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the reinforcing property of alcohol seems to be attenuated for some drinkers, naltrexone is helpful as an adjunct to treatment of alcohol dependence. No studies have reported the use of naltrexone beyond 12 weeks. Nalmefene, an experimental oral opioid antagonist, appears as effective as naltrexone and possibly has less risk of liver toxicity. Acamprosate, an analog of homocysteic acid, has produced higher continuous abstinence rates and fewer drinking days. It seems to affect excitatory amino acid neurotransmitters and possibly the GABA system. It is not yet available in the U S . Gamma hydroxybutyrate has been used to treat alcohol and opiate withdrawal outside the U.S., but it is an abusable drug.

BIBLIOGRAPHY
I . Brewer C: Combining pharmacological antagonists and behavioral psychotherapy in treating addictions. Br J Psychiatry 157:3440, 1990. 2. Fuller RF, Branchey L, Brightwell DR, et al: Disulfiram treatment of alcoholism: A Veterans Administration cooperative study. JAMA 256:1449-1455, 1986. 3. Garbutt JC, West SL, Carey TS, et al: Pharmacological treatment of alcohol dependence: A review of the evidence. JAMA 281:1318-1325, 1999. 4. Johnston SC, Pelletier LL Jr: Enhanced hepatoxicity of acetorninophen in the alcoholic patient. Medicine (Baltimore) 76:185-191, 1997. 5. OConnor PG, Schottenfeld R: Patients with alcohol problems. New Engl J Med 338:592400, 1998. 6. OMalley SS: Opioid antagonists in the treatment of alcohol dependence: Clinical efficacy and prevention of relapse. Alcohol Alcohol 31(Suppl 1):77-81, 1996. 7. Sass H, Soyka M, Mann K, Zieglgansberger W: Relapse prevention by acamprosate. Arch Gen Psychiat 53~673-680, 1996. 8. Stibler H: Carbohydrate-deficient transferrin in serum: A new marker of potentially harmful alcohol consumption reviewed. Clin Chem 37:2029-2037, 1991.

2 1. OPIOID USE DISORDERS

Jane A. Kennedy, D.O.
1. What are opioids?
Opioids include naturally occurring substances such as opium and morphine, semisynthetic drugs such as heroin and hydromorphone, and totally synthetic drugs such as methodone or meperidine. These substances act at specific opioid receptors in the brain and the body, as do the endogenous opioids (endorphins, enkephalins, and dynorphins).

2. Who abuses opioids? Opioid abusers sometimes are divided into heroin addicts and prescription opioid abusers (medical addicts). In the United States, approximately one-half million people are dependent on heroin, but only about 140,000 are in methadone maintenance treatment. In 1995, there were 141,000 new users, and most were under age 26; in 1997,2.1% of high school seniors reported using heroin at least once. Although most users are still injecting heroin, there is an increase in intranasal use and smoking, due to increased purity and fear of HIV transmission with needles. Prescription drug abusers frequently are patients with real or fabricated pain, or health professionals with access to medications by prescription or diversion.

3. Describe the signs and symptoms of opioid intoxication.

Soon after injecting heroin, the person may vomit because of activation of the chemoreceptor trigger zone in the medulla; for the heroin user, this reaction often indicates good heroin. Feeling sedation, warmth, and euphoria (flush and rush), the user nods, with the head dropping toward

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the chest. Speech may be slurred, and attention and memory are impaired. The pupils are pinpoint, and the users may scratch as they nod because of histamine release. The feeling of warmth is probably due to peripheral vasodilation, and hypotension may occur; respiratory depression and suppression of the cough reflex are centrally mediated.

