Black Box Warning: Methadone
Methadone can cause life-threatening QT prolongation as well as severe respiratory depression. Because of the long half-life of methadone, it should only be prescribed by health care providers with special training in chronic pain management.
Buprenorphine
Buprenorphine is an agonist-antagonist opioid. Like methadone, buprenorphine can be substituted for the opioid on which an addict is physically dependent and can thereby prevent symptoms of withdrawal. After the addict is stabilized on buprenorphine, the dosage is gradually reduced, thereby keeping symptoms of withdrawal to a minimum. Use of buprenorphine for maintenance therapy is discussed below.
Clonidine-Assisted Withdrawal
Clonidine is a centrally acting alpha2-adrenergic agonist. When administered to an individual physically dependent on opioids, clonidine can suppress some symptoms of abstinence. Clonidine is most effective against symptoms related to autonomic hyperactivity (nausea, vomiting, diarrhea). Modest relief is provided from muscle aches, restlessness, anxiety, and insomnia. Opioid craving is not diminished. The basic pharmacology of clonidine is discussed in Chapter 15
.
Drugs for Long-Term Management of Opioid Addiction
Three kinds of drugs are employed for long-term management: opioid agonists, opioid agonist-antagonists, and opioid antagonists. Opioid agonists (methadone) and agonist-antagonists (buprenorphine) substitute for the abused opioid and are given to patients who are not yet ready for detoxification. In contrast, opioid antagonists (naltrexone) are used to discourage renewed opioid use after detoxification has been accomplished. Drugs used for long-term management of opioid addiction are shown in Table 33.2.
TABLE 33.2
Drugs for Long-Term Management of Opioid Addiction
| Drug | Trade Name | Formulation | Dosing Schedule | CSA Schedule | Comments |
| OPIOID AGONIST | |||||
| Methadone | Methadose, Diskets | Dispersible tablets used to make an oral suspension | Once a day | II | Methadone maintenance may be provided only by Opioid Treatment Programs certified by the federal Substance Abuse and Mental Health Services Administration and approved by the designated state authority. |
| Methadose | Concentrated oral liquid | Once a day | |||
| OPIOID AGONIST-ANTAGONIST | |||||
| Buprenorphine | Subutex | Sublingual tablet | Once a day | III | Subutex and Suboxone may be prescribed in a primary care setting by any physician or nurse practitioner who has received authorized training and has registered with the Substance Abuse and Mental Health Services Administration. |
| Suboxone* | Sublingual tablet | Once a day | |||
| Suboxone* | Sublingual film | Once a day Once a day | |||
| Bunavail* | Buccal film | ||||
| OPIOID ANTAGONIST | |||||
| Naltrexone | ReVia | Oral tablet | Once a day | NR | Naltrexone is not a controlled substance and hence prescribers do not require special training or certification. Intramuscular naltrexone [Vivitrol] is the only drug approved for opioid addiction that is given monthly, rather than daily. Before receiving naltrexone, patients must undergo opioid detoxification. |
| Vivitrol | Extended-release suspension for IM injection | Once a month | |||
Methadone
In addition to its role in facilitating opioid withdrawal, methadone [Methadose, Diskets] can be used for maintenance therapy and suppressive therapy. These strategies are employed to modify drug-using behavior in addicts who are not ready to try withdrawal.
Methadone maintenance consists of transferring the addict from the abused opioid to oral methadone. By taking methadone, the addict avoids both withdrawal and the need to procure illegal drugs. Maintenance dosing is done once a day. Maintenance is most effective when done in conjunction with nondrug measures directed at altering patterns of drug use.
Suppressive therapy is done to prevent the reinforcing effects of opioid-induced euphoria. Suppression is achieved by giving the addict progressively larger doses of methadone until a very high dose (120 mg/day) is reached. Building up to this dose creates a high degree of tolerance, and hence no subjective effects are experienced from the methadone itself. Because cross-tolerance exists among opioids, after the patient is tolerant to methadone, taking street drugs, even in high doses, cannot produce significant desirable effects. As a result, individuals made tolerant with methadone will be less likely to seek out illicit opioids.
Use of methadone to treat opioid addicts is restricted to opioid treatment programs approved by the designated state authority and certified by the federal Substance Abuse and Mental Health Services Administration. These restrictions on the nonanalgesic use of methadone are needed to control abuse of methadone, a Schedule II drug with the same abuse liability as morphine and other strong opioids.
