What is the best approach to manage benzodiazepine (benzo) withdrawal symptoms in a patient with a history of substance abuse and potential underlying conditions such as epilepsy?

Management of Benzodiazepine Withdrawal

Benzodiazepine withdrawal must be managed with a slow, gradual taper reducing the dose by 10-25% of the current dose every 1-2 weeks, with benzodiazepine tapering taking priority over opioid tapering when both medications are present due to the life-threatening risks of benzodiazepine withdrawal including seizures and death. 1

Critical Safety Framework

Abrupt discontinuation of benzodiazepines can cause seizures and death and is never appropriate. 2, 3 Benzodiazepine withdrawal carries greater risks than opioid withdrawal and must always be conducted gradually. 1 Withdrawal seizures have been reported even with less than 15 days of use at therapeutic dosages, though they occur most commonly in patients taking high doses for prolonged periods. 4

Priority When Multiple Substances Are Involved

When a patient is taking both opioids and benzodiazepines and both need discontinuation, taper the benzodiazepines first due to higher withdrawal risks, while maintaining the opioid (such as buprenorphine) dose stable. 1 This represents updated guidance that supersedes older recommendations suggesting opioid tapering first. 1

Specific Tapering Protocol

Standard Tapering Schedule

Reduce the benzodiazepine dose by 10-25% of the current dose (not the original dose) every 1-2 weeks. 1 This percentage-based approach prevents disproportionately large final reductions. 1 For patients on benzodiazepines for more than 1 year, consider extending the taper to 10% per month rather than 10-25% every 1-2 weeks. 1

Example Tapering Schedule

For a patient on diazepam 20 mg/day: 1

• Weeks 1-2: Reduce to 15 mg/day (25% reduction)
• Weeks 3-4: Reduce to 11-12 mg/day (20-25% of current dose)
• Continue: Reduce by 10-25% of the current dose every 1-2 weeks

Adjusting Taper Rate

The taper rate must be determined by the patient's tolerance to withdrawal symptoms, not by a rigid schedule. 1, 5 Pauses in the taper are acceptable and often necessary when withdrawal symptoms emerge. 1 Clinically significant withdrawal symptoms signal the need to further slow the taper rate. 1 The taper will likely take 6-12 months minimum, and possibly longer. 1

Final Dosing Strategy

Once the smallest available dose is reached, extend the interval between doses before complete discontinuation. 1

Benzodiazepine Selection for Tapering

Long-acting benzodiazepines (diazepam, chlordiazepoxide) provide more protection against seizures and delirium during withdrawal. 6 However, short and intermediate-acting benzodiazepines (lorazepam, oxazepam) are safer in elderly patients and those with hepatic dysfunction. 6

For alcohol withdrawal syndrome specifically, diazepam has the shortest time to peak effect and longest elimination half-life, resulting in smoother withdrawal with lower incidence of breakthrough symptoms. 7

Monitoring Withdrawal Symptoms

Common Withdrawal Symptoms to Monitor

Monitor for the following withdrawal symptoms at each visit: 1, 5

• Anxiety, panic attacks, and increased irritability
• Tremor and hyperreflexia
• Insomnia and sleep disturbances
• Sweating and tachycardia
• Headache and muscle aches
• Nausea and vomiting
• Confusion or altered mental status
• Perceptual hypersensitivity (including tinnitus)
• Seizures (medical emergency)

Assessment Tools

The Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) is useful in clinical practice for alcohol withdrawal syndrome, with a score >8 indicating moderate withdrawal and ≥15 indicating severe withdrawal. 6 While insufficiently validated specifically for benzodiazepine withdrawal in patients with alcohol-related liver disease, similar symptom-triggered approaches can be applied. 6, 8

Follow-up Schedule

Follow up at least monthly during the taper, with more frequent contact needed during difficult phases. 1, 5 Team members including nurses, pharmacists, and behavioral health professionals can support patients through telephone contact, telehealth, or face-to-face visits. 1

Pharmacological Adjuncts for Withdrawal Management

Gabapentin

Gabapentin can mitigate withdrawal symptoms during benzodiazepine tapering. 5 Start with 100-300 mg at bedtime or three times daily, increasing by 100-300 mg every 1-7 days as tolerated. 1, 5 Adjust dosage in patients with renal insufficiency. 1 Titrate cautiously to avoid dose-dependent dizziness and sedation. 1

Carbamazepine

Carbamazepine may assist benzodiazepine discontinuation, particularly in patients receiving benzodiazepines in daily dosages of 20 mg/d or greater of diazepam equivalents (200-800 mg/d of carbamazepine). 9 However, carbamazepine may affect alprazolam metabolism. 1 Note that antiseizure medications themselves require tapering to avoid substituting one drug dependence for another. 1

Pregabalin

Pregabalin has shown potential benefit in facilitating benzodiazepine tapering. 1, 5

Antidepressants

SSRIs, particularly paroxetine, may help manage underlying anxiety during tapering, though they do not directly treat withdrawal symptoms. 1, 5 Around 28% of patients may require antidepressant therapy for depression or panic during or after benzodiazepine discontinuation. 9

