This chapter acts as a practical summary guide to deprescribing benzodiazepines and z-drugs.

• The indications for deprescribing are:

  • adverse effects,
  • loss of efficacy (tolerance or tachyphylaxis),
  • use >1 month, ^{1, 2, 3}
  • patient wishes to stop, and
  • rationalising medication (e.g. reducing polypharmacy).

• Patients at higher risk from continuing benzodiazepines are those who are: ¹

  • age >65,
  • taking more than 1 benzodiazepine or z-drug,
  • also taking opioids or gabapentinoids (pregabalin or gabapentin),
  • at risk of falls,
  • diagnosed with COPD, severe or uncontrolled respiratory disease, or risk of respiratory depression,
  • have a substance use disorder or a history of overdose,
  • contemplating pregnancy ^{4, 5, 6} or breastfeeding. ⁷
• Deprescribing decisions should be agreed between patient and prescriber. Forced tapers are not recommended (except in the case of acute severe adverse effects) and may provoke patients to seek medication from other sources. ⁸

• Education about benzodiazepines and z-drugs should be provided (see first section of this chapter) - this intervention itself has been shown to increase the chances of successful cessation. ⁹

  • Benefits: These drugs have clear short-term benefits for anxiety and insomnia. However, owing to tolerance, these benefits diminish over time and are unlikely to be effective in long-term use. ^{10, 11} They may impair the efficacy of psychotherapeutic approaches such as exposure therapy. ¹²
  • Risks: Adverse effects include cognitive, neurological and affective symptoms, sometimes including worsening anxiety and depression over time. ^{13, 14, 15} The patient may not always connect this to the use of the medication.
  • Alternatives: CBT for insomnia is more effective than hypnotics for sleep. Several evidence-based alternatives to benzodiazepines for the treatment of anxiety exist. ^{16, 17, 18}
• Initiating the offer of deprescribing with a letter can be effective and it is enhanced if there is also direct face-to-face contact with a prescriber or pharmacist. ¹⁹ Motivational interviewing might help. ¹⁹

• Provide informed consent regarding discontinuation.

  • Benefits. In the long term, may lead to reduced anxiety (after the withdrawal process), ²⁰ improve psychomotor and cognitive function, ²¹ possibly reduced mortality. ^{22, 23} Lower risk of motor vehicle accidents, ²⁴ falls ²⁵ and drug interactions. There are numerous other neurological, cognitive, psychiatric and other symptoms that may also improve. ^{13, 20}
  • Risks: Withdrawal symptoms can occur - which can sometimes be severe and long-lasting - but these can generally be mitigated by tapering more slowly and adjusting the rate to one that is tolerable for the patient. ²⁰ If tapering is performed too quickly then withdrawal effects such as suicidality, akathisia and long-term disability can occur.
  • Alternatives: A patient may remain on their current medication if they choose.

• If deprescribing is declined (or attempted and found to be too difficult): ²⁶

  • patients should be advised of the benefits of stopping,
  • any concerns they have about stopping should be addressed,
  • patients should not be pressurised,
  • if appropriate, readdress discontinuation at future appointments, and
  • continue monitoring for adverse effects.
• Note that some patients may be unable to withdraw completely, and a more suitable goal may be dose reduction or maintenance of the current dose.

• Patients should be warned not to stop benzodiazepines abruptly if they have been used for more than 4 weeks, because in some cases this can cause severe problems (e.g. rarely, seizures) ²⁷ and may provoke long-lasting withdrawal symptoms. ^{20, 28}
• Reassurance may be required for those that have rapidly tapered in the past with intolerable consequences. Inform the patient that if tapering is performed gradually and adjusted to their symptoms, it can be tolerable. ⁸
• Preparation for benzodiazepine tapering may be required: for example, bolstering of existing coping skills or development of new ones. These skills can include intentional relaxation (mindfulness, progressive muscle relaxation ²⁶), controlled breathing exercises, ^{29, 30} physical exercise (if tolerated), sleep hygiene, acceptance, distraction techniques, CBT for insomnia, peer support and stress reduction. ³¹ There is a wide variety of other coping skills that people might find helpful. Sometimes lightening work or family duties may be useful.

