Ebook Principles of addiction medicine the essentials: Part 1

treatment of cocaine dependence because they block the development of
cocaine-induced kindling in animals.
Kindling (increased neuronal sensitivity to a drug because of prior intermittent exposure) has been
hypothesized as a neurophysiologic mediator of cocaine craving in humans.
At the neurotransmitter level, anticonvulsants might be effective because they increase inhibitory
g-aminobutyric acid (GABA) activity and decrease excitatory glutamate activity in the brain, both actions that
would decrease the response to cocaine in the dopaminergic corticomesolimbic brain reward circuit.

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Carbamazepine, the most-studied anticonvulsant, has not shown efficacy, nor have gabapentin or baclofen.
Other anticonvulsants studied in recent trials with some beneficial effects on cocaine use:
Tiagabine, topiramate, vigabatrin
Phenytoin (300 mg daily) significantly reduced cocaine use in one controlled clinical trial, especially at
serum concentrations above 6.0 mg/mL.

Nutritional Supplements and Herbal Products
Nutritional Supplements The use of amino acid mixtures, either alone or with other nutritional supplements (vitamins and minerals), has been widely publicized in the drug abuse treatment field, encouraged by
their freedom from the regulations imposed on prescription medications and their perceived safety and absence
of side effects. The majority of these studies have shown little benefit.

Herbal Products Various herbal and plant-derived products have been touted as treatments for drug abuse,
but few have undergone controlled clinical evaluation.

Calcium Channel Blockers
Calcium channel blockers have been suggested as treatment for cocaine dependence. However, amlodipine
showed no efficacy in a controlled clinical trial.

Other Physical Treatments
Acupuncture of the outer ear (auricular) has enjoyed growing popularity as a treatment for drug withdrawal,
especially using five standard locations recommended by the National Acupuncture Detoxification Association
(NADA): kidney, liver, lung, shen men, and sympathetic. Meta-analyses of nine published studies (six using the
NADA locations) did not find a significant benefit of active acupuncture over sham treatment.
Transcranial magnetic stimulation (TMS) involves activation of brain cells by magnetic fields generated by
electromagnetic coils placed on the scalp.
Single and multiple sessions of rTMS of the prefrontal cortex (either right or left) have been reported to
reduce cocaine craving.

AMPHETAMINE DEPENDENCE
Many of the medications evaluated for the treatment of cocaine dependence have also been studied for the treatment of amphetamine dependence, often for the same pharmacologic rationale. As with cocaine dependence,
most controlled clinical trials do not show efficacy.
The most promising approaches to date appear to be agonist substitution with stimulants and enhancement
of GABA activity.
Two of three controlled clinical trials with D-amphetamine found a significant reduction in amphetamine
use compared with placebo.
Slow-release methylphenidate (54 mg daily) reduced amphetamine use significantly more than did placebo
in one controlled clinical trial.
Modafinil (200 mg twice daily) reduced amphetamine use in a case report and is currently undergoing a
controlled clinical trial.
Vigabatrin, an anticonvulsant that increases GABA activity by inhibiting the breakdown of GABA by
GABA transaminase, substantially reduced methamphetamine use in two open-label trials.

SPECIAL TREATMENT SITUATIONS
Mixed Dependence

Opioid Dependence Concurrent opioid use, including dependence, is a common clinical problem among
cocaine-dependent individuals. Some individuals use cocaine and opioids simultaneously (as in the so-called
speedball) to enhance the drugs’ subjective effects.
Up to 20% or more of opioid-dependent patients in MMT also use cocaine for a variety of reasons,
including continuation of prior polydrug abuse, replacement for the “high” no longer obtained from opioids,

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self-medication for the sedative effects of high methadone doses, or attenuation of opioid withdrawal
symptoms.
Three different pharmacologic approaches have been used for the treatment of such dual cocaine and opioid
dependence:
1. Adjustment of methadone dose
2. Maintenance with another opioid medication, e.g., high-dose buprenorphine (16–32 mg daily)
3. Addition of medication targeting the cocaine dependence
Higher methadone doses (usually 60 mg or more daily) generally are associated with less opioid use by patients
in methadone maintenance. This relationship also holds in general for cocaine use among patients in methadone maintenance, although exceptions have been reported.
Increasing the methadone dose as a contingency in response to cocaine use can be effective in reducing such
use (and more so than decreasing the methadone dose in response to a cocaine-positive urine sample).

Alcohol Dependence Alcohol dependence is a common problem among cocaine-dependent individuals,
both in the community and in treatment settings, with rates of comorbidity as high as 90%.
Alcohol use by cocaine-dependent patients is associated with poorer treatment outcome.

Due to
1. Production of the toxic psychoactive metabolite cocaethylene
2. Stimulation of cocaine craving by alcohol
3. Alteration of medication metabolism by the hepatic effects of alcohol
Two medications used in the treatment of alcohol dependence have been studied in the treatment of outpatients
concurrently dependent on cocaine and alcohol, disulfiram and naltrexone.
Both separate and combined treatment with disulfiram and/or naltrexone (100–150 mg daily) significantly
improved abstinence from cocaine and alcohol.

