AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Opioids are the most powerful known pain relievers. Their use and abuse date back to antiquity. The pain relieving and euphoric effects of opioids were known to Sumerians (4000 BC) and Egyptians (2000 BC). International awareness of opioid abuse was stimulated early in the 20th century when President Theodore Roosevelt convened the Shanghai Opium Commission in 1909 to aid the Chinese empire in stamping out opioid addiction, especially opium smoking.

In 1913, President Woodrow Wilson's administration drafted legislation to limit the use of narcotics, requiring prescription in good faith; it became effective in 1915. Legitimate providers of narcotics and cocaine preparations were required to register with the Bureau of Internal Revenue and were mandated to keep records of most of the transactions. According to the act, legal possession by the consumer was dependent on the physician's or dentist's prescription. Legal actions were taken against the "dope doctors." However, only after many years of zealous campaign, the Harrison Act was fully enforced.

By 1918, the practice of maintaining opiate-dependent individuals on opiates was seriously questioned. The Treasury Department's special committee on Narcotic Traffic persuaded Congress to pass legislation against prescribing narcotics to people who were addicted and have no other problem.

The Narcotic Drug Import and Export Act of 1922 permitted import of crude narcotics to be manufactured into pure substances by American drug companies only.

Although opiate use dropped during World War II, the Federal Bureau of Narcotics, based on the reported post–World War I surge, anticipated resumption of opiate use and influenced Congress, which lead to legislation for mandatory minimum sentences. The death penalty also was allowed to be used at the discretion of the jury in dealing with certain drug sales.

The widespread use of methadone for opiate maintenance in the early 1960s was the major development that moderated the nation's narcotic control policy.

Opium is extracted from the plant Papaver somniferum. The main active ingredient is alkaloid morphine. Opioids, meaning opiate-like, are derivatives of opium. All opioids can produce euphoria and can be used as analgesics. Opioids can be classified as the following:

• Naturally occurring opium derivatives - Morphine
• Partially synthetic derivatives of morphine - Heroin, oxycodone, oxymorphone
• Synthetic compounds - Fentanyl, alfentanil, levorphanol, meperidine, methadone, codeine, propoxyphene

The term narcotic means drugs producing narcosis or sleep. Although narcotics do produce sleep, the term does not indicate their major therapeutic use today.

Pathophysiology

Opioid receptors in the mammalian CNS include mu, kappa, sigma, delta, and epsilon subtypes. These receptors are located in the brain (mostly in the periaqueductal grey), spinal cord, peripheral nerves, adrenal medulla, ganglia, and gut.

Stimulation of mu and sigma receptors produces intense feelings of well being and euphoria. Kappa-receptor stimulation produces dysphoria. Antagonism at these receptors may produce dysphoria, but not consistently. Antagonists block euphoria produced by opioids. Endogenous opioids, though not highly selective, have a preference for specific receptor types. Beta-endorphin is an endogenous ligand for the mu-receptor; enkephalins and dynorphins have an affinity for sigma- and kappa-receptors, respectively. The dopaminergic mesolimbic system, which originates in the ventral tegmental area (VTA) of the midbrain and projects to the nucleus accumbens, is crucial in (1) the reward effects of intracranial self-stimulation, (2) the natural rewards of water and food intake, and (3) the action of drugs of abuse, including opioids.

Basal activity of this system, expressed in dopamine release in the nucleus accumbens, is under the tonic control of 2 opposing opioid systems, activation of mu- and sigma-receptors increases, while kappa-receptor activation decreases the basal activity of the mesolimbic system. Experimental evidence with laboratory animals supports the idea that manipulation of these receptors with opioids and other substances of abuse (as well as electrical stimulation) affects self-administering behavior. These reward pathways are thought to have evolved for the natural rewards such as food and water intake (see Image 1).

Frequency

United States

A survey by the National Institutes of Health (NIH) demonstrates an upward trend in new heroin use since 1991. The prevalence of past 30-day heroin use (at least 1 instance of heroin use in the last 30 d) increased from 68,000 in 1993 to 216,000 in 1996; the lifetime prevalence of nonmedicinal use of narcotics is even higher. According to the National Comorbidity Survey performed in 1990-1992, 20-32% of people who are lifetime heroin users became dependent, while only 7.5 % of people who used analgesics became dependent.

According to the national, school-base Monitoring the Future Study, the percentage of 8th, 10th, and 12th graders who have used heroin has more than doubled since the late 1990s. This increase has largely been attributed to decreased price and increased purity in the last decade.

Epidemiologic data indicate that the nonmedical use and abuse of prescription opioids is increasing in the United States. Results from a surveillance program called the researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) system has determined that OxyContin, a sustained-release preparation of oxycodone hydrochloride, is the most commonly abused prescription opioid analgesic. Prevalence of abuse was rank ordered as follows:

1. OxyContin
2. Hydrocodone
3. Other oxycodone preparations
4. Methadone
5. Morphine
6. Hydromorphone
7. Fentanyl
8. Buprenorphine

Mortality/Morbidity

The death rate of people who use opioids is disproportionately high compared with that of people who use other IV drugs such as cocaine and phencyclidine (PCP). Heroin overdose comprises a substantial component of opioid-related mortality. Most deaths occur among IV heroin addicts in their late 20s or early 30s who have used heroin for 5-10 years. A recent period of abstinence may reduce tolerance and increase risk of overdose, and addicts have a 7-fold risk of overdosing in the first 2 weeks after leaving a residential treatment program.

