Diazepam

Diazepam also known under the brand name Valium, belongs to a class of medications called benzodiazepines, that acts as an anxiolytic used to relieve anxiety. Diazepam or valium is used to treat anxiety, and seizures or fits. Diazepam is also used along with other medications to control muscle spasms and spasticity caused by certain neurological disorders such as cerebral palsy (condition that causes difficulty with movement and balance), paraplegia (inability to move parts of the body), athetosis (abnormal muscle contractions), and stiff-person syndrome (a rare disorder with muscle rigidity and stiffness). Diazepam is also used in hospital to reduce alcohol withdrawal symptoms, such as agitation, trembling, confusion and anxiety or difficulty sleeping. Diazepam or valium can also be taken to help you relax before an operation or other medical or dental treatments. This is known as a pre-med. To get diazepam, you need a prescription written for you by a doctor. Your doctor may have prescribed diazepam for another reason. If you are unsure about why you are taking diazepam, ask your doctor.

Diazepam is a benzodiazepine. Benzodiazepines belong to the group of medicines called central nervous system (CNS) depressants, which are medicines that slow down the nervous system. Diazepam works by increasing the levels of a calming chemical in your brain, a neurotransmitter called gamma-aminobutyric acid (GABA), which work by calming abnormal overactivity in the brain. The sedative activity of the benzodiazepines is mediated by their ability to enhance gamma-aminobutyric acid (GABA) mediated inhibition of synaptic transmission through binding to the GABA-A receptor.

Diazepam comes as tablets, a solution, and as a concentrate (liquid) to take by mouth, or in a rectal tube – medicine that’s squeezed into your bottom (anus). It can also be given as an injection in hospital. Diazepam is usually taken 1 to 4 times a day and may be taken with or without food. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take diazepam exactly as directed.

Diazepam concentrate comes with a specially marked dropper for measuring the dose. Ask your pharmacist to show you how to use the dropper. Dilute the concentrate in water, juice, or carbonated beverages just before taking it. It also may be mixed with applesauce or pudding just before taking the dose. Stir the mixture gently for a few seconds. Take the entire mixture immediately; do not store it for future use.

After oral administration of diazepam >90% is absorbed, the average time to achieve peak plasma concentrations is 1 to 1.5 hours. Absorption is delayed and decreased when administered with a meal. There is an increase in the mean time to achieve peak concentrations to approximately 2.5 hours in the presence of food.

Diazepam is mostly broken down by the microsomal enzymes CYP2C19 and CYP3A4 enzymes to several active metabolites, mainly desmethyldiazepam. Other minor active metabolites include oxazepam and temazepam. The average half-lives of oral diazepam and desmethyldiazepam are about 46 and 100 hours, respectively ¹.

You’ll usually take diazepam for no longer than 2 to 4 weeks. If you’re prescribed diazepam for more than 4 weeks, your dose may be reduced gradually when you stop taking it to prevent withdrawal symptoms.

If you are taking diazepam along with other medications to control seizures, do not stop taking diazepam without talking to your doctor, even if you experience side effects such as unusual changes in behavior or mood. If you suddenly stop taking diazepam, your seizures may get worse. Your doctor will probably decrease your dose gradually.

Diazepam helps most people with anxiety but some people have side effects.

The most common side effects of diazepam include:

• tiredness
• sleepiness
• muscle weakness
• unsteadiness

It can also make you forgetful and dizzy.

There are other rare side effects. Tell your doctor at once or go to the emergency room of your nearest hospital if you experience any of these symptoms:

• sudden excitation or anxiety
• feelings of restlessness, agitation or anger
• abnormal behavior
• hallucinations (hearing, seeing or smelling things that aren’t there)
• difficulties in breathing
• serious sleep disturbances

In general, diazepam should be used only for short periods, around 2 to 4 weeks, unless advised by your doctor. Long-term use can result in tolerance, dependence, and withdrawal symptoms on dose reduction. Abrupt stopping after long-term use can be potentially dangerous. After stopping, cognitive problems may persist for six months or longer.

Diazepam is not recommended during pregnancy or breastfeeding. An increase in congenital malformations has been suggested with minor tranquilizer use, especially during the first trimester.

• If diazepam (valium) is used during pregnancy, or if the patient becomes pregnant while taking diazepam (valium), the patient should be apprised of the potential harm to the fetus.
• Neonates exposed to single high doses of diazepam (valium) during labor and delivery should be monitored for irregularities in fetal heart rate, hypotonia, poor sucking, hypothermia, and moderate respiratory depression.
• If used during pregnancy, monitor the newborn for acute withdrawal syndrome symptoms during the postnatal period.
• A pregnancy exposure registry is available here (https://www.aedpregnancyregistry.org).

Figure 1. Diazepam chemical structure

Before taking diazepam

• tell your doctor and pharmacist if you are allergic to diazepam, alprazolam (Xanax), chlordiazepoxide (Librium, in Librax), clonazepam (Klonopin), clorazepate (Gen-Xene, Tranxene), estazolam, flurazepam, lorazepam (Ativan), oxazepam, temazepam (Restoril), triazolam (Halcion), any other medications, or any of the ingredients in diazepam products. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, and nutritional supplements, you are taking. Be sure to mention any of the following: antihistamines; barbiturates such as phenobarbital (Luminal); cimetidine (Tagamet); digoxin (Lanoxin); disulfiram (Antabuse); fluoxetine (Prozac); fluvoxamine (Luvox); isoniazid (Laniazid, in Rifamate, in Rifater); ketoconazole; medications for anxiety, depression, mental illness, seizures, Parkinson’s disease, asthma, colds, or allergies; metoprolol (Lopressor, Toprol XL); monoamine oxidase (MAO) inhibitors including isocarboxazid (Marplan), linezolid (Zyvox), methylene blue, phenelzine (Nardil), selegiline (Eldepryl, Emsam, Zelapar), and tranylcypromine (Parnate); muscle relaxants; phenothiazine medications for mental illness or nausea such as chlorpromazine, fluphenazine, prochlorperazine (Compro, Procomp), and promethazine (Promethegan); omeprazole (Prilosec); probenecid (Probalan, in Col-Probenecid); propranolol (Hemangeol, Inderal, Innopran); ranitidine (Zantac); rifampin (Rifadin, Rimactane, in Rifamate, in Rifater); sedatives; sleeping pills; theophylline (Elixophyllin, Theo 24, Theochron); tranquilizers; or valproic acid (Depakene). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have myasthenia gravis (a disorder of the nervous system that causes muscle weakness), sleep apnea (condition in which a person briefly stops breathing many times during the night), or lung or liver disease. Also, tell your doctor if you have narrow angle glaucoma (a serious eye condition that may cause loss of vision. Your doctor will probably tell you not to take diazepam. Diazepam should not be used in infants younger than 6 months of age.
  tell your doctor if you have or have ever had open-angle glaucoma (increase in internal eye pressure that damages the optic nerve); depression or other mental illness; seizures; or heart disease.
• tell your doctor if you are pregnant or plan to become pregnant. If you become pregnant while taking diazepam, call your doctor immediately.
• tell your doctor if you are breastfeeding. Do not breastfeed while you are taking diazepam.
• talk to your doctor about the risks and benefits of taking diazepam if you are 65 years of age or older. Older adults should not usually take diazepam because it is not as safe as other medications that can be used to treat the same conditions.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking diazepam.
• you should know that this drug may make you drowsy. Do not drive a car or operate machinery until you know how this medication affects you.
• you should know that your mental health may change in unexpected ways and you may become suicidal (thinking about harming or killing yourself or planning or trying to do so) while you are taking diazepam for the treatment of epilepsy. A small number of adults and children 5 years of age and older (about 1 in 500 people) who took anticonvulsants such as diazepam to treat various conditions during clinical studies became suicidal during their treatment. Some of these people developed suicidal thoughts and behavior as early as one week after they started taking the medication. There is a risk that you may experience changes in your mental health if you take an anticonvulsant medication such as diazepam, but there may also be a risk that you will experience changes in your mental health if your condition is not treated. You and your doctor will decide whether the risks of taking an anticonvulsant medication are greater than the risks of not taking the medication. You, your family, or your caregiver should call your doctor right away if you experience any of the following symptoms: panic attacks; agitation or restlessness; new or worsening irritability, anxiety, or depression; acting on dangerous impulses; difficulty falling or staying asleep; aggressive, angry, or violent behavior; mania (frenzied, abnormally excited mood); talking or thinking about wanting to hurt yourself or end your life; withdrawing from friends and family; preoccupation with death and dying; giving away prized possessions; or any other unusual changes in behavior or mood. Be sure that your family or caregiver knows which symptoms may be serious so they can call the doctor if you are unable to seek treatment on your own.

