Best practice for prescribing drugs with dependence potential

Introduction

Medications associated with physical dependence and withdrawal — including opioids, benzodiazepines, Z-drugs, gabapentinoids, antidepressants and psychomotor stimulants — are widely prescribed across healthcare settings to manage conditions, such as chronic pain, anxiety disorders, insomnia, depression and attention-deficit hyperactivity disorder (ADHD)^​1​. These medications have an important role in improving symptom control, functional status and quality of life for patients. However, concerns regarding physical dependence, withdrawal, misuse and addiction have increased, prompting national efforts in the UK to improve safer prescribing and deprescribing practices^​1–3​.

In England, about 67 million prescription items for dependency-forming medications were issued during the 2024/2025 financial year to about 7 million patients^​4​. Opioids accounted for the largest proportion of prescribing activity, with around 39 million dispensed items. Prescribing rates are higher among older adults and people living in socio-economically deprived areas, contributing to significant health inequalities. Furthermore, national data suggest that around 26% of adults in England receive at least one dependence-forming medication each year^​4,5​.

These medications have clear benefits; however, public health risks — including medication-related morbidity, overdose, impaired quality of life and healthcare inequalities — cannot be ignored^​6–8​. These risks must also be considered alongside the potential harms with the undertreatment of pain, mental health and other chronic conditions^​6,9​.

This article is aimed to provide healthcare professionals with an evidence-based overview of medications associated with dependence and withdrawal, supporting informed clinical decision-making to optimise therapeutic outcomes while minimising the risks of dependence, withdrawal, misuse, diversion and medication-related harm.

Understanding dependence and addiction

The terms ‘dependence’ and ‘addiction’ are frequently used interchangeably in clinical practice; however, they describe distinct phenomena with important implications for patient care, prescribing practice and overall patient health.

Physical dependence is characterised by physiological and behavioural adaptations that develop following repeated exposure to a substance, including the emergence of tolerance and withdrawal symptoms^{​10–12​}. Importantly, withdrawal reactions may occur in patients who have taken medications as prescribed and do not necessarily indicate misuse^​13,14​.

In contrast, addiction (i.e. substance use disorder) involves behavioural features such as compulsive drug use, impaired control, craving and continued use despite harm^​10,12​. Addiction may include behaviours such as unauthorised dose escalation, obtaining medication from multiple healthcare providers or persistent drug-seeking behaviour^​15​.

The distinction between dependence and addiction is particularly important when managing prescribed medications associated with withdrawal phenomena. Clinicians should avoid equating withdrawal symptoms and dependence with addictive disorders, as distinguishing these terms is essential for effective clinical management, and to avoid stigma, inappropriate treatment decisions and unnecessary abrupt discontinuation^{​11,16–18​}.

Common medications associated with dependence potential

Opioids

Opioids — such as morphine, codeine, oxycodone, tramadol and fentanyl — are effective analgesics for acute and selected chronic pain^​19​. Significant risks are associated with long-term use, including tolerance, dependence, opioid-induced hyperalgesia, sedation, constipation, endocrine effects and overdose. Risk increases with prolonged use and when opioids are used in combination with other central nervous system (CNS) depressants (e.g. benzodiazepines or alcohol), because this elevates the risk of respiratory depression and fatal overdose^{​20–23​}. Current clinical guidelines recommend using the lowest effective dose for the shortest duration, with frequent review of pain control, functional outcomes and ongoing clinical need^​24,25​.

Benzodiazepines

Benzodiazepines — such as diazepam, lorazepam and temazepam — are used for short-term management of anxiety, agitation, seizures and alcohol withdrawal^​26,27​. However, physiological dependence can develop, particularly with prolonged use^​24​. Abrupt discontinuation may result in withdrawal symptoms including rebound anxiety, insomnia, autonomic instability and, in severe cases, seizures^​28​. Therefore, gradual dose reduction is recommended when discontinuing treatment^​29​. Adverse effects can include sedation, cognitive impairment, psychomotor slowing, increased risk of falls, impaired driving and, in some cases, paradoxical agitation, especially among older patients^​26​.

Z-drugs

Zopiclone, zolpidem and eszopiclone are hypnotics used for short-term management of insomnia owing to their sedative effects mediated via the GABA_A receptor complex^​30,31​. Although initially considered safer than benzodiazepines, Z-drugs exhibit comparable risks of tolerance, dependence and withdrawal^​32​. Long-term use can lead to rebound insomnia, thereby reinforcing chronic prescribing patterns. Other risks include cognitive impairment, increased risk of falls and fractures, impaired psychomotor performance and impaired driving, particularly in older patients^​32​. Clinical guidance recommends restricting use to short courses, not exceeding four weeks, to minimise the risk of dependence and withdrawal^​31​.

