Substance Use and Addictive Disorders

4.4 Opioid-Related Disorders

• Opioids are psychoactive compounds related to opiates (alkaloid compounds in the opium poppy plant, Papaver somniferumi).

• Synthetic opioids include meperidine, methadone, pentazocine, and propoxyphene.

• Opioids have been used for analgesia and other medicinal purposes for thousands of years, with a long history of misuse for psychoactive effects.

• Continued misuse can cause abuse, dependence, and disturbances in mood, behavior, and cognition.

• Heroin is the most frequently abused opioid in developed countries, but prescription opioids are also a growing public health concern.

• Opioid addiction affects all demographics.

• Opioid use disorder is a chronic, relapsing disorder that is amenable to medical treatment and intervention.

Opioids Available in the United States

• The following opioids are used therapeutically in the United States (excluding heroin):

  • Morphine

  • Hydromorphone (Dilaudid)

  • Oxymorphone (Numorphan)

  • Levorphanol (Levo-Dromoran)

  • Methadone (Dolophine)

  • Meperidine (Demerol, Pethadol)

  • Fentanyl (Sublimaze)

  • Codeine

  • Hydrocodone (Hycodan, others)

  • Drocode (Synalgos-Dc, Compal)

  • Oxycodone (Roxicodone, Oxycontin, Percodan, Percocet, Vicodin)

  • Propoxyphene (Darvon, others)

  • Buprenorphine (Buprenex, Sublocade)

  • Pentazocine (Talwin)

  • Nalbuphine (Nubain)

  • Butorphanol (Stadol)

Clinical Features

• Opioids can be taken orally, intranasally, or intravenously/subcutaneously.

• Subjectively addictive due to the euphoric high ("rush"), especially with intravenous use.

• Symptoms include warmth, heavy extremities, dry mouth, itchy face (especially the nose), and facial flushing.

• Sedation follows euphoria, known as "nodding off."

• Opioid use can induce dysphoria, nausea, and vomiting in opioid-naive persons.

Diagnosis

• DSM-5 and ICD-10 include diagnoses for opioid use disorder, opioid intoxication, opioid withdrawal, opioid-induced sleep disorder, and opioid-induced sexual dysfunction.

• Opioid intoxication delirium can occur in hospitalized patients.

• Opioid-induced psychotic disorder, mood disorder, and anxiety disorder are uncommon with µ-agonist opioids but can occur with mixed agonist-antagonists.

• Opioid-related disorder not elsewhere classified is for situations that don't meet criteria for other opioid-related disorders.

Opioid Use Disorder

• Maladaptive use of an opioid drug, leading to clinically significant impairment or distress within 12 months.

• Example: A public relations executive sneaking codeine-containing cough medicine into the hospital after a hernia repair, due to previous codeine use from a back operation 5 years prior. The patient increased his intake to 60 to 90 mg daily and lost two jobs because of lax work habits, and his wife divorced him.

Opioid Intoxication

• Maladaptive behavioral changes and specific physical symptoms of opioid use.

• Altered mood, psychomotor retardation, drowsiness, slurred speech, and impaired memory and attention strongly suggest opioid intoxication.

Opioid Withdrawal

• Develops after cessation or reduction in heavy, prolonged opioid use.

• Also occurs when administering an opioid partial agonist (buprenorphine) or antagonist (naloxone, naltrexone) to a patient regularly taking an opioid agonist.

• Withdrawal symptoms are generally the physiological opposite of the intoxication symptoms.

• Symptoms: Severe muscle cramps and bone aches, profuse diarrhea, abdominal cramps, rhinorrhea, lacrimation, piloerection (gooseflesh, "cold turkey"), yawning, fever, pupillary dilation, hypertension, tachycardia, and temperature dysregulation (hypothermia/hyperthermia).

• Opioid withdrawal is rarely fatal unless there is a severe preexisting physical illness such as cardiac disease.

• Residual Symptoms: Insomnia, bradycardia, temperature dysregulation, and craving for opioids can persist for months after withdrawal.

• Associated features include restlessness, irritability, depression, tremor, weakness, nausea, and vomiting.

• A single injection of morphine or heroin eliminates all the symptoms.

• 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.

• Exception: Narcotic antagonist-precipitated withdrawal after long-acting opioid misuse can be severe.