Psychiatric Comorbidities
Treatment-seeking, cocaine-dependent individuals have high rates of psychiatric comorbidity (i.e., psychiatric
diagnoses other than another substance use disorder), with rates as high as 65% for lifetime disorders and 50%
for current disorders.
The most common comorbid disorders tend to be major depression, bipolar spectrum, phobias, and posttraumatic
stress disorder.
Personality disorders are common among treatment-seeking, cocaine-dependent individuals, with rates in
this population as high as 69%. The most common of these is antisocial personality disorder.

Depression Desipramine, imipramine, and bupropion have usually, but not always, been found effective,
whereas selective serotonin reuptake inhibitors (e.g., fluoxetine) are usually not effective.
Bipolar Disorder Case series and open-label trials suggest that anticonvulsants such as valproate, divalproex,
lamotrigine, and carbamazepine have some efficacy in reducing cocaine use in dually diagnosed patients.
Combining lithium with an anticonvulsant may be helpful in treatment-resistant patients.
The second-generation antipsychotics have generated mixed results in cocaine-dependent patients with
comorbid bipolar disorder.
Attention Deficit/Hyperactivity Disorder Up to one fourth of cocaine-dependent adults have either adult
ADHD or a history of childhood ADHD.
Stimulant and dopaminergic medications are the mainstay of treatment for ADHD, suggesting that some
of these patients may be self-medicating their ADHD with cocaine.
Case series and clinical trials generally find that such medications successfully treat ADHD symptoms and

reduce cocaine use in adults: dextroamphetamine (up to 60 mg per day), methamphetamine (15 mg per day),
and bupropion (up to 100 mg three times a day).

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Schizophrenia Although schizophrenia is not a common comorbid psychiatric disorder among
cocaine-dependent individuals, cocaine use and abuse are common among treatment-seeking patients with
schizophrenia.
Clinical experience indicates that first-generation antipsychotics, at doses that are effective in the treatment
of schizophrenia, do not significantly alter cocaine craving or use.
Depot flupenthixol (40 mg of decanoate intramuscularly every 2 weeks) reduced cocaine use and improved
psychopathology in a small case series of cocaine-using patients with schizophrenia.
Several case series and open-label trials suggest that the second-generation antipsychotics, including
clozapine, olanzapine, quetiapine, risperidone, and aripiprazole, may be more effective in reducing cocaine
and other drug use among patients with schizophrenia.
The use of cocaine or amphetamines can exacerbate or provoke antipsychotic-induced movement disorders
and increase vulnerability to the neuroleptic malignant syndrome.
Gender-Specific Issues
Women tend to be excluded from or underrepresented in many clinical trials of cocaine dependence
pharmacotherapy, in part because of concern, embodied in former FDA regulations, over risk to the fetus and
neonate should a female subject become pregnant.
In the absence of directly relevant and systematically collected data, caution should be used when prescribing
medications to pregnant women with stimulant dependence and to those with pregnancy potential, keeping in

mind both the risks of medication and the risks of continued stimulant use.
Tricyclic antidepressants, bupropion, and buprenorphine appear to have little potential for morphologic
teratogenicity or disruption of pregnancy, although there are little or no data on behavioral teratogenicity.
Amantadine is associated with pregnancy complications, lithium with cardiac malformations and neonatal
toxicity, anticonvulsants with increased risk of congenital malformations, and antipsychotics with nonspecific
congenital anomalies and neonatal withdrawal.
Disulfiram and naltrexone may generate different treatment responses in men versus women. The reasons
for such gender differences are poorly understood, but may include differences in
1. Medication pharmacokinetics
2. Hormonal interactions
3. Subjects’ psychological/socioeconomic status

Age
Although adolescents make up a substantial minority of heavy cocaine users, they have been largely excluded
from clinical trials of cocaine pharmacotherapies because of legal and informed consent considerations.

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CHAPTER

52
Summary Author: Ashok Krishnamurthy
Richard D. Hurt • Jon O. Ebbert • J. Taylor Hays

Pharmacologic Interventions
for Tobacco Dependence
PATHOPHYSIOLOGY OF TOBACCO DEPENDENCE