Diazepam pregnancy warnings

Diazepam is classified as a former FDA pregnancy category D, indicating positive evidence of human fetal risk. Still, the benefits from use in pregnant women may be acceptable despite the risk ². Animal models have revealed evidence of teratogenicity, decreased number of pregnancies, lower surviving offspring numbers, and long-term changes in cellular immune responses, brain neurochemistry, and behavior. Cleft palate, central nervous system malformations/encephalopathy, and permanent functional disturbances occurred in animal models at maternally toxic doses. Neonatal flaccidity, respiratory/feeding difficulties, and hypothermia have been reported in humans. Use during the first and third trimesters may be associated with an increased risk of teratogenicity and withdrawal symptoms in the newborn, respectively. However, additional studies are needed to confirm.

Diazepam readily crosses the placental barrier, and use during pregnancy may result in neonatal withdrawal soon after birth ². Symptoms of neonatal withdrawal include high-pitched cry, hypertonia, tremor, irritability, feeding difficulties, sleep/wake disturbances, gastrointestinal and autonomic disturbances, respiratory problems, and failure to thrive ². The onset of withdrawal in a neonate whose mother has taken diazepam during the pregnancy could be anywhere from the first days of life to the first few weeks. During the last trimester of pregnancy, diazepam use can result in “floppy infant syndrome,” characterized by hypotonia, hypothermia, lethargy, respiratory distress, and suckling difficulties ³, ⁴.

Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Based on the studies reviewed, using diazepam is not expected to increase the chance of birth defects above the background risk. Older studies suggested a less than 1 in 100 (less than 1%) increased chance of cleft lip and/or cleft palate if a person uses diazepam in the first trimester of pregnancy ⁵, ⁶, ⁷, ⁸, ⁹, ¹⁰. A cleft lip or cleft palate is when the lip and/or roof of mouth formed with a split and can need surgery to correct. More recent studies that are larger and better-designed have not found an increased chance of oral clefts or other birth defects with diazepam use in pregnancy ¹¹, ¹².

Some, but not all, studies have reported an increased chance for preterm delivery (delivery before 37 weeks of pregnancy), low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth), and/or smaller head size in babies born to a person who was using diazepam and other benzodiazepines in pregnancy ¹³, ¹⁴. Two of these studies followed the exposed children as they grew and reported they had reached normal weight ranges by 8-10 months of age ¹¹, ¹³. In one study head circumferences remained smaller than expected at 18 months of age ¹⁵.

Based on the studies reviewed, it is not known if taking diazepam increases the chance for behavior or learning issues. Two studies have followed children who were exposed to diazepam during pregnancy until the children were up to 18 months or 3 years of age. These studies reported that the children were more likely to show certain behaviors, such as anxiety, sadness, and fearfulness ¹⁶, ¹⁷, ¹⁸.

Diazepam breastfeeding warnings

Diazepam gets into breast milk in small amounts. Diazepam stays in the body longer than some other benzodiazepines do. If you use diazepam regularly while breastfeeding there is a chance it could build up in the baby’s system and cause sleepiness or affect your child’s weight gain. If you suspect the baby has any symptoms like trouble feeding, breathing, gaining weight or being overly sleepy, contact your baby’s healthcare provider.

The product label for diazepam recommends people who are breastfeeding not use this medication. But, the benefit of using diazepam may outweigh possible risks. Your healthcare providers can talk with you about using diazepam and what treatment is best for you. If you need to use a benzodiazepine regularly while breastfeeding, it might be preferred to use one that clears from the body more quickly than diazepam does. Be sure to talk to your healthcare provider about all of your breastfeeding questions.

Some studies have shown diazepam’s relative infant dose (RID) to be approximately 9% ². The relative infant dose (RID) is the dose received via breast milk relative to the mothers. A relative dose below 10% is within an acceptable range regarded as reasonably safe in the short term ². However, due to diazepam’s long half-life, its metabolites may accumulate in a breastfed infant. Therefore, you should monitor an infant breastfed by a mother receiving diazepam for drowsiness, decreased feeding, lethargy, and failure to thrive. Discontinue breastfeeding in cases with high doses of diazepam or when repeated administration will be necessary. However, when a single dose of diazepam is required for a procedure or seizure, the clinician should advise the mother to wait six to eight hours before resuming nursing, particularly with a preterm infant ¹⁹, ²⁰.

Excreted into human milk: Yes

Comments:

• Sedation, weight loss, and feeding difficulties have occurred in nursing infants.
• The American Academy of Pediatrics considers diazepam for which the effect on nursing infants is unknown but may be of concern if exposure is prolonged.
• The WHO considers diazepam compatible with breastfeeding if given in a single dose; repeated doses should be avoided, if possible. Breastfed infants should be monitored for drowsiness. Short-acting benzodiazepines (e.g., oxazepam, lorazepam) may be preferred.

Drug interactions

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking diazepam, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using diazepam with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Flumazenil

Using diazepam with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abametapir
• Alfentanil
• Alprazolam
• Amobarbital
• Anileridine
• Benzhydrocodone
• Bromazepam
• Bromopride
• Buprenorphine
• Butabarbital
• Butalbital
• Butorphanol
• Calcifediol
• Calcium Oxybate
• Cannabidiol
• Carbinoxamine
• Carisoprodol
• Cetirizine
• Chloral Hydrate
• Chlorzoxazone
• Clobazam
• Clonazepam
• Cobicistat
• Codeine
• Conivaptan
• Dantrolene
• Daridorexant
• Dexmedetomidine
• Diacetylmorphine
• Difenoxin
• Dihydrocodeine
• Diphenoxylate
• Doxylamine
• Esketamine
• Eslicarbazepine Acetate
• Ethchlorvynol
• Ethylmorphine
• Etravirine
• Fedratinib
• Fentanyl
• Fexinidazole
• Flibanserin
• Fosnetupitant
• Fosphenytoin
• Fospropofol
• Gabapentin
• Gabapentin Enacarbil
• Hydrocodone
• Hydromorphone
• Ketamine
• Ketobemidone
• Lemborexant
• Levocetirizine
• Levorphanol
• Lofexidine
• Loxapine
• Magnesium Oxybate
• Meclizine
• Meperidine
• Mephenesin
• Mephobarbital
• Meprobamate
• Metaxalone
• Methadone
• Methocarbamol
• Methohexital
• Metoclopramide
• Midazolam
• Mirtazapine
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Netupitant
• Nicomorphine
• Opium
• Opium Alkaloids
• Orlistat
• Oxycodone
• Oxymorphone
• Papaveretum
• Paregoric
• Pentazocine
• Pentobarbital
• Periciazine
• Phenobarbital
• Phenytoin
• Piritramide
• Potassium Oxybate
• Pregabalin
• Primidone
• Propofol
• Remifentanil
• Remimazolam
• Ropeginterferon Alfa-2b-njft
• Scopolamine
• Secobarbital
• Sodium Oxybate
• Sufentanil
• Tapentadol
• Thiopental
• Tilidine
• Tramadol
• Trazodone
• Zolpidem

Using diazepam with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Amitriptyline
• Amprenavir
• Clarithromycin
• Dalfopristin
• Desogestrel
• Dienogest
• Disulfiram
• Drospirenone
• Erythromycin
• Estradiol
• Ethinyl Estradiol
• Ethynodiol
• Fluvoxamine
• Gestodene
• Ginkgo
• Isoniazid
• Levonorgestrel
• Mestranol
• Nomegestrol
• Norethindrone
• Norgestimate
• Norgestrel
• Quinupristin
• Rifapentine
• Roxithromycin
• St John’s Wort
• Theophylline
• Troleandomycin

Other interactions

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using diazepam with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use diazepam, or give you special instructions about the use of grapefruit juice. Grapefruit juice may increase the amount of diazepam in your blood. It’s a good idea to avoid grapefruit or grapefruit juice while taking diazepam.