• Opioid craving rarely occurs in the context of analgesic administration for pain; it usually occurs secondary to abrupt cessation in persons with longstanding opioid misuse.

Morphine and Heroin

• Withdrawal begins 6 to 8 hours after the last dose, usually after 1- to 2-week period of continuous use or after administration of a narcotic antagonist.

• Reaches 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.

Methadone

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

Opioid Intoxication Delirium

• Most likely to happen when using opioids in high doses, or mixing them with other psychoactive compounds, or when a person with preexisting CNS disorder (e.g., brain damage or epilepsy) uses them.

Opioid-Induced Psychotic Disorder

• Can begin during opioid intoxication.

• Hallucinations or delusions may be predominant symptoms.

Opioid-Induced Mood Disorder

• Can begin during opioid intoxication.

• Symptoms can have a manic, depressed, or mixed nature.

• Often presents with mixed symptoms like irritability, expansiveness, and depression.

Opioid-Induced Sleep Disorder and Opioid-Induced Sexual Dysfunction

• Common; hypersomnia and insomnia are frequent complaints.

• Common sexual dysfunctions include erectile dysfunction and orgasmic difficulties.

Unspecified Opioid-Related Disorder

• Used for cases that don't fit into other categories but have symptoms of delirium, abnormal mood, psychosis, abnormal sleep, and sexual dysfunction.

Comorbidity

• Nearly 70% of men and 75% of women with opioid use disorder have an additional psychiatric disorder.

• Common comorbid disorders include mood disorders, antisocial personality disorder, anxiety disorders, and alcohol use disorder.

• Association between opioid use and transmission of hepatitis and HIV is a leading national health concern.

Treatment and Rehabilitation

• Methadone is the current gold standard for opioid use disorder with physiologic dependence and is used for detoxification and maintenance.

• Buprenorphine is a partial opioid agonist that binds to the receptor but only partially activates it.

  • It has a high affinity (binding strength) to the receptor and a low dissociation, often functioning as an antagonist.

  • If a patient is actively using an agonist when receiving buprenorphine, it will abruptly displace the agonist, causing a sudden drop in agonist effect and precipitated withdrawal.

  • Used to assist detoxification and as a maintenance agent.

• Opioid antagonists (e.g., naloxone, nalmefene, and naltrexone) bind to the receptor but do not exert any activity.

  • Compete for binding at the receptor with agonists and partial agonists.

  • If the dose is high enough, they may displace the agonist and prevent it from binding and exerting any effect.

  • Naloxone reverses an overdose; short-acting, allowing for accurate dosing without prolonged effect.

  • Naltrexone is a long-acting agent used after detoxification to prevent recurrent physiologic dependence and relapse.

Overdose Treatment

• Ensure an adequate airway: aspirate secretions, and possibly insert an airway.

• Ventilate mechanically until naloxone can be given.

• Administer naloxone intravenously at a slow rate (initially about 0.8 mg per 70 kg of body weight).

• Signs of improvement include increased respiratory rate and pupillary dilation.

• Too much naloxone in physiologically dependent patients may produce signs of withdrawal.

• Repeat naloxone administration after intervals of a few minutes if no response occurs to the initial dosage.

• If there is no response after 4 to 5 mg, nonopioid substances may be contributing to the CNS depression.

• The duration of action of naloxone is short compared with that of many opioids, so repeated administration may be required.

Medically Supervised Withdrawal and Detoxification

METHADONE

• Methadone is a synthetic narcotic (an opioid) that substitutes for heroin to suppress withdrawal symptoms.

• The initial dose of methadone is usually 20 to 30 mg orally; if objective signs of withdrawal persist after the first dose, clinicians can repeat the dose after approximately 2 to 4 hours.

• As a general rule, initial stabilization does not require more than 40 mg during the first 24 hours, although it can be higher in the inpatient setting if clear signs of moderate or severe withdrawal are present after the first 6 to 10 hours of the observation period.

• After 24 to 48 hours of dose stabilization, the patient’s methadone dose can be gradually reduced by 10 to 20 percent or by 5 mg/day.

• Most patients can complete inpatient detoxification within 1 week.

• In the case of detoxification with methadone in an outpatient setting, the first-day dose should not exceed 40 mg.

