135 - References

References

464 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Benzodiazepines, z-­drugs and gabapentinoids: dependence, withdrawal effects and discontinuation In most developed countries, the use of benzodiazepines or z-­drugs is restricted to a maximum 2–4  weeks.1–3 However, long-­term use remains common in the UK, with 300,000 adults taking either a benzodiazepine or z-­drug for more than 12 months.4 Most guidelines, including NICE in the UK, recommend that people on long-­term benzodiazepines or z-­drugs should be advised to stop because of tolerance to these drugs (which can develop after 2–4 weeks) because physical dependence (distinct from addiction) is likely to develop, and because of numerous adverse effects (Box 3.11).5 Gabapentinoids (GABA analogues) can also cause addiction, physical dependence and withdrawal over the same period.6–8 In total, 1.5 million people in England are prescribed gabapentinoids,9 and the number of prescriptions for these medications rose seven-­fold between 2010 and 2020.10 Further details on withdrawal effects and safe deprescribing of these drug classes are outlined in the companion to this text, the Maudsley Deprescribing Guidelines: Antidepressants, Benzodiazepines, Gabapentinoids and Z-­drugs.11 Physical dependence on these classes of drugs does not require misuse, abuse or addiction but simply repeated exposure.12 The vast majority of people who experience withdrawal effects are taking drugs as prescribed by their physician (so-­called ‘iatrogenic dependence’). This is distinct from addiction, which involves craving and compulsion, and can be associated with misuse and abuse, occurring only in 2% of patients.12 Box 3.11  Adverse effects of benzodiazepines Emotional13 Reactions which can be mistaken for a psychiatric disorder14 ■ ■Depression/dysphoria ■ ■Numbness/emotional anaesthesia ■ ■Anxiety/phobias/panic ■ ■Anger/irritability/mood lability ■ ■Excitement/euphoria ■ ■Agitation ■ ■Emotional lability ■ ■Restlessness ■ ■Inter-­dose withdrawal Physical13 Cognitive*15–17 ■ ■Motor incoordination/ataxia ■ ■Dizziness ■ ■Slurred speech ■ ■Sensory alterations (tinnitus/strange tastes/ paraesthesia/numbness/burning) ■ ■Rash ■ ■Autonomic dysfunction (tachycardia/bradycardia/ diaphoresis/hypotension/hypertension) ■ ■Deficits in memory ■ ■Deficits in attention ■ ■Increased reaction time ■ ■Motor incoordination ■ ■Drowsiness ■ ■Nightmares/intrusive thoughts ■ ■Impaired judgement ■ ■Perceptual illusions/hallucinations Increased morbidity16,17 Behavioural13 ■ ■Increased risk of motor vehicle accidents ■ ■Higher risk of falls (elderly) ■ ■Delirium (elderly) ■ ■? Dementia ■ ■? Cancer ■ ■? Infections ■ ■Insomnia ■ ■Avoidance/agoraphobia ■ ■Appetite/weight (anorexia, weight gain) ■ ■Impulsivity/disinhibition ■ ■Suicidality ■ ■Aggression * Some of these impairments can persist after discontinuation.

Depression and anxiety disorders CHAPTER 3 Long-­term use of benzodiazepines is associated with a number of problems (Box 3.10). Patients may be unaware of problems and may only appreciate the issue after stopping the drug.18 Long-­term z-­drug use is associated with similar risks.19 Gabapentinoids have been linked to increased risk of suicide, unintentional overdose, road traffic accidents, and head and body injuries,20 suggesting that limitation of their long-­term use may be prudent. Withdrawal symptoms Stopping these medications is often difficult (Box 3.12). One study found that 90% of patients experience withdrawal symptoms on stopping benzodiazepines, with 32% of people on long half-­life benzodiazepines and 42% of people on short half-­life benzodiazepines unable to cease their medication because of withdrawal symptoms.21 Short-­ acting drugs such as lorazepam are associated with more severe problems on withdrawal than longer-­acting drugs such as diazepam.22,23 As these drugs are somewhat ineffective for anxiety and insomnia in the long term, symptoms that arise on stopping are perhaps just as likely to be withdrawal symptoms as opposed to relapse (though symptoms can be similar).24 Mental state often improves after withdrawal symptoms abate.25 Some of the worst consequences of benzodiazepine withdrawal are akathisia and new-­onset suicidality, which are poorly recognised and often misdiagnosed.11 Withdrawal symptoms can last days or weeks but, for some people, they can last longer than a year, especially in the case of long-­term use,22,25 as highlighted by an FDA black box warning.26 This is called a ‘protracted withdrawal syndrome’.27 The long-­ lasting effects on the nervous system, months or years after stopping benzodiazepines, have been termed ‘benzodiazepine-­induced neural dysfunction’.28 Box 3.12  Withdrawal effects from benzodiazepines29,30 Physical Psychological ■ ■Stiffness ■ ■Fatigue and weakness ■ ■GI disturbance ■ ■Paraesthesia ■ ■Flu-­like symptoms ■ ■Visual disturbances ■ ■Sensory hypersensitivity ■ ■Convulsions* ■ ■Cognitive impairment ■ ■Impaired memory ■ ■Tremor ■ ■Dizziness ■ ■Muscle spasms/cramps ■ ■Chest pain ■ ■Hypertension ■ ■Tachycardia ■ ■Photophobia ■ ■Confusion, delirium* ■ ■Akathisia ■ ■Anxiety/insomnia ■ ■Terror/panic attacks ■ ■Nightmares ■ ■Depersonalisation/derealisation ■ ■Delusions and hallucinations ■ ■Depression ■ ■Psychosis* ■ ■Mood instability ■ ■Paranoia ■ ■Obsessive-­compulsive symptoms ■ ■Suicidal ideation ■ ■Mania * Usually only from very rapid withdrawal.