4. What other effects are seen with use of opioids? Analgesia due to reduced perception of and reaction to pain is common; tolerance to analgesic doses of opioid has been shown experimentally to develop within 48-72 hours. Constipation, sweating, and decreased libido may be chronic side effects of opioid use, but no evidence suggests organ damage from long-term use of opioids. Derangement of the neuroendocrine system can result from chronic opioid administration, but it has been shown that neuroendocrine and immune functions improve in patients on methadone maintenance. Smooth muscle constriction may cause urinary retention and biliary colic. High doses of meperidine and of propoxyphene are associated with a stimulant-like effect that may include seizures and pupillaq dilation; such effects seem to be caused by nor-metabolites. Use of meperidine in the presence of monoamine oxidase (MAO) inhibitors may cause hypertensive crisis.
5. What about tolerance with opioids? Tolerance to euphoria, sedation, respiratory depression, vomiting, and analgesia occurs with regular use, and increased amounts of the drug are needed to create the same effect; however, there is little or no tolerance to constipation or miosis. Exceptions include patients on methadone maintenance, who do not become tolerant to long-term doses once they have been stabilized, and many patients with chronic malignant and nonmalignant pain, who maintain analgesia at a constant dose without development of tolerance. It is possible for patients to build tolerance over time to extremely high doses of opioids that would cause death in nontolerant people. As with alcohol, tolerance dissipates quickly with abstinence but increases rapidly with reintroduction of the drug, obtaining levels of past tolerance within days rather than years (which were required for its development).

6. What happens with overdose of opioids?

The main effect of overdose is respiratory depression, which is the most common cause of death. Patients usually are comatose, cyanotic, and hypotensive with pinpoint pupils, although pupils may dilate as hypoxia occurs. Pulmonary edema frequently is associated with overdose of heroin and seizures with overdose of meperidine.
7. How is overdose treated? Opioid overdose in treated with injection of naloxone (Narcan), an opioid antagonist. In the presence of long-acting opioids such as methadone, repeated doses of naloxone are needed, and a long-acting (T'/z = 1 1 hours) opioid antagonist, nalmefene, is now available parenterally.

8. What are the complications of opioid use? Infections such as HIV, hepatitis, endocarditis, osteomyelitis, meningitis, septicemia, and abscesses may result from unsterile conditions and needle sharing during injection of opioids. Patients using acetaminophen or aspirin in high quantity over time are at risk of hepatic and renal toxicity; gastric irritation also may result from use of aspirin compounds. Two-thirds of heroin addicts have abnormal liver enzymes (which often normalize in methadone treatment); one-third to one-half are positive for hepatitis B, and nearly 80% of injection drug users are positive for hepatitis C. Tuberculosis is more common in heroin addicts than in the general population.

9. What are symptoms of withdrawal from opioids? Early symptoms Intermediate symptoms
Myalgia Nausea Rhinorrhea Sweats Fever Chills

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Lacrimation Piloerection (cold turkey) Increased production Insomnia or restless sleep of phlegm Muscle spasms, often in lower limbs (kicking) Yawning Bone pain (often in thighs) Late symptoms At any stage Vomiting Dilated pupils Diarrhea Anxiety Hypertension Irritability Tachycardia Hyperventilation Opioid withdrawal has been described as a severe flulike syndrome, and addicts use the term sick to mean withdrawal. With short-acting opioids, withdrawal starts 6-24 hours after the last dose, peaks in 1-3 days, and subsides in about 5-7 days. With longer-acting drugs such as methadone or 1-alpha acetyl methadol (LAAM), withdrawal starts after 1-3 days, peaks at 3-6 days, and may take 2 weeks to subside completely. Although withdrawal from the long-acting drugs may be less severe, the longer duration makes it seem worse to many addicts. A syndrome of prolonged low-grade withdrawal (protracted abstinence syndrome) is described by many addicts, especially if they have stopped the drug abruptly; it may last weeks to months and is characterized by dysphoria, low energy, chronic sleep disturbance, and chronic gastrointestinal disturbance.

