C ELDAS S OLARES

Opioid-Related Disorders

Overview

• Opioids have been used for 3,500 years, and in 1806 morphine was first isolated. Heroin is the most abused opioid in developed countries

• Derived from the opium poppy, Papavar somniferum

• Synthetic opioids include meperidine (Demerol), methadone, and propoxyphene (Darvocet)

• Lifetime prevalence of heroin use is 1%, male-to-female use is 3:1, and a heroin habit can cost hundreds of dollars per day, leading to criminal activities and prostitution. This accounts for much of the spread of HIV (prostitution and IV heroin use)

• 90% of patients with opioid dependence have an additional psychiatric disorder, most commonly MDD, ETOH addiction, antisocial PD, and anxiety disorders

• 15% of opioid dependent patients attempt suicide at least once

Neuropharmacology

• Primary effects are on opioid receptors: μ-opioid receptors mediate/ regulate analgesia, respiratory depression, constipation, and dependence; κ-opioid receptors are associated with analgesia, diuresis and sedation; δ-opioid receptors may be associated with analgesia

• Endogenous opioids in the brain include enkephalins and endorphins, involved in neuronal transmission and pain suppression

• The addictive rewarding properties of the opioids are mediated through the activation of the ventral tegmental area with DA neurons projecting to the cortex and limbic system

• Heroin is the most commonly abused opioid and is more potent and lipid soluble than morphine.

Crosses the blood-brain barrier faster and has more rapid onset of action than morphine

• Opioids can be taken orally, snorted intra-nasally, and injected IV

• Detected in the urine for 12-36 hours. Fentanyl is not detected in the urine

Tolerance and Dependence

• Long-term use of opioids results in changes in the number and sensitivity of opioid receptors, which lead to some of the effects of tolerance/ withdrawal

• Long-term use is associated with increased sensitivity of the DA, cholinergic, and serotonergic systems

• The primary mediator of withdrawal is opioid effect on noradrenergic neurons. Short-term use decreases noradrenergic neurons in the locus ceruleus (LC), while long-term use leads to gene alteration and increased LC excitability by NE. Tolerance for opioids results from this increased LC excitability. Withdrawal of opioids leads to rebound hyperactivity/ increased NE

Etiology

• Psychosocial factors: children of divorced parents or single parents are at higher risk for dependence

• Biological/ Genetic factors: monozygotic twins > dizygotic twins

Opioid Use Disorder

A problematic pattern of opioid use leading to meeting at least 2 of the substance use criteria within 12 months. Recall that the diagnosis cannot be met if the only criteria present are tolerance and withdrawal within the context of being medically prescribed. Consequences of use include multiple medical

comorbidities, increased risk for suicide and association with criminal activity.

Opioid Intoxication

During or shortly after use there is clinically significant problematic behavior or psychological changes:

• Initial euphoria followed by apathy and sedation

• Disinhibition

• Psychomotor retardation

• Impaired judgment

Pupillary constriction (or dilation after severe overdose) AND one of the following:

• Drowsiness or coma

• Slurred speech

• Impairment in attention or memory

Severe: respiratory depression, hypoxia, hypotension, and hypothermia. In severe OD anoxia leads to DILATED pupils.

Opioid Withdrawal

1.Presence of either: cessation/reduction in heavy and prolonged use OR administration of an opioid antagonist after a period of opiate use

2.Three or more:

• Dysphoric mood

• Nausea/ vomiting

• Muscle aches

• Lacrimation or rhinorrhea

• Pupillary dilation, piloerection, or sweating

• Diarrhea

• Yawning

• Fever

• Insomnia

Withdrawal of morphine and heroin occurs within 6-8 hours, and subsides within 7-10 days. The key point is that while opiate overdose or intoxication can be fatal, withdrawal is rarely fatal (as opposed to EtOH and BZD withdrawal, which can be fatal).

