Triazolam…to be discontinued

Oral triazolam (Hypam), a short-acting benzodiazepine hypnotic registered for the treatment of insomnia, is being discontinued in New Zealand by its supplier Viatris. Triazolam has been delisted from the New Zealand Pharmaceutical Schedule now that stock has been exhausted.¹ Health professionals were previously advised that no new patients should commence triazolam, and as of 1 June 2023, only endorsed prescriptions were funded for existing patients.^1,2

Triazolam is indicated for management (up to seven days) of transient insomnia; and short term (two to four weeks) for severe or disabling insomnia; and as a short term, intermittent adjunctive treatment in the management of chronic insomnia.³

Almost 14,000 New Zealanders were dispensed triazolam between March 2022 and February 2023. Half of these people were over age 65 and almost two-thirds were women.⁴

Patients who have been taking triazolam regularly long term will need to be withdrawn slowly, or changed to alternative medicine if continued use is necessary.

Benzodiazepines are commonly prescribed for the treatment of insomnia but are also prescribed for other conditions.⁵ They are a group of structurally related hypnotic compounds that increase the effects of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system.⁶

Although differing structurally from the benzodiazepines, the hypnotic zopiclone (a so-called Z-drug) is also a GABA receptor complex agonist and, as such, produces benzodiazepine-like effects and is often prescribed for insomnia.^5,6 Benzodiazepines are Class C5 controlled drugs; zopiclone is currently a prescription medicine but will be scheduled as a Class C5 controlled drug from 1 July 2023.^5,7

A non-pharmacological strategy is preferred first-line for the treatment of insomnia, including behavioural strategies to encourage good sleep hygiene.⁶ Hypnotics can provide short-term relief from insomnia symptoms, but they do not treat the underlying cause of insomnia and are associated with a range of adverse effects. Therefore, they should not be relied upon as the sole treatment of insomnia.^5,6

When hypnotics are used for long periods, the GABA receptor can physically change, reducing sedation potential and sustaining undesirable effects on memory. Studies have detected loss of therapeutic benefit in seven to 28 days; however, many patients are unaware of this and keep taking these drugs indefinitely. This could be harmful, considering the potential for falls, fractures and cognitive problems – including memory loss – especially in the elderly.⁸

In addition to development of tolerance and reduction in therapeutic benefit over time, major concerns about benzodiazepine and zopiclone use include physical and psychological dependence, and therefore withdrawal effects.⁶ Alcohol and other drug dependencies, and personality disorders appear to be elements potentially associated with an increased risk of developing benzodiazepine dependency, along with long-term use, high doses and potency, and use of short-acting agents.⁶

Given these aspects, health professionals should limit these hypnotics to short-term use only – initially for a maximum of two weeks, possibly extended to four weeks after review – and consider whether they are still clinically indicated every time a patient requests a repeat prescription.^5,9 Should triazolam be used consecutively for more than 2–3 weeks, complete re-evaluation of the patient is recommended.³

If hypnotics are deemed necessary, a short-acting drug (eg, zopiclone or the benzodiazepine temazepam) at the lowest effective dose for the shortest duration is recommended.^6,10,11 Longer acting benzodiazepines (eg, diazepam) are not appropriate for simple insomnia. Existing comorbidities should be managed and mental state assessed prior to prescribing hypnotics. When taking these agents, patients are encouraged to continue good sleep hygiene practices. These include:^6,8

• avoiding caffeine after noon; and other stimulants within two hours of bedtime – exercise, large meals, nicotine and alcohol
• maintaining regular sleeping hours
• having a suitable environment for sleep – appropriate light and temperature levels
• avoiding napping
• not using the bed or bedroom for anything but sleep (or sex)
• only going to bed when sleepy.

Cognitive behavioural therapy is also effective for the management of chronic adult insomnia and has been endorsed as first-line therapy by multiple societies and guideline panels.⁸

Patient’s values and those of their whānau play an important role in shared decision-making about stopping hypnotics. A useful first step for health professionals is to engage patients in a discussion about patient goals and preferences regarding their use of hypnotics.