10. Describe the treatment for opioid withdrawal. Opioid withdrawal does not cause seizures and is not life-threatening, although addicts may feel
that it is. Addicts usually treat withdrawal with more opioid drugs; if they are not available, alcohol, barbiturates, or benzodiazepines may be used for sedation. Because cross-tolerance with such drugs is incomplete, the most effective way to alleviate opioid withdrawal is with an opioid drug; methadone is most commonly used, but there are several alternatives. Relapse rates after detoxification are high. Below are suggestions for short-term detoxification, but note that patients need longterm treatment to maintain abstinence. Methadone.Treatment of opioid withdrawal with opioids requires a special license. Methadone may be used for short-term (days) detoxification in hospitalized patients as well as long-term detoxification (up to 6 months) in licensed treatment programs. It is hard to know the extent of a patients addiction by self-report during withdrawal; the patient may exaggerate because of fear that the physician will not help at all. Generally the first dose should not exceed 20-30 mg, and the total dose on the first day should not exceed 40 mg. Because methadone has an average half-life of 24 hours, doses accumulate during the first 5 days; overdose is a risk without careful titration. For short-term withdrawal in the hospital, patients usually can be stabilized on 40 mg and tapered by 10-20% per day. Clonidine. Withdrawal causes increased beta-adrenergic activity because opioids suppress the adrenergic neurons in the locus ceruleus. Clonidine, an alpha,-adrenergic agonist used as an antihypertensive agent, suppresses some symptoms of withdrawal and provides some sedation. Usually the need for clonidine follows the same curve as the withdrawal symptoms; maximal doses for outpatients should not exceed 1.2 mg/day, usually prescribed as 0.1-0.2 mg every 3 4 hours. Hypotension may occur, and patients should be monitored after the first dose and daily. The hypotensive effect makes clonidine less useful for women, who generally have a lower baseline blood pressure than men. Buprenorphine. Buprenorphine is not yet available in the U.S. except as a parenteral analgesic, but ongoing studies suggest its usefulness for opioid withdrawal as well as for maintenance treatment. It is a partial mu agonist, with a long-acting (24 hours) effect similar to that of methadone. It has several advantages over methadone: withdrawal from buprenorphine is mild and short-lived, risk of overdose is low, and induction on naltrexone is more rapid.

11. What is opioid maintenaneekeplacementtreatment? Although the most researched approach in the field, opioid maintenance treatment remains controversial. It has been shown repeatedly to decrease morbidity and mortality, reduce crime, and improve

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health and social functioning for opioid addicts. When opioid maintenance therapy is combined with adjuvant psychosocial services, outcomes are improved even further. In addition, nonopioid alternatives have not shown equal success. However, because it does not fit the abstinence philosophy in the treatment field, opioid maintenance treatment remains stigmatized and underused. Opioid maintenance can be used only in specially licensed treatment programs. Federal regulations require that physiologic evidence of opioid dependence must be demonstrated before starting a patient on methadone; if a patient in seen i n the emergency department or hospital, withdrawal symptoms must be carefully documented. Research has clearly shown that retention in treatment is improved and illicit opioid use is decreased if patient doses are stabilized at > 60 mg/day with an optimal range of 60-100 mg. LAAM, a long-acting synthetic opioid, also is used in licensed treatment programs. It is taken every other day, thus reducing the need for take-home doses of medication. Also, buprenorphine will soon be released for use in opioid replacement treatment.

12. What complications or problems are associated with opioid maintenance treatment? The most common side effects are constipation and sweating, but patients also may have problems with decreased libido, weight gain, fluid retention, and sexual dysfunction. Medications that induce liver enzymes may interfere with methadone metabolism; the most common examples are rifampin, carbamazepine, and dilantin. Valproic acid does not seem to interfere. Agonist-antagonist drugs such as Stadol, Talwin, or Nubain should not be prescribed for patients on methadone or LAAM, as the antagonists cause an abstinence syndrome. There is no known organ toxicity with long-term opioid administration. 13. How long should a patient stay on opioid maintenance? Research has demonstrated that the longer a patient stays in methadone treatment, the better the prognosis and the less the risk of HIV infection. For some patients treatment may last 1 year; for others it may be life-long. Recent research showed that 80% of patients relapsed in the first year off methadone: because of the risk of HIV infection now associated with relapse, most patients are not encouraged to withdraw from methadone. Medical maintenance clinics have been developed to manage stable, long-term patients who receive monthly supplies of methadone at a doctors office, similar to treatment of hypertension or other medical problems. These patients are monitored for drug use and diversion by random urine tests and random calls to bring in remaining medication for counting. 14. Should methadone maintenance be used to treat pregnant opioid addicts? The fetus is highly affected by going in and out of withdrawal as the mother uses short-acting opioids, and the mother is less likely to obtain prenatal care. Both factors result in more complications of pregnancy and lower birth weights. Methadone maintenance is strongly indicated for the pregnant opioid addict; healthier infants are born. Methadone doses should be high enough to keep the mother from using opioid drugs (to avoid both drug effect and risk of HIV for the fetus) but as low as possible to decrease withdrawal for the infant. Mothers already on methadone may want to decrease their dose, with slow tapering at 1-2 mg/week. Tapering is done most safely during the second trimester. Although there is no risk of seizure in adults who withdraw from opioids, it is a risk in infants, who should be closely monitored for withdrawal symptoms and treated with phenobarbital or paregoric if they occur. Note that LAAM has not been approved for use in pregnancy.
15. Describe the treatment of pain in opioid maintenance patients. Most methadone-maintained patients develop tolerance to its analgesic effects. For injuries and surgical procedures, patients need their regular methadone dose for opioid dependence treatment as well as whatever short-acting analgesics are usually prescribed for other patients undergoing the same procedure. Patients with chronic pain sometimes get long-term analgesia from methadone, as may patients with chronic pain and addiction problems. Few controlled studies have examined this issue in a systematic manner. Pain medications should not be withheld from any substance abuser due to fears of