Caffeine is a stimulant and may reduce the calming effects of diazepam. It’s best not to have drinks like coffee, tea, cola and energy drinks because they contain caffeine.

Do not drink alcohol while you’re taking diazepam.

Other medical problems

The presence of other medical problems may affect the use of diazepam. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol or drug abuse or dependence, or history of, or
• Depression, or history of or
• Lung or breathing problems (eg, respiratory depression) or
• Mental health problems, or history of or
• Seizures, history of—Use with caution. May make these conditions worse.
• Breathing problems, severe or
• Glaucoma, narrow-angle or
• Liver disease, severe or
• Myasthenia gravis or
• Sleep apnea (temporary stopping of breathing during sleep)—Should not be used in patients with these conditions.
• Kidney disease or
• Liver disease, mild or moderate—Use with caution. The effects may be increased because of slower removal of diazepam from the body.

Is diazepam addictive?

It is possible to become addicted to diazepam. To reduce the risk of becoming addicted, it’s best to take the lowest diazepam dose that treats your symptoms, and to take it for only a short time (2 to 4 weeks). You’re more likely to get addicted if you need to take a higher diazepam dose for a longer time, or if you’ve ever had problems with alcohol or drugs.

What will happen if I stop taking diazepam?

If you have been taking a high dose of diazepam or have been taking it for a long time, your doctor will probably recommend reducing your dose gradually.

If you suddenly stop taking diazepam, you may get some side effects, such as:

• confusion
• seizures or fits
• depression
• feeling nervous or irritable
• sweating
• diarrhea

You’re less likely to get these side effects if you reduce your diazepam dose gradually.

Can I drink alcohol while taking diazepam?

Do not drink alcohol while you’re taking diazepam. Alcohol can increase the effects of diazepam. It can make you go into a very deep sleep. There’s a risk you will not be able to breathe properly, and you may have difficulty waking up.

Who can take diazepam?

Most adults aged 18 years and over can take diazepam tablets and liquid. People aged over 65 might need to take a lower dose.

Children aged 1 month and older can take it for muscle spasms.

Diazepam rectal tubes can be used by adults and children.

Who may not be able to take diazepam?

Diazepam is not suitable for some people. To make sure it’s safe for you, tell your doctor before starting to take diazepam if you:

• have ever had an allergic reaction to diazepam or any other medicine
• have liver or kidney problems
• have myasthenia gravis, a condition that causes muscle weakness
• have sleep apnoea, a condition that causes breathing problems when you’re asleep
• have depression or thoughts of harming yourself or suicide
• have been diagnosed with a personality disorder
• have ever had problems with alcohol or drugs
• have recently had a loss or bereavement
• have arteriosclerosis, a condition that affects the blood flow to your brain
• have low levels of a protein called albumin in your blood
• are trying to get pregnant, are already pregnant or breastfeeding
• are over 65
• are going to be put to sleep (have a general anaesthetic) for an operation or other medical treatment.

When will I feel better after taking diazepam?

Diazepam will work quite quickly or more slowly depending on what you’re taking it for:

• seizures or fits – diazepam rectal tubes should start to work within 10 minutes
• anxiety – you should start to feel a bit better within a few hours, but it may take a week or 2 for you to feel the full effects
• muscle spasms – you should begin to feel less pain after 15 minutes. Your muscles will start to relax when you have been taking diazepam regularly for a few days.

Oral diazepam tablets have a more reliable absorption and controlled release when compared to intramuscular (IM). When administered intravenously (IV), diazepam has an onset of action within 1 to 3 minutes, while oral dosing onset ranges between 15 to 60 minutes. In addition, diazepam is long-lasting, with a duration of action of more than 12 hours.

Will diazepam affect my contraception?

Diazepam will not affect any type of contraception, including the combined pill and emergency contraception. But some contraceptive pills can keep diazepam in your body for longer and increase its effect.

You can also get bleeding in between your periods if you take diazepam and contraceptive pills together. But your contraception will still work.

I need to take diazepam throughout my entire pregnancy. Will it cause withdrawal symptoms in my baby after birth?

Babies that were exposed to diazepam throughout pregnancy or late in pregnancy might have withdrawal symptoms starting soon after delivery or within several days of birth. Symptoms might include breathing problems, jitteriness, excessive crying, and trouble maintaining their body temperature. Some newborns may have loose muscle tone, sluggishness, and trouble latching on to feed (called “floppy infant syndrome”). Some babies might need to spend more time in the hospital to help manage these symptoms. The symptoms are expected to go away within a few weeks.

If a male takes diazepam, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects?

Based on the studies reviewed, it is not known if the use of diazepam can affect fertility or increase the chance of birth defects above the background risk. In general, exposures that fathers or sperm donors have are unlikely to increase risks to a pregnancy.

Can I drive or ride a bike when I’m taking diazepam?

Do not drive a car or ride a bike if diazepam makes you sleepy, gives you blurred vision, or makes you feel dizzy, clumsy or unable to concentrate or make decisions. This may be more likely when you first start taking diazepam, but it could happen at any time, for example when starting another medicine.

It’s an offence to drive a car if your ability to drive safely is affected. It’s your responsibility to decide if it’s safe to drive. If you’re in any doubt, do not drive.

Even if your ability to drive is not affected, the police have the right to request a saliva sample to check how much diazepam is in your body.

Can I operate machinery or tools while I’m taking diazepam?

Do not operate machinery or tools if you get any side effects, such as feeling sleepy, being forgetful, or poor co-ordination.

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 ²¹. 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 ²².

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

Generic name	Brand name	Type
Diazepam	Ducene®, Valium®	Long-acting
Oxazepam	Alepam®, Murelax®, Serepax®	Short-acting
Nitrazepam	Alodorm®, Mogadon®	Intermediate-acting
Temazepam	Euhypnos®, Normison®	Short-acting
Alprazolam	Xanax®, Kalma®, Alprax®	Short-acting

[Source ²² ]

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 ²³. 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 ²⁴. 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 ²⁵.

How does diazepam work?

Diazepam is a benzodiazepine. 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. Specifically, benzodiazepines bind at an allosteric site at the interface between the alpha and gamma subunits on GABA-A receptor chloride ion channels ²⁶. The allosteric binding of diazepam at the GABA-A receptor increases the frequency at which the chloride channel opens, leading to an increased conductance of chloride ions. This shift in charge leads to a hyperpolarization of the neuronal membrane and reduced neuronal excitability ²⁶.

Specifically, the allosteric binding within the limbic system, thalamus, and hypothalamus leads to the anxiolytic effects seen with diazepam ²⁷. Allosteric binding within the spinal cord and motor neurons is the primary mediator of the myorelaxant effects seen with diazepam ²⁸. Mediation of the sedative, amnestic, and anticonvulsant effects of diazepam is through receptor binding within the cortex, thalamus, and cerebellum ¹.

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 ²⁹. 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 ³⁰. 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.

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.

Diazepam uses

Diazepam is FDA approved for the management of anxiety disorders, short-term relief of anxiety symptoms, spasticity associated with upper motor neuron disorders, adjunct therapy for muscle spasms, preoperative anxiety relief, management of certain refractory epilepsy patients, and adjunct in severe recurrent convulsive seizures, and an adjunct in status epilepticus. Off-label (non-FDA approved) use for diazepam includes sedation in the ICU and short-term treatment of spasticity in children with cerebral palsy ³¹. In 2020, diazepam (Valtoco) was approved for use in the United States as a nasal spray to interrupt seizure activity in people with epilepsy ³². Diazepam is also the most commonly used benzodiazepine for “tapering” benzodiazepine dependence due to the drug’s comparatively long half-life, allowing for more efficient dose reduction. Benzodiazepines have a relatively low toxicity in overdose ³³. To get diazepam, you need a prescription written for you by a doctor. Your doctor may have prescribed diazepam for another reason. If you are unsure about why you are taking diazepam, ask your doctor.

