Definition and Epidemiology
The Fourth Diagnostic and Statistical Manual (DSM-IV) of the American Psychiatric Association defines opioid dependence as repeated use of a drug of this class to the point of causing multiple problems. The definition requires evidence of three or more problems in the same year, including tolerance, withdrawal, use of greater amounts of opiates than intended, and use despite consequences. Patients who do not have dependence but demonstrate repeated opioid-related difficulties with the law, impaired ability to meet obligations, use in hazardous situations, or continued use despite problems can be labeled as having abuse.

The use of opioids for intoxication is less prevalent than the use of alcohol, marijuana, and several other drugs. A 2002 national survey of adolescents and young adults reported that 10% of 12th graders (high school seniors) had tried an opioid outside of a doctor’s prescription, including almost 2% who had used heroin. Figures for young adults and college students in 2001 were almost 12% and 2%, respectively. In all studies, prevalence rates were only slightly higher in males than females. None of the national surveys offered data regarding the prevalence of dependence, which is estimated as a lifetime risk of about 1%.

Genetics
One large study of >3000 male twin pairs reported that there are genetic influences that relate uniquely to heroin dependence and also noted additional genetic factors related to an overall vulnerability toward substance-related problems. The genetic influences operate in the context of additional environmental factors that are likely to relate both to the family of upbringing and the general environment. Genetic factors might influence personality characteristics such as impulsivity and sensation-seeking or susceptibility to develop antisocial personality disorder. Genes relating to the actions of the drug on specific neurochemical systems such as dopamine are also potential candidates for an enhanced vulnerability toward developing opioid dependence.

Natural History
While an opioid use disorder can develop in anyone, at least three groups are at increased risk for dependence or misuse. First, a minority of persons with chronic pain syndromes (e.g., back, joint, and muscle disorders) misuse their prescribed drugs. If physical dependence is established, any drop in opioid blood levels can then intensify the pain and promote continued drug intake. Physicians can avoid contributing to physical dependence by helping the patient to accept the goal of moderation rather than disappearance of the pain and to recognize that discomfort may not be completely eliminated. Analgesic medication should be only one component of treatment and limited to the oral administration of the least potent analgesic that is able to “take the edge off” the pain (e.g., ibuprofen or, if needed, propoxyphene). Behavior-modification techniques, such as muscle relaxation and meditation, and carefully selected exercises should be used as appropriate to help increase function and decrease pain. Finally, nonmedicinal approaches, including electrical transcutaneous neurostimulation for muscle and joint disease, may be useful.

The second group at high risk are physicians, nurses, and pharmacists, primarily because of easy access to opioids. Physicians may begin use to help with sleep or to reduce stress or physical aches and pains, and then escalate doses as tolerance develops. Because of the growing awareness of these problems, programs have been developed to identify and aid substance-impaired physicians, providing peer support and education before problems escalate to the point of licensure revocation. All physicians are advised never to prescribe opioids for themselves or family members.

The third group are those who buy street drugs to get high. While some of these individuals have prior histories of severe antisocial problems, most have a relatively high level of premorbid functioning. The typical person begins using opioids occasionally, often after experimenting with tobacco, then alcohol, then marijuana, and then brain depressants or stimulants. Occasional opiate use, or “chipping,” might continue for some time, and some individuals never escalate their intake to the point of developing dependence.

Opioid-dependent individuals are likely to continue to have experience with other drugs. Alcohol may be used to moderate withdrawal problems, to enhance the opioid high, and to serve as a substitute when the opioid is not available, including during methadone and other treatments. Problematic drinking, including alcohol dependence, is seen in about half of opioid-dependent persons. Cocaine appears to be taken for many of the same reasons as alcohol, and is often administered intravenously with the opioid in a mixture known as a “speedball.” Another relevant class of drugs is the benzodiazepines, especially among people in methadone maintenance.

Once persistent opioid use is established, severe problems are likely to develop. At least 25% of habitual users die within 10 to 20 years (a mortality rate 15-fold higher than the general population) from suicide, homicide, accidents, or infectious diseases such as tuberculosis, hepatitis, or AIDS. The latter has become an epidemic among injection drug users, with an estimated 60% of these men and women carrying HIV. Although the majority of opioid-dependent persons experience frequent exacerbations and remissions, it is important to remember that even without treatment 35% achieve long-term, often permanent, abstinence, expecially after the age of 40. As is true with most drugs of abuse, a favorable prognosis is associated with a prior history of marital and employment stability and fewer prior criminal activities unrelated to drugs.

