Carrie’s experience with benzodiazepines and with medical providers is not at all uncommon. As a family physician and addictionist for more than 3 decades, I had thought BZDs were well understood, easy to use, relatively benign, generally beneficial for long-term use and a nuisance to stop. That perspective changed, however, at a conference in 2017, where a panel of benzodiazepine survivors like Carrie shared their personal narratives (Fig. 1).
“Stories” and “challenges” do not begin to express the extent and severity of their articulated experiences. Despite the wide variety of BZD accounts, there was consistency. There was unanimity about failed efforts to have medical providers understand and validate their conditions, much less provide effective professional assistance. There was credibility: each had a good understanding of these medications, including physiologic dependence, which had played out into nightmare discontinuation scenarios. BZDs were not discarded outright, but rather a more nuanced and narrower role was suggested, differing significantly from the received “knowledge” I as a prescriber had been taught.
Carrie, as did these other survivors, reported that BZDs were initiated by prescribers without providing sufficient (if any) informed consent and without offering alternative options [11, 12]. First-line indications for BZD use are actually quite limited (Table 2). Yet, they are most frequently prescribed for non-first-line indications like insomnia and anxiety when cognitive behavioral therapy (CBT) with a more favorable risk/benefit profile is preferred [13, 14].
Even more, CBT benefit can extend a year or more after completion of treatment [15, 16] in contrast to BZD efficacy, which may fade over time [11, 17,18,19]. Loss of significant initial improvement can prompt increased dosing that may be ineffective as well. In fact, it appears some individuals may experience worsening anxiety due to these medications themselves [11, 20].
Paradoxical anxiogenesis is among a number of BZD-related adverse effects that may be misdiagnosed as unrelated to those agents [8, 11] (Table 3). If a causal nexus between such symptoms and BZD use goes unrecognized, misdirected treatment and cascading polypharmacy can ensue. When Carrie, for example, reported suicidal ideation to her PCP, she was told that it was unrelated to alprazolam and was directed to increase the dosage even though research shows BZDs are associated with suicidality .
Addiction and physiologic dependence are also serious adverse reactions related to exposure to BZDs and other substances. The former is an involuntary brain disease involving the reward system, which is behaviorally defined and diagnosed by compulsive use, loss of control and continued use despite negative consequences . Addiction involves the non-medical use (NMU) of a substance, though BZD NMU more often occurs voluntarily and unprompted by the craving that characterizes addiction. BZD NMU is not unusual, whereby the user intends to amplify or ameliorate the effects of or withdrawal from other addiction-prone substances [8, 23]. BZD addiction or use disorder per se is a subset of NMU but is seen infrequently [8, 22]. Indeed, the vast majority of those struggling with BZDs are not addicted to them, and for them traditional addiction treatment approaches are unsuccessful [8, 11].
Physiologic dependence, on the other hand, is an expected and very common response that may occur with as little as 1–2 weeks of BZD exposure  and/or at therapeutic, normal or low BZD dosages . It is due to neurophysiologic adaptations of at least the gamma-aminobutryic acid receptor subtype A (GABAA), glutaminergic, adenosine A2A and translocator protein receptor systems and the hypothalamic-pituitary-adrenal axis. Though only hypothetical, its pathophysiology may involve a biochemical cascade that generates toxic oxygen species, which then may become propagated and perpetuated through interacting pernicious feedback cycles in susceptible individuals who end up experiencing protracted withdrawal states.
BZD physiologic dependence may be evident as tolerance or the loss of effect with repeated exposure [8, 27]. Principally, though, it is distinguished by symptoms that emerge with discontinuation or dosage reduction [2,3,4,5,6,7,8]. A withdrawal picture may also be present in the absence of dose decrements due to developing tolerance in the context of waning BZD blood (brain) levels prior to the next scheduled dose: interdose withdrawal [8, 28]. Although many withdrawal symptoms are well recognized, there are those that go unrecognized (Table 1), particularly when they fluctuate dramatically in the absence of any change in environmental stressors . This becomes a real challenge for patient and prescriber alike.
Fundamental and critical to addressing physiologic dependence and BZD cessation is a very slow tapering process [4,5,6, 8]. For Carrie, this required 38 months. For some, discontinuation can proceed fairly rapidly (weeks), but this cannot be predicted. For many, a brisk tapering trajectory results in a severe adverse course, so it cannot be recommended at the outset. Rather, a gradual initial pace is advised, one that anticipates at least 12–18 months to complete . A fixed schedule is ill-advised, as patient responses vary so widely. In addition, as tapering proceeds, patient tolerability requires slowing its rate in a nonlinear, hyperbolic fashion [8, 29].
After tapering is initiated, its pace should be adjusted up or down depending on the patient’s response. This calls for the expertise of both prescriber and patient through shared decision-making. Prescriber expertise includes understanding and outlining BZD pharmacology, the deprescribing process, its anticipated flexible course and informed consent. As tapering proceeds, however, it is the patient’s expertise—her/his actual response to sequential BZD dose reductions—that assumes an ascendant role. This somewhat upends the shared decision-making model as it is usually practiced, whereby although shared, ongoing medical management choices tend to tilt toward reliance upon the provider’s expertise. Reliance upon the patient’s expertise, however, is the more dependable pathway to successful BZD cessation, as indeed Carrie discovered.
Aside from a clear recommendation for slow tapering [4,5,6, 8], published research offers only limited guidance to aid BZD discontinuation. Self-management, nutritional approaches and many plausible modalities have not been examined. CBT, though, does appear to have value . Published investigations suggest potential roles for adjunctive medications [31,32,33] (Table 4), but their value is uncertain because of mixed results, flawed research methodology and the lack of long-term outcomes including the likely need for tapering certain adjuncts themselves . No confident recommendation regarding any of these agents, therefore, can be made.
Ultimately, Carrie achieved significant success through a supportive network of medical providers, family and peer survivors. Because she originally found that her prescribers had insufficient BZD knowledge and even discredited her, she, like tens of thousands of others, sought out support and guidance in online communities. It was there she ascertained a pathway that led to favorable outcomes: information and practical approaches she had not previously found in traditional medicine sources. She was subsequently able to find medical providers willing to listen and employ a reasonable BZD discontinuation course.
The plight faced by Carrie and a cohort of BZD survivors has received scant attention in the literature. Traditional studies to date have not been sufficiently informative nor have they employed observation periods of the months and years needed to identify the extent and severity of difficulties, which are far more common [6,7,8] than appreciated by many medical providers. In fact, only two published [11, 34] and two unpublished [35, 36] qualitative surveys of long-term BZD-affected individuals have been identified. Together, these studies identify themes consistent with Carrie’s account: disabling symptoms lasting months or years and prescribers often untrained to provide effective assistance.
Although some published studies on managing BZD use have value, practitioners have made inferences beyond study parameters. A type of cognitive bias termed extension neglect can result in invalid conclusions derived from studies with small sample sizes and/or short observation periods. Many prescribers are anchored in the false assumption that investigations demonstrating short-term value of BZDs necessarily assure long-term benefit and safety. To generalize that “most” do well with a specific intervention does not address the major challenges faced by a significant minority. Evidence-based research methodology by necessity requires inclusion and exclusion criteria that essentially portrays “typical” patients with characteristics that may not match those of the affected person seeking medical assistance. In addition, some outcomes are truly unknowable because of wide variability of patient treatment response to BZD-related interventions. These factors lead back to the essential principle of individualizing care for those needing and seeking medical help.