Diazepam has a number of uses, including:

• Treatment of anxiety, panic attacks, and states of agitation ³⁴
• Treatment of neurovegetative symptoms associated with vertigo ³⁵
• Treatment of the symptoms of alcohol, opiate, and benzodiazepine withdrawal ³⁶
• Short-term treatment of insomnia ³⁷
• Treatment of muscle spasms
• Treatment of tetanus, together with other measures of intensive treatment ³⁸
• Adjunctive treatment for the relief of skeletal muscle spasm due to reflex spasm to local pathology (such as inflammation of the muscles or joints, or secondary to trauma), spasticity caused by upper motor neuron disorders (such as cerebral palsy and paraplegia), athetosis, stroke, multiple sclerosis and spinal cord injury (long-term treatment is coupled with other rehabilitative measures) ³⁹
• Palliative treatment of stiff-person syndrome
• Pre- or postoperative sedation, anxiolysis or amnesia (e.g., before endoscopic or surgical procedures) ³⁹
• Treatment of complications with stimulant overdoses and psychosis, such as cocaine or methamphetamine ⁴⁰
• Used in treatment of organophosphate poisoning and reduces the risk of seizure induced brain and cardiac damage.
• Preventive treatment of oxygen toxicity during hyperbaric oxygen therapy ⁴¹
• Diazepam is used for the emergency treatment of eclampsia, when IV magnesium sulfate and blood-pressure control measures have failed ⁴², ⁴³

Diazepam dosage

Diazepam dosages should be determined on an individual basis, depending on the condition being treated, severity of symptoms, patient body weight, and any other conditions the person may have. Take diazepam exactly as prescribed by your doctor. Follow the directions on your prescription label and read all medication guides or instruction sheets. Never use diazepam in larger amounts, or for longer than prescribed. Tell your doctor if you feel an increased urge to use more of diazepam. MISUSE CAN CAUSE ADDICTION, OVERDOSE, OR DEATH. Keep diazepam where others cannot get to it. Selling or giving away diazepam is against the law.

• Treatment of acute alcohol withdrawal symptoms: Initial dosing should be 10 mg IM or IV. If needed, a follow-up dose of 5 to 10 mg is permissible 3 to 4 hours later. If using the oral tablet, dosing is 10 mg every 6 to 8 hours within the first 24 hours, then 5mg every 6 to 8 hours after that as needed ³¹
• Treatment of anxiety: 2 to 10 mg can be given orally 2 to 4 times daily. If given parentally, dosing can be 2 to 10 mg and repeated in 3 to 4 hours, if needed ⁴⁴
• Treatment of muscle spasms: 2 to 10 mg can be given orally 3 to 4 times daily. If given parentally, an initial dose of 5 to 10 mg can be followed by another 5-10mg dose in 3 to 4 hours, if necessary ²¹
• Treatment of preoperative anxiety: Dosing is 10 mg IM before surgery ⁴⁵
• For sedation in the ICU: Loading dose of 5 to 10 mg for initial administration, followed by a maintenance dose of 0.03 to 0.10 mg/kg every 0.5 to 6 hours ⁴⁶
• Treatment of seizures: 2 to 10 mg orally dosed 2 to 4 times daily as adjunctive maintenance therapy. Rectal gel 0.2mg/kg is an option for intermittent management of seizures. It may be repeated in 4 to 12 hours if needed. Do not exceed five uses per month or more than one dose every five days.
• Skeletal muscle relaxant: 2 to 10 mg, dosed 3 to 4 times daily as an adjunct therapy.
• Treatment of status epilepticus: 0.15 to 0.20 mg/kg IV per dose and may be repeated once needed. Do not exceed 10 mg per single dose. Rectal administration of 0.2 to 0.5 mg/kg administered one time. Do not exceed 20 mg per dose ⁴⁷.

Adult dose for anxiety

Use: Management of anxiety disorders and short-term relief of anxiety symptoms

• Oral: 2 to 10 mg orally 2 to 4 times a day
• Parenteral:
  • Moderate Anxiety Disorders and Symptoms: 2 to 5 mg IM or IV, repeated in 3 to 4 hours if necessary
  • Severe Anxiety Disorders and Symptoms: 5 to 10 mg IM or IV, repeated in 3 to 4 hours if necessary

Comments:

• Oral doses should be determined by the severity of symptoms.
• Anxiety associated with the stress of everyday life usually does not require treatment with this drug.

Adult dose for alcohol withdrawal symptoms

Use: Symptomatic relief of acute agitation, tremor, impending/acute delirium tremens, and hallucinations in acute alcohol withdrawal

• Oral:
  • Initial dose: 10 mg orally 3 to 4 times a day for the first 24 hours
  • Maintenance dose: 5 mg orally 3 to 4 times a day as needed
• Parenteral: 10 mg IM or IV once, then 5 to 10 mg IM or IV in 3 to 4 hours if necessary

Adult dose for muscle spasm

Use: Adjunctive treatment for the relief of skeletal muscle spasm due to reflex spasm to local pathology, spasticity caused by upper motor neuron disorders, athetosis, and stiff-man syndrome (e.g., inflammation of the muscles/joints secondary to trauma, cerebral palsy, paraplegia)

• Oral: 2 to 10 mg orally 3 to 4 times a day
• Parenteral: 5 to 10 mg IM or IV, then 5 to 10 mg IM or IV in 3 to 4 hours if necessary

Comment: Larger parenteral doses may be necessary for patients with tetanus.

Adult dose for seizures

Uses:

• Management of selected, refractory patients with epilepsy on stable regimens of antiepileptic drugs who require intermittent use of this drug to control bouts of increased seizure activity
• Adjunctive treatment for convulsive disorders

Oral: 2 to 10 mg orally 2 to 4 times a day

Rectal:

• Initial dose: 0.2 mg/kg rectally, rounded upward to the next available dose. A 2.5 mg rectal dose may be given as a partial replacement if patients expel a portion of the initial dose
• If necessary, a second dose of 0.2 mg/kg may be given rectally 4 to 12 hours after the first dose.
• Maximum Frequency: May be used to treat up to 1 seizure episode every 5 days, and no more than 5 episodes/month

Adult dose for status epilepticus

Use: Adjunct to status epilepticus and severe recurrent convulsive seizures

Parenteral:

• Initial dose: 5 to 10 mg IV once, repeated at 10 to 15 minute intervals to a maximum dose of 30 mg if necessary

Comments:

• The IV route is preferred; however, the IM route may be used if IV administration is impossible.
• Treatment may be repeated every 2 to 4 hours, but active metabolites may persist during readministration.
• Patients with chronic lung disease or unstable cardiovascular conditions should be given this drug with extreme caution.

Adult dose for light anesthesia

Use: Premedication for the relief of anxiety and tension in patients undergoing surgical procedures

Preoperative Medication: 10 mg IM once before surgery

Comments:

• The IM route is preferred when given as a preoperative medication.
• Atropine, scopolamine, and other premedications should be administered in separate syringes.

Adult dose as premedication for endoscopy or radiology

Uses:

• Adjunct prior to endoscopic procedures if apprehension, anxiety, or acute stress reactions are present and to diminish recall of the procedures
• Prior to cardioversion for the relief of anxiety and tension and to diminish the patient’s recall of the procedure

Cardioversion: 5 to 15 mg IV once 5 to 10 minutes before the procedure

Endoscopic Procedures:

• IV: Usually less than 10 mg, but some patients require up to 20 mg IV, especially when narcotics are omitted
• IV titration: The IV dose should be titrated to desired sedative response (e.g., slurring of speech) with slow administration immediately before the procedure.
• IM: 5 to 10 mg IM once 30 minutes prior to the procedure

Comments:

• Narcotic dosing should be reduced by approximately 33%, and may be omitted in some patients.
• The IV route is preferred, but IM administration may be used if IV administration is not possible.