Treatment
One key to diagnosis is to discard the erroneous stereotype that opioid-dependent individuals are always unemployed and homeless. Abuse or dependence is possible in any patient who demonstrates symptoms of what might be opioid withdrawal; anyone who has a chronic pain syndrome; physicians, nurses, and pharmacists or others with easy access to opioids; and all patients who repeatedly seek out prescription analgesics. Therefore, before prescribing an opioid analgesic, it is important to gather a complete history that elucidates patterns of life problems and any history of opioid use. If a problem with opioids is suspected, gathering further data from a relative or close friend can be helpful. Additionally, clinicians should search for physical stigmata of misuse (e.g., needle marks) and, when appropriate, screen blood or urine for opioids.

After identifying opioid dependence, the next step is intervention as described for alcoholism here. The need for continuing treatment even after the patient achieves abstinence can be presented, and the availability of help in establishing a drug-free life-style can be emphasized.

Symptoms of Withdrawal
Withdrawal symptoms, generally the opposite of the acute effects of the drug, include nausea and diarrhea, coughing, lacrimation, mydriasis, rhinorrhea, profuse sweating, twitching of muscles, and piloerection (or “goose bumps”) as well as mild elevations in body temperature, respiratory rate, and blood pressure. In addition, diffuse body pain, insomnia, and yawning occur, along with intense drug craving. Drugs with shorter half-lives, such as morphine or heroin, usually cause symptoms within 8 to 16 h of the last dose; intensity peaks within 36 to 72 h after discontinuation of the drug; and the acute syndrome disappears within 5 to 8 days. A protracted abstinence phase of mild moodiness, autonomic dysfunction, and changes in pain threshold and sleep patterns may persist for 6 months and probably contributes to relapse.

Treatment of the Withdrawal Syndrome
A thorough physical examination, including an assessment of neurologic function and a search for focal and systemic infections, especially abscesses, is mandatory. Laboratory testing includes assessment of liver function and, in intravenous users, HIV and hepatitis B and C status. Proper nutrition and rest must be initiated as soon as possible.

One treatment of withdrawal requires administration of any opioid (e.g., 10 to 25 mg of methadone bid) on day 1 to decrease symptoms. After several days of a stabilized drug dose, the opioid is then decreased by 10 to 20% of the original day’s dose each day. However, detoxification with opioids is proscribed or limited in most states. Thus, pharmacologic treatments often center on relief of symptoms of diarrhea with loperamide, of “sniffles” with decongestants, and pain with nonopioid analgesics (e.g., ibuprofen). Comfort can be enhanced with administration of the 2-adrenergic agonist clonidine in doses up to 0.3 mg given two to four times a day to decrease sympathetic nervous system overactivity. Blood pressure must be closely monitored. Some clinicians augment this regimen with low to moderate doses of benzodiazepines for 2 to 5 days to decrease agitation. An ultra-rapid detoxification procedure using deep sedation and withdrawal precipitated by naltrexone has been proposed, but has many inherent dangers and little evidence of efficacy.

A special case of opioid withdrawal is seen in the newborn made passively dependent through the mother’s drug abuse during pregnancy; withdrawal consists of irritability, crying, a tremor, increased reflexes, increased respiratory rate, diarrhea, vomiting, and sneezing/yawning/hiccuping. Treatment follows the same general steps used in the treatment of the physically dependent adult but using paregoric (0.2 mL orally every 3 to 4 h), methadone (0.1 to 0.5 mg/kg per day), phenobarbital (8 mg/kg per day), or diazepam (1 to 2 mg/kg every 8 h) in decreasing dosages for 10 to 20 days. Dependent infants of mothers on methadone maintenance also benefit by breast feeding while the mother continues to take methadone.

Rehabilitation
Despite some differences in demographics, the same general rules for rehabilitation apply to opioid-dependent persons as to alcoholics. The basic strategy includes detoxification and establishment of realistic goals, along with counseling and education to increase motivation toward abstinence. A long-term commitment by the patient to rebuilding a life-style without the substance is essential for preventing relapse.

In most programs, patients are educated about their responsibility for improving their lives, and motivation for abstinence is increased by providing information about the medical and psychological problems that can be expected if dependence continues. Patients and families are encouraged to establish an opioid-free life-style by learning to cope with chronic pain and develop realistic vocational planning (e.g., for pharmacists, physicians, and nurses). The dependent person is also advised to establish a drug-free peer group and to participate in self-help groups such as Narcotics Anonymous. Another important treatment component is relapse prevention aimed at identifying triggers for a return to drugs and developing appropriate coping strategies.

Much of this advice and counseling can be given by the physician or by referring the patients to formal drug programs, including methadone maintenance clinics, programs using narcotic antagonists, and therapeutic communities. Long-term follow-up of treated patients indicates that approximately one-third are completely drug free, and 60% no longer use opioids.

