36.22 - Mirtazapine

Authors: Sadock, Benjamin James; Sadock, Virginia Alcott

Title: Kaplan & Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry, 10th Edition

Copyright ©2007 Lippincott Williams & Wilkins

> Table of Contents > 12 - Substance-Related Disorders > 12.10 - Opioid-Related Disorders


Opioid-Related Disorders

More than 20 chemically distinct opioid drugs are in clinical use throughout the world. In the developed countries, the opioid drug most frequently associated with abuse and dependence is heroin—a drug that is not approved for therapeutic purposes in the United States. These drugs are all prototypical µ-opioid receptor agonists and all produce similar subjective effects. The patterns of use and some aspects of opioid toxicity are powerfully influenced, however, by the route of administration and the metabolism of the specific opioid, as well as by the social conditions that determine its price and purity and the sanctions attached to nonmedical use.

Opioids have been used for at least 3,500 years, mostly in the form of crude opium or in alcoholic solutions of opium. Morphine was first isolated in 1806 and codeine in 1832. Over the next century, pure morphine and codeine gradually replaced crude opium for medicinal purposes, although nonmedical use of opium (as for smoking) still persists in some parts of the world.

Table 12.10-1 lists various opioids that are used therapeutically in the United States with the exception of heroin.

The text revision of the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) divides opioid-related disorders into opioid use disorders (opioid abuse and opioid dependence) and nine other opioid-induced disorders (e.g., intoxication, withdrawal).

Opioid dependence is a cluster of physiological, behavioral, and cognitive symptoms, which together indicates repeated and continuing use of opioid drugs, despite significant problems related to such use. Drug dependence, in general, has also been defined by the World Health Organization (WHO) as a syndrome in which the use of a drug or class of drugs takes on a much higher priority for a given person than other behaviors that once had a higher value. These brief definitions each have as their central features an emphasis on the drug-using behavior itself, its maladaptive nature, and how the choice to engage in that behavior shifts and becomes constrained as a result of interaction with the drug over time.

Opioid abuse is a term used to designate a pattern of maladaptive use of an opioid drug leading to clinically significant impairment or distress and occurring within a 12-month period, but one in which the symptoms have never met the criteria for opioid dependence.

Table 12.10-1 Opioids

Proprietary Name Trade Name
Heroin (diacetylmorphine)
Hydromorphone (dihydromorphinone) Dilaudid
Oxymorphone (dihydrohydroxymorphinone) Numorphan
Levorphanol Levo-Dromoran
Methadone Dolophine
Meperidine (pethidine) Demerol, Pethadol
Hydrocodone (dihydrocodeinone) Hycodan, others
Drocode (dihydrocodeine) Synalgos-DC, Compal
Oxycodone (dihydrohydroxycodeinone) Roxicodone, OxyContin, Percodan, Percocet, Vicodin
Propoxyphene Darvon, others
Buprenorphine Buprenex
Pentazocine Talwin
Nalbuphine Nubain
Butorphanol Stadol

The opioid-induced disorders as defined by DSM-IV-TR include such common phenomena as opioid intoxication, opioid withdrawal, opioid-induced sleep disorder, and opioid-induced sexual dysfunction. Opioid intoxication delirium is occasionally seen in hospitalized patients. Opioid-induced psychotic disorder, opioid-induced mood disorder, and opioid-induced anxiety disorder, by contrast, are quite uncommon with µ-agonist opioids, but have been seen with certain mixed agonist-antagonist opioids acting at other receptors. DSM-IV-TR also includes opioid-related disorder not otherwise specified for situations that do not meet the criteria for any of the other opioid-related disorders.

In addition to the morbidity and mortality associated directly with the opioid-related disorders, the association between the transmission of the human immunodeficiency virus (HIV) and intravenous opioid and opiate use is now recognized as a leading national health concern. The words opiate and opioid come from the word opium, the juice of the opium poppy, Papaver somniferum, which contains approximately 20 opium alkaloids, including morphine.

Many synthetic opioids have been manufactured, including meperidine (Demerol), methadone (Dolophine), pentazocine (Talwin), and propoxyphene (Darvon). Methadone is the current gold standard in the treatment of opioid dependence. Opioid antagonists have been synthesized to treat opioid overdose and opioid dependence. This class of drugs includes naloxone (Narcan), naltrexone (ReVia), nalorphine, levallorphan, and apomorphine. Compounds with mixed agonist and antagonist activity at opioid receptors have been synthesized and they include pentazocine, butorphanol (Stadol), and buprenorphine (Buprenex). Studies have found buprenorphine to be an effective treatment for opioid dependence.