Nicotine binds to and causes conformational changes in nicotinic acetylcholine receptors (located in all areas
of the human brain) → receptor stimulated → release of dopamine, norepinephrine, glutamate, vasopressin,
serotonin, g-aminobutyric acid, b-endorphins, and other neurotransmitters.
High concentrations of nicotinic acetylcholine receptors exist in the mesolimbic dopamine system and locus
coeruleus.
Although not completely understood, up-regulation of the high affinity a4b2 nicotinic acetylcholine receptor
is critical for the development of tolerance to and dependence on nicotine.
Repeated exposure to high concentrations of nicotine causes up-regulation of the a4b2 nicotinic acetylcholine
receptors, leading to an absolute increase in their numbers.
Neuroadaptation of the mesolimbic system in smokers and its target neurons in the nucleus accumbens may
be longer lasting than previously thought, which could explain the observation that cravings to smoke last for
months after a smoker stops smoking.
The mesolimbic system area is also involved with the positive reinforcing effects of amphetamines, cocaine,
and opiates.
Nicotine-induced dose-dependent increases in feelings of pleasure have been observed to occur simultaneously
with increases in the functional MRI of neuronal activity in the nucleus accumbens, amygdala, cingulate, and
frontal lobes.
In laboratory animals, self-administered intravenous nicotine increases the sensitivity of brain reward systems
and imprints an indelible memory of its effects in reward systems, an action that appears unique to nicotine among
drugs of abuse. This may partially explain the rapid relapse to former levels of smoking that frequently follows
a smoker having a few cigarettes after a prolonged period of smoking abstinence.
Tobacco dependence may carry a genetic component as well.
Twin studies have confirmed an inherited component for tobacco use and dependence, and familial
transmission of smoking behavior has been observed across three generations of families.
The evidence for a contribution of specific genes to smoking behavior remains modest.
Further work is needed to study the spectrum of heritable traits that influence genetic susceptibility to
tobacco dependence.

MEASURING NICOTINE EXPOSURE
One approach to the therapeutic use of nicotine replacement therapy (NRT) for the treatment of tobacco

dependence is to determine the patient’s level of nicotine exposure. After this exposure is determined, a nicotine
replacement dose approximating the dose the individual receives from smoking can be prescribed.
Factors making the above difficult:
1. Smokers exposed to the same amount of nicotine through inhaled tobacco smoke have marked interindividual
differences in venous nicotine concentrations.

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2. Cigarette smoking produces initial arterial nicotine concentrations that are severalfold higher than
concomitant venous nicotine levels.
3. In addition, nicotine has a short half-life (i.e., 120 minutes) and, with smoking, tends to have peaks and
troughs in both the venous and the arterial circulation.
Cotinine, the major metabolite of nicotine, has a half-life of 18 to 20 hours and can be used to quantify an
individual’s exposure to nicotine.
Venous nicotine concentrations (albeit less than arterial levels) reflect acute nicotine exposure, whereas
cotinine reflects nicotine exposure over 2 to 3 days.
Anabasine is a tobacco alkaloid that is not a metabolic product of nicotine. Anabasine is present in the
urine of tobacco users but not in the urine of patients using NRT. Anabasine thus can be especially useful in
distinguishing abstinent tobacco users who are using NRT from those who are continuing to use tobacco.

NICOTINE REPLACEMENT THERAPY

Every patient who is willing to make an attempt to stop smoking should be offered counseling and medications.
Clinical trials have shown that adding pharmacotherapy to a behavioral intervention generally doubles smoking
abstinence rates and that the combination of medication and counseling is more effective than either alone.
NRT remains a mainstay of pharmacotherapy for the treatment of tobacco dependence.
To date, the FDA has approved five nicotine replacement products: nicotine gum, nicotine patches, nicotine
nasal spray, a nicotine vapor inhaler, and nicotine lozenges. Gum, patches, and lozenges are available over the
counter; nasal spray and inhaler are available by prescription only.
The dose and duration of therapy should be based on the patient’s subjective need for relief of withdrawal
symptoms and support of smoking abstinence.

Nicotine Gum
Nicotine gum is available as an over-the-counter product in both the 2- and 4-mg doses and has been shown to
be effective as monotherapy or in combination with other NRT.
Venous nicotine concentrations achieved through the proper use of nicotine gum are relatively low compared
with those produced by smoking cigarettes.
The 4-mg dose is indicated for use in smokers who are more dependent and is recommended for those who
smoke 25 or more cigarettes per day.
Patients should be instructed to bite into a piece of nicotine gum a few times until a mild tingling or
peppery taste indicates nicotine release. Patients then should “park” the gum between the cheek and gum for
several minutes before chewing it again.
Because the absorption of nicotine is lowered by a more acidic pH, patients should be instructed not to
drink beverages or eat for several minutes before and while using the gum.
When nicotine gum is used as a single agent, most patients should use a minimum of 10 to 15 pieces per
day to achieve initial smoking abstinence.
The most common adverse effects of nicotine gum are nausea and indigestion, which can be minimized
with the proper “chew-and-park” technique. Other adverse effects reported include gingival soreness and mouth
ulcerations.

Nicotine Lozenge
The nicotine lozenge is available in 2- and 4-mg doses.

The 4-mg strength is used in “high” dependence smokers (i.e., time to first cigarette of the day, 30 minutes
after arising).
The lozenge is simpler to use than the gum and likely will demonstrate improved patient compliance.
As with the other short-acting NRT products, it can be used alone or in combination with other NRT.