The basic pharmacology of methadone is presented in Chapter 22.
Buprenorphine
Buprenorphine [Subutex, Suboxone, Bunavail] is an agonist-antagonist opioid. The drug is a partial agonist at mu receptors and a full antagonist at kappa receptors. Buprenorphine can be used for maintenance therapy and to facilitate detoxification (see earlier). When used for maintenance, buprenorphine alleviates craving, reduces use of illicit opioids, and increases retention in therapeutic programs.
Unlike methadone, which is available only through certified opioid treatment programs, buprenorphine can be prescribed and dispensed in general medical settings, such as primary care offices. Prescribers must receive at least 8 hours of authorized training and must register with the Substance Abuse and Mental Health Services Administration.
Buprenorphine has several properties that make it attractive for treating addiction. Because it is a partial agonist at mu receptors, it has a low potential for abuse—but can still suppress craving for opioids. If the dosage is sufficiently high, buprenorphine can completely block access of strong opioids to mu receptors and can thereby prevent opioid-induced euphoria. With buprenorphine, there is a ceiling to respiratory depression, which makes it safer than methadone. Development of physical dependence is low, and hence withdrawal is relatively mild.
Buprenorphine is currently available in four formulations that are dosed once a day. One formulation—sublingual tablets marketed as Subutex—contains buprenorphine alone. The other three formulations—sublingual tablets, sublingual films, and buccal film, marketed as Suboxone and Bunavail—contain buprenorphine combined with naloxone. Subutex is used for the first few days of treatment, and then Suboxone is used for long-term maintenance. The newest film, Bunavail, is placed on the inside of each cheek and is used for long-term maintenance. The naloxone in Suboxone is there to discourage IV abuse. If taken intravenously, the naloxone in Suboxone will precipitate withdrawal. However, with sublingual administration, very little naloxone is absorbed, and hence, when the drug is administered as intended, the risk for withdrawal is low. Nonetheless, because there is a small risk with sublingual Suboxone, treatment is initiated with Subutex, thereby allowing substitution of buprenorphine for the abused opioid. Thereafter, Suboxone is taken for maintenance.
The basic pharmacology of buprenorphine is presented in Chapter 22.
Naltrexone
After a patient has undergone opioid detoxification, naltrexone [ReVia, Vivitrol], a pure opioid antagonist, can be used to discourage renewed opioid abuse. Benefits derive from blocking euphoria and all other opioid-induced effects. By preventing pleasurable effects, naltrexone eliminates the reinforcing properties of opioid use. When the former addict learns that taking an opioid cannot produce the desired response, drug-using behavior will cease. Naltrexone is not a controlled substance, and hence prescribers require no special training or certification.
Naltrexone is available in oral and intramuscular (IM) formulations. The oral formulation, sold as ReVia, is dosed once a day. The IM formulation, sold as Vivitrol, is dosed once a month. At this time, Vivitrol is the only long-acting drug for managing opioid addiction. All other drugs must be taken every day.
The basic pharmacology of naltrexone is presented in Chapter 22.
General Central Nervous System Depressants
The family of CNS depressants consists of barbiturates, benzodiazepines, alcohol, and other agents. With the exception of the benzodiazepines, all of these drugs are more alike than different. The benzodiazepines have properties that set them apart. The basic pharmacology of the benzodiazepines, barbiturates, and most other CNS depressants is presented in Chapter 27; the pharmacology of alcohol is presented in Chapter 31. Discussion here is limited to abuse of these drugs.
Barbiturates
The barbiturates embody all of the properties that typify general CNS depressants and hence can be considered prototypes of the group. Depressant effects are dose dependent and range from mild sedation to sleep to coma to death. With prolonged use, barbiturates produce tolerance and physical dependence.
The abuse liability of the barbiturates stems from their ability to produce subjective effects similar to those of alcohol. The barbiturates with the highest potential for abuse have a short to intermediate duration of action. These agents—amobarbital, pentobarbital, and secobarbital—are classified under Schedule II of the Controlled Substances Act. Other barbiturates appear under Schedules III and IV. Despite legal restrictions, barbiturates are available cheaply and in abundance.
