StatPearls, Jan/19: Latest information on diazepam

https://www.ncbi.nlm.nih.gov/books/NBK537022/#article-20488.s1

 

Diazepam

 

Jaberpreet S. Dhaliwal; Abdolreza Saadabadi.

Author Information

 

Authors

Jaberpreet S. Dhaliwal1; Abdolreza Saadabadi2.

 

Affiliations

1 Kaweah Delta Hospital

2 Western University/ Kaweah Delta

 

Last Update: January 30, 2019.

 

Indications

 

Diazepam is an anxiolytic benzodiazepine, first patented and marketed in the United States in 1963. It is a fast-acting, long-lasting benzodiazepine commonly used in the treatment of anxiety disorders, as well as alcohol detoxification, acute recurrent seizures, severe muscle spasm, and spasticity associated with neurologic disorders. In the setting of acute alcohol withdrawal, diazepam is useful for symptomatic relief of agitation, tremor, alcoholic hallucinosis, and acute delirium tremens.[1]

 

When administered intravenously, diazepam has been shown to act within 1 to 3 minutes, while oral dosing onset ranges between 15 to 60 minutes. Diazepam is long-lasting with a duration of action of more than 12 hours.

 

Benzodiazepines have largely replaced barbiturates in the treatment of anxiety and sleep disorders because of their improved safety profile, fewer side effects, and the availability of the antagonist flumazenil to reverse oversedation and benzodiazepine intoxication.

 

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.[2]

 

Mechanism of Action

 

Benzodiazepines exert their effects by facilitating the activity of GABA at various sites. Specifically, benzodiazepines bind at an allosteric site at the interface between the alpha and gamma subunits on GABA-A receptor chloride ion channels. The allosteric binding of diazepam at the GABA-A receptor leads to an increase in 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 excitability of the neuron.[3]

 

Specifically, the allosteric binding within the limbic system leads to the anxiolytic effects seen with diazepam. Allosteric binding within the spinal cord and motor neurons is the primary mediator of the myorelaxant effects seen with diazepam. Mediation of the sedative, amnestic, and anticonvulsant effects of diazepam is through receptor binding within the cortex, thalamus, and cerebellum.[4]

 

Once in the body, diazepam is mainly broken down by the CYP2C19 and CYP3A4 enzymes to several active metabolites, mainly desmethyldiazepam. Other minor active metabolites include oxazepam and temazepam. The average half-life of oral diazepam and desmethyldiazepam are about 46 hours and 100 hours, respectively. Strong inhibition of the 2C19 enzyme by certain drugs (fluoxetine and chloramphenicol) and 3A4 enzymes by certain drugs (ketoconazole, protease inhibitors, erythromycin) may cause increased levels of diazepam, while inducers of 2C19 (rifampicin and prednisone) and 3A4 (carbamazepine, topiramate, phenytoin, St. John's wort, rifampin, or barbiturates) may cause lower levels. Metabolites of diazepam are conjugated with glucuronide and excreted almost entirely in the urine.[5][6][7]

 

Administration

 

Diazepam is available in multiple formulations, including oral tablets, intramuscular injections (IM), intravenous injection (IV), or rectal gel. Of note, oral tablets have a more reliable absorption and controlled release when compared to IM.

 

Treatment of acute ethanol withdrawal: Initial dosing should be 10mg IM or IV. If needed, a follow-up dose of 5 to 10mg is permissible 3 to 4 hours later. If using the oral tablet, dosing is 10mg every 6 to 8 hours within the first 24 hours, then 5mg every 6 to 8 hours thereafter as needed.

 

Treatment of anxiety: 2 to 10mg can be given orally 2 to 4 times daily. If given parentally, dosing can be 2 to 10mg and repeated in 3 to 4 hours, if needed.

 

Treatment of muscle spasm: 2 to 10mg can be given orally 3 to 4 times daily. If given parentally, an initial dose of 5-10mg can be followed by another 5-10mg dose in 3 to 4 hours, if necessary.

 

Treatment of preoperative anxiety: Dosing is 10mg IM prior to surgery

 

For sedation in the ICU: Loading dose of 5 to 10mg for initial administration, followed by a maintenance dose of 0.03 to 0.10mg/kg every 0.5 to 6 hours (Barr 2013)

 

Treatment of seizures: 2 to 10mg orally dosed 2 to 4 times daily as adjunctive maintenance therapy. For intermittent management of seizures, rectal gel 0.2mg/kg is an option. It may be repeated in 4 to 12 hours if needed. Do not exceed five uses per month or more than one dose every 5 days.

