Anxiety Disorders ____________________________________________________________________________
Risks/Drawbacks While alprazolam remains the most-prescribed benzodiazepine for anxiety disorders, evidence suggests that relative to other benzodiazepines, alprazolam is no more effective and may have specific drawbacks [171]. Alprazolam may have greater potential for dependence than other benzodiazepines due to its rapid onset of anxiolysis and short half-life. With the short half-life, persons prescribed fixed-interval alprazolam (e.g., every six to eight hours) can experience morning with- drawal symptoms following the last nighttime dose. This is frequently mistaken as relapse in anxiety for which the drug was originally prescribed, confirming the continuing need for the drug [228]. The alprazolam product monograph states that such emergence of interdose symptoms reflect insufficient plasma levels, best managed by adding the same dose for four times daily administration (but breakthrough anxiety and alprazolam withdrawal are not differentiated). The document also states that alprazolam treatment of panic disorder differs from sub-syndromal anxiety, in that recommended dosing is as close to around-the-clock as possible, or three or four times per day [232]. Long-term benzodiazepine use can result in added symptoms during stable-dose maintenance, including increasing anxiety and withdrawal-associated symptoms such as perceptual distur- bances and paresthesia. This emerging withdrawal syndrome despite ongoing benzodiazepine use is much more likely with highly potent and rapidly eliminated alprazolam or lorazepam and is temporarily alleviated by dose escalation. As craving, dysphoria, and other withdrawal symptoms develop over time between doses, the motivation to continue benzodiazepine use for anxiolysis gradually merges with the need to avoid withdrawal symptoms [233]. Benzodiazepine prescriptions are associated with nonmedical use and the development of benzodiazepine use disorder unre- lated to co-occurring drug use or anxiety disorder diagnosis/ severity [221]. Acute cognitive-impairing side effects are drowsi- ness, increased reaction time, ataxia, motor incoordination, and anterograde amnesia. In one study, long-term use of an average 17 mg/day diazepam equivalent led to substantial cognitive decline that did not resolve three months after ces- sation [234]. Motor vehicle accident risks during benzodiaz- epine therapy are comparable to driving with a blood alcohol concentration of 0.050% to 0.079% [235]. Hip fracture risk is increased by ≥50% in older persons who take benzodiazepines; with zolpidem, the risk is increased 200% in persons older than 65 years of age [236]. The risk of overdose is particularly great when benzodiazepines are combined with sedative drugs such as opioids or alcohol. Personality traits associated with long-term use, emotional dependence, and more severe/protracted benzodiazepine withdrawal have been described. Long-term benzodiazepine users often have poor stress coping abilities. Benzodiazepines compensate for these deficits, but their use interferes with learning stress coping strategies, including behavioral therapy
for agoraphobia. Passive-dependent personality traits and lack of internal and external stress coping resources increases vulnerability to withdrawal symptoms and motivation for continued use. In these patients, benzodiazepine deprivation renders them unprotected from stress and re-exposes their coping deficits. Chronically anxious people have been found innately hypersensitive to punishing stimuli and punishment; benzodiazepines can be described as “depunishing” drugs [233]. Withdrawal Withdrawal symptoms following benzodiazepine cessation are appropriately concerning and a liability of this drug class that all prescribers should understand. In patients with panic disorder discontinuing alprazolam following 1.5 to 22 months of treatment, 33% to 100% were unable to completely taper [181]. These data did not include the 50% of long-term ben- zodiazepine users who do not consent to withdrawal studies or who later quit the study. The experience of benzodiazepine withdrawal is known to deter patients from future attempts [237]. An estimated 25% to 76% of patients prescribed benzodiazepines are long-term users. Defining high-dose benzodiazepine varies, but users of high-dose benzodiazepines commonly have comorbid disorders and are unlikely to benefit from current discontinuation and withdrawal strategies that expose them to greater risk of impairment and injury [237]. Despite comparable dosing, patients with panic disorder often show greater difficulty tapering than patients with GAD. Problems during alprazolam tapering are most severe during the last half of the taper. Patients with panic disorder receiving diazepam or alprazolam had fewer problems during taper of the top 50% of daily dose. However, with abrupt discontinuation of the remaining dose, alprazolam caused significantly more anxiety, relapse, and rebound. This may reflect greater problems withdrawing from short half-life, high-potency benzodiazepines like alprazolam [181]. The patient experience of benzodiazepine withdrawal was studied in 41 high-dose benzodiazepine-using inpatients deciding to withdraw (median dosage: 70 mg/day diazepam equivalent; median duration: six years) [237]. Driving this decision were health concerns of cognitive and physical impair- ments; feeling addicted; belief benzodiazepine use was a moral burden that limited autonomy; and pressure or coercion by relatives or institutional or governmental bodies to change benzodiazepine consumption patterns. The patients had long histories of repeated unsuccessful attempts to stop taking benzodiazepines and disappointment and frustration by the outcomes. However, many wanted to withdraw completely, with abstinence the goal. Most subjects described benzodiaz- epine withdrawal symptoms as severe, unpredictable, diverse in manifestation, and of duration difficult to anticipate. Common symptoms included chills, weakness, headache, muscle pains, abdominal pain, nausea, vomiting, diarrhea, tachycardia, diz- ziness, vision disorders, irritability, nervousness, restlessness, difficulties sleeping, depression, anxiety, tickling sensations,
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