• Over the next few days, clinicians may titrate the dose (generally by no more than 10-mg increments every 2 to 3 days) until the patient has no discernible withdrawal symptoms.

• In most cases, the dose of 40 to 60 mg/day is sufficient to prevent any opioid withdrawal; however, this dose may not be adequate to eliminate craving.

• If the patient continues to use opioids, the dose of methadone can increase. In that case, clinicians should postpone detoxification and the goal becomes stabilization—no withdrawal symptoms, craving, or opioid use.

• Generally, a period of dose stabilization, at a minimum of 4 weeks in duration, is necessary before a slow dose reduction schedule.

• In the outpatient setting, gradual dose reductions (e.g., 3 percent per week), have a higher likelihood of success, with even slower reductions once the total daily dose is down to 20 to 30 mg/day.

BUPRENORPHINE

• As with methadone, buprenorphine is an opioid agonist used for treating opioid withdrawal.

• Physicians can dispense it on an outpatient basis, but they must demonstrate that they have received specialized training in its use.

• Buprenorphine is available in several formulations, including as monotherapy or combination therapy with buprenorphine plus naloxone.

• The monotherapy versions include a parenteral formulation and an extended-release subcutaneous injection. The combination product is preferred, as it carries a lower risk of diversion and misuse.

• Buprenorphine can be used for detoxification in an inpatient setting.

Opioid Withdrawal Symptom Management

• Non-opioid medications target specific withdrawal symptoms:

  • Sweating, restlessness, tremor, rhinorrhea: α2-agonist Clonidine.

  • Anxiety and psychomotor agitation: Benzodiazepines (Lorazepam), typically in inpatient settings.

  • Insomnia: Hypnotics (Zolpidem, Zopiclone), sedating antidepressants (Trazodone), atypical antipsychotics (Quetiapine).

  • Musculoskeletal pain: Nonsteroidal anti-inflammatory drugs (Ibuprofen), antispasmodic agents (Cyclobenzaprine).

  • GI distress and diarrhea: Antiemetic agents (Prochlorperazine), peripheral μ-opioid receptor agonists (Loperamide).

Opioid Use Disorder (OUD) Treatment

• Opioid substitution therapy (Methadone, Buprenorphine) for those who fail or are not ready for detoxification.

• Antagonist therapy (Naltrexone) for maintaining abstinence post-detoxification.

Opioid Substitution Therapy Advantages:

• Reduces IV heroin/illicit opioid use, thus lowers HIV/hepatitis transmission via needles.

• Opioid agonists provide minimal euphoria and rarely cause drowsiness or depression long-term.

• Enables patients to engage in employment, reducing criminal activity.

• Disadvantage: Continues narcotic dependence.

Methadone

• Superior to non-medication treatments for retention and reducing illicit opioid use.

• Decreases non-opioid drug use, criminal behavior, depression, increases employment.

• Effectiveness depends on dose and services offered.

• Optimal dose: 80-120 mg/day.

• Side effects: Constipation, sweating, decreased libido, sexual dysfunction.

• Administered via SAMHSA-certified OTPs, with supervised daily doses until stability is achieved for take-home doses.

Buprenorphine/Naloxone Combination

• Buprenorphine: High-affinity partial μ-opioid receptor agonist, kappa-receptor antagonist, and ORL-1 agonist.

• Dose-dependent opiate effect up to 16 mg, ceiling effect at higher doses limits respiratory depression.

• Naloxone added to deter abuse; minimal sublingual bioavailability, but if injected, it blocks buprenorphine effects and may precipitate withdrawal.

• Best for those with mild withdrawal symptoms.

• Less overdose concern than methadone during initiation.

• Combining with benzodiazepines/sedatives can cause excessive sedation, potential fatalities with parenteral misuse.

• Side effects: Constipation, nausea, headache, upset stomach, excessive sweating, somnolence, decreased libido.

• Requires physician training and DEA waiver to prescribe.

Opioid Antagonists

• Block opioid effects without narcotic effects or dependence.

• Naloxone: Reverses opioid overdose.

• Naltrexone: Longest-acting (72 hours).

• Theory: Blocking euphoria discourages substance-seeking behavior.

• Weakness: No mechanism ensures continued use.

• Available as oral or long-acting injectable.

