Summary by Karen J. Hartwell, MD, and Kathleen T. Brady, MD, PhD
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Based on “Principles of Addiction Medicine” Chapter by Karen J. Hartwell, MD, Todd K. Magro, MD, and Kathleen T. Brady, MD, PhD
Numerous studies suggest that anxiety disorders and substance use disorders (SUDs) commonly co-occur. Anxiety disorders may be a risk factor for the development of SUDs. Anxiety disorders modify the presentation and outcome of treatment for SUDs, just as substance use and SUDs modify the presentation and treatment outcome for anxiety disorders.
PREVALENCE
Epidemiologic studies have concluded that anxiety disorders and SUDs co-occur more commonly than would be expected by chance alone. The National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) is one of the most recent and largest surveys focused on psychiatric disorders and SUDs designed to distinguish between independent (i.e., not attributed to withdrawal or intoxication) and substance-induced mood and anxiety disorders. Approximately 18% of respondents with an SUD in the past year also met criteria for an independent anxiety disorder, and conversely about 15% of those with any anxiety disorder in the past year had at least one comorbid SUD. Cannabis use disorders were the most common drug use disorder among individuals with anxiety disorders (15%) followed by cocaine (5%), amphetamine (5%), hallucinogen (4%), and sedative (3%) use disorders.
SCREENING AND DIFFERENTIAL DIAGNOSIS
Based on prevalence data, individuals seeking treatment for anxiety should be assessed for SUDs, and conversely, individuals seeking substance abuse treatment should be assessed for comorbid psychiatric disorders including anxiety disorders. The best way to differentiate substance-induced, transient symptoms of anxiety from anxiety disorders that warrant treatment is through observation of symptoms during a period of abstinence. The duration of abstinence necessary for accurate diagnosis remains controversial and is likely to be based on both the diagnosis being assessed and the substance used. A family history of anxiety disorders, the onset of anxiety symptoms before the onset of SUD, and sustained anxiety symptoms during lengthy periods of abstinence all suggest an independent anxiety disorder.
GENERAL TREATMENT CONSIDERATIONS
Cognitive behavioral therapies (CBT) are among the most effective treatments for both anxiety disorders and SUDs. However, some research suggests that traditional therapies, including those focused on Alcoholics Anonymous and Narcotics Anonymous, may be more challenging for some individuals with anxiety disorders. Pharmacotherapy should generally follow routine clinical practice for treatment of the anxiety disorder with some exceptions. It is important to pay attention to potential toxic interactions between the medications and illicit drugs and alcohol in case of relapse. It is also important to use the agent with the least abuse potential.
Selective serotonin retake inhibitors (SSRIs) as a class are generally considered as first-line medications for the treatment of anxiety disorders due to overall effectiveness, tolerability, and safety. Serotonin–norepinephrine reuptake inhibitors (SNRIs) are typically seen as alternate first-line medications with the majority of the research focused on venlafaxine, which has Food and Drug Administration indications for generalized anxiety disorder (GAD), panic disorder (PD), and social anxiety disorder (SAD). Mirtazapine has shown promise in several open trials in PD and SAD. Other antidepressants such as the tricyclic antidepressants and monoamine oxidase inhibitors are generally used as second- or third-line medications primarily due to problems with tolerability.
Benzodiazepine use is generally avoided in substance-using populations because of the abuse potential. Benzodiazepines may be considered as adjunctive medication during the early treatment phase when onset of the antidepressant action is an issue. These should be considered for chronic treatment only when other pharmacologic and nonpharmacologic treatment options have been exhausted. If needed, benzodiazepines with a low abuse potential such as oxazepam and chlordiazepoxide may be considered. Controlled clinical trials of atypical antipsychotics are still quite limited.
Because of its limited effectiveness, buspirone is most commonly utilized for the treatment of uncomplicated GAD. Anticonvulsants are receiving increasing attention for the treatment of a variety of psychiatric disorders. Pregabalin for the treatment of GAD has the greatest amount of positive support from the literature. Although beta-blockers are effective for some individuals, controlled trials do not support the use of beta-blockers for GAD. Individuals with SAD may need treatment targeting their social anxiety before being able to benefit from group interventions. There are no controlled studies of pharmacologic treatment of co-occurring obsessive–compulsive disorder (OCD) and SUDs. Finally, the use of agents targeting substance use, such as naltrexone or disulfiram, for individuals with comorbid SUDs and anxiety disorders remains underexplored.