The use and dependence rates derived from national surveys do not accurately reflect fluctuations in drug use among opioid-dependent and previously opioid-dependent populations. When the supply of illicit heroin increases in purity or decreases in price, use among that vulnerable population tends to increase, with subsequent increases in adverse consequences (emergency room visits) and requests for treatment. The number of current heroin users in the United States has been estimated to be between 600,000 and 800,000. The number of people estimated to have used heroin at any time in their lives (lifetime users) is estimated at approximately 3 million.

In 2004, an estimated 118,000 persons had used heroin for the first time within the past 12 months. The average age of first use among recent initiates was 24.4 years in 2004. No significant changes were seen in the number of initiates or in the average age of first use from 2002 to 2004. Opioid use in the United States experienced a resurgence in the 1990s, with emergency department visits related to heroin abuse doubling between 1990 and 1995. This increase in heroin use was associated with an increase in heroin purity and a decrease in its street price. In the late 1990s, heroin use increased among people who were 18 to 25 years of age and a brief upsurge was seen in the use of oxycodone (OxyContin) from pharmaceutical sources. Methods of administration other than injecting, such as smoking and snorting, increased in popularity. In 2004, the number of new nonmedical users of OxyContin was 615,000, with an average age at first use of 24.5 years. Comparable data on past year OxyContin initiation are not available for prior years, but calendar year estimates of OxyContin initiation show a steady increase in the number of initiates from 1995, the year this drug was first available, through 2003. The male-to-female ratio of persons with heroin dependence is about 3 to 1. Users of opioids typically started to use substances in their teens and early 20s; currently, most persons with opioid dependence are in their 30s and 40s. According to DSM-IV-TR, the tendency for dependence to remit generally begins after age 40 years and has been called “maturing out.” Many persons, however, have remained opioid dependent for 50 years or longer. In the United States, persons tend to experience their first opioid-induced experience in their early teens or even as young as 10 years of age. Early induction into the drug culture is likely in communities in which substance abuse is rampant and in families in which the parents are substance abusers. A heroin habit can cost a person hundreds of dollars a day; thus, a person with opioid dependence needs to obtain money through criminal activities and prostitution. The involvement of persons with opioid dependence in prostitution accounts for much of the spread of HIV. According to DSM-IV-TR, the lifetime prevalence for heroin use is about 1 percent, with 0.2 percent having taken the drug during the prior year.


The primary effects of the opioids are mediated through the opioid receptors, which were discovered in the second half of the 1970s. The µ-opioid receptors are involved in the regulation and mediation of analgesia, respiratory depression, constipation, and dependence; the κ-opioid receptors, with analgesia, diuresis, and sedation; and the δ-opioid receptors, possibly with analgesia.

In 1974, enkephalin, an endogenous pentapeptide with opioid-like actions, was identified. This discovery led to the identification of three classes of endogenous opioids within the brain, including the endorphins and the enkephalins. Endorphins are involved in neural transmission and pain suppression. They are released naturally in the body when a person is physically hurt and account, in part, for the absence of pain during acute injuries.

The opioids also have significant effects on the dopaminergic and noradrenergic neurotransmitter systems. Several types of data indicate that the addictive rewarding properties of opioids are mediated through activation of the ventral tegmental area dopaminergic neurons that project to the cerebral cortex and the limbic system (Fig. 12.10-1).

FIGURE 12.10-1 Scheme illustrating opioid actions in the locus ceruleus (LC). Opioids acutely inhibit LC neurons by increasing the conductance of a K+ channel (light cross-hatch) via coupling with subtypes of Gi and/or Go and by decreasing an Na+-dependent inward current (dark cross-hatch) via coupling with Gi/o and the consequent inhibition of adenylyl cyclase. Reduced levels of cAMP decrease PKA and the phosphorylation of the responsible channel or pump. Inhibition of the cyclic adenosine monophosphate (cAMP) pathway also decreases phosphorylation of numerous other proteins and thereby affects many additional processes in the neuron. For example, it reduces the phosphorylation state of CREB, which may initiate some of the longer-term changes in LC function. Upper bold arrows summarize effects of repeated morphine administration in the LC. Repeated morphine administration increases levels of adenylyl cyclase, PKA, and several phosphoproteins, including CREB. These changes contribute to the altered phenotype of the drug-addicted state. For example, the intrinsic excitability of LC neurons is increased via enhanced activity of the cAMP pathway and Na+-dependent inward current, which contributes to the tolerance, dependence, and withdrawal exhibited by the these neurons. This altered phenotypic state appears to be maintained, in part, by upregulation of CREB expression. (From

Nestler EJ. Molecular mechanisms underlying opiate addiction: Implications for medications development. Semin Neurosci. 1997;0:84

, with permission.)


