Benzodiazepine withdrawal syndrome

Figure 2. Recommendations for tapering benzodiazepines

When will benzodiazepine withdrawal syndrome stop?

Your benzodiazepine withdrawal syndrome will usually stop after a few weeks. But they can last longer for a small amount of people. You may not get benzodiazepines withdrawal symptoms when you stop your benzodiazepine medication. You should talk to your doctor or local pharmacist if you are worried about the withdrawal effects of benzodiazepines.

Is there anything that can help with my symptoms through benzodiazepine withdrawal?

Antidepressant and mood stabilizing drugs may help with the withdrawal effects of benzodiazepines.

If you have insomnia you may benefit from treatment with melatonin. Melatonin may help benzodiazepine reduction in older people with insomnia ⁴.

If you have a panic disorder you may benefit from cognitive behavioral therapy (CBT) whilst you are coming off the medication.

Should every patient be withdrawn from benzodiazepine?

There may be a small number of patients whose quality of life improves with the stable use of benzodiazepines ⁴. This may justify long-term benzodiazepine therapy. The decision to continue long-term benzodiazepine treatment needs to be clearly documented ⁴. The decision may also involve a second opinion by a specialist in an area relevant to the patient’s needs ⁴. These patients still require regular, ongoing review and re-assessment of the risks and benefits of benzodiazepine use ⁴.

Attempts at benzodiazepine withdrawal are more likely to succeed if the patient is able to contemplate the ultimate goal of cessation, and the doctor and patient are able to work together in a productive therapeutic relationship to achieve this.

Some patients struggle to reduce and cease benzodiazepine use. However, this group can often reduce their daily dose markedly and this is accompanied by a decrease in risk and side effects ⁴. They may continue on low-dose benzodiazepines (e.g., 2 to 5 mg diazepam daily) for an extended period ⁴. Continued regular review may assist in the majority of patients who will successfully cease benzodiazepines in the longer term ⁴. This decision should be made on a case-by-case basis ⁴.

For patients who have complex, multiple morbidities, doctors should seek advice from mental health and addiction specialists, as well as other relevant specialists (eg neurologists) to assist with development of the best plan to assist the patient ⁴.

What are benzodiazepines?

Benzodiazepines are drugs that belong to the group of medicines called central nervous system (CNS) depressants or sedatives, which are medicines that slows down messages traveling between your brain and your body. Other central nervous system (CNS) depressants include alcohol, cannabis and heroin. The central nervous system (brain and spinal cord) effects of benzodiazepines are believed to be mediated by activation of gamma aminobutyric acid (GABA) A receptors and modulation of their inhibition of neurotransmission ¹². Because benzodiazepines are controlled substances with abuse potential, they are available only with your doctor’s prescription with special attention directed toward the patient’s addiction history before these agents are prescribed.

Benzodiazepines are also minor tranquilizers, usually prescribed by doctors to relieve stress and anxiety and to help people sleep. Benzodiazepines can also be used to treat alcohol withdrawal symptoms and epilepsy. However, medical professionals have become concerned about their risks, particularly when they are used for a long time.

Benzodiazepines may be prescribed to:

• treat the symptoms of anxiety disorders
• relieve insomnia
• help with treatment of symptoms experienced by cancer patients
• control epilepsy
• help relax muscles during certain medical procedures (such as endoscopy)
• treat alcohol withdrawal.

Benzodiazepines are relatively safe and, with overdose, rarely result in death. However, used chronically, benzodiazepines can be addicting. These agents are often taken in combination with other drugs of abuse by patients with addiction disorders. Some people misuse benzodiazepines to get high or to help with the ‘come down’ effects of stimulants such as amphetamines or cocaine.

Benzodiazepines can cause a person to overdose, particularly when used with alcohol or other drugs. Benzodiazepines are associated with dependence and withdrawal symptoms, even after a short period of use which is why benzodiazepines are not the first option for pharmacological treatment of insomnia (difficulty falling asleep or staying asleep), anxiety or other health concerns ¹³.