Psychotherapy

• Various modalities suitable for opioid-related disorders: individual, behavioral, CBT, family therapy, support groups (NA), social skills training.

Therapeutic Communities

• Residential settings for individuals with substance abuse problems.

• Focus on complete lifestyle change: abstinence, honesty, responsibility, social skills, eliminating antisocial behavior.

• Requires high motivation for admission.

Education and Needle Exchange

• Addresses HIV transmission, safe-sex practices.

• Needle-exchange programs reduce unsafe needle sharing; common in those with legal issues, severe substance problems, psychiatric symptoms.

Narcotic Anonymous (NA)

• Modeled on AA, offers group support.

• Observational studies support effectiveness; encourages participation alongside pharmacological treatments.

Pregnant Women with OUD

• Illicit opioid use has adverse effects: infections, preeclampsia, miscarriage, premature rupture of membranes, premature labor, stillbirths, premature infants, low birth weight, neonatal opioid withdrawal (neonatal abstinence syndrome).

• Risks reduced with methadone or buprenorphine maintenance.

• Infants are at risk of HIV and SIDS.

Epidemiology of Opioid Use

• National surveys may not reflect fluctuations in opioid-dependent populations.

• Increased heroin purity/decreased price increases use, adverse consequences.

• 475,000 current heroin users in the US (ages 12+).

• 3.3 million current pain reliever misusers.

• 53% of pain relievers are obtained from friends/family.

• 11.8 million individuals (ages 12+) used opioids in the past year.

Pathology of Opioid Use

• Effects: respiratory depression, pupillary constriction, smooth muscle contraction, constipation, blood pressure/heart rate/body temperature changes.

• Brainstem mediates respiratory depression.

• Adverse effects: hepatitis/HIV transmission via needles, allergic reactions (anaphylactic shock, pulmonary edema), drug interaction between meperidine and MAOIs (autonomic instability, agitation, coma, seizures).

• Opioids and MAOIs should not be given together.

Opioid Overdose

• Death usually from respiratory arrest.

• Symptoms: unresponsiveness, coma, slow respiration, hypothermia, hypotension, bradycardia.

• Clinical triad: coma, pinpoint pupils, respiratory depression.

• Inspect for needle tracks.

Neuropharmacology

• Effects mediated via opioid receptors: μ, κ, Δ.

• μ-opioid receptors: analgesia, respiratory depression, constipation, drug dependence.

• κ-opioid receptors: analgesia, diuresis, sedation.

• Δ-opioid receptors: analgesia.

• Endogenous opioids: endorphins, dynorphins, enkephalins.

• Endorphins involved in neural transmission and pain suppression.

• VTA dopaminergic neurons mediate rewarding properties of opioids.

• Heroin is more lipid-soluble than morphine, crosses the blood-brain barrier faster.

• Codeine transforms into morphine in the body.

• Opioids decrease cerebral blood flow (CBF).

• Naltrexone mitigates alcohol addiction.

Tolerance and Dependence

• Tolerance varies; cancer patients may require high morphine doses (200-300 mg/day).

• Withdrawal occurs after long-term use or abrupt cessation.

• Long-term use changes opioid receptor number/sensitivity.

• Noradrenergic neurons are primary mediators of withdrawal symptoms.

• Clonidine, an α2-adrenergic receptor agonist, is useful in treating opioid withdrawal.

Etiology of Opioid Use

• Psychosocial Factors: social attitudes, peer pressure, individual temperament, drug availability.

• Transition from prescription opioids to heroin due to cost/tolerance.

• High crime rates, unemployment, poor school systems reduce resistance to opioid use.

• Most urban heroin users are children of single/divorced parents with a family history of substance-related disorders.

• Biologic and Genetic Factors: genetic vulnerability increases the likelihood of drug dependence.

• Twin studies estimate 50-60% of heroin addiction liability is genetic.

Sedative-, Hypnotic-, or Anxiolytic-Related Disorders

• Drugs in this category exist on a continuum, displaying anxiolytic, sedative, and hypnotic effects.

• Used as antiepileptics, muscle relaxants, anesthetics, and anesthetic adjuvants.

• Alcohol and drugs of this class are cross-tolerant, and their effects are additive.

• Physical and psychological dependence develops, and all are associated with withdrawal symptoms.