Geriatric dose for seizures

Uses:

• Management of selected, refractory patients with epilepsy on stable regimens of antiepileptic drugs who require intermittent use of this drug to control bouts of increased seizure activity
• Adjunctive treatment in convulsive disorders

Oral: Initial dose: 2 to 2.5 mg orally once to 2 times a day

Rectal:

• Initial dose: 0.2 mg/kg rectally, rounded downward to the next available dose. A 2.5 mg rectal dose may be given as a partial replacement if patients expel a portion of the initial dose
• If necessary, a second dose of 0.2 mg/kg may be given rectally 4 to 12 hours after the first dose.
• Maximum Frequency: May be used to treat up to 1 seizure episode every 5 days, and no more than 5 episodes/month

Comment: Oral doses may be increased gradually as needed and tolerated, but should be limited to the smallest effective amount

Geriatric dose for alcohol withdrawal symptoms

Uses:

• Management of anxiety disorders and short-term relief of anxiety symptoms
• Symptomatic relief of acute agitation, tremor, impending/acute delirium tremens, and hallucinations in acute alcohol withdrawal
• Adjunctive treatment for the relief of skeletal muscle spasm due to reflex spasm to local pathology, spasticity caused by upper motor neuron disorders, athetosis, and stiff-man syndrome (e.g., inflammation of the muscles/joints secondary to trauma, cerebral palsy, paraplegia)

Oral: Initial dose: 2 to 2.5 mg orally once to 2 times a day

Parenteral: Initial dose: 2 to 5 mg IM or IV, repeated in 3 to 4 hours if necessary

Comments:

• Doses may be increased gradually as needed and tolerated, but should be limited to the smallest effective amount.
• Maintenance doses should be determined by clinical need and patient tolerance.

Geriatric dose for anxiety

Uses:

• Management of anxiety disorders and short-term relief of anxiety symptoms
• Symptomatic relief of acute agitation, tremor, impending/acute delirium tremens, and hallucinations in acute alcohol withdrawal
• Adjunctive treatment for the relief of skeletal muscle spasm due to reflex spasm to local pathology, spasticity caused by upper motor neuron disorders, athetosis, and stiff-man syndrome (e.g., inflammation of the muscles/joints secondary to trauma, cerebral palsy, paraplegia)

Oral: Initial dose: 2 to 2.5 mg orally once to 2 times a day

Parenteral: Initial dose: 2 to 5 mg IM or IV, repeated in 3 to 4 hours if necessary

Comments:

• Doses may be increased gradually as needed and tolerated, but should be limited to the smallest effective amount.
• Maintenance doses should be determined by clinical need and patient tolerance.

Geriatric dose for muscle spasm

Uses:

• Management of anxiety disorders and short-term relief of anxiety symptoms
• Symptomatic relief of acute agitation, tremor, impending/acute delirium tremens, and hallucinations in acute alcohol withdrawal
• Adjunctive treatment for the relief of skeletal muscle spasm due to reflex spasm to local pathology, spasticity caused by upper motor neuron disorders, athetosis, and stiff-man syndrome (e.g., inflammation of the muscles/joints secondary to trauma, cerebral palsy, paraplegia)

Oral: Initial dose: 2 to 2.5 mg orally once to 2 times a day

Parenteral: Initial dose: 2 to 5 mg IM or IV, repeated in 3 to 4 hours if necessary

Comments:

• Doses may be increased gradually as needed and tolerated, but should be limited to the smallest effective amount.
• Maintenance doses should be determined by clinical need and patient tolerance.

Diazepam dose adjustments for debilitated patients

Oral: Initial dose: 2 to 2.5 mg orally once or 2 times a day

Parenteral: Initial dose: 2 to 5 mg once a day

Rectal:

• Initial dose: 0.2 mg/kg rectally, rounded downward to the next available dose. A 2.5 mg rectal dose may be given as a partial replacement if patients expel a portion of the initial dose
• If necessary, a second dose of 0.2 mg/kg may be given rectally 4 to 12 hours after the first dose.
• Maximum Frequency: May be used to treat up to 1 seizure episode every 5 days, and no more than 5 episodes/month

What should I do if I forget a dose?

If you take several doses per day and miss a dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Children dose for seizures

Uses:

• Management of selected, refractory patients with epilepsy on stable regimens of antiepileptic drugs who require intermittent use of this drug to control bouts of increased seizure activity
• Adjunctive treatment in convulsive disorders

Oral: 6 months and older: Initial dose: 1 to 2.5 mg orally 3 to 4 times a day

Rectal:

• 2 to 5 years:
  • Initial dose: 0.5 mg/kg rectally, rounded upward to the next available dose. A 2.5 mg rectal dose may be given as a partial replacement if patients expel a portion of the initial dose
  • If necessary, a second dose of 0.5 mg/kg may be given rectally 4 to 12 hours after the first dose.
  • Maximum Frequency: 1 episode every 5 days, and no more than 5 episodes/month
• 6 to 11 years:
  • Initial dose: 0.3 mg/kg rectally, rounded upward to the next available dose. A 2.5 mg rectal dose may be given as a partial replacement if patients expel a portion of the initial dose
  • If necessary, a second dose of 0.3 mg/kg may be given rectally 4 to 12 hours after the first dose.
  • Maximum Frequency: 1 episode every 5 days, and no more than 5 episodes/month
• 12 years and older:
  • Initial dose: 0.2 mg/kg rectally, rounded upward to the next available dose. A 2.5 mg rectal dose may be given as a partial replacement if patients expel a portion of the initial dose
  • If necessary, a second dose of 0.2 mg/kg may be given rectally 4 to 12 hours after the first dose.
  • Maximum Frequency: May be used to treat up to 1 seizure episode every 5 days, and no more than 5 episodes/month

Comment: Oral doses may be increased gradually as needed and tolerated, but should be limited to the smallest effective amount.

Children dose for status epilepticus

Use: Adjunct in status epilepticus and severe recurrent convulsive seizures

Parenteral:

• 30 days to less than 5 years: 0.2 to 0.5 mg slow IV injection every 2 to 5 minutes, up to a maximum dose of 5 mg. Repeat in 2 to 4 hours if needed.
• 5 years and older: 1 mg slow IV injection every 2 to 5 minutes, up to a maximum dose of 10 mg. Repeat in 2 to 4 hours if needed.

Comment: EEG monitoring may be helpful to monitor seizure activity.

Children dose for anxiety

Uses:

• Management of anxiety disorders and short-term relief of anxiety symptoms
• Symptomatic relief of acute agitation, tremor, impending/acute delirium tremens, and hallucinations in acute alcohol withdrawal
• Adjunctive treatment for the relief of skeletal muscle spasm due to reflex spasm to local pathology, spasticity caused by upper motor neuron disorders, athetosis, and stiff-man syndrome (e.g., inflammation of the muscles/joints secondary to trauma, cerebral palsy, paraplegia)

Oral: 6 months and older: Initial dose: 1 to 2.5 mg orally 3 to 4 times a day

Comments:

• Doses may be increased gradually as needed and tolerated, but should be limited to the smallest effective amount.
• Maintenance doses should be determined by clinical need and patient tolerance.

Children dose for muscle spasm

Uses:

• Management of anxiety disorders and short-term relief of anxiety symptoms
• Symptomatic relief of acute agitation, tremor, impending/acute delirium tremens, and hallucinations in acute alcohol withdrawal
• Adjunctive treatment for the relief of skeletal muscle spasm due to reflex spasm to local pathology, spasticity caused by upper motor neuron disorders, athetosis, and stiff-man syndrome (e.g., inflammation of the muscles/joints secondary to trauma, cerebral palsy, paraplegia)

Oral: 6 months and older: Initial dose: 1 to 2.5 mg orally 3 to 4 times a day

Comments:

• Doses may be increased gradually as needed and tolerated, but should be limited to the smallest effective amount.
• Maintenance doses should be determined by clinical need and patient tolerance.

Children dose for seizure prophylaxis

Uses:

• Management of anxiety disorders and short-term relief of anxiety symptoms
• Symptomatic relief of acute agitation, tremor, impending/acute delirium tremens, and hallucinations in acute alcohol withdrawal
• Adjunctive treatment for the relief of skeletal muscle spasm due to reflex spasm to local pathology, spasticity caused by upper motor neuron disorders, athetosis, and stiff-man syndrome (e.g., inflammation of the muscles/joints secondary to trauma, cerebral palsy, paraplegia)

Oral: 6 months and older: Initial dose: 1 to 2.5 mg orally 3 to 4 times a day

Comments:

• Doses may be increased gradually as needed and tolerated, but should be limited to the smallest effective amount.
• Maintenance doses should be determined by clinical need and patient tolerance.

Children dose for tetanus

Use: Tetanus

Parenteral:

• 30 days to 5 years: 1 to 2 mg IM or slow IV injection, repeated every 3 to 4 hours as necessary
• 5 years and older: 5 to 10 mg IM or slow IV injection, repeated every 3 to 4 hours as necessary to control spasms

Comment: Respiratory assistance should be available for patients.

