A clear distinction should be made between dependence and withdrawal from therapeutic or somewhat higher doses within the medical context and abuse of benzodiazepines in the context of recreational and illicit use (Lader 2014). Benzodiazepines are widely misused, although patterns vary from country to country and from region to region. One type takes the form of binges, say at weekends, another regular sustained high-dose usage. Some misusers keep to oral use, whereas others inject intravenously or sniff intranasally like with cocaine use. The abuse of benzodiazepines depends on their formulation, bioavailability and pharmacokinetics. Temazepam and flunitrazepam are known to be often misused. Although benzodiazepines may be misused alone, they may also be misused along with other drugs, for example, to potentiate the euphorigenic effects of opioids, lessen the impact following the effects of cocaine or interact in a complex way with amphetamines or other drugs of abuse. Drug abusers may turn to benzodiazepines if other drugs of abuse become scarce and expensive. The risks of benzodiazepine abuse such as viral infection or local tissue necrosis are well known and are associated with intravenous drug use. Overdose is a hazard, particularly in combination with other psychotropic drugs. Another danger is related to the potentiation of the depressant effects of alcohol by benzodiazepines. This has been associated with an increased likelihood of criminal acts, often accompanied by amnesia. The misuse of benzodiazepines is undoubtedly dangerous, and the potential for misuse should be a consideration when deciding to prescribe these drugs.

Adverse effects of benzodiazepines are generally unpleasant but may not be severe; most adverse effects are reversible. However, recent data suggest that use of benzodiazepines may be associated with excess mortality (Charlson et al. 2009; Kripke et al. 2012). A systematic review has examined the risk of death associated with benzodiazepine use in studies published from 1990 onwards (Charlson et al. 2009). Data from six cohort and three registry studies indicate that regular users and illicit benzodiazepine users had a higher risk of mortality compared to non-users. A recent matched cohort study, based on electronic medical records and involving 10,529 people who received hypnotic agents (including both benzodiazepine and non-benzodiazepine hypnotics) and 23,676 controls with no hypnotic prescriptions, estimated the mortality risks, using proportional hazard regression models (Kripke et al. 2012). For patients prescribed 0.4–18, 18–132 and >132 pills/year, the hazard ratios were 3.60 (95 % CI 2.92, 4.44), 4.43 (3.67, 5.36) and 5.32 (4.50, 6.30), respectively. Thus, even occasional hypnotic users had over three times the background risk of dying in 2.5 years. Selective prescription of hypnotics for ailing patients was ruled out as the main explanation. The presence of co-morbidities was associated with a significant increase in the risk of death among patients receiving hypnotics, but this accounted for only a small proportion of the excess risk.

Skin manifestations such as generalised reactions, contact dermatitis, photodermatitis and Stevens-Johnson syndrome are rarely associated with benzodiazepine treatment.

In April 2013, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) issued a warning about tetrazepam, a benzodiazepine that has been used to treat painful muscle spasms (such as low-back pain and neck pain) and spasticity (excessive stiffness of muscles) in some European countries (European Medicines Agency 2013). The alert was prompted by the occurrence of life-threatening skin reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms syndrome), as described by the French National Agency for the Safety of Medicine and Health Products (Proy-Vega et al. 2014). After an assessment of available data on the risk of skin reactions, the PRAC concluded that tetrazepam is indeed associated with a low but increased risk of serious skin reactions compared to other benzodiazepines. The Coordination Group for Mutual Recognition and Decentralized Procedures of medicines for human use of the EMA agreed with the PRAC conclusion that the benefits of tetrazepam do not outweigh its risks, and on 29 May 2013, EMA adopted a final decision and suspended the marketing authorizations of tetrazepam across the European Union (EMA 2013). Proy-Vega et al. (2014) have recently commented on the clinical evidence leading to tetrazepam withdrawal, underlining the lack of randomised controlled clinical trials evaluating tetrazepam efficiency and safety. In their conclusion, they claim that ‘it is very important to foster a strong interaction between pharmacovigilance agencies, scientific publications and health professionals, in order to improve and optimise exchange of knowledge on clinical cases of ADRs’.

In December 2013, the FDA released a warning that clobazam, a benzodiazepine medication approved as adjunctive therapy to treat seizures that accompany Lennox-Gastaut syndrome, may cause serious skin events, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and acute generalised exanthematous pustulosis (AGEP), and consequently approved changes to clobazam label and medication guide (FDA 2013a). The FDA identified 20 cases of severe skin reactions from its Adverse Event Reporting System database: all cases had resulted in hospitalisation, one case in blindness and one in death. These reactions can occur at any time during clobazam treatment, but the risk is greater during the first 8 weeks of treatment or when clobazam is stopped and then restarted. However, no comparative pharmacovigilance analysis was conducted for other anticonvulsant benzodiazepines, including clonazepam, clorazepate, diazepam and lorazepam.

Buspirone is an azapirone used in the treatment of generalised anxiety disorder. While the anxiolytic effects of benzodiazepines usually occur within a few days of therapy, buspirone requires chronic treatment for effectiveness (Chessick et al. 2006). Buspirone lacks the sedative, muscle relaxant and anticonvulsant properties of the benzodiazepines. The underlying mechanism of action of buspirone is not clear; however, it is thought that its anxiolytic effects are mediated through interactions with the serotonin 5HT_1A receptor, where it acts as a partial agonist (Loane and Politis 2012). The most common side effects of buspirone are dizziness, headache and light-headedness. Buspirone does not impair psychomotor performance or results in abuse, dependence or withdrawal. Like benzodiazepines, buspirone appears to be safe even when given in very high doses.