• Benzodiazepines are the most clinically important drug class in psychiatry and addiction medicine related to this class of substance-related disorders.

• The three major groups of drugs associated with this class of substance-related disorders are benzodiazepines, barbiturates, and barbiturate-like substances.

Benzodiazepines

• Differ primarily in their half-lives.

• Examples are diazepam, flurazepam, oxazepam, and chlordiazepoxide.

• Used primarily as anxiolytics, hypnotics, antiepileptics, and anesthetics, as well as for alcohol withdrawal.

• Rapidly became the most prescribed drugs after their introduction in the United States in the 1960s.

• Increasing awareness of the risks for dependence on benzodiazepines and increased regulatory requirements, have decreased the number of benzodiazepine prescriptions.

• The DEA classifies all benzodiazepines as Schedule IV controlled substances.

• Flunitrazepam is a benzodiazepine used in Mexico, South America, and Europe but not available in the United States.

  • When taken with alcohol, it may lead to promiscuous sexual behavior and rape.

  • It is illegal to bring flunitrazepam into the United States.

• Nonbenzodiazepine sedatives such as zolpidem, zaleplon, and eszopiclone (“Z drugs”) have clinical effects similar to the benzodiazepines and are also subject to misuse and dependence.

Barbiturates

• Were popular before the introduction of benzodiazepines, but because of their high abuse potential, their use is much rarer today.

• The first barbiturate, barbital, was introduced in the United States in 1903.

• Barbital and phenobarbital, introduced shortly after that, are long-acting drugs with half-lives of 12 to 24 hours.

• Amobarbital is an intermediate-acting barbiturate with a half-life of 6 to 12 hours.

• Pentobarbital and secobarbital are short-acting barbiturates with half-lives of 3 to 6 hours.

• Barbiturates are useful and effective sedatives but are highly lethal, with only ten times the standard dose producing coma and death.

Barbiturate-Like Substances

• The most commonly abused barbiturate-like substance is methaqualone.

• Methaqualone was produced in the United States until being discontinued in 1985.

• Methaqualone is often used by young persons who believe that the substance heightens the pleasure of sexual activity.

• Other barbiturate-like substances include:

  • Meprobamate, a carbamate derivative that has weak efficacy as an antianxiety agent but has muscle-relaxant effects.

  • Chloral hydrate is a hypnotic that is highly toxic to the GI system and when combined with alcohol, is known as a “Mickey Finn.”

  • Ethchlorvynol is a rapidly acting sedative agent with anticonvulsant and muscle-relaxant properties.

Patterns of Abuse

• Oral use: Sedatives and hypnotics are usually taken orally, either occasionally to achieve a time-limited specific effect or regularly to obtain a constant, usually mild, intoxication state.

  • The occasional use pattern is associated with young persons who take the substance to achieve specific effects such as relaxation for an evening, intensification of sexual activities, and a short-lived period of mild euphoria.

  • The regular use pattern is associated with middle-aged, middle-class persons who usually obtain the substance from a family physician as a prescription for insomnia or anxiety.

• Intravenous use: a severe form of misuse. The users are mainly young adults who are intimately involved with illegal substances.

  • Intravenous barbiturate use is associated with a pleasant, warm, drowsy feeling, and users may be inclined to use barbiturates more than opioids because barbiturates are less costly.

  • The physical dangers of injection include transmission of HIV, cellulitis, vascular complications from accidental injection into an artery, infections, and allergic reactions to contaminants.

  • Intravenous use is associated with rapid and profound tolerance and dependence and severe withdrawal syndrome.

Overdose

• Benzodiazepines:

  • Have a large margin of safety when taken in overdoses.

  • Even when users take grossly excessive amounts (more than 2 g) in suicide attempts, the symptoms include only drowsiness, lethargy, ataxia, some confusion, and mild depression of the user’s vital signs.

  • The most lethal overdoses occur when the user takes a benzodiazepine in combination with other sedatives, such as alcohol. In such cases, small doses of benzodiazepines can cause death.

  • The availability of flumazenil, a specific benzodiazepine antagonist, has reduced the lethality of the benzodiazepines. Flumazenil can be used in emergency departments to reverse the effects of benzodiazepines.