Nicotine Patch
Nicotine patch therapy delivers a steady dose of nicotine for 24 hours after a single application.
The once-daily dosing requires little effort on the part of the patient, which enhances compliance.
Nicotine patches are available without a prescription in doses of 7, 14, and 21 mg, which deliver nicotine
over 24 hours.
In almost every randomized clinical trial performed to date, the nicotine patch has been shown to be
effective compared with placebo usually with a doubling of the stop rate.

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TABLE 52.1

Nicotine Patch Dose Based on
Baseline (While Smoking) Blood
Cotinine Concentration

Cotinine in ng/mL

Nicotine patch dose

<200

14–21 mg/day

200–300

21–42 mg/day

>300

≥42 mg/day

Standard-dose nicotine patch therapy is 21 mg per 24 hours.
However, the standard-dose patch approach is not effective in all smokers. In fact, it has been shown that
a standard dose (21 mg per 24 hours) of nicotine patch therapy achieves a median serum cotinine level of only
54% of the cotinine concentrations achieved through smoking.
Uses of high doses of nicotine patch therapy (i.e., doses >21 mg per day) are appropriate for smokers who
previously failed single-dose patch therapy or for those whose nicotine withdrawal symptoms are not relieved
sufficiently with standard therapy. This approach can be especially important for heavy smokers because they
will be significantly underdosed with single-dose patch therapy.
High-dose nicotine patch therapy has been shown to be safe and well tolerated in patients who smoke
>20 cigarettes per day.
By employing the concept of therapeutic drug monitoring, clinicians can use serum cotinine concentrations
to tailor the nicotine replacement dose so that it approaches 100% replacement.
A baseline cotinine concentration is obtained while the smoker is smoking his or her usual number of cigarettes.
An initial nicotine patch dose based on the baseline cotinine concentration (or cigarettes per day) is prescribed.
After the patient reaches steady state, the serum cotinine concentration is rechecked and the replacement
dose can be adjusted to achieve a steady-state cotinine level that approaches the baseline level.

For special populations in whom a need to use the lowest possible effective dose exists (e.g., pregnant
women), therapeutic drug monitoring with cotinine can be used to maintain nicotine replacement levels close
to baseline.
Serum cotinine is the test of choice for calculating the percentage replacement, even though urine nicotine
or cotinine can be used. If serum cotinine testing is not available, the replacement dose can be estimated based
on the number of cigarettes smoked per day (Tables 52.1 and 52.2).
Abstinence from smoking during the first 2 weeks of patch therapy has been shown to be highly predictive of longterm abstinence. The first 2 weeks of nicotine patch therapy are critical.
If the patient continues to smoke at all during the first 2 weeks, the treatment must be changed by changing
the nicotine patch dose, by adding additional pharmacotherapy, or by intensifying behavioral counseling.
Nicotine patch doses should be increased for patients experiencing pronounced withdrawal symptoms such
as irritability, anxiety, loss of concentration, or craving, or for patients who do not achieve 100% replacement
based on the second serum cotinine concentration.

TABLE 52.2

a

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Recommended Initial Dosing of
Nicotine Patch Therapy Based on
Number of Cigarettes Smoked Daily

Cigarettes/day

Patch dose (mg/day)a

<10

7–14

10–20

14–21

21–40

21–42

>40

42+

Nicotine patches are available in the following doses: 7, 14, and 21 mg.

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Most patients use the nicotine patch for 4 to 8 weeks, but it is safe to use it longer if needed to maintain
abstinence. Optimal length of treatment has not been determined.
Side effects of nicotine patch therapy are relatively mild and include localized skin reactions at the patch
site. Such reactions generally begin to occur about 4 weeks after initiation of patch therapy. Lesions vary from
erythema to erythema plus vesicles. Rotation of the patches to different sites of the skin helps to reduce the
frequency of this side effect.
Although sleep disturbance is another side effect that has been attributed to nicotine patch therapy, it often
is difficult to ascertain whether this is attributable to nicotine withdrawal or to the administration of nicotine

during the evening hours.
If there is a concern that nicotine patch therapy is causing sleep disturbance, the patch can be removed at
night to see if the sleep disturbance resolves.
Some concern was expressed in the lay press that smokers might be at increased risk of myocardial infarction
if they continued to smoke while using the patch. Subsequent studies have shown no adverse effects in smokers with
a history of coronary artery disease receiving the 14- or 21-mg patch doses.
Nicotine patch doses up to 63 mg per day were not associated with short-term adverse cardiovascular effects
in smokers.