• Specific treatments for the conditions for benzodiazepines and z-drugs were originally prescribed (i.e. anxiety and insomnia) can be helpful for the process (but may have limited effectiveness for withdrawal symptoms themselves).

  • People with insomnia may benefit from CBT for insomnia, or sleep hygiene advice. Where circadian rhythm disturbance plays a role this can be addressed. ³²
  • Anxiety disorders may be treated with psychotherapy modalities, or other non-pharmacological approaches. ²⁰
• Establishment of a support system. This can involve family and friends (who may require education) or more regular contact with clinical staff. Sometimes the introduction of patients to a supportive peer group in person or online can be helpful, although beware exposure to 'worst case' scenarios, and sometimes inaccurate information. ⁸
• It is useful to set expectations. For people that have used benzodiazepines long term, the withdrawal process can take 6-18 months, or even longer for those sensitive to the process. ²⁰ People who have been on short-term benzodiazepines or z-drugs may be able to stop completely in a few weeks. ³³
• Past experience of reducing can help predict symptoms that may arise again on tapering so should be noted and can be helpful for monitoring targeted symptoms, as below.
• Familiarity of the patient and the doctor with the wide variety of withdrawal symptoms (see section on withdrawal effects) may help to mitigate unnecessary anxiety when symptoms arise. It should be impressed on patients that unpleasant withdrawal symptoms do not indicate that the drug is needed but that the taper rate should be slowed.
• If inter-dose withdrawal symptoms from benzodiazepines are present before tapering, either:
• advise the patient to take the benzodiazepine more frequently; or
• substitute an equivalent dose of a long-acting benzodiazepine (such as diazepam) with a step-wise cross-over (see drug-specific sections). ²⁶

• Determine whether to perform a direct taper from the benzodiazepine or z-drug being used or to switch to a longer-acting benzodiazepine. Research evidence is equivocal about which approach is best and patient preference should be considered. ^{1, 14, 20, 26} In the drug-specific tapers given in the rest of this chapter both options are provided.

  • Patients who may benefit most from a switch before tapering are those suffering from inter-dose withdrawal, or who are taking medication for which small doses are not easily available.
  • Patients who have had trouble with switching in the past or prefer to proceed with a familiar drug should be supported to do so. ^{34, 35, 36}
• There is consensus that a patient-directed taper, adjusted to symptoms is the most successful approach to cessation. ²⁷ The key elements of a programme of tapering are:
  • that it is flexible and can be adjusted so that the process is tolerable for the patient,
  • that it involves close monitoring of withdrawal symptoms to facilitate timely adjustments to the rate of taper, and
  • that patients are provided with preparations of medication to make the process of creating doses that cannot be made with available tablet doses (e.g. liquid formulations or smaller dose formulations of tablets)

The process of tapering involves the following four steps (Figure 3.5 ).

Patients may be broadly risk stratified according to what is known about risk of withdrawal in a suggested approach below. It is better to err on the side of caution when estimating the risk category, and so the presence of any moderate- or high-risk characteristic should assign a patient to that category. Tapers can always be increased in speed if no difficulties are encountered - but the reverse can be more problematic.

Low-risk patients could start with approximately 20% (or less) dose reductions (e.g. the faster regimens given in the drug-specific sections). This group is characterised by:

• no evidence of tolerance to the medication,
• no evidence of inter-dose withdrawal,
• short-term use ( weeks),
• taking longer half-life benzodiazepines,
• no or mild withdrawal symptoms in the past on stopping or skipping a dose, and
• no or limited history of benzodiazepine (or other psychiatric medication) use and cessation. ^{34, 35, 36}

Note that some patients who have only used benzodiazepines short term can also experience withdrawal effects, ^{34, 35, 36} but this is rarer than in long-term use.