Violence associated with buying or selling narcotics also causes mortalities. In some areas of the United States, death rates from drug-related violence are higher than death rates associated with overdose or HIV.

Screening tests for hepatitis A, B, and C are positive in up to 90% of IV heroin users. HIV infection is also very common in this population, with rates as high as 60% among heroin users in some areas of the United States.

Sex

Males abuse opioids more commonly than females, with the male-to-female ratio being approximately 3:1 for heroin and 1.5:1 for prescription opioids.

In a Polish study published in 1996, the direct mortality rate of people who use IV drugs was 25.7 deaths per 1000 person-years for men and 14.3 deaths per 1000 person-years for women. Compared with the general population, the risk of death was 11 times higher among males who used drugs and 20 times higher among females who used drugs.

Age

New heroin use has a negative association with age. Most people who are new users of heroin are younger than 26 years. Heroin use within the last 30 days was around 0.6 % in people aged 12-17 years, and the incidence of use decreases gradually in older age groups. The lifetime prevalence of opioid use in people aged 12-17 years is around 2.3%, and it is slightly higher in people aged 35-44 years because of peak heroin use in the 1960s and 1970s.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• The Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) defines opioid abuse as a maladaptive pattern of opioid use leading to clinically significant impairment or distress occurring in any of the following areas, within a 12-month period.
• • Failure to fulfill major job obligations at work, school, or home
  • Recurrent opioid use in hazardous situations, such as driving or operating heavy machines while impaired
  • Opioid-related legal problems
  • Social and interpersonal problems caused by or exacerbated by opioid use
• Most individuals who meet the criteria of opioid abuse and continue to use eventually meet the criteria of opioid dependence.
• The DSM-IV-TR defines opioid dependence as a syndrome characterized by a maladaptive pattern of opioid use, leading to clinically significant impairment or distress, as manifested by at least 3 of the following and occurring in a 12-month period.
  • Tolerance (see definition below)
  • Withdrawal (see definition below)
  • Opioids taken in larger amounts or for longer periods than intended
  • Persistent desire or unsuccessful efforts to cut down or control opioid use
  • A significant amount of time is spent in activities to obtain opioids
  • Important social, occupational, or recreational activities are given up or reduced
  • Continued opioid use despite knowledge of having a persistent or recurrent physical or psychological problem

  Tolerance and withdrawal may or may not be associated with dependence.

  The World Health Organization (WHO) defines drug dependence as a syndrome in which the use of a drug or class of drugs takes much higher priority for a given person than behaviors that once had higher value. A decrease in volitional control over the use of opioid drugs is the central part of the behavioral symptoms observed in opioid dependence.

• Tolerance: Tolerance is the need for increasing doses of medication to achieve the initial effect of the drug. Tolerance to the analgesic and euphoriant effects and unwanted adverse effects, such as respiratory depression, sedation, and nausea, may develop. However, little tolerance develops to constipation and meiosis. Opioid tolerance usually does not develop in patients with cancer who are being treated for pain; the need for increasing doses in those patients typically is due to an increasing level of pain. No consistent relationship between intrinsic efficacy and tolerance exists.
• Withdrawal: Continuous administration of opioids leads to physical dependence, the emergence of withdrawal symptoms during abstinence. Physical dependence is expected after 2-10 days of continuous use when the drug is stopped abruptly. The onset and duration of withdrawal varies with the drug used. For example, meperidine withdrawal symptoms peak in 8-12 hours and last for 4-5 days. Heroin withdrawal symptoms usually peak within 36-72 hours and may last for 7-14 days. Symptoms of opioid withdrawal include the following:
  • Autonomic symptoms - Diarrhea, rhinorrhea, diaphoresis, lacrimation, shivering, nausea, emesis, piloerection (the phrase stopping "cold turkey" refers to piloerection, or "gooseflesh")
  • Central nervous system arousal - Sleeplessness, restlessness, tremors
  • Pain - Abdominal cramping, bone pains, and diffuse muscle aching
  • Craving - For the medication
• Addiction: The phenomenon of addiction is seen in a variable number of patients using drugs. Addiction is characterized as a psychological and behavioral syndrome in which the following features are observed:
  • Drug craving
  • Compulsive use
  • Strong tendency to relapse after withdrawal

  Addiction must be defined by the observation of maladaptive behaviors, such as adverse consequences due to drug use, loss of control over drug use, and preoccupation with obtaining opioids, rather than pharmacological phenomenon of physiologic dependence, tolerance, and dose escalation. Do not use the term addiction to describe patients who are merely physically dependent. Also, keep in mind that undertreatment in patients with pain may result in a pseudoaddiction, and opioid-seeking behavior may be mistaken for addiction.