Discussions should include potential risks and benefits associated with cessation of pharmacotherapy, and symptoms of withdrawal – these being generally mild, transient and short term, usually easing once the withdrawal process is complete. Patients may harbour concerns about how they will manage withdrawal and the possible recurrence of insomnia. Continue to offer behavioural advice to encourage good sleep hygiene practices to patients during their withdrawal.^6,8

Patient collaboration in developing a tapering plan that is flexible and tolerable is important. Patients benefit from understanding they are part of the tapering plan, knowing what to expect from the process and being able to control tapering rate and duration.^6,8

Take it slowly

Overall, an estimated 50 per cent of all patients taking benzodiazepines will experience withdrawal symptoms when they stop taking them (Table 1). Withdrawal symptoms can appear following cessation of treatment after as little as one week of therapy with recommended doses of triazolam³ or three weeks after stopping a long-acting benzodiazepine.^6,8 Generally, symptoms are mild and short term (lasting a few days and up to about four weeks).

To safely discontinue benzodiazepines, a slow and gradual tapering of doses is needed rather than abrupt withdrawal. Gradual tapering may not eliminate withdrawal symptoms but it reduces their effects.^8,9 When short-acting benzodiazepines are stopped abruptly, symptoms tend to appear, peak more quickly and be of increased severity relative to when tapering long-acting benzodiazepines.⁸ Abrupt withdrawal has been associated with seizures, delirium and psychosis.¹²

Dose-tapering strategies

The rate of tapering depends on the initial dose of hypnotic, duration of use, and patient clinical response. For example, patients who have taken benzodiazepines for fewer than four weeks can usually taper off within two to four weeks, some may be able to stop abruptly without issues, but longer-term users may require a period of several months or more. Counselling can be helpful both during and after tapering.¹²

Evidence describing how best to taper benzodiazepines is scarce with regard to frequency, degree and duration of dose reduction.⁹ However, a Canadian clinical practice guideline for deprescribing benzodiazepines and Z-drugs has tabulated, but not compared, examples of tapering methods, including two trials that switched patients to dose-equivalent diazepam prior to the tapering process.⁸ Switching out a shorter-acting benzodiazepine for a long-acting agent, such as diazepam, is a common strategy designed to promote a smooth reduction of drug levels over time.^6,8 Several resources (eg, from the New Zealand Formulary and BPACnz) provide useful information and recommendations for withdrawing benzodiazepines using diazepam-dose equivalents.^9,12

However, switching to diazepam is unlikely to be an appropriate strategy for discontinuing triazolam taken nightly for insomnia, as diazepam is too long acting. In addition, there is a lack of published evidence to suggest switching to long-acting benzodiazepines is more effective, or reduces the incidence of withdrawal symptoms, than tapering shorter-acting benzodiazepines or zopiclone.^6,8

Overall, the clinical practice guideline found that very gradual dose reductions to lowest available doses – for example, a 25 per cent reduction every two weeks and a slower taper of 12.5 per cent every two weeks near the end of stopping – followed by periodic drug-free days have been successful in clinical trials. Should dosage forms not allow for a 25 per cent dose reduction, an initial 50 per cent reduction can be considered, using drug-free days during the latter part of tapering.⁸

Some other strategies to assist withdrawal comprise:⁹

• increasing benzodiazepine dispensing frequency, if there is easy access to a pharmacy
• reminding patients taking benzodiazepines or zopiclone for insomnia not to take it routinely, and to only take it if they are unable to fall asleep
• ensuring the tapering plan is written and shared between patient and health professional
• establishing regular contact to track progress, highlight benefits and help with withdrawal symptoms.

If the patient is experiencing difficulty with withdrawal symptom frequency and severity, maintaining the current achieved dose for one to two weeks (or until the patient feels able to continue with the taper) before attempting the next dose reduction should be considered. Dose tapering should then be continued at a slower rate. Increasing the dose once tapering has started is not recommended.^8,9

Monitoring requirements

Although dose tapering can potentially reduce withdrawal symptoms, it may not eliminate them; therefore, a monitoring plan should be developed in collaboration with the patient.⁸

Monitoring can be done at scheduled appointments or via phone call from a health professional. At each step in the taper (usually every one or two weeks over the course of the taper) monitor for:⁸

• severity and frequency of adverse drug withdrawal symptoms – anxiety, irritability, sweating, gastrointestinal symptoms, insomnia
• potential benefits observed with withdrawal – less daytime sedation, improved cognition, reduced falls risk, fewer falls
• changes in mood
• sleep quality and changes in sleep.