Heroin, the most commonly abused opioid, is more potent and lipid soluble than morphine. Because of those properties, heroin crosses the blood–brain barrier faster and has a more rapid onset than morphine. Heroin was first introduced as a treatment for morphine addiction, but heroin, in fact, is more dependence producing than morphine. Codeine, which occurs naturally as about 0.5 percent of the opiate alkaloids in opium, is absorbed easily through the gastrointestinal tract and is subsequently transformed into morphine in the body. Results of at least one study using positron emission tomography (PET) have suggested that one effect of all opioids is decreased cerebral blood flow in selected brain regions in persons with opioid dependence.

Tolerance and Dependence

Tolerance does not develop uniformly to all actions of opioid drugs. Tolerance to some actions of opioids can be so high that a hundredfold increase in dose is required to produce the original effect. For example, terminally ill cancer patients may need 200 to 300 mg a day of morphine, whereas a dose of 60 mg can easily be fatal to an opioid-naïve person. The symptoms of opioid withdrawal do not appear unless a person has been using opioids for a long time or when cessation is particularly abrupt, as occurs functionally when an opioid antagonist is given. The long-term use of opioids results in changes in the number and sensitivity of opioid receptors, which mediate at least some of the effects of tolerance and withdrawal. Although long-term use is associated with increased sensitivity of the dopaminergic, cholinergic, and serotonergic neurons, the effect of opioids on the noradrenergic neurons is probably the primary mediator of the symptoms of opioid withdrawal. Short-term use of opioids apparently decreases the activity of the noradrenergic neurons in the locus ceruleus; long-term use activates a compensatory homeostatic mechanism within the neurons and opioid withdrawal results in rebound hyperactivity. This hypothesis also provides an explanation for why clonidine (Catapres), an α2-adrenergic receptor agonist that decreases the release of norepinephrine, is useful in the treatment of opioid withdrawal symptoms.


About 90 percent of persons with opioid dependence have an additional psychiatric disorder. The most common comorbid psychiatric diagnoses are major depressive disorder, alcohol use disorders, antisocial personality disorder, and anxiety disorders. About 15 percent of persons with opioid dependence attempt to commit suicide at least once. The high prevalence of comorbidity with other psychiatric diagnoses highlights the need to develop a broad-based treatment program that also addresses patients' associated psychiatric disorders (Table 12.10-2).


Psychosocial Factors

Opioid dependence is not limited to low socioeconomic classes, although the incidence of opioid dependence is greater in these groups than in higher socioeconomic classes. Social factors associated with urban poverty probably contribute to opioid dependence. About 50 percent of urban heroin users are children of single parents or divorced parents and are from families in which at least one other member has a substance-related disorder. Children from such settings are at high risk for opioid dependence, especially if they also evidence behavioral problems in school or other signs of conduct disorder.

Table 12.10-2 Non–Substance-Related Axis I Psychiatric Disorders in Opioid Users

Diagnostic Categorya Lifetime Rates % (Current Rates %
Men (N = 378) Women (N = 338) Total
Any Axis I disorder 15.6 (5.0) 33.4 (11.2) 24.0 (8.0)
Mood disorder 11.4 (2.1) 27.5 (5.3) 19.0 (3.6)
   Major depressive disorder 8.7 (1.3) 23.7 (5.3) 15.8 (3.2)
   Dysthymic disorder 2.4 (2.4) 4.4 (4.4) 3.4 (3.4)
   Bipolar I disorder 0.8 (0.8) 0.0 (0.0) 0.4 (0.4)
Anxiety disorder 6.1 (3.4) 10.7 (6.8) 8.2 (5.0)
   Simple phobia 1.9 (1.9) 5.3 (3.6) 3.5 (2.7)
   Social phobia 1.9 (0.8) 3.6 (2.7) 2.7 (1.7)
   Panic disorder 2.1 (0.3) 1.8 (0.9) 2.0 (0.6)
   Agoraphobia 0.0 (0.0) 0.6 (0.3) 0.3 (0.1)
   Obsessive-compulsive disorder 0.5 (0.5) 0.0 (0.0) 0.3 (0.3)
   General anxiety disorder 0.8 (0.8) 0.0 (0.0) 0.1 (0.1)
Eating disorders 0.0 (0.0) 1.5 (0.0) 0.7 (0.0)
   Bulimia nervosa 0.0 (0.0) 0.9 (0.0) 0.4 (0.0)
   Anorexia nervosa 0.0 (0.0) 0.6 (0.0) 0.3 (0.0)
Schizophrenia 0.0 (0.0) 0.3 (0.3) 0.1 (0.1)
aMultiple disorders possible.
(Adapted from Brooner RK, King VL, Kidorf M, Schmidt CW, Bigelow GE. Psychiatric and substance use comorbidity among treatment-seeking opioid abusers. Arch Gen Psychiatry. 1997;54:71.)