  Long-acting medications, such as methadone and sustained-release morphine, tend to have slower onset of action, and the rush or high experienced with more rapid-onset medications is not as prominent. Thus, the longer-acting opioids are less likely to be abused.

Physical

• Dependence
• • Mental status effects include depression with any or all of its symptoms, such as sleep disturbances, lack of interest, selflessness, suicidal ideation, and poor coping skills.
  • Physiological effects: Because tolerance to many of the actions of the opioids develops, it is not likely for even a careful observer to notice the effects of opioids. Small-sized pupils may be the only observation because only very mild tolerance develops for miosis. Inflamed nasal mucosa may be seen if heroin is snorted.
• Withdrawal
• • Mental status effects include purposive behaviors, such as complaints and manipulations directed at getting more drug, and anxiety.
  • Physiologic effects
    • Autonomic signs - Tachycardia, high blood pressure, fever, piloerection (goose flesh), mydriasis, and lacrimation
    • Central nervous system arousal - Irritability
    • Yawning
  • In milder abstinence syndrome, clinical features may be limited to dysphoria, craving, yawning, lacrimation, rhinorrhea, and restlessness. In moderate-to-severe cases, piloerection, mydriasis, increased BP and pulse, and GI symptoms are seen as well.
• Intoxication
• • Mental status effects include euphoria, sedation, decreased anxiety, a sense of tranquility, and indifference to pain produced by mild-to-moderate intoxication. Severe intoxication can lead to delirium and coma.
  • Physiological effects
    • Respiratory depression (may occur while the patient maintains consciousness)
    • Alterations in temperature regulations
    • Hypovolemia (true as well as relative), leading to hypotension
    • Miosis
    • Needle marks or soft tissue infection
    • Increase sphincter tone (can lead to urinary retention)
• Addiction
• • The physical examination provides little information to add in the diagnosis of addiction. However, symptoms of opioid withdrawal and track marks are suggestive of addiction.
  • Constipation is a common occurrence due to almost continuous use of narcotics.

Causes

Opioid dependence is considered a biopsychosocial disorder. Pharmacological, social, genetic, and psychodynamic factors interact to influence abuse behaviors associated with drugs. However, pharmacological factors can be especially prominent, more so than in other types of drug use disorders.

• Pharmacological factors: Opioids are strongly reinforcing agents because of the euphoric effects and reported ability to reduce anxiety, increase self esteem, and help coping with daily problems. Most opioids associated with abuse and dependence are mu-agonists, such as heroin, morphine, hydrocodone, oxycodone, and meperidine. Some partial mu-agonists, such as buprenorphine, or some that have no mu-agonism, such as pentazocine, also can possess reinforcing properties. Rapid development of physical dependence and a protracted abstinence syndrome are unique to opioid use and can make abstinence difficult.
• Social factors: Easy drug availability and acceptable social attitudes make experimentation easy. A high rate of drug use is seen in areas of the city with poor parental functioning and higher crime and unemployment rates. Except for the association between higher exposure to the drug and higher rates of addiction, the precise role of social factors in creating dependent and addictive behaviors is uncertain. Of US service personnel in Vietnam between 1970 and 1972, 42% tried heroin; one half of those personnel became physically dependent, but very few continued to use heroin in their civilian life.
• Psychological factors: Ego defects in certain patients are postulated to form the basis of drug use. Opioids are theorized to help the ego in managing painful effects such as anxiety, guilt, and anger. Behavioral theory postulates that basic reward-punishment mechanisms perpetuate addictive behavior
• Genetic factors: Genetic epidemiologic studies suggest a high degree of heritable vulnerability for opioid dependence. Gene polymorphisms for dopamine receptors/transporters, opioid receptors, serotonin receptors/transporters, proenkephalin, and catechol-O-methyltransferase (COMT) all appear to be associated with vulnerability to opioid dependence. Future interventions for opioid dependence may include medications identified through genetic research.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Sepsis
Antisocial personality
Panic attack
Pontine infarct or hemorrhage
Depressed mood

Although GI symptoms of nausea, vomiting, and abdominal pain are predominant and common in opioid withdrawal, they may warrant consideration of gastroenteritis, pancreatitis, peptic ulcer disease, and intestinal obstruction.

Sympathetic overactivity must lead to consideration of panic attacks and CNS stimulants, such as amphetamines.

Because multi-drug abuse is common, investigate intoxication by drugs other than narcotics (benzodiazepines, barbiturates) in unconscious patients. A person who abuses opioids may conceal information about other abusive drugs. Because opioid intoxication generally does not cause tremulousness, delirium, and seizures, their presence should raise suspicion of alcohol and benzodiazepine dependence.

Small-sized pupils are observed in opioid intoxication, pontine lesions, and local cholinergic drops.

An antisocial personality may be mistaken as addictive behaviors (and vice versa), especially if confrontation with the law is involved.