Diazepam side effects

Diazepam may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• drowsiness
• dizziness
• tiredness
• muscle weakness
• headache
• dry mouth
• nausea
• constipation
• confusion
• difficulty urinating
• frequent urination
• changes in sex drive or ability

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.

Some side effects can be serious. If you experience any of these symptoms or those listed in the IMPORTANT WARNING section above, see your doctor immediately or get emergency medical treatment:

• loss of control of bodily movements
• uncontrollable shaking of a part of the body
• slurred speech
• slowed breathing and heartbeat

Diazepam may cause other side effects. See your doctor if you have any unusual problems while taking diazepam.

After you stop using diazepam, get medical help right away if you have symptoms such as:

• unusual muscle movements,
• being more active or talkative,
• sudden and severe changes in mood or behavior,
• confusion,
• hallucinations,
• seizures,
• suicidal thoughts or actions.

Some withdrawal symptoms may last up to 12 months or longer after stopping this medicine suddenly. Tell your doctor if you have ongoing anxiety, depression, problems with memory or thinking, trouble sleeping, ringing in your ears, a burning or prickly feeling, or a crawling sensation under your skin.

Diazepam tolerance and withdrawal

Diazepam, as with other benzodiazepine drugs, can cause tolerance, physical dependence, substance use disorder, and benzodiazepine withdrawal syndrome ⁴⁸. Withdrawal from diazepam or other benzodiazepines often leads to withdrawal symptoms similar to those seen during barbiturate or alcohol withdrawal. The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms ⁴⁹.

Benzodiazepine withdrawal symptoms can occur from standard dosages and also after short-term use, and can range from insomnia and anxiety to more serious symptoms, including seizures and psychosis. Withdrawal symptoms can sometimes resemble pre-existing conditions and be misdiagnosed. Diazepam may produce less intense withdrawal symptoms due to its long elimination half-life ³¹.

Benzodiazepine treatment should be discontinued as soon as possible by a slow and gradual dose reduction regimen ⁵⁰. Tolerance develops to the therapeutic effects of benzodiazepines; for example tolerance occurs to the anticonvulsant effects and as a result benzodiazepines are not generally recommended for the long-term management of epilepsy. Dose increases may overcome the effects of tolerance, but tolerance may then develop to the higher dose and adverse effects may increase. The mechanism of tolerance to benzodiazepines includes uncoupling of receptor sites, alterations in gene expression, down-regulation of receptor sites, and desensitisation of receptor sites to the effect of GABA. About one-third of individuals who take benzodiazepines for longer than four weeks become dependent and experience withdrawal syndrome on cessation ³³.

Differences in rates of withdrawal (50–100%) vary depending on the patient sample. For example, a random sample of long-term benzodiazepine users typically finds around 50% experience few or no withdrawal symptoms, with the other 50% experiencing notable withdrawal symptoms. Certain select patient groups show a higher rate of notable withdrawal symptoms, up to 100% ⁵¹

Rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or other benzodiazepines ⁵². Diazepam is therefore only recommended for short-term therapy at the lowest possible dose owing to risks of severe withdrawal problems from low doses even after gradual reduction ⁵³. The risk of pharmacological dependence on diazepam is significant, and patients experience symptoms of benzodiazepine withdrawal syndrome if it is taken for six weeks or longer ⁵⁴. In humans, tolerance to the anticonvulsant effects of diazepam occurs frequently ⁵⁵.

Diazepam dependence

Improper or excessive use of diazepam can lead to dependence. At a particularly high risk for diazepam misuse, substance use disorder or dependence are:

• People with a history of a substance use disorder or substance dependence. Diazepam increases craving for alcohol in problem alcohol consumers. Diazepam also increases the volume of alcohol consumed by problem drinkers ⁵⁶.
• People with severe personality disorders, such as borderline personality disorder ⁵⁷

Patients from the aforementioned groups should be monitored very closely during therapy for signs of abuse and development of dependence. Therapy should be discontinued if any of these signs are noted, although if dependence has developed, therapy must still be discontinued gradually to avoid severe withdrawal symptoms. Long-term therapy in such instances is not recommended.

People suspected of being dependent on benzodiazepine drugs should be very gradually tapered off the drug. Withdrawals can be life-threatening, particularly when excessive doses have been taken for extended periods of time. Equal prudence should be used whether dependence has occurred in therapeutic or recreational contexts ⁵⁸.

Diazepam is a good choice for tapering for those using high doses of other benzodiazepines since it has a long half-life thus withdrawal symptoms are tolerable ⁵⁹. The process is very slow (usually from 14 to 28 weeks) but is considered safe when done appropriately ⁶⁰.

Diazepam contraindications

Use of diazepam should be avoided, when possible, in individuals with:

• Ataxia
• Severe hypoventilation
• Acute narrow-angle glaucoma
• Severe hepatic deficiencies (hepatitis and liver cirrhosis decrease elimination by a factor of two)
• Severe renal deficiencies (for example, patients on dialysis)
• Liver disorders
• Severe sleep apnea
• Severe depression, particularly when accompanied by suicidal tendencies
• Psychosis
• Pregnancy or breast feeding
• Caution required in elderly or debilitated patients
• Coma or shock
• Abrupt discontinuation of therapy
• Acute intoxication with alcohol, narcotics, or other psychoactive substances (with the exception of hallucinogens or some stimulants, where it is occasionally used as a treatment for overdose)
• History of alcohol or drug dependence
• Myasthenia gravis, an autoimmune disorder causing marked fatiguability
• Hypersensitivity or allergy to any drug in the benzodiazepine class

Caution

• Benzodiazepine abuse and misuse should be guarded against when prescribed to those with alcohol or drug dependencies or who have psychiatric disorders ⁶¹.
• Pediatric patients
  • Less than 18 years of age, this treatment is usually not indicated, except for treatment of epilepsy, and pre- or postoperative treatment. The smallest possible effective dose should be used for this group of patients ⁶²
  • Under 6 months of age, safety and effectiveness have not been established; diazepam should not be given to those in this age group ⁶²
• Elderly and very ill patients can possibly experience apnea or cardiac arrest. Concomitant use of other central nervous system depressants increases this risk. The smallest possible effective dose should be used for this group of people. The elderly metabolise benzodiazepines much more slowly than younger adults, and are also more sensitive to the effects of benzodiazepines, even at similar blood plasma levels ³³. Doses of diazepam are recommended to be about half of those given to younger people, and treatment limited to a maximum of two weeks. Long-acting benzodiazepines such as diazepam are not recommended for the elderly. Diazepam can also be dangerous in geriatric patients owing to a significant increased risk of falls ⁶³.
• Intravenous or intramuscular injections in hypotensive people or those in shock should be administered carefully and vital signs should be monitored.
• Benzodiazepines such as diazepam are lipophilic and rapidly penetrate membranes, so rapidly cross over into the placenta with significant uptake of the drug. Use of benzodiazepines including diazepam in late pregnancy, especially high doses, can result in floppy infant syndrome ⁶⁴. Diazepam when taken late in pregnancy, during the third trimester, causes a definite risk of a severe benzodiazepine withdrawal syndrome in the neonate with symptoms including hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Floppy infant syndrome and sedation in the newborn may also occur. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth ⁶⁵.

Diazepam overdose

The most common symptom of a diazepam overdose is falling into a deep sleep or “coma” while still being able to breathe well enough. Other symptoms may include:

• Bluish-colored lips and fingernails
• Blurred vision, double vision
• Breathing is slow, labored, or stopped
• Confusion
• Depression
• Dizziness
• Drowsiness, lack of alertness
• Loss of consciousness
• Excitability
• Hiccups
• Rapid side-to-side movement of the eyes
• Rash
• Stomach upset
• Tiredness
• Tremor
• Weakness, uncoordinated movement

In case of overdose, call the poison control helpline or your local emergency services number. Information is also available online at https://www.poisonhelp.org/help. If the victim has collapsed, had a seizure, has trouble breathing, or can’t be awakened, immediately call your local emergency services number.

