Concomitant use of any three of opioids, benzodiazepines, z-drugs, gabapentinoids or antidepressants: CNS Triple Whammy

This hot topic considers the impact of concurrent prescribing of any three of: opioids; benzodiazepines; z-drugs; gabapentinoids or antidepressants.^{155,224,233,298} This increases sedation, falls, severe respiratory depression, the potential for dependency and possible withdrawal reactions when these medicines are stopped.

Benzodiazepines may be considered essential in people receiving them for certain conditions including alcohol or drug withdrawal, multiple sclerosis, intractable epilepsy, palliative care, or premedication for anaesthesia. They are not essential when used for the management of insomnia or anxiety.

Gabapentinoids if used for the management of epilepsy can be considered essential, but not for the management of pain.

Z-drugs, opioids and antidepressants are not regarded as essential medicines.

Although not considered essential medicines, stopping any of these medicines abruptly can cause discontinuation/withdrawal symptoms, such as dizziness/drowsiness, insomnia, irritability, headache, nausea and vomiting.

All of these medicines are associated with dependency and potential for discontinuation/withdrawal reactions and this should be discussed with the individual before initiation. The risk of harm increases with the increasing number of these medicines taken concurrently.²⁹⁹ Each has a risk of dependence, so there should be assessment of risk factors such as history of problem substance/alcohol use. Pharmacological and non-pharmacological approaches should be considered as treatment options and reviewed regularly for effectiveness.

Opioids are used for the management of acute pain.^300,301 Due to lack of evidence for efficacy and evidence of significant long-term risks, they are not recommended long-term for the management of non-cancer chronic pain.

Antidepressants are mainly used for the management of anxiety and depression. They may also be used for the management of neuropathic pain.

Benzodiazepines and z-drugs are used for the short-term treatment of insomnia, and/or anxiety disorders but use should be limited to less than four weeks on an ‘as required’ basis, and the benefits and risks of treatment must be balanced and therapeutic objectives agreed. They are associated with:

• avoidable harm such as falls, cognitive dysfunction, and increased mortality in some populations
• dependence. Assess risk factors such as history of problem substance/alcohol use

Gabapentin and pregabalin are antiseizure medications but they are commonly used for the management of neuropathic pain and anxiety. However, they have a significant risk of adverse effects including drowsiness or somnolence, dizziness, nausea, weight changes (abnormal appetite), severe respiratory depression, cognition and speech problems/ataxia.³⁰²

Antidepressants

The effectiveness of antidepressants needs to be reviewed (after one to two weeks, maximum four weeks) and switched to an alternative if this is not effective, rather than increasing the dose.

Opioids

Opioids are used for the management of acute pain. They should not be used long-term for the management of chronic pain.^300,301

• exercise and physical activity can contribute to a reduced need for medicines in osteoarthritis. This can improve mood and well-being
• for those with osteoarthritis the first-line medicines are paracetamol and/or topical analgesia, e.g. diclofenac and ibuprofen gels/sprays or capsaicin cream
• intra-articular injections of corticosteroids can be a useful alternative to oral NSAID for osteoarthritic flares in some individuals
• a weak opioid, such as codeine may be required for some people. If pain is ongoing and severe, consider a stronger opioid at the lowest effective dose to manage pain for short-term use and with regular review. Note that there is an increased risk of serotonin syndrome with SSRIs and tramadol, and also hyponatraemia

Gabapentinoids

• In the management of pain, they are licensed for the treatment of neuropathic pain.
• Pregabalin is licensed for the management of generalised anxiety disorder.
• Their use should be reviewed if prescribed for other indications.

Benzodiazepines and z-drugs

These should only be used for short-term use and reduced and stopped after two to four weeks when used for non-essential purposes.

Where possible, when used for non-essential use, these medicines should be stopped. (See above for essential use where these medicines should not be stopped without specialist input).

Reduction of therapy should be controlled, not sudden, to manage the risk of discontinuation/withdrawal symptoms. Further information on reduction schedules is available in Quality prescribing for antidepressants: guide for improvement 2024 to 2027 and Quality prescribing for benzodiazepines and z-drugs: guide for improvement 2024 to 2027.