Besides opioid-induced psychiatric disorders, a high prevalence of non–opioid-related psychiatric disorders exists. In Baltimore during the early 1990s, a study of people who were addicted and treated with methadone was performed, and the lifetime prevalence of comorbid mood and anxiety disorders was 19% and 8.2%, respectively. Lifetime rates of personality disorders in decreasing frequency were as follows:

• Antisocial disorder (25.1%)
• Avoidant disorder (5.2%)
• Borderline disorder (5.2%)
• Passive aggressive disorder (4.1%)
• Paranoid disorder (3.2%)

In the same study, comorbid dependence was also observed for cocaine (64.7%), cannabis (50.8%), alcohol (50%), and sedatives (46.6%).

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Abuse and dependence
• • Urine drug screen
  • Detection of drugs in sweat and hair is a recent addition to drug abuse detection technology. However, it is not used widely.
• Withdrawal
• • Electrolytes
  • CBC count
  • Urine drug screen is rarely useful.
• Intoxication
• • Comprehensive urine drug testing is performed when the drug abuse habit of the patient is unknown but suspected. Some labs use the inexpensive thin-layer chromatography (TLC) procedure. This test has low sensitivity for commonly used drugs. TLC cannot detect fentanyl.
  • Enzyme immunoassay and radioimmunoassay are more sensitive than TLC, but they are less specific because molecules with similar functional groups cross-react with antibodies. These are relatively inexpensive tests.
  • Gas-liquid chromatography (GLC) and gas chromatography-mass spectrometry (GC-MS) are very sensitive and specific tests, but they are time consuming, labor intensive, and expensive.
  • In drug abuse detection, knowing the half-life of the drug, the biotransformation of the drug, and the excretion route of the drug are important.
  • Screening and confirmation cut-off concentration for heroin, methadone, morphine, and codeine is 300 ng/mL and are detected in urine within 1-4 days.
  • False-negative results occur more easily than false positives, simply because once a test is screened negative, it is not tested further. The federal government requires that the results of the drug testing programs go directly to medical review offices to prevent improper interpretation of drug testing data.
  • Blood alcohol levels also may be tested.
• Addiction: In case of historical or clinical evidence of IV drug abuse, perform the following:
• • LFT
  • Rapid plasma reagent (RPR)
  • Hepatitis viral testing
  • HIV testing
  • Blood cultures (in appropriate clinical setting)

Imaging Studies

• For addiction, in case of historical or clinical evidence of IV drug abuse, perform an x-ray of the lungs (eg, history of injecting drugs contaminated with microcrystalline talc) to search for evidence of pulmonary fibrosis.

Other Tests

• Naloxone challenge test: This test is performed to assess physical dependence. As an intramuscular injection or IV, 0.2-0.8 mg of naloxone is administered.
• • A positive test is indicative of physical dependence and consists of typical withdrawal symptoms and signs. These symptoms and signs usually last for 30-60 minutes.
  • This test is found to be very helpful before starting opiate antagonists for maintenance therapy. Starting opioid antagonists, such as naltrexone, soon after detoxification may cause withdrawal symptoms and discourage patients from further treatment.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Acute opioid-related disorders that require medical management include opioid intoxication, opioid overdose, and opioid withdrawal. Issues pertaining to treatment of chronic opioid abuse include opioid agonist therapy (OAT), psychotherapy, and treatment of acute pain in patients already on maintenance therapy.