Nicotine Nasal Spray
This device delivers nicotine more rapidly than other therapeutic nicotine replacement delivery systems and
reduces withdrawal symptoms more quickly than nicotine gum.
Each spray contains 0.5 mg of nicotine, and one dose is one spray in each nostril (a total of 1 mg).
Recommended dosing is one to two doses per hour, not to exceed five doses per hour or 40 doses per day.
When using the nicotine nasal spray as a single agent, most patients initially use 12 to 16 doses per day. The
recommended length of treatment is up to 12 weeks of ad lib use, followed by a tapering schedule.
Patients should be instructed to spray against the lower nasal mucosa and not to sniff the spray into the
upper nasal passages or to attempt to inhale it.
The most common adverse side effects are rhinorrhea, nasal and throat irritation, watery eyes, and sneezing.
These irritant side effects decrease significantly within the 1st week of use.
Nicotine nasal spray should be used with caution in patients with reactive airway disease.
There is no abuse liability with the nicotine spray.

Nicotine Inhaler
This device is a plastic holder into which a cartridge containing a cotton plug impregnated with 10 mg of
nicotine is inserted. The device delivers a nicotine vapor that is absorbed across the oral mucosa.
Although the device is called an inhaler, this is a misnomer because little of the nicotine vapor reaches the
pulmonary alveoli even with deep inhalations.
When the nicotine inhaler is used as a single therapy, efficacy is increased when more than six cartridges
per day are used.

The recommended initial dose of the nicotine inhaler when used alone is 6 to 16 cartridges per day. The
recommended length of treatment is approximately 12 weeks followed by a tapering schedule, although the
inhaler could be used longer. This device requires frequent puffing to deliver substantial amounts of nicotine
and to some smokers the puffing mimics some of the behavior of smoking.
Adverse effects generally are mild and most often involve mouth or throat irritation, with occasional
coughing.

NONNICOTINE PRODUCTS
Bupropion SR
Smokers are more likely than nonsmokers to have a history of major depression.
During the course of an attempt to stop smoking, many smokers develop a depressed affect and some
become overtly depressed.
The development of a depressed affect during an attempt to stop smoking is associated with relapse to smoking.
Among the antidepressants evaluated, bupropion is the first nonnicotine pharmacologic treatment approved
for the treatment of tobacco dependence. Bupropion is a monocyclic antidepressant that inhibits reuptake of
both norepinephrine and dopamine. Dopamine release in the mesolimbic system and the nucleus accumbens is
thought to be the basis for the reinforcing properties of nicotine and other drugs of addiction.

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The efficacy of bupropion in smoking cessation is hypothesized to stem from its dopaminergic activity on
the pleasure and reward pathways in the mesolimbic system and nucleus accumbens.
Bupropion also has been shown to have an antagonist effect on nicotinic acetylcholine receptors.

Treatment with bupropion SR alone or in combination with the nicotine patch resulted in a significantly
higher long-term rate of abstinence from smoking than did use of either the nicotine patch alone or placebo.
Treatment with bupropion SR should be initiated about 1 week before the patient’s stop date at an initial
dose of 150 mg per day for 3 days, then 150 mg twice daily. The usual length of treatment is 6 to 12 weeks, but
bupropion SR can be used safely for much longer. As with other antidepressants, a small risk (0.1%) of seizures
is associated with this medication.
Bupropion SR is contraindicated in patients who have a history of seizures, serious head trauma with skull fracture
or a prolonged loss of consciousness, an eating disorder (i.e., anorexia nervosa or bulimia), or concomitant use
of medications that lower the seizure threshold.
The most common adverse side effects are insomnia and dry mouth. Treatment-emergent hypertension
can occur rarely during treatment with bupropion SR, especially when it is used in combination with nicotine
patch therapy.
However, lower smoking rate, prior abstinence from smoking for brief periods (<24 hours) or long periods
(>4 weeks), and male gender all were predictors of better outcome independent of the bupropion SR dose.
The extended use of bupropion SR for relapse prevention is effective for smokers with or without a history
of depression.
Because of the high prevalence of a history of depression in smokers, clinicians often encounter smokers
who want to stop smoking but already are being treated with an antidepressant. No drug–drug interactions
exist to preclude the use of bupropion SR with either selective serotonin reuptake inhibitors (SSRIs) or tricyclic
antidepressants. Thus, adding bupropion SR to an SSRI is preferable to discontinuing that medication and
using bupropion SR only.

Varenicline
Varenicline is a partial nicotine agonist/antagonist that selectively binds to the nicotinic a4b2 acetylcholine
receptor.
Varenicline both blocks nicotine from binding to the receptor (antagonist effect) and stimulates (agonist effect) receptor-mediated activity leading to the release of dopamine, which reduces craving and nicotine
withdrawal symptoms.
Varenicline:
•
•

•
•
•
•

Rapidly absorbed after one administration
Reaches peak serum concentration in 4 hours
Steady-state serum concentrations after 4 days
Is not metabolized
Excreted virtually unchanged in the urine
Half-life is approximately 17 hours