*Barbiturates:
* Lethal when taken in an overdose because they induce respiratory depression.
* Accidental or unintentional overdoses are common.
* Barbiturates in home medicine cabinets are a common cause of fatal drug overdoses in children.
* The lethal effects of the barbiturates are additive to those of other sedatives or hypnotics, including alcohol and benzodiazepines.
* Barbiturate overdose can induce coma, respiratory arrest, cardiovascular failure, and death.

• Barbiturate-Like Substances:

  • Vary in their lethality and are usually intermediate between the relative safety of the benzodiazepines and the high lethality of the barbiturates.

  • An overdose of methaqualone, for example, can result in restlessness, delirium, hypertonia, muscle spasms, convulsions, and, in very high doses, death.

  • Unlike barbiturates, methaqualone rarely causes severe cardiovascular or respiratory depression, and most fatalities result from combining methaqualone with alcohol.

Diagnosis

Sedative, Hypnotic, or Anxiolytic Use Disorder

• The DSM-5 and ICD-10 include several diagnoses related to sedatives, and they generally follow the template for all substance use disorders (see Section 4.1 and Tables 4-1 through 4-3).

Sedative, Hypnotic, or Anxiolytic Intoxication

• The intoxication syndromes induced by all these drugs are similar.

• Blood toxicology is the best way to confirm the diagnosis.

• Benzodiazepines

  • Behavioral disinhibition is a typical result of benzodiazepine intoxication.

  • Benzodiazepine intoxication is associated with less euphoria than is intoxication by other drugs in this class. This characteristic is the basis for the lower abuse and dependence potential of benzodiazepines than of barbiturates.

• Barbiturates and Barbiturate-Like Substances

  • The clinical syndrome of barbiturate (and barbiturate-like substance) intoxication is indistinguishable from alcohol intoxication, at least in lower doses.

  • Sluggishness usually resolves after a few hours, but, depending primarily on the half-life of the abused substance, the effects on judgment, mood, and motor skills may remain for 12 to 24 hours.

Sedative, Hypnotic, or Anxiolytic Withdrawal

• Benzodiazepines:

  • The severity of the withdrawal syndrome associated with the benzodiazepines varies with the average dose and the duration of use, but a mild withdrawal syndrome can follow even short-term use of relatively low doses of benzodiazepines.

  • The onset of withdrawal symptoms usually occurs 2 to 3 days after the cessation of use, but with long-acting drugs, such as diazepam, the latency before onset can be 5 or 6 days.

  • The symptoms include anxiety, dysphoria, intolerance for bright lights and loud noises, nausea, sweating, muscle twitching, and sometimes seizures (generally at dosages of 50 mg a day or more of diazepam/day).

• Barbiturates and Barbiturate-Like Substances:

  • The withdrawal syndrome for barbiturate and barbiturate-like substances range from mild symptoms (e.g., anxiety, weakness, sweating, and insomnia) to severe symptoms (e.g., seizures, delirium, cardiovascular collapse, and death).

  • Most symptoms appear in the first 3 days of abstinence, and seizures generally occur on the second or third day, when the symptoms are worst.

  • A psychotic disorder, if it develops, starts on the third to the eighth day.

Other Sedative-, Hypnotic-, or Anxiolytic-Induced Disorders

• Delirium

  • Delirium that is indistinguishable from DTs associated with alcohol withdrawal is seen more commonly with barbiturate withdrawal than with benzodiazepine withdrawal.

• Neurocognitive Disorders

  • The diagnosis of this disorder is complex because it is difficult to know whether a neurocognitive disorder is due to the substance use itself or associated features of substance use.

• Psychotic Disorders

  • The psychotic symptoms of barbiturate withdrawal can be indistinguishable from those of alcohol-associated DTs.

  • Psychotic symptoms associated with intoxication or withdrawal are more common with barbiturates than with benzodiazepines.

  Treatment and Rehabilitation

Withdrawal

• Benzodiazepines

  • Symptoms of withdrawal can continue to develop for several weeks.

• Barbiturates

  • To avoid sudden death during barbiturate withdrawal, clinicians must follow conservative clinical guidelines.

  • Clinicians should not give barbiturates to a comatose or grossly intoxicated patient.

Epidemiology

• According to the NSDUH, approximately 500,000 individuals aged 12 and older used sedatives in the past month.