Symptomatic Management

For specific symptoms during tapering: 1

• Insomnia: Trazodone for short-term management (avoid substituting another benzodiazepine or Z-drug)
• Muscle aches: NSAIDs or acetaminophen

Non-Pharmacological Interventions

Cognitive Behavioral Therapy

Integrating cognitive behavioral therapy (CBT) during the taper significantly increases success rates and should be incorporated. 1, 5 CBT is particularly helpful for patients struggling with benzodiazepine discontinuation. 1

Additional Supportive Measures

Incorporate the following non-pharmacological approaches: 1, 5

• Mindfulness and relaxation techniques
• Sleep hygiene education
• Exercise and fitness training
• Patient education about benzodiazepine risks and benefits of tapering (improves outcomes and engagement)
• Psychological support and reassurance about the temporary nature of withdrawal symptoms

Special Populations

Elderly Patients

Use lower doses and more gradual tapers for elderly patients. 1 Benzodiazepines in elderly patients are associated with cognitive impairment, reduced mobility, unsafe driving, falls, fractures, loss of functional independence, and dementia (particularly with higher-dose hypnotics). 1 Long-acting agents like diazepam pose particular concerns due to sedation and fall risk. 1

Patients with Hepatic Dysfunction

Short and intermediate-acting benzodiazepines (lorazepam, oxazepam) are safer in patients with hepatic dysfunction. 6 The notion that diazepam should be avoided in liver disease is based on conjecture; clinical evidence suggests diazepam is safe when administered using a symptom-based approach. 7

Pregnant Patients

Pregnant patients should not taper benzodiazepines during pregnancy without specialist consultation, as withdrawal can cause spontaneous abortion and premature labor. 1 Use of benzodiazepines late in pregnancy can result in neonatal sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms in newborns. 2

Patients with Epilepsy

When several different types of seizure disorders coexist, benzodiazepines may increase the incidence or precipitate generalized tonic-clonic seizures, requiring addition of appropriate anticonvulsants or dosage increases. 3 Concomitant use of valproic acid and clonazepam may produce absence status. 3

Patients with Substance Use Disorder

For patients with co-occurring substance use disorder, consider medication-assisted treatment with buprenorphine or methadone in combination with behavioral therapies. 1 Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse due to risk of abuse. 2 Both benzodiazepines and clomethiazole carry potential risk of abuse, and clinicians should avoid use beyond the initial 10-14 days of treatment for alcohol withdrawal syndrome. 6

When to Refer to a Specialist

Immediate specialist referral is indicated for: 1, 5

• Patients with a history of withdrawal seizures
• Unstable psychiatric comorbidities
• Co-occurring substance use disorders
• Previous unsuccessful office-based tapering attempts
• Patients requiring concurrent management of multiple CNS depressants

Consider involving pharmacists and pain specialists as part of the management team when benzodiazepines are prescribed along with other CNS depressants. 1

Critical Pitfalls to Avoid

Never Taper Too Quickly

Research shows that even a 10% reduction every 3 days resulted in only 24% of patients completing withdrawal successfully. 1 Short tapers of 2-4 weeks down to therapeutic minimum doses show minimal benefits over abrupt discontinuation and are often not tolerated. 10

Never Abandon the Patient

Maintain the therapeutic relationship even if tapering is unsuccessful. 1 If the patient refuses to taper, establish goals for continued benzodiazepine therapy and maximize non-pharmacologic treatments. 1 Consider maintenance therapy rather than forcing discontinuation. 1

Avoid Concurrent CNS Depressants

Avoid prescribing opioids and benzodiazepines simultaneously whenever possible due to increased risk of respiratory depression and death. 1 The concomitant use of benzodiazepines and opioids increases respiratory depression risk because of actions at different receptor sites (GABA-A sites and mu receptors). 2, 3 If concurrent use is necessary, limit dosage and duration, and monitor closely for respiratory depression and sedation. 2, 3

Avoid prescribing additional CNS depressants during the tapering period. 1 Concomitant use with alcohol is not recommended due to enhancement of sedative effects. 2

Drug Interactions to Consider

Compounds that inhibit hepatic enzymes (particularly cytochrome P450 3A and 2C19) may lead to increased and prolonged sedation with diazepam, including cimetidine, ketoconazole, fluvoxamine, fluoxetine, and omeprazole. 2 Clonazepam has the potential to influence phenytoin concentrations, requiring monitoring. 3

Realistic Expectations and Goals

Patient agreement and interest in tapering is a key component of success. 1 Use shared decision-making and explain the risks of continued use versus benefits of discontinuation. 1 Some patients may need to extend their taper over many months to years to avoid debilitating withdrawal symptoms. 5

Tapers may be considered successful as long as the patient is making progress, with the goal of durability of the taper, not speed. 1 Around half of patients dispensed benzodiazepines have been treated continuously for at least 12 months, often beyond guideline recommendations. 5 In some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with symptoms lasting weeks to more than 12 months. 2, 3

Monitor for depression, anxiety, and substance use disorders that may emerge during tapering, and screen for suicidal ideation. 1 Advise patients of increased overdose risk if they return to previous doses after tolerance is lost. 1