Varenicline was more effective at achieving smoking abstinence compared to placebo or bupropion SR,
with end-of-treatment continuous smoking abstinence rates of 44% versus 30% for bupropion SR and 18%
for placebo, in two key clinical trials.
Varenicline showed better smoking abstinence outcomes compared with NRT and was equally effective
and safe in smokers with or without a mental illness.
Varenicline has not been studied systematically in combination with other medications to treat tobacco
dependence.
Varenicline is not recommended for use in combination with NRT; however, some patients may need
short-acting NRT for nicotine withdrawal symptom control, especially in the first few days per weeks of
varenicline therapy.
Bupropion SR and varenicline have different mechanisms of action and no drug interactions between these
drugs are likely. Clinical trials assessing this combination are ongoing. However, no clinical trial data to support
this treatment approach are available.
The most frequent adverse effect of varenicline is nausea reported by approximately 30% of the participants.
However, the nausea was most often mild to moderate, and participant dropouts related to nausea were infrequent.
In February 2008, the FDA issued a public health advisory because of reports of suicidal thoughts and
aggressive and erratic behavior in a patient who have taken varenicline. In addition, some case reports have

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suggested that varenicline could exacerbate psychiatric symptoms in individuals with severe mental illness, so these
types of patients should be monitored carefully when on varenicline.

Nortriptyline
Nortriptyline is a tricyclic antidepressant recommended as a second-line drug for treating tobacco dependence.
Systematic reviews demonstrate the efficacy of nortriptyline in contrast to SSRIs, which have not been
shown to help smokers stop.
Nortriptyline seems to be as efficacious as bupropion SR in treating smokers with chronic obstructive pulmonary disease.
The most common adverse effects with nortriptyline are sedation and dry mouth. Nortriptyline produces
higher smoking abstinence rates than placebo, independent of a history of depression.
Nortriptyline is contraindicated in combination with an MAOI (monamine oxidase inhibitor) or within 14 days
of discontinuing one, nortriptyline allergy, or in the acute recovery phase after a myocardial infarction.

Clonidine
Clonidine is a centrally acting alpha-agonist that can be used as a second-line drug. The transdermal form is
easier to use with a recommended dose of 0.2 mg per day for 3 to 10 weeks. The clonidine patch should be
initiated a week before the patient’s stop date and changed weekly thereafter. Common side effects include dry
mouth and drowsiness. The only contraindication to its use is a clonidine allergy.

COMBINATION PHARMACOTHERAPIES
The 2008 United States Public Health Service (USPHS) Guideline states that certain combinations of first-line

medications have been shown to be effective. Long-term (>14 weeks) nicotine patch therapy combined with
nicotine gum or nicotine nasal spray, nicotine patch therapy plus nicotine inhaler, and nicotine patch therapy
plus bupropion SR are cited as examples.
Whether the superiority of combination therapy is due to the use of two types of delivery systems or to the
fact that two delivery systems tend to produce higher blood nicotine levels remains unclear.
Combination pharmacotherapy or higher than usual doses of NRT effectively relieve withdrawal symptoms
especially in more dependent smokers.
Based on the treatment of over 45,000 smokers, the Mayo Clinic’s Nicotine Dependence Center offers
the following clinical pearls: (1) Nicotine patch therapy, bupropion SR, and/or varenicline are the “foundation
medications” on which to begin building a patient’s pharmacotherapeutic regimen. (2) Most medication regimens for treating tobacco dependence should contain at least one if not more than one of these medications.
(3) Short-acting NRT products (such as nicotine gum, nicotine inhaler, nicotine lozenge, or nicotine nasal
spray) are added to “foundation medications” to help control intermittent withdrawal symptoms or cravings.
Short-acting NRT should rarely be used alone. (4) Patients with tobacco dependence will usually require combination therapy, and those with more severe dependence often need three or more products simultaneously.

CLINICAL DECISIONS ABOUT PHARMACOTHERAPY
The 2008 USPHS Guideline observes that there is stronger evidence that counseling is an effective tobacco dependence treatment strategy and that counseling adds significantly to the efficacy of the approved medications.
Practical counseling (problem solving/skills training) and social support delivered as part of treatment are
especially effective.
Guidelines state that the combination of counseling and medication is more effective than either alone;
thus, both should be routinely offered to smokers.

Self-Help Materials and Longer Term Pharmacotherapy for Relapse Prevention
Specific self-help materials, such as the National Cancer Institute’s Forever Free, have been effective in helping
smokers maintain smoking abstinence.
Longer use of pharmacotherapy is useful in some patients to maintain smoking abstinence long enough to
stabilize the initial treatment effect. The optimal length of pharmacotherapy has not been established for any of
the available medications.