Gabapentinoids

Gabapentin and pregabalin (i.e. gabapentinoids) are used for neuropathic pain, epilepsy and anxiety (i.e. pregabalin) through modulation of voltage-gated calcium channels to reduce excitatory neurotransmitter release^​33,34​. Evidence shows potential for misuse and dependence, especially among individuals with a history of substance misuse^{​35–37​}. In response to escalating concerns regarding abuse and associated mortality risk, both gabapentin and pregabalin were reclassified in the UK as schedule 3 controlled substances in 2019 under the Misuse of Drugs Regulations^​38​. The risk profile of these agents is significantly heightened when co-prescribed with other CNS depressants, owing to additive effects on sedation and respiratory function^​39​.

Antidepressants

Antidepressants are widely prescribed for depressive and anxiety disorders. While not considered addictive, they may cause discontinuation symptoms, particularly with short half-life drugs such as paroxetine and venlafaxine^​13,40​. Discontinuation symptoms include dizziness, anxiety, insomnia, nausea, mood changes and sensory disturbances (e.g. ‘electric shock’ sensations or ‘brain zaps’)^{​41–43​}. These effects are more likely to occur following abrupt cessation or rapid dose reduction, especially after prolonged treatment duration or higher doses. Consequently, abrupt discontinuation should be avoided and gradual hyperbolic tapering is recommended to minimise withdrawal-related morbidity^​44,45​. Patients should be counselled prior to initiation of therapy regarding the potential for discontinuation symptoms, to support informed decision-making and improve adherence to tapering strategies^​45,46​.

Stimulants

Methylphenidate and lisdexamfetamine are primarily used in the management of ADHD, but carry risks of misuse and recreational use, particularly among younger adults^{​47–49​}. Modified-release formulations are generally preferred in clinical practice because they provide more stable plasma concentrations, reduce peak-related reinforcing effects and are associated with a lower potential for abuse compared with immediate-release preparations^​50​.

Risk assessment

Comprehensive risk assessment is a fundamental component of safe prescribing and should be undertaken prior to initiating medications associated with dependence, with regular reassessment throughout the course of treatment^​24​. The primary aim of risk assessment is to identify factors that may increase an individual’s susceptibility to dependence, withdrawal-related complications, misuse, overdose or other medication-related harms. However, susceptibility varies considerably between individuals and reflects a complex interaction of biological, psychological and social factors rather than discrete risk categories alone^​51​. This heterogeneity supports an individualised, patient-centred approach to prescribing and deprescribing, incorporating ongoing review and shared decision-making^​24,52​.

Important clinical risk factors include both medical and psychiatric comorbidities, particularly a personal or family history of substance misuse, depression, anxiety, chronic pain, respiratory disease, cognitive impairment and frailty^{​24,53–57​}. Concomitant use of sedating or interacting medications further heightens risk, particularly with combinations such as opioids with benzodiazepines or gabapentinoids, benzodiazepines with alcohol, and serotonergic antidepressants, which may precipitate serotonin syndrome^{​22,39,58​}.

Beyond clinical considerations, social determinants — including socio-economic deprivation, social isolation, unemployment, housing instability and limited healthcare access — contribute to increased susceptibility to dependence and medication-related harm^​59​.

While validated screening tools exist to assess dependence and misuse risk, such instruments should be used to support, rather than replace, comprehensive clinical assessment and professional judgement^{​24,60–62​}.

Considerations for initiating treatment

Medications associated with dependence should only be initiated where there is a clear evidence-based indication and where the benefits outweigh the risks of dependence, withdrawal and other adverse outcomes^​24​.

Non-pharmacological interventions should be considered first line where appropriate, including psychological therapies, such as cognitive behavioural therapy, physiotherapy and exercise-based approaches for chronic pain, and other social prescribing interventions^{​63–65​}. These approaches can reduce reliance on long-term pharmacotherapy and support more sustainable clinical outcomes.

The decision to initiate treatment should be grounded in shared decision-making, whereby clinicians and patients consider the potential benefits, risks, alternatives and uncertainties associated with treatment^​66​. Prior to prescribing, patients should be fully informed of expected benefits, limitations, risks, alternatives, duration of therapy and review arrangements to support informed consent^​24,65​. This approach promotes patient autonomy and has been associated with improved treatment adherence, greater patient satisfaction and enhanced clinical outcomes across healthcare settings^​67​.