Tolerance
Regular use of barbiturates produces tolerance to some effects, but not to others. Tolerance to subjective effects is significant. As a result, progressively larger doses are needed to produce desired psychological responses. Unfortunately, very little tolerance develops to respiratory depression. Consequently, as barbiturate use continues, the dose needed to produce subjective effects moves closer and closer to the dose that can cause respiratory arrest. (Note that this differs from the pattern seen with opioids, in which tolerance to subjective effects and to respiratory depression develop in parallel.) Individuals tolerant to barbiturates show cross-tolerance with other CNS depressants (e.g., alcohol, benzodiazepines, general anesthetics). However, little or no cross-tolerance develops to opioids.
Physical Dependence and Withdrawal Techniques
Chronic barbiturate use can produce substantial physical dependence. Cross-dependence exists between barbiturates and other CNS depressants, but not with opioids. When physical dependence is great, the associated abstinence syndrome can be severe—sometimes fatal. In contrast, the opioid abstinence syndrome, although unpleasant, is rarely life threatening.
One technique for easing barbiturate withdrawal employs phenobarbital, a barbiturate with a long half-life. Because of cross-dependence, substitution of phenobarbital for the abused barbiturate suppresses symptoms of abstinence. After the patient has been stabilized, the dosage of phenobarbital is gradually tapered off, thereby minimizing symptoms of abstinence.
Acute Toxicity
Overdose with barbiturates produces a triad of symptoms: respiratory depression, coma, and pinpoint pupils—the same symptoms that accompany opioid poisoning. Treatment is directed at maintaining respiration and removing the drug; endotracheal intubation and ventilatory assistance may be required. Details of management are presented in Chapter 27. Barbiturate overdose has no specific antidote. Naloxone, which reverses poisoning by opioids, is not effective against poisoning by barbiturates.
Benzodiazepines
Benzodiazepines differ significantly from barbiturates. Benzodiazepines are much safer than the barbiturates, and overdose with oral benzodiazepines alone is rarely lethal. However, the risk for death is greatly increased when oral benzodiazepines are combined with other CNS depressants (e.g., alcohol, barbiturates) or when benzodiazepines are administered intravenously. If severe overdose occurs, signs and symptoms can be reversed with flumazenil [Romazicon, Anexate 
], a benzodiazepine antagonist. As a rule, tolerance and physical dependence are only moderate when benzodiazepines are taken for legitimate indications but can be substantial when these drugs are abused. In patients who develop physical dependence, the abstinence syndrome can be minimized by withdrawing benzodiazepines very slowly—over a period of months. The abuse liability of the benzodiazepines is much lower than that of the barbiturates. As a result, all benzodiazepines are classified under Schedule IV of the Controlled Substances Act. Benzodiazepines are discussed in Chapter 27.
Psychostimulants
Discussion here focuses on two CNS stimulants that have a high potential for abuse: cocaine and methamphetamine. Because of their considerable abuse liability, these drugs are classified as Schedule II agents.
Cocaine
Cocaine is a stimulant extracted from the leaves of the coca plant. The drug has CNS effects similar to those of the amphetamines. In addition, cocaine can produce local anesthesia as well as vasoconstriction and cardiac stimulation. Among abusers, a form of cocaine known as “crack” is used widely. Crack is extremely addictive, and the risk for lethal overdose is high.
According to the National Survey on Drug Use and Health, cocaine use has declined. In 2014, 1.8 million Americans 12 years and older reported using cocaine in any form, compared with 5.5 million in 2005.
Forms
Cocaine is available in two forms: cocaine hydrochloride and cocaine base (alkaloidal cocaine, freebase cocaine, “crack”). Cocaine base is heat stable, whereas cocaine hydrochloride is not. Cocaine hydrochloride is available as a white powder that is frequently diluted (“cut”) before sale. Cocaine base is sold in the form of crystals (“rocks”) that consist of nearly pure cocaine. Cocaine base is widely known by the street name “crack,” a term inspired by the sound the crystals make when heated.
Routes of Administration
Cocaine hydrochloride is usually administered intranasally. The drug is “snorted” and absorbed across the nasal mucosa into the bloodstream. A few users (about 5%) administer cocaine hydrochloride intravenously. Cocaine hydrochloride cannot be smoked because it is unstable at high temperature.