Before calling emergency, have this information ready:

• Person’s age, weight, and condition
• Name of product (ingredients and strength, if known)
• Time it was swallowed
• Amount swallowed
• If the medicine was prescribed for the person

Take the container to the hospital with you, if possible.

At the hospital emergency room, the doctors will measure and monitor vital signs, including temperature, pulse, breathing rate, and blood pressure.

Tests that may be done include:

• Blood and urine tests
• Chest x-ray
• CT scan
• ECG (electrocardiogram, or heart tracing)

Treatment may include:

• Fluids through a vein (by IV)
• Medicine like flumazenil (Anexate) to reverse the effect of the diazepam overdose and treat other symptoms
• Activated charcoal
• Laxatives
• Breathing support, including a tube through the mouth into the lungs and connected to a breathing machine (ventilator)

The oral LD50 (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats. D. J. Greenblatt and colleagues ⁶⁶ reported in 1978 on two patients who had taken 500 and 2000 mg of diazepam, respectively, went into moderately-deep comas, and were discharged within 48 hours without having experienced any important complications, in spite of having high concentrations of diazepam and its metabolites desmethyldiazepam, oxazepam, and temazepam, according to samples taken in the hospital and as follow-up.

Recovery from a diazepam overdose is very likely. Complications such as pneumonia, muscle damage from lying on a hard surface for a long period of time, or brain damage from lack of oxygen may result in permanent disability ⁶⁷, ⁶⁸.. People who inject large amounts of this drug through a vein (intravenously or IV) have a worse outcome than those who swallow too many pills. Furthermore, overdoses of diazepam with alcohol, opiates, or other depressants may be fatal ⁶⁹.