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CHAPTER

53
Summary Author: Ashok Krishnamurthy
Jeffery N. Wilkins • Mark Hrymoc • David A. Gorelick*

Pharmacologic Interventions for Other
Drug and Multiple Drug Addictions
MARIJUANA
There is no recognized or proven role for pharmacotherapy in the short- or long-term treatment of marijuana
abuse or dependence.
The development of specific agonists or antagonists for the cannabinoid CB1 receptor (which mediates the
psychoactive effects of marijuana) could lead to a pharmacologic treatment for marijuana abuse.
Agonist substitution with oral synthetic 9-tetrahydrocannabinol (dronabinol; marinol) suppresses cannabis withdrawal in human laboratory studies and outpatient settings. A recent case report found that dronabinol
reduced cannabis use in two outpatients.
The CB1 receptor antagonist rimonabant (developed for the treatment of obesity and the metabolic syndrome,
but no larger marketed) blocks the physiologic and psychologic effects of marijuana in animals and humans.

ANABOLIC STEROIDS
There is no established medication for the treatment of anabolic steroid abuse.
Two pharmacologic treatment approaches have been suggested:
1. Hormonal treatments to restore hypothalamic-pituitary-gonadal dysfunction caused by use of steroids
2. Medications to relieve specific psychiatric symptoms associated with steroid withdrawal
The first approach could be implemented with tapering doses of a long-acting steroid such as testosterone
enanthate. This approach could be considered analogous to treating heroin withdrawal with a long-acting opiate such as methadone.
The second approach uses standard psychotropic medications to target the depression, irritability, and
aggression often associated with anabolic steroid use, although these symptoms often resolve without medication. SSRI antidepressants are most often used.

The use of tricyclic antidepressants has been discouraged on theoretical grounds because their cardiovascular
and anticholinergic effects might exacerbate the cardiotoxicity and urinary retention (because of prostatic hypertrophy) associated with anabolic steroid use.
Low-dose neuroleptics (such as phenothiazine-equivalent doses of about 200 mg daily) have been reported
effective for managing steroid-induced psychosis, hostility, and agitation.

PHENCYCLIDINE
There is little systematic experience with pharmacologic treatment of phencyclidine (PCP) addiction.
Both desipramine and the anxiolytic buspirone have significantly improved psychologic symptoms such
as depression in small outpatient-controlled clinical trials, but neither medication significantly reduced PCP use
when compared with a double-blind placebo.
*Dr. Gorelick is supported by the Intramural Research Program, NIH, National Institute on Drug Abuse.

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INHALANTS
Inhalants are a heterogeneous group of volatile abused substances that include adhesives, aerosols, solvents,
anesthetics (including nitrous oxide), gasoline, cleaning agents, and nitrites.
Many inhalant abusers entering treatment have co-occurring psychiatric and addictive disorders, typically
involving alcohol and marijuana that can complicate treatment.
The mainstay of treatment is psychosocial, including techniques such as cognitive-behavioral therapy, multisystem and family therapy, Twelve-Step facilitation, and motivational enhancement.

NICOTINE WITH OTHER DRUGS
Among US adults with current nicotine dependence, 8.2% have a current (nonalcohol) drug use disorder, an
odds ratio of 3.2 for having a drug use disorder compared with those without nicotine dependence.
Conversely, 52.4% of those with a current drug use disorder are nicotine dependent. Comorbidity rates may
exceed 70% among patients in treatment.
Most studies find that smoking cessation treatment does not adversely influence the outcome of drug abuse treatment.
Limited evidence suggests that polydrug abusers (e.g., alcohol and stimulants and cannabis) may respond better to the combination of nicotine replacement therapy (NRT) and bupropion than to either treatment alone.

Nicotine and Alcohol
Among adults with nicotine dependence, 22.8% have an alcohol use disorder (an odds ratio (OR) of 4.4).
Conversely, among adults with an alcohol use disorder, 34.5% have nicotine dependence (OR of 2.7).
Tobacco-related diseases are a greater cause of morbidity and mortality in patients with alcohol use disorders
than are alcohol-related medical conditions, highlighting the importance of smoking cessation treatment for this
population.
Cigarette smokers with a current alcohol use disorder (but not those in remission) tend to have more severe
nicotine dependence, and so may need more intensive treatment, including higher doses of medication.
Most, but not all, studies suggest that nicotine and alcohol dependence can be successfully treated at the same time
without adversely affecting outcome.

Nicotine and Opioids
More than three fourths of individuals with opioid dependence (including patients in methadone maintenance
treatment) smoke cigarettes.
Opiate drugs, including methadone, may acutely increase cigarette smoking.
Limited evidence suggests that nicotine replacement therapy, with or without bupropion, can be effective
for smoking cessation in patients on methadone maintenance.
Treatment outcomes are improved with concurrent psychosocial treatment.

OPIOIDS WITH OTHER DRUGS
Opioids and Alcohol
Heavy drinking, alcohol abuse, or alcohol dependence occur in one third or more of opioid-dependent

individuals, including those in methadone maintenance treatment (MMT) and is associated with poor treatment outcome.
There does not appear to be a strong association between methadone dose and alcohol use.
Buprenorphine, a partial mu-opioid receptor agonist marketed for the treatment of opioid dependence, reduces
alcohol intake in animal studies, but has not yet been evaluated for this in clinical trials.
Disulfuram, at typical doses used to treat alcohol dependence, can be effective in reducing alcohol intake
among patients in MMT.
Other medications being studied for the treatment of dually dependent patients include acamprosate and
memantine.