Some consistent behavior patterns seem to be especially pronounced in adolescents with opioid dependence. These patterns have been called the heroin behavior syndrome: underlying depression, often of an agitated type and frequently accompanied by anxiety symptoms; impulsiveness expressed by a passive-aggressive orientation; fear of failure; use of heroin as an antianxiety agent to mask feelings of low self-esteem, hopelessness, and aggression; limited coping strategies and low frustration tolerance, accompanied by the need for immediate gratification; sensitivity to drug contingencies, with a keen awareness of the relation between good feelings and the act of drug taking; feelings of behavioral impotence counteracted by momentary control over the life situation by means of substances; disturbances in social and interpersonal relationships with peers maintained by mutual substance experiences.

Biological and Genetic Factors

Evidence now exists for common and drug-specific, genetically transmitted vulnerability factors that increase the likelihood of developing drug dependence. Individuals who abuse a substance from any category are more likely to abuse substances from other categories. Monozygotic twins are more likely than dizygotic twins to be concordant for opioid dependence. Multivariate modeling techniques indicated that not only was the genetic contribution high for heroin abuse in this group, but also a higher proportion of the variance because of genetic factors was not shared with the common vulnerability factor—that is, it was specific for opioids.


A person with an opioid-related disorder may have had genetically determined hypoactivity of the opiate system. Researchers are investigating the possibility that such hypoactivity may be caused by too few, or less-sensitive, opioid receptors, by release of too little endogenous opioid, or by overly high concentrations of a hypothesized endogenous opioid antagonist. A biological predisposition to an opioid-related disorder may also be associated with abnormal functioning in either the dopaminergic or the noradrenergic neurotransmitter system.

Psychodynamic Theory

In psychoanalytic literature, the behavior of persons addicted to narcotics has been described in terms of libidinal fixation, with regression to pregenital, oral, or even more archaic levels of psychosexual development. The need to explain the relation of drug abuse, defense mechanisms, impulse control, affective disturbances, and adaptive mechanisms led to the shift from psychosexual formulations to formulations emphasizing ego psychology. Serious ego pathology, often thought to be associated with substance abuse, is considered to indicate profound developmental disturbances. Problems of the relation between the ego and affects emerge as a key area of difficulty.


The DSM-IV-TR lists several opioid-related disorders (Table 12.10-3) but contains specific diagnostic criteria only for opioid intoxication (Table 12.10-4) and opioid withdrawal (Table 12.10-5) within the section on opioid-related disorders. The diagnostic criteria for the other opioid-related disorders are contained within the DSM-IV-TR sections that deal specifically with the predominant symptom—for example, opioid-induced mood disorder (see Table 15.3-10).

Table 12.10-3 DSM-IV-TR Opioid-Related Disorders

Opioid use disorders
Opioid dependence
Opioid abuse
Opioid-induced disorders
Opioid intoxication
Specify if:
   With perceptual disturbances
Opioid withdrawal
Opioid intoxication delirium
Opioid-induced psychotic disorder, with delusions
Specify if:
   With onset during intoxication
Opioid-induced psychotic disorder, with hallucinations
Specify if:
   With onset during intoxication
Opioid-induced mood disorder
Specify if:
   With onset during intoxication
Opioid-induced sexual dysfunction
Specify if:
   With onset during intoxication
Opioid-induced sleep disorder
Specify if:
   With onset during intoxication
   With onset during withdrawal
Opioid-related disorder not otherwise specified
(From American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text rev. Washington, DC: American Psychiatric Association; copyright 2000, with permission.)