Cocaine base is administered by smoking, a process referred to as “freebasing.” Smoking delivers large amounts of cocaine to the lungs, where absorption is very rapid. Subjective and physiologic effects are equivalent to those elicited by IV injection.
Subjective Effects and Addiction
At usual doses, cocaine produces euphoria similar to that produced by amphetamines. In a laboratory setting, individuals familiar with the effects of cocaine are unable to distinguish between cocaine and amphetamine. Cocaine causes euphoria through inhibition of neuronal reuptake of dopamine and thereby increases activation of dopamine receptors in the brain’s reward circuit.
As with many other psychoactive drugs, the intensity of subjective responses depends on the rate at which plasma drug levels rise. Because cocaine levels rise relatively slowly with intranasal administration, and almost instantaneously with IV injection or smoking, responses produced by intranasal cocaine are much less intense than those produced by the other two routes.
When crack cocaine is smoked, desirable subjective effects begin to fade within minutes and are often replaced by dysphoria. In an attempt to avoid dysphoria and regain euphoria, the user may administer repeated doses at short intervals. This use pattern—termed binging—can rapidly lead to addiction.
Acute Toxicity: Symptoms and Treatment
Overdose is frequent, and deaths have occurred. Mild overdose produces agitation, dizziness, tremor, and blurred vision. Severe overdose can produce hyperpyrexia, convulsions, ventricular dysrhythmias, and hemorrhagic stroke. Angina pectoris and myocardial infarction may develop secondary to coronary artery spasm. Psychological manifestations of overdose include severe anxiety, paranoid ideation, and hallucinations (visual, auditory, and/or tactile). Because cocaine has a short half-life, symptoms subside in 1 to 2 hours.
Although there is no specific antidote to cocaine toxicity, most symptoms can be controlled with drugs. Intravenous diazepam or lorazepam can reduce anxiety and suppress seizures. Diazepam may also alleviate hypertension and dysrhythmias because these result from increased central sympathetic activity. If hypertension is severe, it can be corrected with IV nitroprusside. Dysrhythmias associated with prolonging the QT interval may respond to hypertonic sodium bicarbonate. Although beta blockers can suppress dysrhythmias, they might further compromise coronary perfusion (by preventing beta2-mediated coronary vasodilation). Reduction of thrombus formation with aspirin can lower the risk for myocardial ischemia. Hyperthermia should be reduced with external cooling.
Chronic Toxicity
When administered intranasally on a long-term basis, cocaine can cause atrophy of the nasal mucosa and loss of sense of smell. In extreme cases, necrosis and perforation of the nasal septum occur. Nasal pathology results from local ischemia secondary to chronic vasoconstriction. Injury to the lungs can occur from smoking cocaine base.
Tolerance, Dependence, and Withdrawal
In animal models, regular administration of cocaine results in increased sensitivity to the drug, not tolerance. Whether this holds true for humans is not clear.
The degree of physical dependence produced by cocaine is in dispute. Some observers report little or no evidence of withdrawal after cocaine discontinuation. In contrast, others report symptoms similar to those associated with amphetamine withdrawal: dysphoria, craving, fatigue, depression, and prolonged sleep.
Treatment of Cocaine Addiction
Although achieving complete abstinence from cocaine is extremely difficult, treatment can greatly reduce cocaine use. For the cocaine addict, psychosocial therapy is the cornerstone of treatment. This therapy is directed at motivating users to commit to a drug-free life, and then helping them work toward that goal. A combination of individual therapy and group drug counseling is most effective, producing a 70% reduction in cocaine use at 12-month follow-up.
Can medication help with cocaine addiction? To date, no drug has been proved broadly effective in treating cocaine abuse. However, ongoing work with two agents is encouraging:
• Anticocaine vaccine—Subjects receiving the vaccine develop antibodies that bind with cocaine and thereby render the cocaine inactive. The higher the antibody titer, the greater the reduction in cocaine use. The vaccine has been tested in mice. Human testing may start in 2016.
• Disulfiram [Antabuse]—Subjects receiving a combination of disulfiram plus cognitive behavioral therapy reduced their cocaine use from 2 or 3 times daily to 0.5 times daily. Disulfiram is the same drug discussed in Chapter 31 for treating alcohol abuse.
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