• Persons older than 26 years have the highest use.

• In 2016, more than 600,000 individuals met the criteria for a tranquilizer use disorder in the past year.

• Benzodiazepines are probably not abused as frequently as other substances to get “high,” or inducing a euphoric feeling. Instead, people use them to experience a general relaxed feeling.

Pathology

Neuropharmacology

• The benzodiazepines, barbiturates, and barbiturate-like substances all have their primary effects on the GABAA receptor complex, which contains a chloride ion channel, a binding site for GABA, and a well-defined binding site for benzodiazepines.

• The barbiturates and barbiturate-like substances probably bind somewhere on the GABAA receptor complex.

Misuse Liability and Other Risks of Long-Term Use

• The vast majority of medical and psychiatric patients use benzodiazepines appropriately, although rates of misuse by patients dependent on alcohol and other drugs may be higher than individuals with anxiety or insomnia without a history of substance use problems.

• long-term use is high among patients with psychiatric disorders and the elderly

• long-term use of benzodiazepines may increase the risk of developing dementia.

Stimulant Related Disorders

Types of Stimulants

• Amphetamines

  • The current US FDA–approved indications for amphetamine are limited to ADHD; however, they are used for many symptoms.

  • These drugs go by such street names as ice, crystal, crystal meth, and speed.

  • The typical amphetamines are used to increase performance and to induce a euphoric feeling, for example, by students studying for examinations, by long-distance truck drivers on trips, by business people with pressing deadlines, by athletes in competition, and by soldiers during wartime.

  • Other amphetamine-like substances are ephedrine, pseudoephedrine, and phenylpropanolamine (PPA).

  • Amphetamine-type drugs with abuse potential also include phendimetrazine, and diethylpropion, benzphetamine, and phentermine.

  • Methamphetamine is a potent form of amphetamine that abusers of the substance inhale, smoke, or inject intravenously.

• Cocaine

  • Cocaine and cocaine use disorders became a major public health issue in the 1980s when an epidemic of use spread throughout the country.

  • Cocaine is an alkaloid derived from the shrub Erythroxylum coca, which is indigenous to South America, where the leaves of the shrub are chewed by local inhabitants to obtain the stimulating effects.

  • Although users can take cocaine orally, they rarely do this as it is the least effective route.

Crack

• Crack, a freebase form of cocaine, is extremely potent.

• Crack cocaine is highly addictive; even one or two experiences with the drug can cause an intense craving for more.

Substituted Amphetamines

• MDMA is one of a series of substituted amphetamines that also includes MDEA, MDA, DOB, PMA, and others.

• FDA never approved the drug.

• The DEA made MDMA a Schedule I drug under the CSA, along with LSD, heroin, and marijuana.

• After taking usual doses (100 to 150 mg), MDMA users experience an elevated mood and, according to various reports, increased self-confidence and sensory sensitivity, peaceful feelings coupled with insight, empathy, and closeness to persons, and decreased appetite.

Bath Salts

• Catha edulis, or “Khat,” is a plant indigenous to Eastern Africa and Southern Arabia that releases a variety of psychoactive chemicals, including the stimulants cathinone and cathine.

• In the mid-2000s, synthetic cathinones began to appear, marketed as “legal high” chemicals.

Club Drugs

• Club drugs is a generic term for drugs associated with dance clubs, bars, and all-night dance parties (raves).

• GHB, ketamine, and Rohypnol are sometimes called date rape drugs because they produce disorienting and sedating effects, and often users cannot recall what occurred during all or part of an episode under the influence of the drug.

Diagnosis

• Stimulant Use Disorder: The DSM-5 and ICD-10 include several diagnoses related to stimulant use disorder, and they generally follow the template for all substance use disorders.

• Individuals with cocaine use disorder often excuse themselves from work or social situations every 30 to 60 minutes to find a secluded place to inhale more cocaine.

Stimulant Intoxication

• The diagnostic criteria for stimulant intoxication emphasize behavioral and physical signs and symptoms of stimulant use

  Stimulant Withdrawal

• After stimulant intoxication, a “crash” occurs with symptoms of anxiety, tremulousness, dysphoric mood, lethargy, fatigue, nightmares, headache, profuse sweating, muscle cramps, stomach cramps, and insatiable hunger.

