Nobody doubts that benzodiazepines (“benzos” or BZs) are effective in treating a wide range of anxiety disorders, but many believe that they are addictive, difficult and perhaps dangerous to stop taking, and that they cover up anxiety instead of truly treating it. Well, how valid are these concerns? After all, benzos offer some unique advantages: they work quickly, they are the only agents that can be used to treat an ongoing anxiety attack, they can be taken PRN, and they do not generally cause sexual side effects. So let’s take a closer look at each of the concerns.
Benzos are addictive. It is crucial to understand three terms related to addiction: misuse, abuse, and dependence. Misuse refers to taking a medication other than how it is prescribed. Thus, a patient who is prescribed Klonopin (clonazepam) 1 mg TID who comes into your office and informs you that he increased the frequency to QID due to increased anxiety has misused his Klonopin prescription.
Abuse implies using a BZ specifically for inappropriate reasons such as to get high. How prone to abuse are BZs? Most clinical trials with placebo controls have found little evidence for preference of BZs over placebo (Arch Gen Psychiatry 1986; 43:533-41) , though former alcoholics sometimes report positive mood changes in response to BZs. Epidemiological studies have consistently shown that the overwhelming majority of patients in the community, even former substance abusers, take fewer BZs than prescribed, rarely become “dose escalators,” and decrease rather than increase their dose over time ( J Clin Psychopharmacol 1992; 12:316-21) . When true BZ abuse does occur, it is almost always in the context of other drug abuse. For example, in one study involving 30 patients who presented with BZ dependence (on an average dose of 140 mg/day of valium or its equivalent!), 28 of 30 were actively abusing other substances while the other two had a history of drug abuse (J Clin Psychopharmacol 1996; 16:51-57) .
Dependence is frequently labeled once a patient has difficulty coming off a BZ. However, this may represent physiological dependence in the same way that patients may have withdrawal symptoms when coming off Paxil (paroxetine) or Effexor XR (venlafaxine XR). Physiological dependence is certainly a risk for patients who take BZs daily for an extended period of time, but usually is not much of a concern for short term use (i.e., less than 3-6 months—see JAMA 1983;250:767-771 ). It is often impossible, however, to distinguish between a true BZ withdrawal syndrome and the unmasking of an underlying anxiety disorder syndrome, and because of this, there is no way to clearly estimate the prevalence of BZ dependence. The best insight that we can offer is to examine success rates of BZ discontinuation for patients who present for that specific purpose. In this situation, between 40-50% of BZ-dependent individuals can successfully be withdrawn from their BZ and remain BZ free thereafter (Arch Gen Psychiatry 1990; 47:899-907, Arch Gen Psychiatry 1990; 47:908-915) . Keep in mind, however, there is no way to know whether the remaining patients were unsuccessful because their anxiety disorder reemerged or whether they were truly unable to stop because of withdrawal symptoms.
Benzodiazepines certainly can be abused —most of us have had patients who show up in the ER mimicking symptoms of panic and then get angry and leave when questioned about their frequent visits, or who have a number of doctors and prescriptions on file at a variety of pharmacies. Active substance abusers should not be given BZs, but, according to a comprehensive review on this topic (Am J Addictions 1991; 10:48-68), they can safely be given to alcoholics in recovery.
BZs are difficult or dangerous to stop taking. Because BZs induce physiological dependence, they do need to be tapered for patients who have been taking them for more than 6 months. The oft-cited 25% per week tapering guideline is too difficult for most patients, according to the major study to examine this issue (Arch Gen Psych 1990; 47:908-915). Instead, go 25% for the first two weeks, then slow the taper way down, to 10% per week or less. The specter of danger arises with the concern about withdrawal seizures. In a study of 153 BZ-dependent patients, a 3% withdrawal seizure rate was reported, and these patients were on very high doses of BZs that were often stopped abruptly (Pharmacopsychiatry 1995; 28:257-62). If you are concerned about seizures in particular patients, you can prescribe an anti-seizure medication such as Depakote or Tegretol and inform them not to drive over the next few days. If they decline this plan, you can recommend a short stay in the nearest psychiatric facility to monitor their withdrawal symptoms.
Benzos only “cover up” the underlying anxiety disorder and do not treat the source. The same concern was expressed not so long ago about antidepressants for treating depression, but today most people accept the validity of treating symptoms. There is, however, some evidence that BZs inhibit the gains that can be made from cognitive-behavioral therapy (CBT). Since CBT works by teaching patients how to manage their anxiety, patients on BZs may be deprived of the opportunity of experiencing their anxiety and learning how to overcome it. This is a real concern, and should prompt a collaborative discussion with your patient and the CBT therapist.
So, are benzos “bad?" Not inherently. Like most drugs, they do have potential side effects, including drowsiness, cognitive impairment, and decreased coordination. While they should generally be reserved as a second-line treatment after SSRIs and CBT, and should be avoided in active substance abusers, they are a useful tool in our armamentarium and, when managed appropriately, incur minimal risk.
Two “New” Benzos: Pushing the Patent Envelope
Xanax XR was approved for panic disorder in January of2003, and is essentially good old Xanax (alprazolam) packaged in a delivery system that releases it gradually into the bloodstream; because of this, you can dose it QD or BID instead of QID. While FDA approval was fairly recent, Xanax XR has been kicking around Pharmacia & Upjohn for quite a while. Back in 1995, a paper was published comparing Xanax IR with Xanax XR in 14 volunteers with histories of sedative abuse. Hands down, they rated Xanax IR as more abusable than placebo, whereas Xanax XR did not differ from placebo along this dimension (Clin Pharmacol Ther 1995; 57:356-65). Whether it poses any advantages over long half-life BZs such as Klonopin remains to be seen. FYI, you won’t see many more ads pushing Xanax XR, because its patent just expired, and it is now available as a generic from Mylan Laboratories.
Klonopin wafers (clonazepam) have been available at pharmacies since May of 2003, although they were initially approved by the FDA back in 1997. Standard Klonopin pills were first approved back in 1975 and are available generically. The wafers are being pushed by Solvay as unique because they disintegrate on the tongue, and for this reason can be taken “discreetly” (yes, this is their language). The clinically helpful aspect of this “new” product is that it comes in two lower dosage forms than standard Klonopin – 0.125 mg and 0.25 mg. So gradual dosage titration is easier. As with Xanax XR, Klonopin Wafer’s patent recently expired, and Barr Pharmaceuticals received FDA approval in August 2005 to market a generic version.