ALCOHOL AND ANXIETY
The highly comorbid relationship between alcohol and anxiety has received more attention than that of other substances of abuse. As alcohol is legal and readily available, many individuals with anxiety report using alcohol to relieve anxiety. However, short-term relief of anxiety from alcohol use in combination with long-term anxiety induction from chronic drinking and withdrawal can initiate a feed-forward cycle of worsening anxiety symptoms and alcohol use.
Generalized Anxiety Disorder
NESARC found that approximately 50% of those with lifetime GAD had a lifetime comorbid SUD, and of those with both GAD and SUD, over 90% had an AUD. Self-medication with alcohol was more prevalent in GAD than with other anxiety disorders. In adolescents, the presence of GAD is associated with a more rapid progression from age of first drink to alcohol dependence. Comorbid SUD also decreases the likelihood of recovery from GAD and increases the risk of exacerbation.
Buspirone has been examined in the treatment of highly anxious alcoholics with mixed results. Bupropion should be avoided or used with caution in individuals at risk for seizures, such as alcoholics with a history of withdrawal seizures. Topiramate has been shown to reduce anxiety, alcohol craving, and relapse in early studies. Pregabalin has demonstrated efficacy for GAD and alcohol withdrawal syndrome but has not been evaluated in comorbid AUD and GAD.
Social Anxiety Disorder
In the recent NESARC, the lifetime prevalence of SAD among individuals with AUD is at least 20%, and the prevalence of an AUD with SAD was 48%. SAD serves as a risk factor for alcohol dependence as those with social anxiety may use alcohol to self-medicate, and SAD precedes AUD about 80% of the time. Fear of performance or in social situations is specific to SAD and not generally associated with substance use or withdrawal. Current guidelines for SAD recommend pharmacotherapy in combination with integrated psychosocial treatment. However the research regarding combination alcohol and SAD treatment is mixed. Some studies of combination treatment have found improvement in anxiety but not alcohol outcomes. Several studies of individual CBT for AUD versus concurrent therapy for AUD and comorbid anxiety disorders showed no benefit in drinking measures of integrated treatment and in fact may worsen alcohol outcomes. The investigators in one study hypothesized that exposure to anxiety-provoking social situations in concurrent treatment may have increased drinking. Several studies have found that treatment of SAD with an SSRI, one study with and without CBT, demonstrated improved anxiety outcomes but not alcohol outcomes.
Obsessive–Compulsive Disorder
Previous research has found that OCD was either negatively correlated with AUD or no significant associations were found. Craving in SUDs has been compared to the intrusive recurrent thoughts that drive behavior in OCD, but thoughts and compulsions in individuals with SUDs are restricted to alcohol and drug use and easily distinguished from OCD.
Panic Disorder
Recent literature indicated that the risk of PD is two to four times higher in the presence of AUDs. Individuals with panic attacks may use alcohol to decrease panic symptoms and consequently develop an AUD. Alcohol withdrawal-related panic attacks should markedly improve during the first several weeks of abstinence and may respond to support and reassurance. However, if the panic attacks continue or increase over several weeks of abstinence, the diagnosis of PD should be made. Without PD treatment, the risk of relapse is increased. In one prospective study of alcoholics recruited from acute treatment, PD was the most common psychiatric diagnosis and was predictive of relapse. Of note, after 4 months, approximately 50% of those who had initially met criteria for an anxiety disorder no longer met criteria. In one controlled trial of standard alcohol treatment versus combined CBT for PD plus AUD, improvement of panic symptoms and relapse rates did not differ between the two groups. A more recent study comparing hybrid CBT targeting both alcohol and panic versus treatment-as-usual showed that hybrid CBT improved drinking and panic outcomes.