Table 12.10-4 DSM-IV-TR Diagnostic Criteria for Opioid Intoxication

  1. Recent use of an opioid.
  2. Clinically significant maladaptive behavioral or psychological changes (e.g., initial euphoria followed by apathy, dysphoria, psychomotor agitation or retardation, impaired judgment, or impaired social or occupational functioning) that developed during, or shortly after, opioid use.
  3. Pupillary constriction (or pupillary dilation due to anoxia from severe overdose) and one (or more) of the following signs, developing during, or shortly after, opioid use:
    1. drowsiness or coma
    2. slurred speech
    3. impairment in attention or memory
  4. The symptoms are not due to a general medical condition and are not better accounted for by another mental disorder.
Specify if:
   With perceptual disturbances
(From American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text rev. Washington, DC: American Psychiatric Association; copyright 2000, with permission.)

Opioid Dependence and Opioid Abuse

Opioid dependence and opioid abuse are defined in DSM-IV-TR according to the general criteria for these disorders (see Tables 12.1-3, 12.1-4, and 12.1-5).

Table 12.10-5 DSM-IV-TR Diagnostic Criteria for Opioid Withdrawal

  1. Either of the following:
    1. cessation of (or reduction in) opioid use that has been heavy and prolonged (several weeks or longer)
    2. administration of an opioid antagonist after a period of opioid use
  2. Three (or more) of the following, developing within minutes to several days after Criterion A:
    1. dysphoric mood
    2. nausea or vomiting
    3. muscle aches
    4. lacrimation or rhinorrhea
    5. pupillary dilation, piloerection, or sweating
    6. diarrhea
    7. yawning
    8. fever
    9. insomnia
  3. The symptoms in Criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
  4. The symptoms are not due to a general medical condition and are not better accounted for by another mental disorder.
(From American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text rev. Washington, DC: American Psychiatric Association; copyright 2000, with permission.)


A 42-year-old executive in a public relations firm was referred for psychiatric consultation by his surgeon, who discovered him sneaking large quantities of a codeine-containing cough medicine into the hospital. The patient had been a heavy cigarette smoker for 20 years and had a chronic, hacking cough. He had come into the hospital for a hernia repair and found the pain for the incision unbearable when he coughed.

An operation on his back 5 years previously had led his doctors to prescribe codeine to help relieve the incisional pain at that time. Over the intervening 5 years, however, the patient had continued to use codeine-containing tablets and had increased his intake to 60–90 mg tablets daily. He stated that he often “just took them by the handful—not to feel good, you understand, just to get by.” He spent considerable time and effort developing a circle of physicians and pharmacists to whom he would “make the rounds” at least three times a week to obtain new supplies of pills. He had tried several times to stop using codeine, but had failed. During this period he lost two jobs because of lax work habits and was divorced by his wife of 11years. (Courtesy of DSM-IV-TR Casebook.)

Opioid Intoxication

The DSM-IV-TR defines opioid intoxication as including maladaptive behavioral changes and some specific physical symptoms of opioid use (Table 12.10-4). In general, altered mood, psychomotor retardation, drowsiness, slurred speech, and impaired memory and attention in the presence of other indicators of recent opioid use strongly suggest a diagnosis of opioid intoxication. DSM-IV-TR allows for the specification of “with perceptual disturbances.”

Opioid Withdrawal

The general rule about the onset and duration of withdrawal symptoms is that substances with short durations of action tend to produce short, intense withdrawal syndromes and substances with long durations of action produce prolonged, but mild, withdrawal syndromes. An exception to the rule, narcotic antagonist-precipitated withdrawal after long-acting opioid dependence can be severe.

An abstinence syndrome can be precipitated by administration of an opioid antagonist. The symptoms can begin within seconds of such an intravenous injection and peak in about 1 hour. Opioid craving rarely occurs in the context of analgesic administration for pain from physical disorders or surgery. The full withdrawal syndrome, including intense craving for opioids, usually occurs only secondary to abrupt cessation of use in persons with opioid dependence.

Morphine and Heroin

The morphine and heroin withdrawal syndrome begins 6 to 8 hours after the last dose, usually after a 1- to 2-week period of continuous use or after the administration of a narcotic antagonist. The withdrawal syndrome reaches its peak intensity during the second or third day and subsides during the next 7 to 10 days, but some symptoms may persist for 6 months or longer.