• A person in the state of withdrawal can experience powerful and intense cravings for cocaine since it eliminates the unpleasent symptoms.

Stimulant Intoxication Delirium

• Delirium associated with stimulant use generally results from high doses of a stimulant or sustained use, and so sleep deprivation affects the clinical presentation.

Stimulant-Induced Psychotic Disorder

• The hallmark of stimulant-induced psychotic disorder is the presence of paranoid delusions and hallucinations

Stimulant-Induced Mood Disorder

• Stimulant-induced mood disorder includes the diagnoses of stimulant-induced bipolar disorder and stimulant-induced depressive disorder, either of which can begin during either intoxication or withdrawal.

Stimulant-Induced Anxiety Disorder

• The onset of stimulant-induced anxiety disorder can occur during intoxication or withdrawal.

Stimulant-Induced Obsessive-Compulsive Disorder

• The onset of stimulant-induced obsessive-compulsive disorder (OCD) can occur during intoxication or withdrawal.

Stimulant-Induced Sexual Dysfunction

• People sometimes use amphetamines as an antidote to the sexual side effects of serotonergic agents such as fluoxetine, but stimulants are often misused by persons to enhance sexual experiences.

Comorbidity

• Studies of the prevalence of non–substance-related psychiatric disorders among individuals with stimulant use disorders have consistently found elevated levels of psychiatric disorders in this population.

Treatment and Rehabilitation

Detoxification and Early Treatment

• The stimulant withdrawal syndrome is distinct from that of opioids, alcohol, or sedative–hypnotic agents as the physiologic effects are not severe enough to require inpatient or residential drug withdrawal.

• Frequent, unscheduled urine testing is almost always necessary to monitor patients’ continued abstinence, especially in the first weeks and months of treatment.

  Psychosocial Therapies

• Psychological intervention usually involves individual, group, and family modalities.

Network Therapy

• Network therapy is a specialized type of combined individual and group therapy designed to ensure greater success in the office-based treatment of addicted patients. Network therapy uses both psychodynamic and cognitive-behavioral approaches to individual therapy while engaging the patient in a group support network.

  Pharmacologic Adjuncts

• Presently, no pharmacologic treatments produce decreases in stimulant use.
  Amphetamines: Multiple medications have been investigated as potential treatment options, though the results have been mostly disappointing.
  Cocaine: A variety of pharmacologic agents, most approved for other uses, have and are being tested clinically for the treatment of cocaine use disorder and relapse.

Epidemiology

Amphetamines

• According to the 2017 National Survey on Drug Use and Health (NSDUH), 0.3 percent of persons 12 years or older were current users of methamphetamine, and 5.4 percent have a lifetime history of methamphetamine use.

Cocaine

• In 2016, 1.9 million (0.7 percent) persons aged 12 years or older used cocaine in the past month.

• In 2016, more than 850,000 (0.3 percent) persons aged 12 or older met the criteria for a cocaine use disorder.

Pathology

• Adverse Effects: Stimulant use can cause medical complications as a result of both, direct toxic effects and complications related to the administration method.

• Stimulant misuse can also precipitate behaviors that place an individual at increased risk of harm by violence or accidental injury.

  Neuropharmacology

• Amphetamines: Effects are particularly potent for the dopaminergic neurons projecting from the VTA to the cerebral cortex and the limbic area (reward circuit pathway).

Etiology

• Genetic Factors: higher concordance rates for stimulant use disorder (cocaine, amphetamines, and amphetamine-like drugs) in monozygotic twins.

• Sociocultural Factors Social, cultural, and economic factors are potent determinants of initial use, continuing use, and relapse.

• Learning and Conditioning:

  • Each inhalation or injection of cocaine yields a “rush” and a euphoric experience that reinforces the antecedent drug-taking behavior.

  • Learning and Conditioning:

    • Learning and conditioning are also considered important in perpetuating cocaine use.

    • Each inhalation or injection of cocaine yields a “rush” and a euphoric experience that reinforces the antecedent drug-taking behavior.

    • Also, the environmental cues associated with substance use become associated with the euphoric state so that, long after a period of cessation, such cues (e.g., white powder and paraphernalia) can elicit memories of the euphoric state and reawaken craving for cocaine.