NICOTINE AND ANXIETY DISORDERS
In a detailed NESARC analysis, the 12-month prevalence rate of nicotine dependence (ND) among individuals with anxiety disorders was almost double the rate in the general population, and conversely, the prevalence rates of ND were also increased in individuals with anxiety disorders (PD 40%, SAD 27%, and GAD 33%). A recent review suggested that smoking, and nicotine in particular, can alleviate anxiety, but other studies indicate that nicotine use and withdrawal can cause anxiety. One longitudinal study of adolescents found a strong association between trait anxiety and all measures of tobacco use and ND.
Differential Diagnosis
Prospective research suggests that nicotine withdrawal symptoms typically return to baseline within 10 days and anxiety decreases within 4 weeks of quitting among smokers without comorbid psychiatric disorders. Anxiety symptoms that persist beyond the withdrawal period warrant further investigation.
Panic Disorder
NESARC data have found that individuals with PD had elevated 12-month prevalence rates of ND. Daily smoking is associated with an increased risk for the first occurrence of a panic attack or PD, and the risk is higher in active smokers than past smokers. Early smoking increases the risk for the development of PD, and the initiation of smoking may precede the onset of PD by many years.
Social Anxiety Disorder
Some studies have failed to demonstrate a relationship between ND and SAD; however, one prospective longitudinal study of adolescents and young adults found that both social fears and SAD were significantly associated with higher rates of ND with about 50% reporting onset of social anxiety before smoking.
Generalized Anxiety Disorder
Higher rates of smoking have been observed among individuals with GAD. In longitudinal study of adolescents and young adults, heavy smoking (≥20 cigarettes per day) was associated with an increased risk of GAD (OR 5.5) during young adulthood. A confounding issue was the high rates of co-occurrence of GAD between other anxiety and depressive disorders.
Obsessive–Compulsive Disorder
The prevalence of smoking is lower in individuals with OCD compared with other anxiety disorders. One prospective longitudinal study of youth found no association between smoking and OCD. Another study found ND individuals had an increased risk for developing OCD. Nicotine administration decreases some forms of compulsive behavior in both human and animal studies, and obsessive thoughts can be reduced by transdermal nicotine in humans.
Treatment
Current guidelines for treating ND include a combination of counseling, behavior therapy, and pharmacotherapy. Pharmacotherapy is recommended in all individuals attempting to quit unless there is a contraindication. Medications that reliably increase long-term smoking abstinence include all forms of nicotine replacement therapy, bupropion, and varenicline. Bupropion treatment can be associated with anxiety and agitation, so it should be used with caution in anxious patients. A recent large study that included individuals with anxiety disorders compared the efficacy of six brief individual counseling sessions in combination with six randomized double-blind pharmacotherapies: nicotine patch, nicotine lozenge, bupropion SR, bupropion SR and nicotine lozenge, nicotine patch and lozenge, or placebo. Compared to placebo, the combination treatments doubled the quit rate, though participants with a history of an anxiety disorder were less likely to be abstinent at 2 or 6 months, and neither the monotherapies nor combination therapies were superior to placebo at 6 months. These results suggest that for smokers with anxiety disorders, many of the first-line medications may be less effective. In contrast, no association was found between anxiety disorders and the cumulative probability of remission from ND in a NESARC analysis. Little information about the use of varenicline is available. Interoceptive exposure therapy may be helpful in reducing distress and anxiety during withdrawal by teaching individuals to tolerate internal cues such as negative affect, craving, and withdrawal symptoms. CBT, mindfulness, and acceptance-based treatments may also be helpful.
OPIOIDS AND ANXIETY DISORDERS
In the NESARC, lifetime prevalence of opioid use disorders was more than double in individuals with anxiety disorders compared to those without, with much higher rates in opioid dependence than abuse. In one outcome study, the presence of a comorbid SUD decreased the likelihood of recovery from GAD by nearly fivefold and increased the risk of recurrence threefold.
Differential Diagnosis
Studies have shown that anxiety and the endogenous opioid system are linked. The release of endogenous opioids in response to stress has a modulating effect on anxiety, and blocking the opioid system with an antagonist produces anxiety symptoms in human volunteers and anxiety- linked behaviors in animal models. Further complicating the clinical picture is that anxiety is a key feature of opioid withdrawal.