• Opioid intoxication and/or overdose
  • General supportive measures for opioid intoxication are as follows:
    • Assess patient to clear airway.
    • Provide support ventilation, if it is needed.
    • Assess and support cardiac function.
    • Provide IV fluids.
    • Frequently monitor the vital signs and cardiopulmonary status until the patient has cleared opioids from the system
    • Give IV naloxone if necessary. Naloxone is a specific opiate antagonist with no agonist or euphoriant properties. When administered intravenously or subcutaneously, it rapidly reverses the respiratory depression and sedation caused by heroin intoxication.
• Opioid overdose
  • Naloxone is very effective in treating acute overdose, and is first-line treatment.
  • Because overdoses usually occur in the presence of other people and because medical care is often not sought or is sought too late, at-home naloxone programs have been piloted in several countries. This is a controversial treatment that raises concerns about condoning heroin use, discouraging medical care, and producing side effects that cannot be managed at home. However, the efficacy of these pilot programs should be carefully monitored, as the potential for reducing mortality is high.
  • Opioid agonist therapy (OAT): Pharmacologic therapy for heroin addiction has focused on ameliorating withdrawal symptoms and reducing cravings. By replacing heroin with legally obtained opioid agonists, many risk factors of the drug-abusing lifestyle can be mitigated.
• Methadone maintenance therapy (MMT) has been the standard of care for more than 30 years. However, the recent advent of buprenorphine maintenance therapy (BMT) is changing the landscape of treatment for opioid-dependent patients.
  • Methadone
    • Methadone, a long-acting synthetic opioid agonist, can be dosed once daily and replaces the necessity for multiple daily heroin doses. As such, it stabilizes the drug-abusing lifestyle, reducing criminal behaviors, and also reducing needle sharing and promiscuous behaviors leading to transmission of HIV and other diseases.
    • However, methadone is a highly regulated Schedule II medication, only available at specialized methadone maintenance clinics. It is estimated that established methadone clinics can accommodate only 15-20% of US heroin addicts.
    • Methadone clinics often generate controversy in communities fearful of addicts in various stages of recovery. In addition, some patients are unable to travel to clinics, and others will not enter MMT because of fear of stigmatization. Clearly other options would be beneficial for treatment of chronic opioid abuse.
  • Buprenorphine
    • Buprenorphine is a mu-opioid partial agonist that, like methadone, suppresses withdrawal and cravings. However, the property of partial agonism confers a "ceiling effect," at which higher doses of buprenorphine cause no additional effects. This ceiling effect affords a wider margin of safety than methadone, which can be lethal in overdose. The increased safety of buprenorphine has allowed it to become available by prescription as a Schedule III medication.
    • Buprenorphine has been combined with naloxone in a 4:1 ratio (Suboxone) in order to alleviate concerns that the sublingual tablet would be dissolved and injected by addicts. Naloxone is an opioid antagonist that is poorly absorbed sublingually and orally but is well-absorbed intravenously. As a result, an opioid-dependent patient injecting buprenorphine/naloxone will suffer a withdrawal syndrome secondary to naloxone's occupation of mu-opioid receptors.
    • Office-based treatment of opioid addiction is now possible with BMT. Physicians wishing to prescribe buprenorphine must meet several criteria, including requirements outlined in the Drug Abuse Treatment Act of 2000. However, physicians who do not meet these criteria can take an 8-hour training course to become certified to prescribe buprenorphine. Currently, physicians are limited to 30 buprenorphine patients, but this restriction may soon be lifted.
  • LAAM: Historically, l-alpha-acetylmethadol (LAAM) has also been used for opioid-dependence maintenance pharmacotherapy. However, LAAM is associated with prolonged QT interval, and several cases of cardiac arrhythmia and death have been reported. Therefore, LAAM was recently removed from the market in the European Union and was given a black box label by the FDA.
  • Cochrane reviews: Several Cochrane Database Systematic Reviews about the efficacy of OAT have been published in recent years. While all of these reviews stress the need for larger, multicenter, randomized clinical trials of longer duration, some conclusions can be drawn from existing data.
    • A review of Cochrane reviews found that high-dose MMT (60-109 mg/d) is more effective in retaining patients in treatment than low-dose MMT (1-59 mg/d). Moreover, methadone at flexible doses was more effective in retaining patients in treatment (RR, 1.23) than buprenorphine. A second systematic review of databases found that low-dose methadone (20 mg/d) was less effective than buprenorphine (2-8 mg/d) and that high-dose methadone (>50-65 mg/d) was more effective than buprenorphine (2-8 mg/d).
    • Another Cochrane review found that oral substitution treatment was associated with significant reductions in heroin injection and needle sharing, as well as a decrease in patients with multiple sexual partners and a reduction in exchanges of sex for drugs or money. Importantly, these changes were correlated with reductions in cases of HIV infection.
    • A recent randomized, placebo-controlled trial suggested that an injectable, sustained-release form of naltrexone (Depotrex) increased retention of patients in treatment for opioid abuse. Further studies are necessary to evaluate the efficacy of this treatment modality.
• Opiate withdrawal
  • Opiate withdrawal generally is considered less likely to produce severe morbidity or mortality compared with barbiturates and benzodiazepines. Safe withdrawal from opioids is termed detoxification and can be performed as outpatient or inpatient therapy, depending upon the following: presence of comorbid medical and psychiatric problems, availability of social support, and polydrug abuse.
  • Methadone, buprenorphine, and alpha-2 agonists, such as clonidine and lofexidine, are commonly used pharmacologic methods of detoxification. The use of methadone and buprenorphine is based on the principle of cross-tolerance in which one opioid is replaced with another and then slowly withdrawn. Alpha-2 agonists appear to be most effective in suppressing autonomically mediated signs and symptoms of abstinence, but they are less effective for subjective symptoms.
  • Two recent Cochrane reviews compared the efficacy of alpha-2 adrenergic agonists to methadone or buprenorphine for management of withdrawal. Patients experienced decreased side effects and stayed in treatment longer using tapered methadone compared to the alpha-2 agonists clonidine or lofexidine.
  • Buprenorphine was associated with fewer adverse effects than clonidine, and patients were more likely to complete withdrawal with buprenorphine compared with clonidine. Moreover, a second multicenter randomized trial demonstrated that buprenorphine-naloxone was more effective than clonidine for opioid detoxification.
  • Buprenorphine was equally effective as methadone for withdrawal completion, but withdrawal symptoms appeared to resolve more quickly with buprenorphine.
  • In summary, data, to date, suggest that buprenorphine and methadone are more effective than alpha-2 agonists, such as clonidine, for opioid detoxification, with buprenorphine associated with a shorter duration of withdrawal symptoms. However, all of these medications are effective, and the choice may depend in part on availability.
• Psychotherapies and support groups: Detoxification alone, without ongoing treatment, is not adequate to manage patients.
  • Patients in methadone programs often benefit from cognitive behavioral, supportive, or analytical-oriented psychotherapies if they are added to standard drug counseling.
  • Cognitive behavior psychotherapy primarily focuses on the patient's thoughts and behaviors. Cognitive behavior–based models are widely used in drug rehabilitation programs. Cognitive behavior theories were aimed at substance abuse beginning in the mid 1980s. The techniques used help patients acquire specific skills for resisting substance use and teach coping skills to reduce problems related to drug use. Two major cognitive behavior theories of substance abuse are the following:
    • Relapse prevention: Based on the work of Marlatt and Gordon, important relapse prevention concepts and techniques include identification and avoidance of high-risk situations, understanding the chain of decisions leading to drug use, and changing one's lifestyle.
    • Cognitive therapy of substance abuse: Developed by Beck and colleagues, cognitive therapy of substance abuse is based on the concept that drug abusers engage in complex behaviors and thought processes, such as positive and negative drug-related beliefs and spontaneous flashes related to drug use before giving in to the actual drug use.
  • Dynamic psychotherapy is based on the concept that all symptoms arise from underlying unconscious psychological conflicts. The major goal of this therapy is to help the patient become aware of these conflicts and develop more adaptive coping mechanisms and healthier methods of resolving intrapsychic conflict.
  • Group therapy is argued to be especially effective because it can target the social stigma attached to having lost control of a substance. The presence of other group members who acknowledge having similar problems can provide support and be therapeutic in developing alternative methods of maintaining abstinence.
  • Aversion therapy involves pairing aversive stimuli to cognitive images of opioid use and conversely conjuring images of socially appropriate behaviors such as employment, education, and nondrug behavior.