The withdrawal syndrome from meperidine begins quickly, reaches a peak in 8 to 12 hours, and ends in 4 to 5 days.


Methadone withdrawal usually begins 1 to 3 days after the last dose and ends in 10 to 14 days.


Opioid withdrawal (Table 12.10-5) consists of severe muscle cramps and bone aches, profuse diarrhea, abdominal cramps, rhinorrhea, lacrimation, piloerection or gooseflesh (from which comes the term cold turkey for the abstinence syndrome), yawning, fever, pupillary dilation, hypertension, tachycardia, and temperature dysregulation, including hypothermia and hyperthermia. Persons with opioid dependence seldom die from opioid withdrawal, unless they have a severe preexisting physical illness such as cardiac disease. Residual symptoms—such as insomnia, bradycardia, temperature dysregulation, and a craving for opioids—can persist for months after withdrawal. Associated features of opioid withdrawal include restlessness, irritability, depression, tremor, weakness, nausea, and vomiting. At any time during the abstinence syndrome, a single injection of morphine or heroin eliminates all the symptoms.

Opioid Intoxication Delirium

Opioid intoxication delirium (see Table 10.2-6) is most likely to happen when opioids are used in high doses, are mixed with other psychoactive compounds, or are used by a person with preexisting brain damage or a central nervous system (CNS) disorder (e.g., epilepsy).

Opioid-Induced Psychotic Disorder

Opioid-induced psychotic disorder can begin during opioid intoxication. The DSM-IV-TR diagnostic criteria are contained in the section on schizophrenia and other psychotic disorders (see Table 14.4-7). Clinicians can specify whether hallucinations or delusions are the predominant symptoms.

Opioid-Induced Mood Disorder

Opioid-induced mood disorder can begin during opioid intoxication (see Table 15.3-10). Opioid-induced mood disorder symptoms can have a manic, depressed, or mixed nature, depending on a person's response to opioids. A person coming to psychiatric attention with opioid-induced mood disorder usually has mixed symptoms, combining irritability, expansiveness, and depression.

Opioid-Induced Sleep Disorder and Opioid-Induced Sexual Dysfunction

Opioid-induced sleep disorder (see Table 24.2-21) and opioid-induced sexual dysfunction (see Table 21.2-17) are diagnostic categories in DSM-IV-TR. Hypersomnia is likely to be more common with opioids than insomnia. The most common sexual dysfunction is likely to be impotence.


Table 12.10-6 DSM-IV-TR Diagnostic Criteria for Opioid-Related Disorder Not Otherwise Specified

The opioid-related disorder not otherwise specified category is for disorders associated with the use of opioids that are not classifiable as opioid dependence, opioid abuse, opioid intoxication, opioid withdrawal, opioid intoxication delirium, opioid-induced psychotic disorder, opioid-induced mood disorder, opioid-induced sexual dysfunction, or opioid-induced sleep disorder.
(From American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text rev. Washington, DC: American Psychiatric Association; copyright 2000, with permission.)

Opioid-Related Disorder Not Otherwise Specified

The DSM-IV-TR includes diagnoses for opioid-related disorders with symptoms of delirium, abnormal mood, psychosis, abnormal sleep, and sexual dysfunction. Clinical situations that do not fit into these categories exemplify appropriate cases for the use of the DSM-IV-TR diagnosis of opioid-related disorder not otherwise specified (Table 12.10-6).

Clinical Features

Opioids can be taken orally, snorted intranasally, and injected intravenously (IV) or subcutaneously (Fig. 12.10-2). Opioids are subjectively addictive because of the euphoric high (the rush) that users experience, especially those who take the substances IV. The associated symptoms include a feeling of warmth, heaviness of the extremities, dry mouth, itchy face (especially the nose), and facial flushing. The initial euphoria is followed by a period of sedation, known in street parlance as “nodding off.” Opioid use can induce dysphoria, nausea, and vomiting in opioid-naïve persons.

The physical effects of opioids include respiratory depression, pupillary constriction, smooth muscle contraction (including the ureters and the bile ducts), constipation, and changes in blood pressure, heart rate, and body temperature. The respiratory depressant effects are mediated at the level of the brainstem.

FIGURE 12.10-2 Skin popper. Circular depressed scars, often with underlying chronic abscesses, can result from skin popping. (Courtesy of Michael Baden, M.D.)