• Moderate-risk patients could start with approximately 10% (or less) dose reduction (e.g. the moderate regimens given in the drug-specific sections). This group is characterised by:

  • some evidence of tolerance to the medication,
  • some experience of inter-dose withdrawal,
  • moderate-length use (months),
  • moderate withdrawal symptoms in the past on stopping or skipping a dose, and
  • some history of benzodiazepine (or other psychiatric medication) use and cessation. ^{14, 20}

• High-risk patients could start with 5% (or less) dose reduction (e.g. the slower regimens given in the drug-specific sections). This group is characterised by:

  • evidence of significant tolerance to the medication,
  • marked experience of inter-dose withdrawal,
  • past history of severe withdrawal symptoms on dose reduction or skipping doses,
  • taking shorter half-life benzodiazepines,
  • older or otherwise physically frail, and
  • repeated cycles of benzodiazepine (or other psychiatric medication) use and cessation (which is thought to lead to sensitisation, a phenomenon sometimes called kindling). ¹⁴
• In order to instil confidence in patients in what can be a daunting process, it may be advisable to start with an even smaller dose reduction in order to alleviate patients' fears about the process.
• None of the suggested regimens should be imposed on the patient but are a starting point to assess how the patient tolerates the process.
• If a patient prefers to try a smaller dose reduction than their risk category suggests this should be supported.
• People taking z-drugs once at night will tend to fall into the lower-risk category because z-drugs are likely to produce less physical dependence than benzodiazepines as they are probably largely eliminated in each 24 hour period. ³⁷

• The most important information to determine the rate of reduction is how the patient experiences the process. Imposed regimens tend to backfire. ^{37, 38} Withdrawal symptoms should be monitored for 1-4 weeks or as long as it takes for symptoms to start to ease.
• Although there are various formal scales used to measure withdrawal symptoms, these can be cumbersome because of the number of items, and potentially miss the importance of one or two significant symptoms. ³⁹ An alternative is to rate a small number of core withdrawal symptoms such as anxiety, insomnia or other prominent symptoms out of 10 (0 = no symptoms, 10 = extreme symptoms) or to rate withdrawal symptoms out of 10 overall. This monitoring often detects a 'wave' pattern of withdrawal symptoms: where symptoms increase, reach a peak, start to resolve and return to or approach baseline (Figure 3.6 ).

The information from monitoring can be used to determine the frequency and size of reductions (Figure 3.7). See further examples in 'Tapering antidepressants in practice' but briefly:

• if symptoms take 2 weeks to resolve and the severity is mild (e.g. less than 4 out 10) then similar-sized reductions (in terms of receptor occupancy) could be made every 1-4 weeks so that subsequent symptoms do not accumulate;
• if symptoms take longer to resolve or their severity is moderate (e.g. 5 to 8 out of 10) then further time between reductions will be required and/or smaller reductions made in future;
• if symptoms are severe (e.g. 9 or 10 out 10) then dose should be increased to the last dose at which the patient was stable, wait for stabilisation and then make reductions at half the rate, or less.

It is important that these decisions are reached jointly and that a too fast rate of taper is not imposed on patients.

• The steps outlined above in steps 2 and 3 should be repeated. Similar-sized reductions (in terms of effect on target receptors) should produce similar withdrawal reactions, but sometimes these vary over time, so ongoing monitoring of withdrawal symptoms is warranted with adjustment of the regimen according to the experience of the patient.

  • Reductions should proceed in a hyperbolic pattern to accommodate the nature of the pharmacological effect of the drugs. ^{38, 39} Examples of such regimens are displayed in the drug-specific sections of this chapter.
  • The taper should be flexible to accommodate periods of stress, increased responsibilities or illness.
  • The dose should be reduced to zero when the dose is low enough that the reduction to zero will not cause a larger change (in terms of effect on target receptors) than previous tolerable reductions have caused. For example, for diazepam the final dose before stopping for diazepam may be 1mg, 0.5mg 0.2mg or even lower (see diazepam section) depending on the size of the reductions tolerated throughout the taper.