Pregabalin is a pharmacological agent approved in many countries for the treatment of neuropathic pain, partial seizures and generalized anxiety disorder (Frampton 2014). Pregabalin is a structural analogue of GABA that neither interacts with GABA receptors nor alters GABA uptake or degradation. On the other hand, pregabalin binds to the α₂δ (alpha-2-delta) subunit of the voltage-dependent calcium channel in the central nervous system so thus decreasing the release of neurotransmitters including glutamate and substance P. The most frequent adverse effects of pregabalin include dizziness, somnolence, dry mouth, peripheral oedema, blurred vision and weight gain (Zaccara et al. 2011).

Following its introduction, accumulating evidence from case reports, databases and a limited number of studies have suggested that pregabalin has the potential to cause abuse and dependence (Gahr et al. 2013). Schwan et al. (2010) analysed data from the Swedish national register of adverse drug reactions and concluded that pregabalin is likely to be associated with an abuse potential based on 16 positive reports. As a result, the prescribing information was changed and now states that cases of pregabalin abuse have been reported and patients with a previous history of psychotropic substance abuse should be monitored closely for signs of pregabalin abuse (Lyrica SPC). However, there is currently limited evidence on this topic. According to recent review articles (Baldwin et al. 2013; Frampton 2014; Schifano 2014), the potential for abuse of pregabalin is low, as its positive psychological effects are weak and not maintained over time. Moreover, unless stopped abruptly, pregabalin seems to carry a limited risk for physical dependence or withdrawal. In this respect, a recent study documented that gradual discontinuation of pregabalin after 4–24 weeks of treatment at a dose ranging from 150 to 600 mg/day was not associated with clinically significant withdrawal symptoms (Kasper et al. 2014).

Post-marketing surveillance studies are needed to identify risk factors for pregabalin abuse and dependence. The assessment of pregabalin’s potential to cause addictive behaviours is also of particular clinical relevance as this agent is currently under evaluation for the treatment of benzodiazepine and alcohol dependence (Oulis and Konstantakopoulos 2012).

Non-benzodiazepine hypnotics, the so-called Z-drugs, including zolpidem, zaleplon, zopiclone and eszopiclone, are a class of drugs structurally unrelated to benzodiazepines, but with a similar mechanism of action. These agents are agonists at the α₁ subunit of GABA-A receptors which mediate sedation. They have become preferred drugs for the treatment of insomnia, in particular among older adults, because of perceived improved safety profiles compared with traditional benzodiazepines. The most common adverse events of non-benzodiazepine hypnotics are drowsiness or fatigue, headache, nightmares and nausea or gastrointestinal disturbances. However, recent evidence in elderly patients over the age of 65 has highlighted potential safety concerns of these medications and zolpidem specifically with regard to effects on balance and memory and on fracture risk (Levy 2014).

On January 2013, the US FDA issued a warning recommending that the bedtime dose of zolpidem should be lowered based on new data showing that blood levels in some patients may be high enough the morning after use to impair activities that require alertness, including driving. Therefore, FDA required manufacturers of zolpidem products to lower the recommended initial dose for women from 10 to 5 mg for immediate-release products and from 12.5 to 6.25 mg for extended-release products (Food and Drug Administration 2013b). Driving simulation and laboratory studies had established a threshold of 50 ng/ml, above which zolpidem is associated with decreased alertness and increased risk of adverse events. A randomised, placebo-controlled trial has shown that a single 5 mg dose of zolpidem resulted in clinically significant balance and cognitive impairments upon awakening from sleep (Frey et al. 2011). In particular, 58 % of older adults (7/12) and 27 % of younger adults (3/11) tested had a loss of balance after taking zolpidem, whereas none of the same participants had a loss of balance during ten pre-sleep practice trials. A loss of balance after zolpidem use was marked and more common in older adults compared to placebo.

Early evidence of zolpidem-associated hip fracture in older adults (Wang et al. 2001) has recently been reinforced by findings from three studies (Finkle et al. 2011; Kang et al., 2012; Berry et al. 2013). In the first study (Finkle et al. 2011), zolpidem was found to have a similar risk of hip fractures compared with diazepam and lorazepam, but significantly lower compared with alprazolam. A second investigation found that fracture risk was significantly greater with zolpidem compared with traditional benzodiazepines (odds ratio [OR]: 1.72 vs. 1.00, respectively) (Kang et al. 2012). A sub-analysis of 135 patients aged 85 or older found an even more pronounced risk with zolpidem compared with benzodiazepines (OR: 4.48 vs. 1.13, respectively). A third study utilised a nursing home population (Berry et al. 2013). Claims data were evaluated in residents who were prescribed zolpidem, eszopiclone or zaleplon during the ‘hazard period’ (within 30 days of a hip fracture) or during the ‘control period’ (60 days or longer before hip fracture). Residents who were prescribed a non-benzodiazepine during the hazard period were more likely to experience a hip fracture compared with residents prescribed a non-benzodiazepine during the control period (OR: 1.66).

Due to a lack of evidence on the optimal selection of zolpidem and other non-benzodiazepines in the elderly, it would be prudent to use these hypnotic agents sparingly and cautiously in older adults.

Benzodiazepines continue to be used in the management of patients with anxiety and insomnia. Based on cognitive and psychomotor impairment as well as abuse and dependence liability associated with benzodiazepines, clinicians must always balance the benefits and risks when prescribing these agents especially in the elderly. Other pharmacological agents used to treat anxiety disorders or insomnia, including pregabalin and non-benzodiazepine hypnotics, may share with benzodiazepines similar tolerability and safety issues. Pharmacovigilance surveillance studies can provide important information on specific adverse event features, patterns of clinical symptoms, severity of the events and, where applicable, fatality rates of various anxiolytics/sedative-hypnotics. Healthcare systems at the local, regional or national levels may wish to employ patient safety monitoring programmes for anxiolytics/sedative-hypnotics based upon pharmacovigilance studies.