Adverse Effects

The most common and most serious adverse effect associated with the opioid-related disorders is the potential transmission of hepatitis and HIV through the use of contaminated needles by more than one person. Persons can experience idiosyncratic allergic reactions to opioids, which result in anaphylactic shock, pulmonary edema, and death if they do not receive prompt and adequate treatment. Another serious adverse effect is an idiosyncratic drug interaction between meperidine and monoamine oxidase inhibitors (MAOIs), which can produce gross autonomic instability, severe behavioral agitation, coma, seizures, and death. Opioids and MAOIs should not be given together for this reason.

Opioid Overdose

Death from an overdose of an opioid is usually attributable to respiratory arrest from the respiratory depressant effect of the drug. The symptoms of overdose include marked unresponsiveness, coma, slow respiration, hypothermia, hypotension, and bradycardia. When presented with the clinical triad of coma, pinpoint pupils, and respiratory depression, clinicians should consider opioid overdose as a primary diagnosis. They can also inspect the patient's body for needle tracks in the arms, legs, ankles, groin, and even the dorsal vein of the penis.

MPTP-Induced Parkinsonism

In 1976, after ingesting an opioid contaminated with methyl-phenyltetrahydropyridine (MPTP), several persons developed a syndrome of irreversible parkinsonism. The mechanism for the neurotoxic effect is as follows: MPTP is converted into 1-methyl-4-phenylpyridinium (MPP+) by the enzyme monoamine oxidase and is then taken up by dopaminergic neurons. Because MPP+ binds to melanin in substantia nigra neurons, MPP+ is concentrated in these neurons and eventually kills the cells. PET studies of persons who ingested MPTP but remained asymptomatic have shown a decreased number of dopamine-binding sites in the substantia nigra. This decrease reflects a loss in the number of dopaminergic neurons in that region.

Treatment and Rehabilitation

Overdose Treatment

The first task in overdose treatment is to ensure an adequate airway. Tracheopharyngeal secretions should be aspirated; an airway may be inserted. The patient should be ventilated mechanically until naloxone, a specific opioid antagonist, can be given. Naloxone is administered IV at a slow rate—initially about 0.8 mg per 70 kg of body weight. Signs of improvement (increased respiratory rate and pupillary dilation) should occur promptly. In opioid-dependent patients, too much naloxone may produce signs of withdrawal as well as reversal of overdosage. If no response to the initial dosage occurs, naloxone administration may be repeated after intervals of a few minutes. Previously, it was


thought that if no response was observed after 4 to 5 mg, the CNS depression was probably not caused solely by opioids. The duration of action of naloxone is short compared with that of many opioids, such as methadone and levomethadyl acetate, and repeated administration may be required to prevent recurrence of opioid toxicity.

Medically Supervised Withdrawal and Detoxification

Opioid Agents for Treating Opioid Withdrawal


Methadone is a synthetic narcotic (an opioid) that substitutes for heroin and can be taken orally. When given to addicts to replace their usual substance of abuse, the drug suppresses withdrawal symptoms. A daily dosage of 20 to 80 mg suffices to stabilize a patient, although daily doses of up to 120 mg have been used. The duration of action for methadone exceeds 24 hours; thus, once-daily dosing is adequate. Methadone maintenance is continued until the patient can be withdrawn from methadone, which itself causes dependence. An abstinence syndrome occurs with methadone withdrawal, but patients are detoxified from methadone more easily than from heroin. Clonidine (0.1 to 0.3 mg three to four times a day) is usually given during the detoxification period.

Methadone maintenance has several advantages. First, it frees persons with opioid dependence from using injectable heroin and, thus, reduces the chance of spreading HIV through contaminated needles. Second, methadone produces minimal euphoria and rarely causes drowsiness or depression when taken for a long time. Third, methadone allows patients to engage in gainful employment instead of criminal activity. The major disadvantage of methadone use is that patients remain dependent on a narcotic.

Other Opioid Substitutes

Levomethadyl (LAAM)

LAAM is an opioid agonist that suppresses opioid withdrawal. It is no longer used, however, because some patients developed prolonged QT intervals associated with potentially fatal arrhythmias (torsades de pointes).


As with methadone and LAAM, buprenorphine is an opioid agonist approved for opioid dependence in 2002. It can be dispensed on an outpatient basis but prescribing physicians must demonstrate that they have revived special training in its use. Buprenorphine in a daily dose of 8 to 10 mg appears to reduce heroin use. Buprenorphine also is effective in thrice-weekly dosing because of its slow dissociation from opioid receptors. After repeated administration, it attenuates or blocks the subjective effects of parenterally administered opioids such as heroin or morphine. A mild opioid withdrawal syndrome occurs if the drug is abruptly discontinued after chronic administrations.

