Benzodiazepines have a variety of uses, but it is commonly used to treat anxiety disorders. This is due to their effect on the neurotransmitter GABA (gamma-aminobutyric acid), which reduces neuronal excitability and thereby produces a calming effect (ScienceDirect). However, benzodiazepines are also known to produce rebound effects, or the return of the symptoms being treated but in a more severe form after the discontinuation of treatment. The severity of rebound symptoms can lead to dependence and addiction on benzodiazepines. Research shows benzodiazepines are highly effective in the treatment of anxiety, but it is a matter of proper usage and monitoring.
When using the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV), the criteria for generalized anxiety disorder (GAD) has only moderate reliability (ScienceDirect1). Some of the symptoms of GAD had a high degree of interrater reliability, while some had a very low degree. This means that someone who has GAD may be diagnosed with another psychological disorder, or vice versa, since the consistency between clinicians diagnosing GAD is only moderate. Additionally, research consistently finds that anxiety disorders are often comorbid with other psychological disorders. When studies limit research participants to those who only suffer from one anxiety disorder, they may be excluding up to 92% of their population of interest (NIH). The most common comorbid psychological disorders are other anxiety disorders and depressive disorders. Benzodiazepines are a common treatment for anxiety disorders, while antidepressants are a common treatment for depressive disorders.
A meta-analysis by Roy-Byrne and Hommer (ScienceDirect) investigated the implications of benzodiazepine withdrawal on anxiety treatment. In the analysis, the researchers found that duration of treatment, discontinuation period, and half-life of the medication were significant contributing factors to the length and severity of withdrawal. For the duration of benzodiazepine treatment, studies found that withdrawal was not significant in short-term treatment, which was defined as benzodiazepine treatment for less than 1 year, and often for less than 6 months. Long-term treatment was associated with a higher likelihood of symptoms and inability to discontinue using benzodiazepines. Therefore, clinicians should prescribe benzodiazepines for shorter durations in their patients to prevent withdrawal symptoms. In addition, the length of the discontinuation process was found to be a significant factor in withdrawal or rebound effects on anxiety. Patients who abruptly discontinued benzodiazepines had higher occurrences of withdrawal symptoms than patients who discontinued their usage on a gradual schedule. Clinicians should attempt to slowly get their patients off of benzodiazepines by giving smaller and smaller dosages of the drug until they are able to discontinue usage without major symptoms. Additionally, the half-life of the benzodiazepines may affect the severity of withdrawal symptoms. Half-life has to do with how quickly the benzodiazepine is metabolized in the body. In the short half-life benzodiazepines (which means they are metabolized quickly), there tends to be a greater severity and incidence of withdrawal symptoms. Those who took benzodiazepines with a long half-life had fewer withdrawal symptoms. Clinicians should be aware of this and factor this into which benzodiazepines they prescribe. All three factors (treatment duration, length of discontinuation, and half-life of benzodiazepine) are important for the clinician to consider ensuring that the patient experiences the maximum benefits and minimum rebound effects.
There are some treatments for benzodiazepine withdrawal. According to the meta-analysis by Roy-Byrne and Hommer (ScienceDirect), anxiety management training has been found to be helpful in some cases. Additionally, in a double-blind placebo-controlled study by Sanchez-Craig et al. (1986), patients who could not discontinue benzodiazepine were put into different groups. The researchers found that in patients who were treated with cognitive therapy, there were no significant differences in withdrawal symptoms between those on an abrupt discontinuation schedule and a gradual discontinuation schedule. This is significant considering that length of discontinuation was found to be a significant factor for withdrawal. In addition to therapy treatments, gradual withdrawal schedules and long-acting benzodiazepines have been found to treat withdrawal and ease the patient into quitting.
The meta-analysis (ScienceDirect) also concluded that little is known about the mental disorders of long-term users, and thus whether continued use of benzodiazepines for an extended period is appropriate. About 1/3 of long-term benzodiazepine users have depressive disorders, and ¼ have panic disorders, and both conditions can be treated with antidepressants. That leaves about ½ of long-term benzodiazepine users with chronic anxiety disorders. Some alternatives to benzodiazepines would include anxiolytics, such as buspirone. There is evidence that chronic anxiety (meaning it lasts for at least 6 months) tends to relapse and remit. It may be best for clinicians to treat the anxiety with benzodiazepines when it is active and to cease benzodiazepine treatment when the symptoms dissipate. Long-term use of benzodiazepines may not be necessary. However, this would involve greater monitoring by doctors, as patients may go months at a time between visits.
The meta-analysis (ScienceDirect) suggested that antidepressants may be a possible replacement for benzodiazepine treatments. This is important, especially since, as established earlier, the reliability of a generalized anxiety disorder diagnosis is only moderate, and anxiety disorders are often comorbid with other disorders, such as depressive disorders and other anxiety disorders. However, there is little research directly comparing benzodiazepines to antidepressants. A study by Rickels and Moeller (Taylor & Francis Online) compared two studies done by the same research group, one of which was on a benzodiazepine called clorazepate and the other of which was on an antidepressant called venlafaxine. Clorazepate acts on GABA to produce a calming effect. Venlafaxine is a selective norepinephrine reuptake inhibitor (SNRI), meaning it prevents the reabsorption of norepinephrine into neurotransmitters, resulting in increased norepinephrine in the brain and increased attention. The study on clorazepate compared the effectiveness of a benzodiazepine to buspirone, while the study on venlafaxine was an open-label relapse prevention trial for anxiety symptoms. Both studies were for those with generalized anxiety disorder, and both lasted for 6 months.
Importantly, at baseline (before the beginning of each study), the anxiety levels of both groups were at similar levels using the Hamilton Anxiety Rating Scale (HAM-A), with both groups having a mean score at about a 25 (Taylor & Francis Online). Scores higher than 24 are indicative of severe anxiety. Lower scores indicate lower levels of anxiety. At 4 weeks, the venlafaxine group had a much lower mean anxiety score (M = 9.6) than the clorazepate group (M = 15.3). However, at 24 weeks, the venlafaxine anxiety score rose to a higher level (M = 19.3) than the clorazepate group (M = 16.3), meaning the anxiety returns. While both medications were effective, the results indicate that benzodiazepines may be more effective in long-term treatment of anxiety than antidepressants since the goal is to reduce and prevent the relapse of anxiety. Both clorazepate and venlafaxine had adverse events. The 3 most common adverse events for clorazepate were drowsiness, fatigue, and incoordination. The 3 most common adverse events for venlafaxine were dry mouth, drowsiness, and light-headedness. It is also hard to compare these studies due to the rates of attrition of participants (with 57% completion in the clorazepate study and 59% completion in the venlafaxine study). It is unknown if the participants who finished were those who were the most successful in their treatments, as this may have affected the results. Additionally, these studies had different procedures. Future research should directly compare benzodiazepines to antidepressants to understand their effectiveness.
Overall, research has shown that there are significant withdrawal symptoms from benzodiazepines. Replacing them with other medications may not be effective. The withdrawal symptoms of benzodiazepines can be prevented with measures such as shorter duration of benzodiazepine treatment, a gradual discontinuation, and using long half-life benzodiazepines. Treating the underlying anxiety with therapeutic approaches can also be helpful to prevent rebound effects. Ultimately benzodiazepines are effective, but it is a matter of how they are used that maximizes their benefit and reduces their harm to the patient.