Adverse Effects

• Most common and most serious adverse effect is potential transmission of hepatitis, bacterial endocarditis, tuberculosis, and HIV through contaminated needles

• Combining meperidine (Demerol) and MAOIs can produce coma, seizures, and death

• Chronic abscesses from subcutaneous injections (“skin popping”) and visible needle tracks can be noted on physical examination

• Death from opioid overdose occurs through respiratory depression in the brainstem. Consider opioid overdose with clinical triad of respiratory depression, pinpoint pupils, and coma

• Pregnancy: malnutrition/ vitamin deficiency, HIV/ sexually transmitted diseases, HTN, pre-eclampsia, miscarriage, premature rupture of membranes, low birth weight, prematurity, stillbirth, neonatal dependence on opioids (50%), and SIDS. Buprenorphine and methadone are preferred treatment in pregnant women with opioid dependence

Treatment and Rehabilitation Treatment of Overdose

• Maintain and adequate airway. Mechanically ventilate until naloxone, a specific opioid antagonist, can be administered. Monitor vital signs and stabilize before considering treatment of opioid dependence/ rehabilitation

Treatment Settings

Five settings: inpatient hospital, outpatient clinics, opioid treatment programs, self-help programs, and therapeutic communities

• Inpatient hospitalization: after overdose, inpatient medical hospitalization is required for stabilization. Reversal of opioid effects through the short-acting opioid antagonist naloxone is needed, and treatment of withdrawal can be done in a medical setting or an inpatient psychiatric hospital

• Outpatient clinics: may use group practices and medication management for the treatment of opioid dependence

• Opioid treatment programs: include methadone maintenance clinics that operate under special federal and state regulations. These programs can be highly effective. A recovering heroin addict must be registered with the DEA in a treatment program to receive opioids

• Self-help programs: Narcotics Anonymous is effective in treating dependence, especially when combined with medication management and other treatment settings

• Therapeutic communities (like a sober living home) participate in a rigid program with other substance users

Medication Management

• Management of withdrawal is symptomatic, including use of clonidine (central α2-adrenergic agonist decreases NE by stimulating autoreceptors), anti-nausea medications, NSAIDS for analgesia, muscle-relaxants, and short-term BZDs (for anxiety and insomnia). Methadone and buprenorphine and highly effective in treating symptoms of withdrawal

• Methadone and LAAM: both are schedule II full mu agonists. LAAM is structurally related to methadone but has longer duration of action (taken off the US market due to cardiac arrhythmias).

Methadone is currently only available through specially licensed opioid treatment programs that are heavily regulated. Goals of treatment are: suppress withdrawal, decrease craving, blocks illicit opioids, stopping illicit opioid use, and enlist the patient in program designed to promote rehabilitation. Side effects include constipation, sweating, and sexual difficulties. The benefits include reduction in the spread of HIV through IV drug use, gainful employment/ less criminal activity, and produces minimal euphoria or depression. The disadvantages are continued dependence on a controlled narcotic

• Buprenorphine: partial µ-agonist/ κ-antagonist that has higher binding affinity for µ-receptors than illicit opioids/ full agonists (knocks illicit opioids off). It is less addictive due to less agonist/ partial agonist effect (pain management without euphoria or respiratory distress) and enters the

bloodstream more slowly than other agonists. Good sublingual bioavailability. Treats opioid withdrawal and chronic pain management. However, it can still be abused if injected. As a result, combination with naloxone (opiate antagonist) leads to less abuse potential (naloxone has better parenteral bioavailability. If the drug is injected to abuse, naloxone blocks the receptor).

• Naltrexone: opioid antagonist similar to naloxone with longer duration of action (72 hours).

Blocking opioid agonist effects, particularly euphoria, naltrexone discourages/ deconditions substance-seeking behavior. Similar to disulfram, this medication is used to treat dependence, not withdrawal. Side effects include dysphoria, anxiety, GI distress, and in higher doses, elevated LFTs

Psychosocial Treatments

All clinical trials for psychosocial interventions have taken place in programs that also provide opioid agonist maintenance (like methadone) or opioid antagonists (like naloxone or naltrexone). Therapy alone may not be a viable option for treatment.

• CBT: helpful in patients with MDD or other co-morbid psychiatric issues. In addition, may reduce high-risk HIV behaviors and decrease criminal behaviors

• Behavioral therapies: uses reinforcers/ rewards (commonly methadone) contingent on abstinence.

Can enhance adherence with naltrexone

• Family therapy enhances treatment adherence

• Self-help groups and 12-step-oriented therapies: Narcotics Anonymous is beneficial by providing peer support, decreasing substance-abusing peers, providing accountability, confronting denial, and intervening early in preventing relapse