Opioid Antagonists

Opioid antagonists block or antagonize the effects of opioids. Unlike methadone, they do not exert narcotic effects and do not cause dependence. Opioid antagonists include naloxone, which is used in the treatment of opioid overdose because it reverses the effects of narcotics, and naltrexone, the longest-acting (72 hours) antagonist. The theory for using an antagonist for opioid-related disorders is that blocking opioid agonist effects, particularly euphoria, discourages persons with opioid dependence from substance-seeking behavior and, thus, deconditions this behavior. The major weakness of the antagonist treatment model is the lack of any mechanism that compels a person to continue to take the antagonist.

Pregnant Women with Opioid Dependence

Neonatal addiction is a significant problem. About three fourths of all infants born to addicted mothers experience the withdrawal syndrome.

Neonatal Withdrawal

Although opioid withdrawal rarely is fatal for the otherwise healthy adult, it is hazardous to the fetus and can lead to miscarriage or fetal death. Maintaining a pregnant woman with opioid dependence on a low dose of methadone (10 to 40 mg daily) may be the least hazardous course to follow. At this dose, neonatal withdrawal is usually mild and can be managed with low doses of paregoric. If pregnancy begins while a woman is taking high doses of methadone, the dosage should be reduced slowly (e.g., 1 mg every 3 days), and fetal movements should be monitored. If withdrawal is necessary or desired, it is least hazardous during the second trimester.

Fetal AIDS Transmission

Acquired immune deficiency syndrome (AIDS) is the other major risk to the fetus of a woman with opioid dependence. Pregnant women can pass HIV, the causative agent of AIDS, to the fetus through the placental circulation. An HIV-infected mother can also pass HIV to the infant through breast-feeding. The use of zidovudine (Retrovir) alone or in combination with other anti-HIV medication in infected women can decrease the incidence of HIV in newborns.


The entire range of psychotherapeutic modalities is appropriate for treating opioid-related disorders. Individual psychotherapy, behavioral therapy, cognitive-behavioral therapy, family therapy, support groups (e.g., Narcotics Anonymous [NA]), and social skills training may all prove effective for specific patients. Social skills training should be particularly emphasized for patients with few social skills. Family therapy is usually indicated when the patient lives with family members.

Therapeutic Communities

Therapeutic communities are residences in which all members have a substance abuse problem. Abstinence is the rule; to be admitted to such a community, a person must show a high level of motivation. The goals are to effect a complete change of lifestyle, including abstinence from substances; to develop personal honesty, responsibility, and useful social skills; and to eliminate antisocial attitudes and criminal behavior.

The staff members of most therapeutic communities are persons with former substance dependence who often put prospective candidates through a rigorous screening process to test their motivation. Self-help through the use of confrontational groups and isolation from the outside world and from friends associated with the drug life are emphasized. The prototypical community for persons with substance dependence is Phoenix House, where


the residents live for long periods (usually 12 to 18 months) while receiving treatment. They are allowed to return to their old environments only when they have demonstrated their ability to handle increased responsibility within the therapeutic community. Therapeutic communities can be effective but require large staffs and extensive facilities. Moreover, dropout rates are high; up to 75 percent of those who enter therapeutic communities leave within the first month.

Education and Needle Exchange

Although the essential treatment of opioid use disorders is encouraging persons to abstain from opioids, education about the transmission of HIV must receive equal attention. Persons with opioid dependence who use IV or subcutaneous routes of administration must be taught available safe-sex practices. Free needle-exchange programs are often subject to intense political and societal pressures but, where allowed, should be made available to persons with opioid dependence. Several studies have indicated that unsafe needle sharing is common when it is difficult to obtain enough clean needles and is also common in persons with legal difficulties, severe substance problems, and psychiatric symptoms. These are just the persons most likely to be involved in transmitting HIV.

Narcotic Anonymous

Narcotics Anonymous is a self-help group of abstinent drug addicts modeled on the 12-step principles of Alcoholics Anonymous (AA). Such groups now exist in most large cities and can provide useful group support. The outcome for patients treated in 12-step programs is generally good, but the anonymity that is at the core of the 12-step model has made detailed evaluation of its efficacy in treating opioid dependence difficult.


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