Dr. Carlat has disclosed that he has no relevant relationships or financial interests in any commercial company pertaining to this educational activity.
Among substance abusers, anxiety seems to be more the rule than the exception. Studies show that up to 50% of patients with alcohol dependence or drug dependence have some type of anxiety disorder (Lai HM et al, Drug Alcohol Depend 2015;154:1–13). But anxiety comes in many flavors other than official DSM disorders. In any given substance-abusing patient, anxiety is likely to have multiple causes, such as psychosocial stressors and substance withdrawal, in addition to discrete DSM-5 anxiety disorders. (see table below for a list of typical causes of anxiety in substance abusers).
While benzodiazepines are effective anti-anxiety workhorses for many patients, most guidelines tell us to avoid prescribing them to substance abusers. The concern is that the benzo high will remind patients of their substances of choice, and that benzo withdrawal symptoms will lead to old substance abuse habits. However, one review of the literature concluded that benzos can safely be prescribed for some alcoholics in recovery (Lingford-Hughes A et al, Adv Psychiatr Treat 2002;8(2):107–116), and that most psychiatrists are able to manage such patients by making sure that they do not escalate their doses and do not get early refills.
Psychotherapy is always an option, and it can work well. For example, a two-week pilot trial of CBT-based integrated treatment for panic disorder and alcohol abuse in 48 patients showed benefit over alcoholism treatment alone (Kushner MG et al, J Mental Health 2006;15(6):697–707).
But assuming that therapy has already been tried, what are some non-benzo approaches that are reasonable? Some of the most likely candidates are discussed below (for more information such as FDA-approved indications, mechanism, and recommended dosing, see our table, “Potential Antianxiety Medications for Substance-Abusing Patients,” on page 7).
SSRIs/SNRIs and other antidepressants
Most substance abusers with anxiety will end up rotating through several SSRIs and SNRIs. These are robustly effective medications with few side effects. We all have our own “go to” meds. Paroxetine carries the most FDA-approved indications for disorders on the anxiety spectrum, but it also is the most likely to cause sexual dysfunction, weight gain, sedation, and drug interactions. Sertraline and escitalopram are good choices in terms of minimal side effects and few drug/drug interactions. The SNRIs, especially duloxetine and levomilnacipran, may be especially appropriate if your patient has a comorbid chronic pain condition, because both of these meds carry FDA indications for pain syndromes. The newer antidepressant vilazodone was effective for GAD in one placebo-controlled trial (Gommoll et al, Depress Anxiety 2015;32:451–459). You might also consider mirtazapine (Remeron), effective in a small open-label study of GAD and also helpful for insomnia. Bupropion, while not effective for anxiety disorders per se, is effective for anxiety when it is a symptom of depression—but watch out for its common early side effects of insomnia and jitteriness.
Buspirone has been around a long time, and many of your patients will say they’ve already tried it—maybe they have, maybe they haven’t. Here are two tips to optimize response. First, don’t oversell it as a benzodiazepine substitute—it doesn’t work as quickly or as well, and patients expecting the benzo feeling will be disappointed and will stop taking it. Second, get the dose high enough to be effective before throwing in the towel. A robust dose is 60 mg a day, either split up twice daily or three times a day. Dizziness and sedation may limit the dose.
Hydroxyzine (Atarax, Vistaril)
Some are surprised to hear that hydroxyzine has an actual FDA indication for anxiety (albeit an old one). It is effective—for example, in one large randomized placebo-controlled trial, patients with GAD randomly assigned to hydroxyzine 50 mg/day did just as well as those assigned to bromazepam 6 mg/day (bromazepam is a benzodiazepine approved in Europe; 6 mg is equivalent to about 10 mg of diazepam). Patients on the benzodiazepine experienced more sedation (Llorca PM et al, J Clin Psychiatry 2002;63(11):1020–1027).
Pregabalin is a Schedule V controlled substance (same category as cough suppressants with codeine), so it would seem an odd choice to treat anxiety in patients with substance abuse histories. Wouldn’t it pour fuel on the fire? Apparently not. In fact, pregabalin has been compared with naltrexone as a treatment for alcohol dependence; in one small randomized controlled trial, pregabalin was as effective as naltrexone, and led to greater improvement in anxiety (Martinotti G et al, J Psychopharmacol 2010;24(9):1367–1374). Pregabalin’s efficacy for GAD (in the absence of substance abuse) is pretty well established. Clinical trials have shown that the drug is as effective as lorazepam and alprazolam, and more effective than venlafaxine for GAD.
Placebo-controlled trials have also shown that it is more effective than placebo for patients who have had only a partial response to SSRIs or SNRIs (for a recent review of these studies, see Reinhold JA and Rickels K, Expert Opin. Pharmacother 2015;16:1669–1681). Start at 100 mg QHS, and gradually titrate to 300 mg BID. In addition to pregabalin’s addictive properties, potential drawbacks include high rates of dizziness and sedation (20%–30% of patients), and an average weight gain of about 5 lbs after 4 weeks. There aren’t any drug-drug interactions currently noted for pregabalin.
Gabapentin was originally used to prevent seizures as an anti-epilepsy drug. Its off-label uses include treatment for anxiety disorders as well as withdrawal from alcohol or benzodiazepines. (The drug was once also touted as a treatment for bipolar disorder, but well-designed trials discredited this use.) One small placebo-controlled trial found gabapentin (average dose 2,868 mg/day) superior to placebo for social phobia, but the response rates were low: 32% for gabapentin, 14% for placebo (Pande AC et al, J Clin Psychopharmacol 1999;19:341–348). For alcohol dependence, in one large double-blind trial, a rapid 4-day taper of gabapentin (from 1,200 mg/day to 800 mg/day) was more effective than a taper of lorazepam in terms of preventing relapse (Myrick H et al, Alcohol Clin Exp Res 2009:33(9):1582–1588. Epub 2009 May 26). Common gabapentin side effects include dizziness and sedation.
Quetiapine is hardly the first antipsychotic to be used or approved for anxiety. Stelazine (trifluoperazine) is approved for the short-term treatment of GAD, while Triavil (the combination of the antipsychotic perphenazine and the antidepressant amitriptyline) is approved for “depression and anxiety.” In addition, many clinicians use low-dose chlorpromazine (Thorazine) off-label for anxiety. The advantage of quetiapine is that its efficacy evidence is more robust, with placebo-controlled trials of over 2,600 patients showing that the medication eases symptoms of GAD better than placebo, paroxetine, and escitalopram (for a review of these studies, see Gao K et al, Expert Rev Neurother 2009;9(8):1147–1158). Lower doses of quetiapine XR, 50–150 mg QD, appear to be more effective than higher doses. Quetiapine has not won FDA approval for GAD, probably because its disadvantages literally outweigh its advantages (quetiapine is one of the worst antipsychotics in terms of weight gain and metabolic disturbances).
Don’t forget to try some of the herbal medications. While they rarely are backed up by the same quantity or quality of randomized controlled trials we expect for conventional meds, many of them have a long history of safe and presumably effective use. As covered in our July/August 2013 issue of TCPR, valerian root is often helpful for both sleep and anxiety. Its presumed mechanism is enhancing the action of gamma-aminobutyric acid (GABA). Typical recommended doses include 450 mg of valerian extract at bedtime for sleep, and 200–300 mg in the morning for anxiety. Valerian is quite safe, though there have been very rare cases of mild liver enzyme elevations, which normalized after stopping the extract.