Conclusion

The authors summarize the harmful and understudied aspects of the overuse of benzodiazepines. Increased and longer-term use of benzodiazepines has been observed to lead to side effects such as sedation, cognitive issues, abuse, and dependence, as well as many other unanticipated side effects that do not fit their known mechanism of action in the central nervous system. Data also shows a correlation between concomitant use of benzodiazepines and opioids and increased risk of death from overdose. The authors advocate for stricter guidelines for prescribing benzodiazepines, as well as close clinical monitor and shorter-term treatment plans.

Benzodiazepines Today and Tomorrow

Benzodiazepines (BZDs) and related drugs are widely used for treating a variety of conditions (with varying degrees of evidence-base), but their long-term use (more than 2–4 weeks) can be problematic. They were originally thought (or claimed) to be nonproblematic substitutes for barbiturates, but it is now clear that they have their own set of problems. In addition, they are commonly, albeit ill-advisedly, co-prescribed or used nonmedically in combination with other drug substances. The result of such combinations, particularly with the opioids, can be lethal. Administrative and statutory actions notwithstanding, it appears that reducing problems with BZDs will depend on a comprehensive approach that includes improved education for patients, prescribers, regulators, insurers, and the public. First and foremost, however, there is a pressing need for the government to improve its drug-abuse data collection, specifically how it monitors drug-related morbidity and mortality. This chapter reviews the information that demonstrates how an understanding of all of the dynamics is essential for designing effective public-health strategies to reduce BZD-associated problems.

Drug Withdrawal

Drug withdrawal has long been considered a key symptom in the diagnosis of alcohol and substance use disorders. In this chapter, it is also conceptualized as a major motivational factor that drives compulsive drug taking. Drawing from the negative emotional components of withdrawal, termed hyperkatifeia (i.e., the negative emotional and motivational signs of withdrawal), the hypothesis here is that withdrawal sets up another major source of reinforcement—namely, negative reinforcement—for drug seeking in substance use disorders. From the perspective of the hyperkatifeia phenotype, withdrawal then returns to being a key part of moderate to severe alcohol and substance use disorders to become the primary factor that motivates sustained drug seeking. Such hyperkatifeia is mediated by a multidetermined neurocircuitry that compromises within-system neurochemical systems that are involved in the rewarding effects of drugs and promotes the activation of pro-stress neuromodulators that combine with a weakening or inadequate anti-stress response. Altogether, these neurocircuitry, neurochemical, and molecular changes lead to a negative emotional state (hyperkatifeia) that sets up an allostatic hedonic load that drives negative reinforcement. Under this framework, strong multidetermined buffers, if activated and sufficient to allow the reward and pro-stress systems to recover, may help return the organism to homeostasis.

The Evolution of Benzodiazepine Receptor Agonists

Benzodiazepines have been touted as safer alternatives to their barbiturate predecessor since their arrival on the market in 1960. Their proposed improved safety is based on their reported reduced drug interactions, lower abuse potential, and decreased respiratory depression. Benzodiazepines bind to the GABAA receptor and positively modulate GABAergic transmission and hyperpolarization of neuronal membranes. Individual agents are utilized differently depending on their varying degrees of hypnotic, anxiolytic, antiepileptic, muscle relaxant, and amnestic properties. Benzodiazepines are frequently classified by their half-life (t½), a key pharmacokinetic parameter that dictates the agents’ ability to precipitate dangerous withdrawals. The majority of benzodiazepines undergo phase I hepatic metabolism via cytochrome p450 that introduce the potential for drug interactions. Following hepatic metabolism, almost all agents within this drug class have active metabolites that have extended half-lives beyond that of the parent drug that prolong the duration of activity. Urine drug screens are an essential component of medication monitoring and require a foundational understanding of the parent drug, its metabolites, and what the available immunoassay is designed to detect. A similar drug class that is frequently grouped with benzodiazepines are Z-drugs. These agents were developed in attempt to create a sleep aid that lacked the undesirable qualities of benzos with an improved safety profile. Z-drugs share the common characteristic of being short-acting in nature and are proposed to cause less disruption in the normal sleep cycle than benzodiazepines.

In Search of Benzodiazepine Guidelines

Benzodiazepines are widely prescribed and used, but there is a paucity of guidance about their use. There are indications for benzodiazepine use, but they are often inappropriately prescribed (such as for posttraumatic stress disorder and bipolar disorder)/ Benzodiazepines are indicated for short-term use only and should not be continued beyond two to four weeks. Although benzodiazepines are indicated for treating insomnia, insomnia tends to be a chronic condition; benzodiazepines are not appropriate for long-term use. Discontinuing benzodiazepines can be challenging and should be accomplished using a shared decision-making model, a tapering plan, and good clinical support throughout.

Benzodiazepine Receptors in the Periphery

The benzodiazepines are almost universally thought to produce one and only one pharmacologic effect: positive allosteric modulation of GABAA receptors located in the brain. This results in an increased Cl−ion influx, greater negative transmembrane potential difference, and neurons that are less likely to fire in response to anxiety-producing stimulation. Unfortunately, the simplicity and success of this mono-target belief has distracted researchers and clinicians from studying and appreciating their other pharmacology. A glaring example is the general lack of awareness of the peripheral benzodiazepine receptor. The peripheral benzodiazepine receptor alters mitochondrial function (energy supply), cholesterol transport, and immune function. A patient who is on long-term benzodiazepine therapy (or withdrawing from them) will have these sites affected, just as are the sites located in the brain. One can easily imagine that the adverse effects associated with the peripheral sites would be fundamental, varied, and potentially profound—involving lack of energy, altered cholesterol metabolism, and aberrant immune function.