Withdrawal symptoms can be monitored using rating scales. The Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ) is a 20-item self-report questionnaire. The Clinical Institute Withdrawal Assessment for Benzodiazepines (CIWA-B) scale combines self-reported symptoms with clinician observations.

If a patient has been unable to withdraw from and stop triazolam, or triazolam is still clinically indicated, health professionals will need to switch patients to an alternative medicine in anticipation of triazolam discontinuation. Some patients may find this challenging.

Dose equivalence data between hypnotics are available in the scientific literature but are approximate only and generally reported as ranges (see Table 2). This is due to inter-patient variability, different drug half-lives and receptor-binding properties, differing sedative effects, and a scarcity of evidence supporting exact conversions. Equivalent doses provided in the literature should be viewed as approximate, applied cautiously, and interpreted using clinical and pharmaceutical knowledge. Doses should be titrated against patient response.^12,13

Alternative drug options

Short-acting oral hypnotics that may be suitable alternatives to triazolam and are approved for the treatment of insomnia include temazepam and zopiclone.¹⁴ Of note, both these agents have a longer duration of action than triazolam, which is the shortest acting benzodiazepine. UK NICE guidance considers there is no compelling evidence to support a clinically useful difference between the Z-drugs and shorter-acting benzodiazepine hypnotics with regard to their effectiveness, adverse effects or potential for dependence or abuse.⁷

As a hypnotic, temazepam is indicated for severe or disabling insomnia characterised by difficulty in falling asleep, frequent nocturnal awakenings and/or early morning awakening.¹¹ The adult dosage range is 10mg to 30mg, but this should be individualised to the lowest effective dose. As with all benzodiazepines, temazepam use is not recommended for more than four weeks. Intermittent use may be appropriate.

The medium and longer-acting benzodiazepines, lorazepam and diazepam, are not preferred short-term treatments for insomnia.¹⁵ Diazepam, with its half-life of 20–80 hours, is likely to cause next-day impairment. Neither agent is considered a first-line treatment for anxiety.^5,15,16

Zopiclone is indicated for the treatment of short-term and chronic insomnia in adults. This includes difficulties with falling asleep, and night-time awakening.¹⁰ The usual adult dose of zopiclone is 7.5mg, although many people may find 3.75mg is effective. Zopiclone works very quickly, so patients should be in bed immediately after taking it. Like benzodiazepines, zopiclone should only be used short term (up to a maximum of four weeks) or intermittently for insomnia. Older people should take an initial dose of 3.75mg due to poorer metabolism, to reduce the risk of impairment the following day.¹⁰

Melatonin is a tryptophan derivative. The recommended dose is 2mg taken one to two hours prior to bedtime and after food.¹⁷ Dosage forms containing ≤3mg (immediate release) or ≤2mg (modified release) can be supplied by a pharmacist when used as monotherapy for the short-term treatment, up to 13 weeks, of primary insomnia in people aged 55 or over.¹⁸ For all other scenarios, melatonin is a prescription medicine.

Low-dose amitriptyline, a tricyclic antidepressant (TCA), may provide some benefit due to its sedative effects but does not have Medsafe approval for the treatment of insomnia.¹⁴ This agent may not be suitable for elderly people as they are particularly vulnerable to many of the adverse effects of TCAs. Amitriptyline may also prolong QT intervals and increase risk of torsade de pointes.¹⁹

A caution about the possibility of next-day impairment is required for people taking sedating medicines at night, especially as they may feel they have slept well and that they are not impaired. Driving or other activities requiring mental alertness the day after administration are not recommended. See the data sheets for full prescribing information.^10,11

Health professionals who are managing a patient’s withdrawal from benzodiazepines or a switch to an alternative treatment are encouraged to reach out to mental health and addiction services, if needed. Addiction services can provide advice on benzodiazepine withdrawal and discontinuation, and help with medically managed withdrawal (eg, when and how to slow down a tapering regimen).

Several online resources and groups are available to provide support to patients who wish to stop taking benzodiazepines, including:

• The Level
• Alcohol and Drug Helpline