Patients can taper in steps ('cut and hold', e.g. at intervals of 1-4 weeks) as outlined above or, alternatively, they can taper in smaller amounts (e.g. every day), often called micro-tapering. There are pros and cons to each approach:

• Tapering in steps is simpler and can often be performed with existing tablet formulations of some medications (e.g. halving and quartering 2mg diazepam tablets). Larger, less frequent reductions can cause greater symptoms (see Figure 3.4).
• Micro-tapering involves more complicated calculations and use of formulations other than tablets (e.g. manufacturers' liquids or suspensions of tablets). It can reduce the severity of symptoms making the process of tapering more tolerable by 'spreading' out changes to established equilibria. ⁴⁰ See the drug-specific section for example regimens (e.g. by reducing by 0.05mg per day from 20mg of diazepam).

A variety of different formulations can be used for tapering:

• Commercially available tablets: small doses are preferable, with round tablets able to be divided into halves and quarters using a tablet cutter (more accurate than breaking along a score line). ⁴¹
• Manufacturers' liquids: using a syringe for precise measurement. Further dilution in water is sometimes required for small doses.
• Compounded tablets or liquids: specialist pharmacies can prepare lower-dose tablet formulations or liquid suspensions. One example is 'tapering strips'. ⁴²
• Suspending tablets or capsules: tablets can be crushed and dispersed in water or milk. Capsules can be emptied to disperse in water or milk. Suspension of tablets is an off-label but widely recommended method by authoritative pharmaceutical guidance ^{43, 44, 45} and is commonly used by patients. ^{20, 46}

After tapering

Some patients can have ongoing withdrawal symptoms following cessation. Sometimes this lasts just for several days or weeks but occasionally is extended for months or sometimes years, termed protracted withdrawal syndrome. ^{47, 48} See the subsequent section 'Management of complications of benzodiazepine and z-drug discontinuation' for further details.

Other considerations

• Extending the dosing interval ('skipping doses') to taper is ill-advised as it can lead to inter-dose withdrawal symptoms, unless involving benzodiazepines with very long half-lives such as diazepam. It is preferable to give smaller doses each day using one of the techniques outlined previously.
• Withdrawal symptoms are best managed by adjustment of the taper rate, rather than 'white-knuckling' through the process. It is thought that severe withdrawal effects may make a protracted withdrawal syndrome more likely. ²⁶

• Adjunctive medication has mixed evidence, with authoritative guidance recommending against its use ^{51, 52} and it should be reserved for very severe cases. ^{53, 54}

  • Short-term use of propanolol, ^{20, 28} and perhaps antihistamines might be warranted in severe withdrawal. Carbamazepine might be reserved for extremely difficult cases.

• People can become sensitised to various medications during the process of withdrawal for reasons that are not well understood. ²⁰

  • The most noteworthy of these include alcohol and antibiotics (especially fluoroquinolones which can displace benzodiazepines from the GABA receptor). ⁵⁵
  • There are reports of sensitivities to steroids, other medications, caffeine, nicotine, supplements and even specific foods. ^{20, 28}
  • The use of some of these medications may be unavoidable, but greater caution than usual should be exercised with any supplement or medication. ²⁰

Potential pitfalls

• Physiological dependence can develop in a matter of days so some people will have withdrawal symptoms after just short-term use.
• Physiological dependence and the experience of withdrawal effects does not indicate addiction. Addiction centres are therefore not advised for people suffering withdrawal effects from benzodiazepines without abuse or misuse - sometimes treatment at these centres involves abrupt cessation with other medications added in to 'cover' withdrawal effects, or inappropriate 12-step approaches irrelevant to medication taken as prescribed.
• Some symptoms can seem bizarre but should not be discounted as many of these are recognised withdrawal symptoms (see section on withdrawal effects) (e.g., depersonalization/derealization, agoraphobia, intrusive thoughts, burning nerve pain, irritable bowel). ^{49, 56}
• Symptoms of benzodiazepine withdrawal can mimic other conditions, leading to misdiagnosis (e.g. functional neurological disorder, medically unexplained symptoms, psychosomatic conditions, chronic fatigue syndrome, anxiety disorder, depression, bipolar disorder, neurological disorders) and unnecessary testing and medical treatment. ^{56, 57}
• The drug-specific taper protocols in the following sections are meant to be a guide only: flexibility is key. The patient's experience of withdrawal symptoms should be the main guide to the rate of taper.
• Post-withdrawal recovery may take 12-18 months, and sometimes longer.

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