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addiction, but relapse risk should be discussed with the patient, and a collaborative approach should be used whenever possible.

16. What is the role of naltrexone? Naltrexone is an oral, long-acting opioid receptor antagonist that has been shown to be a successful, nonopioid treatment in certain populations. It works by blocking the opioid receptors; thus if a person tries to get high, the effect is blocked. Naltrexone has been quite successful in treating health professionals who may have easy access to opioids on the job, and it is often recommended for opioid addicts who have been incarcerated and are returning to areas where opioids are again accessible. Patients cannot have any opioids in their system when starting naltrexone; otherwise, the drug precipitates an abstinence syndrome that may last over 24 hours. For many opioid addicts, this is the biggest difficulty with starting naltrexone: they must abstain from short-acting opioids for 5-7 days and from long-acting opioids for 10-14 days. Many patients withdraw from opioids using clonidine during this period. They then are given an injection of naloxone before starting the oral, long-acting antagonist to be sure that opioids are no longer present.

BIBLIOGRAPHY
1. Ball JC, Lange WR, Myers CP, Friedman SR: Reducing the risk of AIDS through methadone maintenance treatment. J Health SOC Behav 29:214-226, 1988. 2. Gerstein DR: The effectiveness of drug treatment. Res Pub1Assoc Res Nerv Ment Dis 70:253-273, 1988. 3. McLellan AT, Arndt 10, Metger DS, et al: The effects of psychosocial services in substance abuse treatment. JAMA 269: 1953-1959, 1993. 4. Novick DM, Pascarelli EF, Joseph H: Methadone maintenance patients in general medical practice. JAMA 259:3299-3302, 1988. 5. Romac DR: Safety of prolonged, high-dose infusion of naloxone hydrochloride for severe methadone overdose. Clin Pharmacol5:251-254, 1986. 6. Wang DS, Sternbach G, Varon J: NaImefene: A long-acting opioid antagonist. Clinical applications in emergency medicine. J Emer Med 16:471475, 1998.

22. SEDATIVE-HYPNOTIC USE DISORDERS

lane A. Kennedy, D.O.
1. What drugs are considered sedative-hypnotics?
Sedative-hypnotic drugs include the barbiturates, barbiturate-like drugs, and benzodiazepines. They are a diverse group of synthetic drugs with clear medical uses and may be prescribed as anxiolytics (tranquilizers), hypnotics (to induce sleep), anticonvulsant medications, and muscle relaxants. Short-acting and long-acting forms are available; all have the potential for abuse. Most are taken orally, but some may also be injected intramuscularly or intravenously. Sedative-hypnotics are extensively prescribed in the United States. Barbiturates were introduced in 1903 but for the most part have been replaced by the benzodiazepines, which were introduced in 1960.

2. Who abuses sedative-hypnotics?

Sedative-hypnotics are abused by both street addicts and patients who are receiving them by prescription. Street addicts may use them as adjuvants to boost the effect of drugs such as opioids, to take the edge off stimulants, or to help manage drug or alcohol withdrawal. Prescription addicts may use the drugs alone, seeking sedation or euphoria, but usually combine them with other substances. Community surveys estimate that about 5% of the general population have used sedative-hypnotics for nonmedical puiposes; prevalence is markedly greater in certain populations, such as patients on methadone maintenance.