Monitoring and review

Regular, structured medication review is essential to ensure safe ongoing use and should be available to all patients prescribed medications associated with dependence potential, with frequency determined by individual risk factors, including patient preference, clinical risk, medication type, dose and duration^​24​. Review frequency should be adjusted in response to changes in clinical or social circumstances, dose modification or patient-reported concerns^​53,54​.

Reviews should assess effectiveness, functional outcomes, adverse effects, tolerance or dependence, misuse, mental health status and ongoing clinical need^{​24,25,31,65​}. Where appropriate, clinicians should consider opportunities for dose reduction, treatment optimisation or deprescribing^​68​. In the context of long-term opioid therapy, assessment should focus not solely on pain intensity, but also on functional capacity, quality of life and meaningful patient-centred outcomes^​53​.

Multidisciplinary approaches are important in the monitoring and review of medications associated with dependence, with collaboration needed between physicians, pharmacists, nurses, addiction specialists, psychologists, social workers and physiotherapists supporting safer prescribing, risk reduction and patient-centred care^{​69–71​}. Research has highlighted that pharmacists play a role in monitoring and ongoing review through identification of prescribing risks, monitoring for misuse and adverse effects, and supporting deprescribing and tapering strategies, which can improve medicines optimisation and reduce dependence-related harm^{​69,72–74​}.

Community pharmacy could also play a role in detecting early signs of misuse through monitoring dispensing patterns (e.g. early refills, multiple prescribers, dose escalation and CNS polypharmacy) and identifying behavioural red flags at the point of supply (e.g. sedation, intoxication, withdrawal or distress about access), which may support early intervention and harm reduction^{​72,75–77​}.

Discontinuation and deprescribing

Discontinuation of medications associated with dependence should be considered when treatment is no longer beneficial, when dependence-related problems or misuse emerge, when the underlying condition has resolved, or when patients express a preference to reduce or stop treatment^​24​.

Deprescribing should be individualised, patient-centred and undertaken through shared decision-making, balancing the potential benefits of discontinuation against the risks of symptom recurrence, relapse and withdrawal effects^​24​. Abrupt cessation should generally be avoided as it may lead to significant withdrawal reactions and associated complications, particularly with opioids, benzodiazepines, gabapentinoids, Z-drugs, antidepressants and psychomotor stimulants. Dependence-associated medicines should generally be tapered gradually, tailored to patient needs and preferences^{​13,24,40​}.

Table 1 summarises the withdrawal features for commonly used drug classes associated with dependence^{​24,29,31,62,68,78–83​}.

Table 1: Summary of withdrawal features for commonly used drug classes

Patient counselling and communication

Effective communication is central to the safe prescribing and management of medications associated with dependence. A patient-centred, collaborative and non-judgemental approach fosters trust, which supports informed decision-making and enhances treatment adherence^​24,84​.

Adequate consultation time should be allocated to explore patient preferences, concerns and expectations, while acknowledging areas of uncertainty where evidence is limited^​18,24​. Particular care should be taken to avoid stigmatising language, as this may undermine therapeutic relationships and discourage patient engagement^​18,24​, for example, describing a patient as a ‘drug seeker’ or suggesting they are ‘addicted’.

Written information and educational resources should be provided, particularly for medications such as opioids, benzodiazepines and gabapentinoids^​85​. Counselling should include discussion of sedation, impairment of driving and operating machinery, alcohol interactions, overdose risk and withdrawal phenomena^​85​. Comprehensive patient education facilitates early recognition of adverse effects, improves adherence and supports safer long-term use^​86​. Signposting to peer-support networks, patient organisations and other community resources may further enhance understanding and engagement with care^​24​. Examples may include peer-led recovery groups, family and carer support services, and community-based recovery or mutual aid programmes that help individuals sustain motivation and reduce relapse risk.

Conclusion

Medications associated with dependence remain essential in contemporary healthcare and provide substantial therapeutic benefit across a range of clinical conditions. However, their use requires careful, evidence-based management to minimise the risks of dependence, withdrawal, misuse and other medication-related harms. A clear understanding of the distinction between physical dependence and addiction is fundamental to reducing stigma and supporting appropriate clinical decision-making. Safe prescribing encompasses comprehensive risk assessment, shared decision-making, structured monitoring and carefully planned discontinuation strategies. Clinical guidance increasingly emphasises person-centred care, reduction of inappropriate long-term prescribing and greater integration of non-pharmacological treatment approaches. Through multidisciplinary collaboration and adherence to evidence-based principles, healthcare professionals can optimise therapeutic outcomes while minimising the potential harms associated with dependence-forming medications.