  Narcotics Anonymous (NA): In 1947, NA was formed in Lexington, Ky. NA is based on principles similar to those of Alcoholics Anonymous (AA), including progression through 12 steps of recovery. Some patients have difficulty engaging in the AA-NA approach to recovery; however, these programs do help some people and can provide much needed support for those attempting abstinence.

• Acute pain management for patients receiving OAT: As more patients with opioid addiction receive OAT, physicians will encounter OAT patients with acute pain syndromes. It is important that acute pain be adequately treated in these patients.
  • Common misconceptions
    • OAT provides analgesia: Maintenance methadone or buprenorphine does not provide sustained analgesia. Although methadone and buprenorphine are potent analgesics, the analgesic properties last only 4-8 hours, while the medications are dosed every 24-48 hours.
    • Use of opioid analgesia may cause addiction relapse: No evidence indicates that exposure to opioid analgesics during acute pain increases relapse rates. In fact, evidence suggests that the stress of unrelieved pain can trigger relapse.
    • The combination of OAT and other opioids may cause respiratory depression: This is a theoretical risk that is not supported by clinical or empirical experience. Tolerance to respiratory and CNS depressant effects occurs rapidly and reliably.
  • Recommendations
    • Reassure patients that their addiction histories will not prevent adequate pain management, and discuss plans in a nonjudgmental manner.
    • Verify methadone and buprenorphine doses with clinics or prescribing physicians, and inform these physicians of any benzodiazepines or opioids given that may be detected on urine drug screening.
    • Aggressively treat pain with conventional opioid analgesics. Opioid cross-tolerance often necessitates higher opioid analgesic doses at shorter intervals.
    • Use continuous scheduled dosing orders rather than as-needed orders.
  • For patients receiving methadone maintenance therapy: Continue methadone maintenance dose and add short-acting opioid analgesics.
  • For patients receiving buprenorphine maintenance therapy: Pain management with opioids is complicated by the high affinity of buprenorphine for the mu receptor. This affinity may cause buprenorphine to compete with opioid analgesics at mu receptors. As buprenorphine's rate of dissociation from mu receptors is highly variable, naloxone should be available, and consciousness and respiration should be closely monitored.
  • Several options are possible, and the most effective approach will be determined with increasing clinical experience:
    • Continue BMT and titrate a short-acting opioid analgesic to effect.
    • Divide buprenorphine dose to 6-8 hours to take advantage of its short-acting analgesic properties.
    • Discontinue BMT, implement opioid analgesia, and restart BMT when opioid analgesia is no longer necessary.
    • In the hospitalized patient, discontinue BMT, initiate MMT, and add short-acting opioids to treat pain. Have naloxone at bedside. Convert back to BMT prior to discharge from hospital.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

The goals of pharmacotherapy are to treat the addiction of the chemical substances that cause them.

Drug Category: Opioid analgesics

Two uses for opioid analgesics are as follows: (1) Oral substitution therapy or maintenance therapy or opioid agonist therapy (OAT) refers to substitution of an oral opioid for injected heroin, with the goal of reducing harmful behaviors associated with heroin use. (2) Detoxification, or controlled withdrawal with the goal of abstinence, is based on the principle of cross-tolerance in which one opioid is replaced with another and then slowly withdrawn.

Drug Category: Antidotes for opioids

Inhibit opioid effects by inhibiting opioid agonists at receptor sites.