Benzodiazepines are known by their chemical (generic) name or their brand name. In each case the drug is the same – it’s just made by a different company. Some common benzodiazepines are:

Table 1. Benzodiazepines pharmaceutical names

More than a dozen benzodiazepines are available by prescription. The following is a list of benzodiazepines in current use, with their initial brand name and year of approval: alprazolam (Xanax, 1981), chlordiazepoxide (Librium, 1960), clonazepam (Klonopin, 1997), clorazepate (Tranxene, 1972), diazepam (Valium, 1963), estazolam (ProSom, 1990), flurazepam (Dalmane, 1970), lorazepam (Ativan, 1977), midazolam (Versed, 1985), oxazepam (Serax, 1965), quazepam (Doral, 1985), temazepam (Restoril, 1981), triazolam (Halcion, 1982), and most recently clobazam (2011).

Benzodiazepines all share similar activity and clinical effects, but variability in dosing, pharmacokinetics, rapidity of uptake and half-life make them more suited for one or another of these indications. Thus, estazolam, flurazepam, quazepam, temazepam and triazolam are generally used as sleeping pills, whereas alprazolam, chlordiazepoxide, diazepam, and lorazepam are used largely for the treatment of anxiety. Clobazam, clonazepam, and clorazepate are used as anticonvulsants, and high dose, parenteral diazepam and lorazepam are used for status epilepticus. Parenteral midazolam, diazepam and lorazepam are also used as anesthetics or anesthetic premedications. Alprazolam (Xanax), clonazepam (Klonopin), diazepam (Valium) and lorazepam (Ativan) are listed among the top 100 most commonly prescribed medications in United States ¹⁴. According to the American Psychiatric Association report on benzodiazepines, 11 to 15 percent of the adult population has taken a benzodiazepine one or more times during the preceding year, but only 1 to 2 percent have taken benzodiazepines daily for 12 months or longer ¹⁵. In psychiatric treatment settings and in substance-abuse populations, however, the prevalence of benzodiazepine use, abuse and dependence is substantially higher than that in the general population ¹⁶.

Types of benzodiazepines

There are three types of benzodiazepines: long, intermediate and short-acting. Short-acting benzodiazepines have stronger withdrawal or ‘come down’ effects and can be more addictive than long-acting ones ¹⁷.

• Benzodiazepines used as sleeping pills (hypnotics) are shorter acting. They are mostly used for treating sleep problems such as insomnia.
• Benzodiazepines used to treat anxiety (anxiolytics) are longer lasting. They are mostly used for treating anxiety.

Table 2. Benzodiazepines used as sleeping pills (hypnotics)

Table 3. Benzodiazepines used to treat anxiety (anxiolytics)

High-potency benzodiazepines

• Drugs with a short half-life
  • Alprazolam (Xanax)
  • Lorazepam (Ativan)
  • Triazolam (Halcion)
• Drugs with a long half-life
  • Clonazepam (Klonopin)

Low-potency benzodiazepines

• Drugs with a short half-life
  • Oxazepam (Serax)
  • Temazepam (Restoril)
• Drugs with a long half-life
  • Chlordiazepoxide (Librium)
  • Clorazepate (Tranxene)
  • Diazepam (Valium)
  • Flurazepam (Dalmane)

How do benzodiazepines work?

Benzodiazepines are central nervous system depressants and they all increase activity at receptors for the neurotransmitter gamma-aminobutyric acid (GABA). The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) inhibits the activity of neurons, slowing down the workings of your brain and nervous system. Benzodiazepines enhance the affinity of the recognition site for GABA by inducing conformational changes that make GABA binding more efficacious. Activation of the benzodiazepine-GABA-chloride ionophor complex is responsible for producing the therapeutic anxiolytic effects of benzodiazepines and for mediating many of the side effects and, possibly, dependence and withdrawal from these drugs ¹⁸.

Similarly, other sites for drug and neurotransmitter binding are associated with the GABA receptor complex, which serves as a primary site of action of benzodiazepines, barbiturates and other sedative-hypnotics, such as alcohol ¹⁸. Benzodiazepines and barbiturates act at separate binding sites on the receptor to potentiate the inhibitory action of GABA. They do so by allosterically altering the receptor (changing its conformation) so that it has a greater binding affinity for GABA. Ethanol modifies the receptor by altering the membrane environment so that it has increased affinity for GABA and the other sedative-hypnotic drugs. That benzodiazepines, barbiturates and ethanol all have related actions on a common receptor type, which explains their pharmacologic synergy and cross tolerance. Thus, benzodiazepines are used during alcohol detoxification.

