How do you treat benzodiazepine withdrawal (patient takes clonazepam 0.1mg TID and has not had it >3 days)

Comment by InpharmD Researcher

Benzodiazepine withdrawal is generally managed with a strategic taper. The World Health Organization (WHO) guideline on withdrawal symptoms presented a benzodiazepine reducing schedule based upon diazepam equivalence (see Table 1 for a sample low-dose strategy). American Addiction Centers discussed adjunctive therapies such as antidepressants, anticonvulsants, or melatonin may be warranted on a patient-by-patient basis. Dose of benzodiazepine may be tapered by about one-eighth to one-tenth of the daily dose every 1–2 weeks. While an optimal duration of 6–8 weeks for withdrawal has been proposed in literature, certain individuals may require a longer period. Withdrawal symptoms may fluctuate; however experts generally do not recommend increasing dose once a formal taper has begun.
Background

The World Health Organization’s clinical guideline on withdrawal management states the safest way to manage benzodiazepine withdrawal is to strategically taper the agent. This helps to relieve benzodiazepine withdrawal symptoms and prevent the development of seizures. The first step in benzodiazepine withdrawal management is to stabilize the patient on an appropriate dose of diazepam. Calculate how much diazepam is equivalent to the dose of benzodiazepine that the patient currently uses, to a maximum of 40 mg of diazepam. For the situation in question, clonazepam 0.1 mg TID, a low-dose benzodiazepine reducing schedule should be employed (see Table 1). The guideline stresses the length of time between each dose reduction should be based on the presence and severity of withdrawal symptoms. Generally, there should be at least one week between dose reductions. Benzodiazepine withdrawal symptoms may fluctuate. They do not recommend increasing the dose when symptoms worsen. The current dose should be maintained until symptoms improve and then continue deescalating the dose. [1]

According to the American Addiction Centers, major withdrawal symptoms can be largely avoided with gradual weaning, or tapering, of clonazepam. Currently, there is not an approved medication to treat benzodiazepine dependence directly. If medical detox is necessary, antidepressants, specifically selective serotonin reuptake inhibitors such as paroxetine and fluoxetine may be helpful to manage depression and suicidal behaviors that may occur during detox and clonazepam withdrawal. If an individual develops complications, such as seizures, anticonvulsants (e.g., carbamazepine) may be useful. Anticonvulsants may also help assist with the withdrawal process related to discontinuation of clonazepam. Melatonin has been used in assisting individuals who develop insomnia during the withdrawal process and may also address other symptoms of clonazepam withdrawal and reverse tolerance. Other medications that influence GABA levels, such as gabapentin, are also being studied for management of clonazepam withdrawal, but data confirming its safety and efficacy in this setting are not provided. Various medications could theoretically be used to address specific symptoms during the withdrawal process, but data indicates that using a tapering process is the most effective means to manage withdrawal from benzodiazepines such as clonazepam. [2-3]

Similarly, a single-author review highlights the key to successful discontinuation during the management of benzodiazepine withdrawal is individualized dose tapering and psychological support if needed. Benzodiazepine dosage should be tapered gradually since abrupt withdrawal and the author recommends a rate of tapering for patients on therapeutic doses of benzodiazepine in steps of about one-eighth to one-tenth of the daily dose every 1–2 weeks. Optimal duration of 6–8 weeks for withdrawal has been proposed in literature, while certain individuals may require a longer period. [4]

For patients taking benzodiazepines for anxiety or using potent benzodiazepines, including clonazepam, use of diazepam for the management of withdrawal carries certain advantages. The slow elimination of diazepam allows a gradual fall in blood concentration and the availability of low-dosage forms permits small dosage reductions. When converting between clonazepam and diazepam, a dose of clonazepam 0.5 mg is reported to be equivalent to 10 mg diazepam. Multiple pharmacological agents have been evaluated for alleviating benzodiazepine withdrawal symptoms, but their efficacy for patients dependent on therapeutic doses seemed to be questionable. [4]

References:

[1] Clinical Guidelines for Withdrawal Management and Treatment of Drug Dependence in Closed Settings. Geneva: World Health Organization; 2009. 4, Withdrawal Management. Available from: https://www.ncbi.nlm.nih.gov/books/NBK310652/
[2] American Addiction Centers. Clonazepam Withdrawal - Symptoms, Length, and Treatment. Updated May 23, 2022. Accessed June 20, 2022. https://americanaddictioncenters.org/withdrawal-timelines-treatments/clonazepam
[3] Rickels K, DeMartinis N, Rynn M, Mandos L. Pharmacologic strategies for discontinuing benzodiazepine treatment. J Clin Psychopharmacol. 1999;19(6 Suppl 2):12S-16S. doi:10.1097/00004714-199912002-00003
[4] Ashton H. The diagnosis and management of benzodiazepine dependence. Current Opinion in Psychiatry. 2005;18(3):249-255. doi:10.1097/01.yco.0000165594.60434.84

Relevant Prescribing Information

BOXED WARNING: WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; AND DEPENDENCE AND WITHDRAWAL REACTIONS
Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation (see WARNINGS and PRECAUTIONS).
The use of benzodiazepines, including clonazepam, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing clonazepam and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (see WARNINGS)
The continued use of benzodiazepines, including clonazepam, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of clonazepam after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue clonazepam or reduce the dosage DOSAGE AND ADMINISTRATION)

WARNIING
Dependence and Withdrawal Reactions: To reduce the risk of withdrawal reactions, use a gradual taper to discontinue clonazepam or reduce the dosage (a patient-specific plan should be used to taper the dose) (see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of clonazepam).

Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use.

Acute Withdrawal Reactions The continued use of benzodiazepines, including clonazepam, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of clonazepam after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) (see DRUG ABUSE AND DEPENDENCE: DEPENDENCE.)

Protracted Withdrawal Syndrome In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months (see DRUG ABUSE AND DEPENDENCE: DEPENDENCE).

Interference with Cognitive and Motor Performance: Since clonazepam produces CNS depression, patients receiving this drug should be cautioned against engaging in hazardous occupations requiring mental alertness, such as operating machinery or driving a motor vehicle. They should also be warned about the concomitant use of alcohol or other CNS-depressant drugs during clonazepam therapy (see PRECAUTIONS: DRUG INTERACTIONS and INFORMATION FOR PATIENTS).

Half-life: Elimination half-life of clonazepam is typically 30 to 40 hours. Clonazepam pharmacokinetics are dose-independent throughout the dosing range.

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

How do you treat benzodiazepine withdrawal (patient takes clonazepam 0.1mg TID and has not had it >3 days)

Please see Table 1 for your response.


 

Low-dose benzodiazepine reducing schedule*
Patients using less than 40mg/day diazepam equivalent    
  Time of dose Total daily dose
  08:00 12:00 20:00
Start 5 mg  5 mg  5 mg  15 mg
1st reduction 5 mg  2.5 mg  5 mg 12.5 mg
2nd reduction 5 mg -- 5 mg 10 mg
3rd reduction 2.5 mg -- 5 mg 7.5 mg
4th reduction -- -- 5 mg 5 mg 
5th reduction -- -- 2.5 mg 2.5 mg

*The length of time between each dose reduction should be based on the presence and severity of withdrawal symptoms. The longer the interval between reductions, the more comfortable and safer the withdrawal. Generally, there should be at least one week between dose reductions.



References:

Adapted from: Clinical Guidelines for Withdrawal Management and Treatment of Drug Dependence in Closed Settings. Geneva: World Health Organization; 2009. 4, Withdrawal Management. Available from: https://www.ncbi.nlm.nih.gov/books/NBK310652/