Opioid Maintenance
Maintenance programs with methadone and the longer-acting LAAM should be used only in combination with education and counseling. The goal is to provide a substitute drug that is legally accessible, safer, can be taken orally, and has a long half-life so that it can be taken once a day. This can help persons who have repeatedly failed in drug-free programs to improve functioning within the family and job, to decrease legal problems, and to improve health. Individuals who stay in methadone maintenance are likely to show improvement in antisocial behavior and employment status.

Methadone is a long-acting opioid optimally dosed at 80 to 120 mg/d (a goal met through slow, careful increases over time). This level is optimally effective in blocking heroin-induced euphoria, decreasing craving, and maintaining abstinence from illegal oipoids. Over three-quarters of patients in well-supervised methadone clinics are likely to remain heroin-free for 6 months. Methadone is administered as an oral liquid given once a day at the program, with weekend doses taken at home. The longer-acting analogues, such as LAAM, can be given in doses up to 80 mg two or three times a week. After a period of maintenance (usually 6 months to 1 year), the clinician can work to slowly decrease the dose by about 5% per week.

An additional medication that has been used for maintenance treatment involves the opioid agonist and antagonist buprenorphine. Administered either as a sublingual liquid or tablet, doses of 8 to 12 mg per day (up to 32 mg in some patients) are usually given between 3 and 7 days per week. This drug has several advantages including low overdose danger, easier detoxification than is seen with methadone, and a probable ceiling effect in which higher doses do not increase euphoria. While many studies report equal effectiveness of buprenorphine and methadone, others suggest higher dropout rates or concomitant drug use with buprenorphine. As with all opioids, there is still a danger of misuse.

In the past, the British have used heroin maintenance with goals and guidelines similar to those of current methadone programs. There is no evidence that heroin maintenance has any advantages over methadone maintenance, but the heroin approach increases the risk that the drug will be sold on the streets.

Opioid Antagonists
The opiate antagonists (e.g., naltrexone) compete with heroin and other opioids at receptors, reducing the effects of the opioid agonists. Administered over long periods with the intention of blocking the opioid “high,” these drugs can be useful as part of an overall treatment approach that includes counseling and support. Naltrexone doses of 50 mg/d antagonize 15 mg of heroin for 24 h, and the possibly more effective higher doses (125 to 150 mg) block the effects of 25 mg of intravenous heroin for up to 3 days. To avoid precipitating a withdrawal syndrome, patients must be free of opioids for a minimum of 5 days before beginning treatment with naltrexone and should first be challenged with 0.4 or 0.8 mg of the shorter-acting agent naloxone to be certain they can tolerate the long-acting antagonist. A test dose of 10 mg of naltrexone is then given, which can produce withdrawal symptoms in 0.5 to 2 h. If none appear, the patient can begin with the usual dose of 40 to 150 mg three times per week.

Drug-Free Programs
Most opioid-dependent individuals enter treatment programs based primarily on the cognitive behavioral approaches of enhancing commitment to abstinence, helping individuals to rebuild their lives without substances, and preventing relapse. Whether carried out in inpatient or outpatient settings, patients do not receive medications.

A variation of this approach can be used for persons who are having problems maintaining a drug-free state. Here, the basic elements of treatment are incorporated into long-term (often a year or more) residence in a therapeutic community. The person begins with almost full immersion in the environment in which other individuals at various stages of recovery become the primary support group, offering advice and a drug-free atmosphere in which the opioid-dependent person progresses through ever-increasing levels of independence, including assuming a job outside the therapeutic atmosphere.

As is true for treatments of all substance-use disorders, it is likely that counseling, behavioral treatments, and relatively simple approaches to psychotherapy add significantly to a positive outcome. Most programs focus on teaching participants to cope with stress, enhancing their understanding of personality attributes, teaching better cognitive styles, and, through the process of relapse prevention, addressing issues that might contribute to increased craving, easy access to drugs, or periods of decreased motivation. A combination of these therapies with the approaches described above appears to give the best results.

Finally, it is important to discuss prevention. Except for the terminally ill, physicians should carefully monitor opioid drug use in their patients, keeping doses as low as is practical and administering them over as short a period as the level of pain would warrant in the average person. Physicians must be vigilant regarding their own risk for opioid abuse and dependence, never prescribing these drugs for themselves. For the nonmedical intravenous drug–dependent person, all possible efforts must be made to prevent AIDS, hepatitis, bacterial endocarditis, and other consequences of contaminated needles both through methadone maintenance and by considering needle-exchange programs.

Opioid Drug Abuse and Dependence

• Acute and Chronic Effects of Opioids
• Opioid Drug Abuse and Dependence: Introduction