Treatment
Stabilization in treatment including pharmacotherapy and psychosocial treatments can significantly reduce withdrawal-related symptoms in as little as 1 week. Initial components should include medical detoxification and consideration of buprenorphine/naloxone or methadone maintenance treatment. Treatment with the α2 agonist clonidine has been shown to reduce acute opioid withdrawal symptoms including panic anxiety. Buprenorphine–naloxone has been shown to reduce withdrawal symptoms including anxiety compared to clonidine.
CANNABIS AND ANXIETY DISORDERS
In 2010, cannabis was the most commonly used drug (77%) by current illicit drug users and was the only drug used by 60% of them. Some research has found an association between anxiety and cannabis use and disorders. Cannabis use increases the long-term risk of anxiety and can result in acute anxiety during intoxication. Early-onset anxiety disorders have been associated with cannabis use disorders. Other researchers have found little evidence to suggest that cannabis use predicted long-term anxiety or anxiety disorders, but it was associated with transient anxiety reactions. Higher anxiety has been associated with increased cannabis-related problems at baseline and follow-up. Cannabis-dependent patients may benefit from the development of skills to manage anxiety as anxiety reduction has been associated with improved outcomes.
STIMULANTS AND ANXIETY DISORDERS
There is little research on co-occurring anxiety disorders and cocaine, methamphetamine, and amphetamine use. These agents stimulate noradrenergic systems, and acute intoxication is often associated with anxiety. Because of these anxiogenic effects, individuals who are vulnerable to anxiety may be less likely to abuse or become dependent on this class of drugs.
Prevalence
In the NESARC, 39% of individuals with amphetamine use disorders and 31% of those with cocaine use disorders reported lifetime anxiety disorders. Of individuals with anxiety disorders, about 5% reported a lifetime amphetamine or cocaine use disorder. Studies of treatment-seeking individuals indicate that anxiety disorders are relatively less common in cocaine-dependent treatment-seeking patients as compared with alcohol and other drug-dependent individuals. In the Methamphetamine Treatment Project, frequency of methamphetamine use was positively associated with severity of general anxiety and phobic anxiety. At 3-year follow-up, 26% of participants met criteria for current or past anxiety disorder, with GAD being most common. Among those with anxiety disorders, treatment adherence was poorer, and self-reported methamphetamine use was significantly higher during the follow-up period. In a review of two community surveys, lifetime noncocaine stimulant use was associated with lifetime diagnoses of nearly every anxiety disorder. Onset for SAD preceded the use of stimulants and other drugs, and onset of GAD tended to occur after stimulant use onset. In a sample of current amphetamine users, one third of respondents reported anxiety symptoms preceding initiation of amphetamine use, two thirds reported experiencing anxiety since initiation of amphetamine use, and at least half reported panic attacks.
Diagnosis
Cocaine has been reported to precipitate panic attacks in patients without previous PD. Stimulant withdrawal symptoms may also include low levels of anxiety in the first few days of abstinence, and withdrawal from cocaine has been associated with heightened anxiety states. The compulsive foraging for misplaced cocaine that has been noted in cocaine addicts has commonalities with OCD. Although this may implicate common neurobiologic processes, these symptoms generally occur only during acute intoxication and withdrawal and do not meet the diagnostic criteria for OCD.
Treatment
In one small case series, patients with cocaine-induced PD had substantial symptom improvement after treatment with either carbamazepine or clonazepam. Because repeated cocaine administration is associated with neuronal sensitization leading to increased limbic excitability, it has been hypothesized that this is the mechanism of cocaine-induced panic. This hypothesis warrants further investigation. A number of psychosocial treatments such as CBT and contingency management have demonstrated efficacy in the treatment of stimulant dependence.
KEY POINTS
1. SUDs and anxiety disorders commonly co-occur.
2. As intoxication and withdrawal can mimic almost every psychiatric disorder, observation during a period of sobriety can clarify the presence of an independent anxiety disorder.
3. Unless contraindicated, SSRIs are effective first-line medications for the treatment of anxiety disorders.
4. Benzodiazepine use for the treatment of anxiety disorders with comorbid SUDs should be avoided if possible.
REVIEW QUESTIONS
1. Which of the following are associated with an increased risk of a substance use disorder?
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