With long-term high-dose use of benzodiazepines (or ethanol), there is an apparent decrease in the efficacy of GABA-A receptors, presumably a mechanism of tolerance ¹⁹. When high-dose benzodiazepines or ethanol are abruptly discontinued, this “down-regulated” state of inhibitory transmission is unmasked, leading to characteristic withdrawal symptoms such as anxiety, insomnia, autonomic hyperactivity and, possibly, seizures.

Benzodiazepines differ mainly in how quickly they are absorbed, how long their effects last, and how long they take to leave the body. Benzodiazepines only treat symptoms of anxiety or insomnia, and do not solve the underlying causes of these conditions.

The effects of benzodiazepines depend on the strength of the dose, the physical make-up of the person taking them and their state of mind.

Common effects of benzodiazepines include:

• relief from anxiety
• muscle relaxation
• sleepiness
• a sense of being disconnected or detached from reality
• dizziness
• loss of inhibitions.

Benzodiazepines can be highly addictive, whether they are taken under medical supervision or used recreationally.

Benzodiazepines uses

Benzodiazepines are central nervous system (CNS) depressants that are commonly prescribed in medicine to treat anxiety, stress, panic disorders, insomnia, alcohol withdrawal symptoms, muscle relaxation, epilepsy and to sedate people before certain medical procedures. It is generally recommended that benzodiazepines only be used for a short term – just days or weeks at a time.

Benzodiazepines clinical uses ²⁰

• Anxiety disorders
  • Acute anxiety
  • Generalized anxiety disorder
  • Panic disorder
  • Phobias (social, simple)
  • Post-traumatic stress disorder (PTSD)
  • Obsessive-compulsive disorder (OCD)
• Insomnia
• Anxiety associated with medical illness
  • Cardiovascular
  • Gastrointestinal
  • Somatoform disorder
• Convulsive disorders
• Acute status epilepticus
  • Neonatal seizures or febrile convulsions
  • Preeclampsia
  • Tetanus
• Adjunct to other anticonvulsants
• Amnestic (before surgery or procedure)
• Spastic disorders and other types of acute muscle spasm
  • Cerebral palsy
  • Multiple sclerosis (MS)
  • Paraplegia secondary to spinal trauma
• Involuntary movement disorders
  • Restless leg syndrome
  • Akathisia associated with neuroleptic use
  • Choreiform disorders
  • Myoclonus
• Detoxification from alcohol and other substances
• Agitation or anxiety associated with other psychiatric conditions
  • Acute mania
  • Psychotic illness
  • Anxiety associated with depression
  • Impulse control disorders
  • Catatonia or mutism
• Other adjunctive uses
  • Surgery
  • Dentistry
  • Diagnostic studies, such as computed tomography, magnetic resonance imaging and endoscopy
  • Cardioversion
  • Chemotherapy

Severe anxiety

You may be given benzodiazepines for the short-term relief of severe anxiety. You should not be given them for long term relief.

Panic disorders

You may be given benzodiazepines:

• When you first start taking antidepressants, OR
• if you don’t respond to antidepressants.

Insomnia

Benzodiazepines can be used to treat insomnia. Insomnia means that you find it difficult to fall asleep or stay asleep.

You should only be offered benzodiazepines to treat insomnia if it is severe, disabling or is causing you a lot of distress.

Benzodiazepines should only be offered for short term use.

Acute alcohol withdrawal

Long acting benzodiazepines are used to help with the effects of acute alcohol withdrawal.

You should stay in hospital during alcohol withdrawal if you have severe alcohol dependence. Alcohol withdrawal without medical support can cause dangerous side effects such as seizures.

Recreational use of benzodiazepines

Some people take benzodiazepines illegally for recreational use. They may use them to feel a sense of euphoria (or high) or mix them with other drugs such as stimulants (cocaine, amphetamines, ecstasy) to ‘come down’. Benzodiazepines can be dangerous when mixed with other drugs (including alcohol) and can put you at risk of overdose or harm.