Opioids and Cocaine
Cocaine use is common among opioid addicts and is associated with greater opioid use, even among those in MMT.
A popular pattern involves simultaneous use of the two drugs (“speed balling”), which is said to provide a
qualitatively better subjective experience (“high”) than either drug alone.

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For patients already in MMT, increasing the methadone dose (usually to >60 mg per day) can reduce both
opioid and cocaine use.
Buprenorphine equivalent to 16 to 32 mg per day as sublingual tablet reduces both cocaine and opioid use
in dually dependent patients, although lower doses do not.

HALLUCINOGENS
Hallucinogens include compounds that influence serotonergic neurotransmission, such as lysergic acid diethylamide

(LSD), psilocybin, and N,N-dimethyltryptamine (DMT), and those that influence catecholaminergic neurotransmission (such as mescaline and amphetamine analogues like 3,4-methylenedioxmethamphetamine [MDMA]).
At present, no pharmacologic treatment is available for the treatment of hallucinogen abuse.
Single doses of the selective serotonin reuptake inhibitor (SSRI) antidepressant citalopram or the 5-HT2A/C
receptor antagonist ketanserin attenuated many of the acute psychologic effects of MDMA in human experimental studies.
The mainstay of treatment remains psychosocial intervention, which can require residential treatment in
patients with severe personality disorganization.
Prolonged psychotic reactions appear to occur chiefly in individuals who have preexisting psychiatric disorders; these can be difficult to distinguish from hallucinogen-induced precipitation or exacerbation of a preexisting
psychotic disorder such as schizophrenia. Low doses of a high-potency neuroleptic have been recommended.
LSD use has been associated with perceptual abnormalities, such as illusions, distortions, and hallucinations, persisting or recurring intermittently for long periods (up to years) after the last LSD use.
When these abnormalities occur after a period of normal perceptual functioning, they are termed flashbacks.
Case reports suggest that sertraline, naltrexone, clonidine, or benzodiazepines can be helpful in the treatment of both persisting perceptual abnormalities and flashbacks, while antipsychotics (e.g., haloperidol, risperidone) and SSRIs have been reported to worsen the condition.

HALLUCINOGENS AS PHARMACOLOGIC TREATMENT FOR ADDICTION
MDMA
MDMA (3,4-methylenedioxmethamphetamine, “Ecstasy”) is an amphetamine analog with stimulant and hallucinogenic properties.
Several controlled clinical trials of MDMA-assisted psychotherapy for posttraumatic stress disorder or anxiety associated with advanced-stage cancer are under way in the United States, Israel, and Switzerland.

LSD
LSD was used clinically as a pharmacologic treatment for a variety of psychiatric disorders, including depression,
anxiety, alcoholism, and drug abuse.
LSD was given orally as a psychiatric treatment in two ways: one or two high doses (usually 200–800 mg),
with or without formal psychotherapy, to generate a cathartic or transforming emotional experience, or multiple low doses (usually 25–200 mg) as an adjunct to psychotherapy to break down therapeutic resistance and
enhance access to unconscious material.
There have been case reports of the beneficial effects of LSD for cluster headaches.

Psilocybin
Psilocybin is one of the psychoactive compounds in hallucinogenic mushrooms of the Psilocybe genus.
Psilocybin showed efficacy in a recent open-label study of obsessive-compulsive disorder and in several cases
of cluster headaches. Two clinical trials of psilocybin for relief of anxiety in advanced-stage cancer patients are
under way.

Ketamine
Ketamine is marketed as a dissociative anesthetic and is also used as an analgesic.
A controlled clinical trial of high-dose (“psychedelic-dose”) ketamine-assisted psychotherapy found a
higher rate of abstinence and less craving for heroin over a 2-year follow-up period compared with low-dose
ketamine.

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A clinical trial in patients with alcohol dependence also had positive results. Intravenous ketamine has been
shown to produce rapid (within 2 hours) and robust antidepressant effects in patients with treatment-resistant
depression.

Ibogaine
Ibogaine is a psychoactive alkaloid derived from the West African plant Tabernanthe iboga. In animals, it blocks
the drug-induced release of dopamine in the nucleus accumbens caused by cocaine, opioids, and nicotine.
Open-label case series suggest that single high doses (1 g or more) alleviate withdrawal symptoms, reduce
drug craving, and produce long-term (>3 months) abstinence in patients with cocaine, heroin, and polydrug
dependence. No clinical trials have been conducted because of concern over ibogaine’s neurotoxicity.
This has generated interest in the ibogaine metabolite noribogaine and the structural analogue
18-methoxycoronaridine (18-MC), which appear to be less toxic in animals.

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