Successful reduction requires shared decision-making and the individual’s participation in a person-centred review that considers the personal context. A person-centred assessment of risk versus benefit should occur before reducing or stopping medication to determine the effectiveness of treatment.

• Before prescribing any of these medications, there should be a discussion about the potential risks of dependence and withdrawal.
• Very high-risk combination. Stop if you can. These combinations are associated with increased risk of respiratory depression, sedation and (in the case of antidepressants) serotonin syndrome.^303,304
• Only co-prescribe benzodiazepines with opioids if there is no alternative and, if necessary, the lowest possible doses should be given for the shortest duration.
• Monitor individuals closely for signs of sedation, respiratory depression and falls risk at initiation of treatment and when there is any change in prescribing, such as dose adjustments or co-prescribing of new medication.

Gabapentinoids

Prescribers and individuals should be aware:

• Reduced renal function requires dose reduction to reduce risk of toxicity and side effects.
• MHRA has highlighted the risk of foetal abnormalities, and this should be discussed with people before initiation.

Antidepressants

• With SSRIs, caution is advised in those receiving concomitant medications which could increase the risk of gastrointestinal (GI) toxicity or bleeding (such as nonsteroidals and antiplatelets).³⁰⁵

Opioids

• Higher doses have a greater risk of serious harm (four times higher for 50-100mg morphine equivalent dose (MED), nine times higher for doses greater than 100mg MED).
• Serious harms include overdose and death, opioid misuse, increased risk for falls and major trauma, and increased odds of road accident.¹⁷¹

For each of these medicines, review the continued need. Assess if the condition has resolved.

If more than one medication needs to be stopped, ideally do this one at a time to avoid withdrawal reactions. If there is mixing with street-products then this may be done more rapidly due to increased risk of overdose.

• they should be decreased in a step-wise manner to avoid any potential withdrawal reaction (see Quality prescribing for antidepressants: guide for improvement 2024 to 2027).¹⁰⁵ The rate of reduction should be agreed and discussed with the individual.
• consider introducing non-pharmacological interventions if not already in place.

Supporting people who do not or cannot reduce/stop

• Review continued need for medication and risks and harms of ongoing treatment.
• Encourage non-pharmacological approaches to support reduction where appropriate, such as CBT and physical activity.

Specific areas/situations where medication may need to be introduced or increased

• When reducing doses of any of these medications, individuals may experience discontinuation/withdrawal symptoms. It may be necessary to pause and review the withdrawal schedule.
• Depression can reoccur or the individual can have relapses. In these scenarios the antidepressant may need to be re-introduced at the lowest effective dose, along with non-pharmacological approaches. Other medicines the individual is taking should be reviewed to ensure that there is no increased risk of harm due to combinations.

Does the person understand the outcomes of the review, including risks and benefits?

• Use the shared decision-making tools to discuss the risks and benefits of the combinations.

Is drug therapy tailored to the individual?

• Ensure the individual and carers are aware of these risks of these medicines and their combination, discuss alternatives.

Agree the plan

• Review and agree the reduction plan.
• Discuss non-pharmacological options to support mental health and well-being, and physical activity to manage pain.
• Continue regular review, whether treatment changing or remaining the same.

• self-management/support tools
• decision aids

Reduction schedules for antidepressants

Reduction schedules for benzodiazepines and z-drugs

Reducing and stopping antipsychotics

National Therapeutic Indicators (NTIs) use prescription data in specific areas to provide a measure of prescribing activity for comparison across NHS Boards, Health and Social Care Partnerships (HSCPs), GP clusters and GP practices.

NTIs are available to view online.

NTIs benchmark prescribing across set parameters and are presented in a variety of ways. Examining variation over time can indicate where improvements in prescribing can be made. The indicator detail provides further information and suggested actions.

Indicators for this hot topic include:

• People receiving three or more of benzodiazepine/z-drug, opioid (including tramadol), gabapentinoid, antidepressant or antipsychotic (excluding depots). See the chart below.

People receiving three or more of benzodiazepine/z-drug, opioid (including tramadol), gabapentinoid, antidepressant or antipsychotic (excluding depots)

(Click on image to enlarge)