Some people may give them to others intentionally or without their consent (such as spiking their drink).

Benzodiazepine withdrawal syndrome symptoms

Benzodiazepine withdrawal syndrome symptoms are highly variable, mostly impacted by the level of dose reduction. Other contributing factors can include a history of polydrug dependence, seizures, anxiety, depression or trauma, or when the total daily dose is not clear due to doctor shopping or illegal purchase. Each patient will need tailored withdrawal management plan that will also address any underlying problems and contributing factors. Benzodiazepine withdrawal syndrome symptoms may appear in 1 to 2 days for agents with shorter half-lives, but may not appear until 3 to 7 days for agents with longer half-lives ⁴.

Benzodiazepines withdrawal symptoms may include:

• headaches
• aching or twitching muscles
• dizziness and tremors
• nausea, vomiting and stomach pains
• bizarre dreams, difficulty sleeping and fatigue
• poor concentration
• anxiety and irritability
• altered perception and heightening of senses
• delusions, hallucinations and paranoia
• seizures.

Common physical symptoms of benzodiazepines withdrawal:

• Stiffness
• Weakness
• Stomach problems
• Flu-like symptoms
• Visual problems

Common psychological symptoms of benzodiazepines withdrawal:

• Anxiety
• Insomnia
• Nightmares
• Depersonalization (the persistent feeling of observing oneself from outside one’s body or having a sense that one’s surroundings aren’t real)
• Problems with memory and concentration
• Depression
• Hallucinations. This is when you see, her, smell or feel things that are not there.
• Delusions. This is where you have beliefs that don’t match reality.

Protracted benzodiazepine withdrawal symptoms may include ²¹:

• Anxiety
• Depression
• Diarrhea, constipation, bloating
• Insomnia
• Irritability
• Muscle aches
• Poor concentration and memory
• Restlessness
• Less commonly, perceptual disturbances and panic attacks
• Occasionally, seizures and symptoms of psychosis.

These protracted benzodiazepine withdrawal symptoms do not occur in all benzodiazepine patients ²², but have a reported incidence between 15% and 44% among those taking benzodiazepines on a regular rather than an as-needed (PRN) basis ²³.

Benzodiazepine withdrawal syndrome treatment

Evidence-based recommendations for general management of benzodiazepine withdrawal are difficult due to a lack of clinical data ⁴. The following are general principles for managing benzodiazepine withdrawal syndrome ²⁴, ²⁵, ⁷:

• Review the patients’ prescription records and discuss the situation to those receiving long-term benzodiazepines.
• Send patients letters suggesting methods of tapering off benzodiazepines (this may be enough to motivate them to withdraw).
• Teach patients ways to deal with anxiety and insomnia (either as primary conditions or due to withdrawal).
• Acknowledge that withdrawing from benzodiazepines can be stressful.
• Encourage family and friends to provide encouragement and practical help during withdrawal.
• Refer patients to appropriate services (eg psychologist or support groups). Only refer to drug or alcohol dependence services if the service has shown specific interest in benzodiazepine
• dependence or the patient also has a drug or alcohol problem.
• Advise patients to make changes in lifestyle such as regular exercise.
• Advise patients to avoid alcohol.
• Advise patients to avoid mild stimulants (eg coffee and chocolate [theobromine]) as these can cause anxiety, panic and insomnia.
• Postpone advice on smoking cessation until after the benzodiazepine has been withdrawn ⁶

Benzodiazepine reduction requires a team approach with regular communication between the prescriber and other practitioners involved in the patient’s care (eg pharmacist, counsellor, psychiatrist, addiction services).

The clearest strategy for withdrawing benzodiazepines is to taper the medication (see Figure 2) ⁶. There are three basic approaches to taper a benzodiazepine ⁸, ⁵:

1. Use the same medication for tapering;
2. Switch to a longer-acting equivalent; and
3. Use add-on medications to help reduce potential withdrawal symptoms.