Drug Category: Alpha 2 adrenergic agonists

Used primarily for the treatment of hypertension.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Detoxification is mostly conducted in an inpatient setting, but a few outpatient clinics for methadone detoxification also exist.

Further Outpatient Care

• Opioid abuse treatment also is influenced by managed care, and it is changing rapidly.
• Treatment in outpatient and inpatient settings is equally effective, but significant cost differences exist.
• The ideal program should be comprehensive enough to target individual patient needs and the severity of the illness.

Complications

• In general, the following complications may be observed.
• • Opioid dependence: Constipation, noncardiac pulmonary edema (usually with heroin), and heroin-induced glomerulonephritis may occur. Combination products may lead to acetaminophen or aspirin toxicity. Related to IV drug use, multifocal leukoencephalopathy and myelopathy, which may be related to the parenteral route of administration rather than opioids; HIV; viral hepatitis; and bacteremia may occur. Right-sided endocarditis and valvular damage also may occur.
  • Intoxication - Sedation, respiratory depression, and death

Prognosis

• Catalino et al found that opioid treatment relapse rates vary from 25-97%. Cigarette smokers have higher rates of relapse than nonsmokers.
• Success is measured as improvement in following areas:
• • Social functions
  • Reduction of illicit drug use
  • Performance at work and school
• The prognosis varies according to the type of agent abused and other variables, such as medical care, employment, legal situation, family, and psychological difficulties.
• In general, the success rate is much better in people who abuse opioids and are professionals than in individuals with a poor education level and low job prospects.

Patient Education

• Patient and family education: Understanding the nature of the disease helps formulate a strategy to fight against it. Although information may be provided in a single session, generally it is continuous process that begins at the identification of the problem. Statistical evidence may be provided if needed to facilitate the patient's understanding of the disease. The education must cover the following areas:
• • Inform the patient in no unclear terms about their inability to use the substance in a controlled fashion.
  • Treatment alone is hardly ever successful, and rehabilitation is almost always needed for recovery.
  • Will power is not enough to beat the disease, and the role of Narcotics Anonymous must be emphasized.
  • Recovery is possible, and a significant number of people succeed in that.
  • After a relapse, the patient must be encouraged and informed that it is not unusual and that a slip could be valuable experience.
  • Dysphoric effects after abstinence are the main reason of relapse. Patients should be ready and equip themselves with a coping strategy.
  • Tell patient to value recovery and avoid high-risk situations of active drug use.
• Contrary to the earlier beliefs, most substance abusers are closely tied to their families. In 1972, Levy provided evidence that at 5 years, patients who succeeded in overcoming narcotic abuse most often had family support. Educated family members are likely to provide positive influence without getting frustrated. The following issues must be addressed.
• • Inform the patient about the concept of enabling so that such behaviors may be identified and replaced with assertive but compassionate behaviors.
  • Inform the patient and the family of ways of healthy intrafamily conflict resolution.
  • Keep the expectations reasonable. Relapses may occur often, and it does not mean the patient has to start from zero again.
  • Understand that a patient who abuses opioids and is trying to start life without opioids may develop unacceptable and unfamiliar behaviors, which may be quite painful for family members who are expecting a nice premorbid personality.
  • Inform patients about the availability of family support groups such as spouse support groups.
  • Place emphasis on encouraging patients to attend NA.
• For excellent patient education resources, visit eMedicine's Mental Health and Behavior Center and Substance Abuse Center. Also, see eMedicine's patient education articles Barbiturate Abuse, Drug Dependence and Abuse, Narcotic Abuse, and Substance Abuse.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Be careful not to accidentally overdose a patient requesting opioids for drug withdrawal symptoms, causing excess sedation or respiratory depression. Close monitoring of vital signs and writing prescriptions of narcotics only against objective symptoms of opioid withdrawal is encouraged.

Special Concerns

• Signs and symptoms of abstinence in infants exposed to opioids are very nonspecific. Also consider other diagnoses such as sepsis, electrolyte imbalance, and hypoglycemia. The Finnegan scale is used to evaluate opioid abstinence syndrome. Once diagnosed, paregoric (camphorated tincture of opium) or phenobarbital can used to control opiate abstinence symptoms.
• Pregnant women who are abusing opioids are recommended for treatment with methadone maintenance in almost all cases.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Schematic diagram of the brain-reward circuitry of the mammalian (laboratory rat) brain with sites at which various abusable substances appear to act to enhance brain-reward and, thus, to induce drug-taking behavior and possibly drug craving. Courtesy William & Wilkins Substance Abuse by Eliot L Gardner.KEY - Nucleus accumbens (Acc), ventral tegmental area (VTA), amygdala (AMYG), locus ceruleus (LC), dopaminergic mesolimbic system (DA), ventral pallidum (VP), noradrenergic fibers (NF), enkephalinergic outflow (ENK), frontal cortex (FCX), GABAergic inhibitory fiber system (GABA), dynorphinergic outflow (DYN),component of reward circuitry preferentially activated by electrical intracranial self-stimulation (ICSS).
	View Full Size Image
Media type:  Image

