, long elimination half-life (24–36 h), and production of 
cross-tolerance at doses from 80 to 150 mg are the basis for its efficacy 
in treatment retention and reductions in IV drug use, criminal activ­
ity, and HIV risk behaviors and mortality. Methadone can prolong the 
QT interval at rates as high as 16% above rates in non-methadonemaintained, drug-injecting patients, but it has been used safely in the 
treatment of opioid use disorder for >40 years.
BUPRENORPHINE MAINTENANCE  Sublingual buprenorphine main­
tenance was first approved by the U.S. Food and Drug Administration 
(FDA) in 2002 as a Schedule III drug for managing opioid use disorder. 
Unlike the full agonist methadone, buprenorphine is a partial agonist 
of mu-opioid receptors with a slow onset and long duration of action. 
Its partial agonism reduces the risk of unintentional overdose but lim­
its its efficacy to patients who need the equivalent of only 60–70 mg 
of methadone, and many patients in methadone maintenance require 
higher doses of up to 150 mg daily. Buprenorphine is combined with 
naloxone at a 4:1 ratio to reduce its abuse liability. Because of pediatric 
exposures and diversion of buprenorphine to illicit use, mucosal films 
are now used rather than sublingual pills that can be crushed and 
snorted. A long-acting buprenorphine injection that lasts a month is 
also available to prevent illicit diversion and to enhance compliance.
Primary care physicians often prescribe buprenorphine for opioid 
use disorder, which has reduced opioid-related deaths and druginjection-related medical morbidity with treatment retention as high 
as 70% over a 6-month follow-up period.
Opioid Antagonist Medications 
Antagonist therapy blocks the 
action of self-administered opioids and should eventually extinguish 
the habit, but this therapy is poorly accepted by patients. Naltrexone, 
a long-acting pure opioid antagonist, can be given orally three times a 
week, or by monthly injection, which markedly improves adherence, 
retention, and drug use. Because it is an antagonist, the patient must 
first be detoxified from opioids before starting naltrexone. It is safe 
even when taken chronically for years, is associated with few side effects 
(headache, nausea, abdominal pain), and can be given to patients 
infected with hepatitis B or C without producing hepatotoxicity. How­
ever, most providers refrain from prescribing naltrexone if liver func­
tion tests are three times above normal levels. Naltrexone maintenance 
combined with psychosocial therapy is effective in reducing heroin use.
Medication-Free Treatment 
Most opioid users enter medicationfree treatments in inpatient, residential, or outpatient settings, but 1- to 
5-year outcomes are very poor compared to pharmacotherapy except 
for residential settings lasting 6–18 months. The residential programs 
require full immersion in a regimented system with progressively 
increasing levels of independence and responsibility within a controlled