Slow discontinuation of benzodiazepines is recommended to avoid withdrawal symptoms (e.g., rebound anxiety, agitation, insomnia or seizures) particularly when use exceeds 8 weeks ⁴. However, clear evidence for the optimal rate of tapering is lacking. The dosage reduction mainly depends on the starting dose and whether the patient is tapering as an inpatient or outpatient. For safety reasons, outpatient tapers usually need to be slower than inpatient tapers. Patients taking higher dosages of benzodiazepines can usually tolerate larger reductions than those taking lower dosages ⁶, ²⁶. The initial reduction typically ranges between 5% and 25% of the starting dose, with further reductions of 5% to 25% every one to four weeks as tolerated. The British National Formulary recommends a minimum of 6 weeks ²⁷, while Lader recommends a maximum of 6 months ⁶. The exact rate of benzodiazepine reduction should be individualized according to the drug, dose and duration of treatment. A common first step in benzo withdrawal is to substitute diazepam for the benzodiazepine being taken ⁶. Switching to a longer-acting benzodiazepine equivalent may allow for a smoother taper experience ⁶. The slower elimination of diazepam creates a smoother taper in blood level ⁹. A suggested benzodiazepine taper schedule is available at https://www.va.gov/PAINMANAGEMENT/docs/OSI_6_Toolkit_Taper_Benzodiazepines_Clinicians.pdf

Supratherapeutic doses can initially be reduced by 25% to 30%, then further reduced by 5% to 10% daily, weekly, or monthly as appropriate, based on how well the patient tolerates withdrawal symptoms during the taper. Addition of an anticonvulsant (e.g., gabapentin [Neurontin]) should be considered for high-dosage withdrawal. Studies have shown that add-on medications, such as carbamazepine (Tegretol), imipramine, divalproex (Depakote), and trazodone, can mitigate some of the withdrawal discomfort ⁶. Use of antidepressants, such as duloxetine (Cymbalta) or amitriptyline, may help patients with chronic pain. There is limited evidence that antidepressants help in benzodiazepine withdrawal, unless depression (or anxiety disorders/panic disorders) are present or emerge during withdrawal ¹⁰.

For complex cases, stabilizing the dose at a 50% reduction for several months before resuming the taper may improve tolerability ²⁸. At the end of the taper, some patients may need to reduce the pace with nearly homeopathic dosage reductions to tolerate the withdrawal. Compounding pharmacies can be used to obtain very small doses near the end of the taper.

All patients on a tapering regime must obtain prescriptions from one prescriber and through one pharmacy, where time-limited dispensing may be required (e.g., once or twice a week at a specified time) ⁴. Plans should be in place to cover absences of the usual prescribing doctor from the practice ⁴. Consider working closely with the patient’s pharmacist with staged supply or supervised dosing to assist the patient with dose reduction and cessation, if they are unable to manage this themselves ⁴.

Other considerations

Patients with benzodiazepine use disorder will have more difficulty reducing or stopping the dosage because of cravings. They may report intolerable withdrawal symptoms, request early refills, use benzodiazepines for reasons other than why they were prescribed, or report a need for benzodiazepines to perform normal daily activities. These patients may not be able to taper off without more intensive follow-up and intervention. A taper may be a litmus test for addiction; these patients may benefit from a referral to an addiction specialist ²⁶.

Patients taking ‘therapeutic benzodiazepine doses’

For people who have early or mild benzodiazepine dependence, minimal interventions such as advisory letters, other information provision or doctor advice should be offered. Where benzodiazepine dependence is established, gradual dose reduction of prescribed benzodiazepine is recommended ²⁹.

Switching from a short half-life benzodiazepine to a long half-life benzodiazepine before gradual taper should be reserved for patients having problematic withdrawal symptoms on reduction ²⁹.

Additional psychological therapies increase the effectiveness of gradual dose reduction, particularly in patients with insomnia and panic disorder. Consideration should be given to targeted use of these interventions ²⁹.

Patient taking high doses of benzodiazepines or who are users of illicit drugs (polydrug users)

So called ‘harm-reduction dosing’ or maintenance prescribing of benzodiazepines for patients using polydrugs cannot be recommended on the basis of existing evidence, as prescribing benzodiazepines does not appear to prevent use of other drugs ²⁹. There are some evidence that maintenance dosing of benzodiazepines may reduce high-dose problematic benzodiazepine use in some patients ²⁹.

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