The Central Benzodiazepine Receptor

Benzodiazepines have been used clinically now for more than a half century for the management of anxiety and other conditions. Despite their widespread use, only now are their mechanisms of action and their pharmacologic implications, especially with long-term use, beginning to be appreciated. In the central nervous system, benzodiazepines act on an allosteric site of the GABAA receptor to enhance the activity of this inhibitory neurotransmitter. The GABA receptor consists of 5 subunits, which can vary among 19 different subtypes, resulting in a large number of possible configurations for the GABA receptor. Subunit structure can affect the binding of benzodiazepines to the receptor and can alter the nature of the interaction between the benzodiazepine binding site and the GABA binding site, resulting in different levels of receptor activation and allosteric enhancement. Moreover, the distribution of these different subtypes within the central nervous system, with their varying levels of benzodiazepine efficacy, can mean that benzodiazepines can have differential effects among the different sites of the brain. Consequently, in may be possible to design novel drugs that favor particular subunit configurations and thus produce different pharmacologic profiles. Drugs acting at the benzodiazepine site can be agonists, enhancing the activity of GABA; antagonists, blocking the effect of benzodiazepines at the binding site; or inverse agonists, producing an effect antipodal to that of benzodiazepine agonists.

Use of Benzodiazepines and Z-Drugs in the Geriatric Population

The benzodiazepine (BZD) class of drugs has proven to be a useful addition to therapeutic management of anxiety and sleep disorders in the adult population. However, after many years of experience with BZDs in elderly patients (≥65 years), a large body of evidence indicates that BZDs are no longer recommended for use in this segment of the population, except under special conditions. Several aging-related changes in physiology such as decreases in renal and hepatic function, altered central nervous system function and changes in body composition can lead to impaired excretion of drug, higher plasma levels and accumulation of these drugs in the body. Side effects such as sedation, dizziness, cognitive impairment, and diminished control of gait and balance functions place the elderly at greater risk of various adverse events, especially falls and fractures, compared to younger adults. Another class of drugs, known as Z-drugs is structurally dissimilar from the BZDs but able to bind to GABAA, receptors making them useful for management of insomnia. These drugs have also been found to pose significant hazards to the elderly and are also not recommended for use in elderly patients. Both of these classes of drugs are currently included in the AGS Beers Criteria® of potentially inappropriate medications for use in the elderly. Alternative pharmacologic approaches to managing these conditions include use of either serotonin-norepinephrine reuptake inhibitors or buspirone for anxiety and the use of either low doses of doxepin, melatonin, or the melatonin agonist ramelteon for management of insomnia. Cognitive behavioral therapy and other relaxation techniques offer non-pharmacologic approaches to managing these conditions, thereby decreasing the need for prescribing BZDs or Z-drugs in the elderly.

Benzodiazepines and Pain Management

Chronic pain is widespread and the use of opioids for chronic pain is also common. Frequently benzodiazepines are concomitantly prescribed in these patients, for anxiety, sleep disorders, and muscle pain and spasm. In the United States, Canada, and the European Union, increases in benzodiazepine prescribing has been seen, in some cases over 16% over the last decade. Unfortunately, the combination of opioids and benzodiazepines is correlated with overdose and overdose death. Few data exist to support the use of benzos for sleep, muscle spasm, or the long-term treatment of anxiety in the context of pain. It has been further shown that the use of benzodiazepines carries other adverse events and issues. It is estimated that the elimination of benzodiazepines would decrease overdoses by over 15%. The deprescribing of benzodiazepines should become common practice in the professional pain community and their use drastically limited. The authors suggest an approach to the discontinuation of benzodiazepines that includes extensive patient involvement. Other options for anxiety, sleep disturbances, and muscle relaxation are available and should be considered. For those already on these agents (legacy patients), tapering with the goal of discontinuation in a safe and person-centered process should be undertaken.

Introduction

At the same time that it became apparent that overdose toxicity and adverse effects limited the utility of barbiturates to treat anxiety and insomnia, a new class of drugs emerged in the 1950s and 1960s: benzodiazepines. With a rapid onset of action, these new drugs were highly effective in reducing anxiety and promoting sleep when used short term. Rapidly becoming some of the most prescribed drugs in the world, benzodiazepines brought with them a Pandora’s box of potential risks that weren’t at first fully appreciated. Although rarely fatal when taken alone, benzodiazepines have been shown to be correlated with polydrug overdose mortality. With prolonged exposure these drugs can lead to tolerance, physical dependence, and addiction. They can also launch a vicious cycle of rebound after initially relieving anxiety, they can lead to a state of tolerance with the need for increasing doses to achieve the same effect, resulting in more subjectively experienced anxiety. Rebound insomnia is a well-known feature of the long-term use of these agents. Despite these risks, these drugs were extremely popular upon their introduction into the medical marketplace and they became among the most frequently prescribed pharmaceuticals in America, with a variety of agents in this class of drugs being introduced. There then emerged the so-called Z-drugs (e.g., zolpidem and zaleplon), which were marketed as effective sleep aids and “not a benzodiazepine,” with the implication from sales representatives that, without having the molecular structure of benzodiazepines, they would not present the same rebound or adverse effects as benzodiazepines. However, the “Z-drug” agents are indeed benzodiazepine receptor agonists and are associated with the same downsides as agents in the true benzodiazepine drug class.