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Alford DP, Compton P, Samet JH. Acute pain management for patients receiving maintenance methadone or buprenorphine therapy. Ann Intern Med. Jan 17 2006;144(2):127-34. [Medline].
• Amato L, Davoli M, A Perucci C, et al. An overview of systematic reviews of the effectiveness of opiate maintenance therapies: available evidence to inform clinical practice and research. J Subst Abuse Treat. Jun 2005;28(4):321-9. [Medline].
• American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington DC: American Psychiatric Association;. 2000.
• Cicero TJ, Inciardi JA, Munoz A. Trends in abuse of Oxycontin and other opioid analgesics in the United States: 2002-2004. J Pain. Oct 2005;6(10):662-72. [Medline].
• Comer SD, Sullivan MA, Yu E, et al. Injectable, sustained-release naltrexone for the treatment of opioid dependence: a randomized, placebo-controlled trial. Arch Gen Psychiatry. Feb 2006;63(2):210-8. [Medline].
• Dertwinkel R, Wiebalck A, Zenz M. [Oral opioids for long-term treatment of chronic non-cancer pain]. Anaesthesist. Jun 1996;45(6):495-505. [Medline].
• Dobson KS. Historical and Philosophical bases of the cognitive-behavioral therapies. Handbook of Cognitive-Behavioral Therapies. 1998;3-38.
• Fischer B, Rehm J, Kim G, Kirst M. Eyes wide shut?--A conceptual and empirical critique of methadone maintenance treatment. Eur Addict Res. 2005;11(1):1-9; discussion 10-4. [Medline].
• Gardner EL. Brain Reward Mechanisms. Substance Abuse- A Comprehensive Textbook. 1997;51-70.
• Gowing L, Farrell M, Bornemann R. Substitution treatment of injecting opioid users for prevention of HIV infection. Cochrane Database Syst Rev. 2004;[Medline].
• Gowing L, Ali R, White J. Buprenorphine for the management of opioid withdrawal. Cochrane Database Syst Rev. 2004;[Medline].
• Gowing L, Farrell M, Ali R. Alpha2 adrenergic agonists for the management of opioid withdrawal. Cochrane Database Syst Rev. 2004;[Medline].
• Herz A. Opioid reward mechanisms: a key role in drug abuse?. Can J Physiol Pharmacol. Mar 1998;76(3):252-8. [Medline].
• Jaffe JH. Opioid related disorders. Kaplan HI, Sadock BJ, eds. Comprehensive Textbook of Psychiatry. 6th ed. 1995.
• Jaffe JH, Jaffe AB. Opioid-related disorders. In: Comprehensive Textbook of Psychiatry. Vol 1. 2000:1038-63.
• Kleber HD, Gold MS, Riordan CE. The use of clonidine in detoxification from opiates. Bull Narc. 1980;32(2):1-10. [Medline].
• Kouyanou K, Pither CE, Wessely S. Medication misuse, abuse and dependence in chronic pain patients. J Psychosom Res. Nov 1997;43(5):497-504. [Medline].
• Li L, Smialek JE. Observations on Drug Abuse Deaths in The State of Maryland. J Forensic Sci. 1996;41:106-9. [Medline].
• Ling W, Amass L, Shoptaw S, et al. A multi-center randomized trial of buprenorphine-naloxone versus clonidine for opioid detoxification: findings from the National Institute on Drug Abuse Clinical Trials Network. Addiction. Aug 2005;100(8):1090-100. [Medline].
• Marsch LA, Bickel WK, Badger GJ, et al. Comparison of pharmacological treatments for opioid-dependent adolescents: a randomized controlled trial. Arch Gen Psychiatry. Oct 2005;62(10):1157-64. [Medline].
• McCance-Katz EF. Office-based buprenorphine treatment for opioid-dependent patients. Harv Rev Psychiatry. Nov-Dec 2004;12(6):321-38. [Medline].
• Moskalewicz J, Sieroslawski J. [Mortality of narcotic addicts using injections]. Przegl Epidemiol. 1996;50(3):323-32. [Medline].
• Rounsaville BJ, Galanter M, Frawley PJ. Behavioral Therapies for Addiction. Principles of Addiction Medicine. 1998:595-690.
• Saxon AJ, Oreskovich MR, Brkanac Z. Genetic determinants of addiction to opioids and cocaine. Harv Rev Psychiatry. Jul-Aug 2005;13(4):218-32. [Medline].
• Simoens S, Matheson C, Bond C, et al. The effectiveness of community maintenance with methadone or buprenorphine for treating opiate dependence. Br J Gen Pract. Feb 2005;55(511):139-46. [Medline].
• Smith MO, Khan I. An acupuncture programme for the treatment of drug-addicted persons. Bull Narc. 1988;40(1):35-41. [Medline].
• Sporer KA. Strategies for preventing heroin overdose. British Medical Journal. 2003;326:442-444. [Medline].
• Stine S, Meandzija B, Kosten R. Pharmacologic Therapies for Opioid Addiction. Principles of Addiction Medicine. 1998:545-555.

Article Last Updated: Apr 18, 2006