References

1. Friedman, H., Greenblatt, D.J., Peters, G.R., Metzler, C.M., Charlton, M.D., Harmatz, J.S., Antal, E.J., Sanborn, E.C. and Francom, S.F. (1992), Pharmacokinetics and pharmacodynamics of oral diazepam: Effect of dose, plasma concentration, and time. Clinical Pharmacology & Therapeutics, 52: 139-150. https://doi.org/10.1038/clpt.1992.123
2. Dhaliwal JS, Rosani A, Saadabadi A. Diazepam. [Updated 2022 Sep 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537022
3. Dallmann A, Ince I, Coboeken K, Eissing T, Hempel G. A Physiologically Based Pharmacokinetic Model for Pregnant Women to Predict the Pharmacokinetics of Drugs Metabolized Via Several Enzymatic Pathways. Clin Pharmacokinet. 2018 Jun;57(6):749-768. doi: 10.1007/s40262-017-0594-5
4. Bellantuono C, Tofani S, Di Sciascio G, Santone G. Benzodiazepine exposure in pregnancy and risk of major malformations: a critical overview. Gen Hosp Psychiatry. 2013 Jan-Feb;35(1):3-8. doi: 10.1016/j.genhosppsych.2012.09.003
5. Aarskog D. 1975. Association between maternal intake of diazepam and oral clefts. Lancet 2:921.
6. Laegreid L, et al. 1992. The effect of benzodiazepines on the fetus and the newborn. Neuropediatrics 23(1):18-23.
7. Safra M, Oakley G. 1975. Association between cleft lip with or without cleft palate and prenatal exposure to diazepam. Lancet 2:478–480.
8. Saxen I, Saxen L. 1975. Association between maternal intake of diazepam and oral clefts. Lancet 2:498.
9. Shiono PH, Mills JL. 1984. Oral clefts and diazepam use during pregnancy. N Engl J Med 311:919–920.
10. Ornoy A, et al. 1998. Is benzodiazepine use during pregnancy really teratogenic? Reproductive Toxicology 12(5):511-515.
11. Engeland A, Bjørge T, Daltveit AK, Skurtveit S, Vangen S, Vollset SE, Furu K. Effects of preconceptional paternal drug exposure on birth outcomes: cohort study of 340 000 pregnancies using Norwegian population-based databases. Br J Clin Pharmacol. 2013 Apr;75(4):1134-41. doi: 10.1111/j.1365-2125.2012.04426.x
12. Wikner BN, et al. 2007. Use of benzodiazepines and benzodiazepine receptor agonists during pregnancy: neonatal outcome and congenital malformations. Pharmacoepi & Drug Safety 16(11):1203-10.
13. Freeman MP, Góez-Mogollón L, McInerney KA, Davies AC, Church TR, Sosinsky AZ, Noe OB, Viguera AC, Cohen LS. Obstetrical and neonatal outcomes after benzodiazepine exposure during pregnancy: Results from a prospective registry of women with psychiatric disorders. Gen Hosp Psychiatry. 2018 Jul-Aug;53:73-79. doi: 10.1016/j.genhosppsych.2018.05.010
14. Calderon-Margalit R, et al. 2009. Risk of preterm delivery and other adverse perinatal outcomes in relation to maternal use of psychotropic medications during pregnancy. Am J Obstet Gynecol 201(6):579.e1-579.e8.
15. Czeizel AE, Szegal BA, Joffe JM, Rácz J. The effect of diazepam and promethazine treatment during pregnancy on the somatic development of human offspring. Neurotoxicol Teratol. 1999 Mar-Apr;21(2):157-67. doi: 10.1016/s0892-0362(98)00043-9
16. Brandlistuen R, et al. 2017. Association of prenatal exposure to benzodiazepines and child internalizing problems: A sibling-controlled cohort study. PLoS ONE 12(7):e0181042.
17. Salisbury AL, et al. 2016. The Roles of Maternal Depression, Serotonin Reuptake Inhibitor Treatment, and Concomitant Benzodiazepine Use on Infant Neurobehavioral Functioning Over the First Postnatal Month. Am J Psychiatry 173:2, 147-157.
18. Yonkers KA, et al. 2017. Association of panic disorder, generalized anxiety disorder, and benzodiazepine treatment during pregnancy with risk of adverse birth outcomes. JAMA Psychiatry 74(11): 1145-1152.
19. Brandt R. Passage of diazepam and desmethyldiazepam into breast milk. Arzneimittelforschung. 1976;26(3):454-7.
20. Drugs and Lactation Database (LactMed®) [Internet]. Bethesda (MD): National Institute of Child Health and Human Development; 2006-. Diazepam. [Updated 2022 Nov 30]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK501214
21. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Benzodiazepines. [Updated 2017 Jan 24]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548298
22. Brands B, Sproule B & Marshman J. (eds) (1998) Drugs & Drug Abuse (3rd ed.) Ontario: Addiction Research Foundation.
23. American Druggist. Top 200 drugs of 1995. New York, N.Y.: Hearst Corp, 1996:18–26.
24. Salzman C, for Task Force on Benzodiazepine Dependency, American Psychiatric Association. Benzodiazepine dependence, toxicity, and abuse: a task force report of the American Psychiatric Association. Washington, D.C.: American Psychiatric Association, 1990.
25. Busto UE, Romach MK, Sellers EM. Multiple drug use and psychiatric comorbidity in patients admitted to the hospital with severe benzodiazepine dependence. J Clin Psychopharmacol. 1996;16:51–7.
26. Nutt DJ, Malizia AL. New insights into the role of the GABA(A)-benzodiazepine receptor in psychiatric disorder. Br J Psychiatry. 2001 Nov;179:390-6. doi: 10.1192/bjp.179.5.390
27. Zakusov VV, Ostrovskaya RU, Kozhechkin SN, Markovich VV, Molodavkin GM, Voronina TA. Further evidence for GABA-ergic mechanisms in the action of benzodiazepines. Arch Int Pharmacodyn Ther. 1977 Oct;229(2):313-26.
28. Date SK, Hemavathi KG, Gulati OD. Investigation of the muscle relaxant activity of nitrazepam. Arch Int Pharmacodyn Ther. 1984 Nov;272(1):129-39.
29. Arana GW, Hyman SE. Handbook of psychiatric drug therapy. 2d ed. Boston: Little, Brown, 1991: 128–61.
30. Miller LG. Chronic benzodiazepine administration: from the patient to the gene. J Clin Pharmacol. 1991;31:492–5.
31. Weintraub SJ. Diazepam in the Treatment of Moderate to Severe Alcohol Withdrawal. CNS Drugs. 2017 Feb;31(2):87-95. doi: 10.1007/s40263-016-0403-y
32. https://www.fda.gov/media/145445/download
33. Riss, J., Cloyd, J., Gates, J. and Collins, S. (2008), Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurologica Scandinavica, 118: 69-86. https://doi.org/10.1111/j.1600-0404.2008.01004.x
34. Valium. https://www.nps.org.au/medicine-finder/valium-tablets
35. Cesarani A, Alpini D, Monti B, Raponi G; ENT Department, University of Milan, Milan, Italy. The treatment of acute vertigo. Neurol Sci. 2004 Mar;25 Suppl 1:S26-30. doi: 10.1007/s10072-004-0213-8
36. Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs. 2009;23(1):19-34. doi: 10.2165/0023210-200923010-00002
37. Diazepam. https://go.drugbank.com/drugs/DB00829
38. Okoromah CN, Lesi FE. Diazepam for treating tetanus. Cochrane Database Syst Rev. 2004;2004(1):CD003954. doi: 10.1002/14651858.CD003954.pub2
39. Valium. https://www.rxlist.com/valium-drug.htm
40. Diazepam. https://www.inchem.org/documents/pims/pharm/pim181.htm
41. Kindwall EP, Whelan HT (1999). Hyperbaric Medicine Practice (2nd ed.). Best Publishing Company. ISBN 978-0-941332-78-1.
42. Kaplan PW. Neurologic aspects of eclampsia. Neurol Clin. 2004 Nov;22(4):841-61. doi: 10.1016/j.ncl.2004.07.005
43. Duley L. Evidence and practice: the magnesium sulphate story. Best Pract Res Clin Obstet Gynaecol. 2005 Feb;19(1):57-74. doi: 10.1016/j.bpobgyn.2004.10.010
44. Vinkers CH, Tijdink JK, Luykx JJ, Vis R. Kiezen voor de juiste benzodiazepine: werkingsmechanisme en farmacokinetiek [Choosing the correct benzodiazepine: mechanism of action and pharmacokinetics]. Ned Tijdschr Geneeskd. 2012;155(35):A4900. Dutch.
45. Pekcan M, Celebioglu B, Demir B, Saricaoglu F, Hascelik G, Yukselen MA, Basgul E, Aypar U. The effect of premedication on preoperative anxiety. Middle East J Anaesthesiol. 2005 Jun;18(2):421-33.
46. Barr J, Fraser GL, Puntillo K, Ely EW, Gélinas C, Dasta JF, Davidson JE, Devlin JW, Kress JP, Joffe AM, Coursin DB, Herr DL, Tung A, Robinson BR, Fontaine DK, Ramsay MA, Riker RR, Sessler CN, Pun B, Skrobik Y, Jaeschke R; American College of Critical Care Medicine. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013 Jan;41(1):263-306. doi: 10.1097/CCM.0b013e3182783b72
47. Crawshaw AA, Cock HR. Medical management of status epilepticus: Emergency room to intensive care unit. Seizure. 2020 Feb;75:145-152. doi: 10.1016/j.seizure.2019.10.006. Epub 2019 Oct 24. Erratum in: Seizure. 2020 Aug;80:282.
48. Seldenrijk A, Vis R, Henstra M, Ho Pian K, van Grootheest D, Salomons T, Overmeire F, de Boer M, Scheers T, Doornebal-Bakker R, Ruhé HG, Vinkers CH. Aandacht voor bijwerkingen van benzodiazepinen is belangrijk: een systematisch overzicht [Systematic review of the side effects of benzodiazepines]. Ned Tijdschr Geneeskd. 2017;161:D1052. Dutch.
49. Best KM, Boullata JI, Curley MA. Risk factors associated with iatrogenic opioid and benzodiazepine withdrawal in critically ill pediatric patients: a systematic review and conceptual model. Pediatr Crit Care Med. 2015 Feb;16(2):175-83. doi: 10.1097/PCC.0000000000000306
50. MacKinnon GL, Parker WA. Benzodiazepine withdrawal syndrome: a literature review and evaluation. Am J Drug Alcohol Abuse. 1982;9(1):19-33. doi: 10.3109/00952998209002608
51. Onyett SR. The benzodiazepine withdrawal syndrome and its management. J R Coll Gen Pract. 1989 Apr;39(321):160-3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1711840/pdf/jroyalcgprac00004-0029.pdf
52. Chouinard G, Labonte A, Fontaine R, Annable L. New concepts in benzodiazepine therapy: rebound anxiety and new indications for the more potent benzodiazepines. Prog Neuropsychopharmacol Biol Psychiatry. 1983;7(4-6):669-73. doi: 10.1016/0278-5846(83)90043-x
53. Lader M. Long-term anxiolytic therapy: the issue of drug withdrawal. J Clin Psychiatry. 1987 Dec;48 Suppl:12-6.
54. Murphy SM, Owen R, Tyrer P. Comparative assessment of efficacy and withdrawal symptoms after 6 and 12 weeks’ treatment with diazepam or buspirone. Br J Psychiatry. 1989 Apr;154:529-34. doi: 10.1192/bjp.154.4.529
55. Loiseau P. Les benzodiazépines dans le traitement des épilepsies [Benzodiazepines in the treatment of epilepsy]. Encephale. 1983;9(4 Suppl 2):287B-292B. French.
56. Poulos CX, Zack M. Low-dose diazepam primes motivation for alcohol and alcohol-related semantic networks in problem drinkers. Behav Pharmacol. 2004 Nov;15(7):503-12. doi: 10.1097/00008877-200411000-00006
57. Vorma H, Naukkarinen HH, Sarna SJ, Kuoppasalmi KI. Predictors of benzodiazepine discontinuation in subjects manifesting complicated dependence. Subst Use Misuse. 2005;40(4):499-510. doi: 10.1081/ja-200052433
58. Parr, J.M., Kavanagh, D.J., Cahill, L., Mitchell, G. and Young, R.M. (2009), Effectiveness of current treatment approaches for benzodiazepine discontinuation: a meta-analysis. Addiction, 104: 13-24. https://doi.org/10.1111/j.1360-0443.2008.02364.x
59. Consider this slow-taper program for benzodiazepines. Current Psychiatry. 2013 September;12(9):55-56. https://cdn.mdedge.com/files/s3fs-public/Document/September-2017/055_0913CP_Letters_FINAL_01.pdf
60. https://www.smchealth.org/sites/main/files/file-attachments/benzodiazepinetaper08-12-13.pdf
61. Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, Vennat B, Llorca PM, Eschalier A. Benzodiazepine dependence: focus on withdrawal syndrome. Ann Pharm Fr. 2009 Nov;67(6):408-13. doi: 10.1016/j.pharma.2009.07.001
62. Valium. https://pdrhealth.com/drugs/valium
63. Shats V, Kozacov S. [Falls in the geriatric department: responsibility of the care-giver and the hospital]. Harefuah. 1995 Jun 1;128(11):690-3, 743. Hebrew.
64. Kanto JH. Use of benzodiazepines during pregnancy, labour and lactation, with particular reference to pharmacokinetic considerations. Drugs. 1982 May;23(5):354-80. doi: 10.2165/00003495-198223050-00002
65. McElhatton PR. The effects of benzodiazepine use during pregnancy and lactation. Reprod Toxicol. 1994 Nov-Dec;8(6):461-75. doi: 10.1016/0890-6238(94)90029-9
66. Greenblatt DJ, Woo E, Allen MD, Orsulak PJ, Shader RI. Rapid Recovery From Massive Diazepam Overdose. JAMA. 1978;240(17):1872–1874. doi:10.1001/jama.1978.03290170054026
67. Aronson JK. Diazepam. In: Aronson JK, ed. Meyler’s Side Effects of Drugs. 16th ed. Waltham, MA: Elsevier; 2016:930-937.
68. Gussow L, Carlson A. Sedative hypnotics. In: Walls RM, Hockberger RS, Gausche-Hill M, eds. Rosen’s Emergency Medicine: Concepts and Clinical Practice. 9th ed. Philadelphia, PA: Elsevier; 2018:chap 159.
69. Lai SH, Yao YJ, Lo DS. A survey of buprenorphine related deaths in Singapore. Forensic Sci Int. 2006 Oct 16;162(1-3):80-6. doi: 10.1016/j.forsciint.2006.03.037