 

Treatment of status epilepticus: 0.15 to 0.20mg/kg IV per dose,  and may be repeated once if needed. Do not exceed 10mg per single dose. Rectal administration of 0.2 to 0.5mg/kg administered one time. Do not exceed 20mg per dose.

 

Skeletal muscle relaxant: 2 to 10mg dosed 3 to 4 times daily as adjunct therapy

 

Adverse Effects

 

Like most benzodiazepines, the adverse reactions of diazepam include CNS and respiratory depression, dependence, and benzodiazepine withdrawal syndrome.

 

Serious adverse effects of diazepam include:

 

    Respiratory depression

    Seizures

    Suicidality

    Dependency and abuse

    Withdrawal symptoms

    Cardiovascular collapse

    Bradycardia

    Hypotension

    Syncope

    Paradoxical CNS stimulation

 

Common adverse effects of diazepam include:

 

    Sedation

    Fatigue

    Confusion

    Anterograde amnesia

    Depression

    Ataxia

    Irritability

    Disinhibition

    Local injection site reaction

    Headache

    Tremor

    Dystonia

    Urinary retention

    Incontinence

    Nausea

    Constipation

    Diplopia

    Libido changes

    Rash

    Menstrual irregularities

    ALT and/or AST elevation

 

Contraindications

 

Contraindications to diazepam include patients with a known hypersensitivity to diazepam and, due to a lack of sufficient clinical evidence, diazepam is also contraindicated in patients under 6 months of age. Other contraindications to diazepam include patients with severe respiratory insufficiency, myasthenia gravis,  sleep apnea syndrome, and severe hepatic insufficiency. It is permissible in patients with open-angle glaucoma who are receiving appropriate therapy but is contraindicated in acute narrow-angle glaucoma.

 

Use in Special Populations:

 

Pregnant Patients

 

Diazepam classifies as FDA pregnancy category D, which means that there is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk. The use of diazepam and other benzodiazepines in pregnancy correlates with an increased risk of congenital malformations, premature birth, low birth weight, and other neurodevelopmental abnormalities. However, additional studies are needed to confirm.

 

Diazepam has been shown to readily cross the placental barrier, and use during pregnancy may result in neonatal withdrawal soon after birth. 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. 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. Diazepam use during the last trimester of pregnancy can result in “floppy infant syndrome,” characterized by hypotonia, hypothermia, lethargy, respiratory distress, and suckling difficulties.[8][9]

 

Breastfeeding women

 

Diazepam and its metabolites have been shown to be excreted in breast milk and may produce effects in the nursing infant. Some studies have shown the relative infant dose (RID) of diazepam to be approximately 9%. Relative infant dose (RID) is the dose received via breast milk relative to the mother’s dose. A relative dose below 10% is within an acceptable range regarded as reasonably safe in the short term. However, due to diazepam’s long half-life, metabolites may accumulate in a breastfed infant. Therefore, an infant breastfed by a mother receiving diazepam should undergo monitoring 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.[10]

 

Elderly

 

One should exercise caution when prescribing diazepam to the elderly population. Elderly patients tend to have decreased renal function and clearing capability; therefore this population is at an increased risk for accumulation of diazepam and its major metabolites. It is recommended to limit dosage to the smallest effective amount.

 

Paradoxical reactions of CNS hyperactivity have also been reported with the use of benzodiazepines in the elderly, manifesting as hyperactivity, aggressive behavior, irritability, anxiety, and hallucinations. Should this occur, discontinuation is the recommendation.[11][12]

 

Monitoring

 

It is important to monitor respiratory and cardiovascular status, blood pressure, heart rate, and for symptoms of anxiety in patients taking diazepam.  With long-term use, monitor liver enzymes, CBC, and for signs of propylene glycol toxicity, including serum creatinine, BUN, serum lactate, and osmolality gap. With critically ill patients, monitor the depth of sedation.[13]

 

Toxicity

 

Diazepam Overdose

 

The toxic-to-therapeutic ratio of benzodiazepines is very high, making them relatively safe medications. However, the potential of overdose from diverted diazepam always exists when combined with opioids, alcohol, or other centrally acting agents. Overdose in adults frequently involves co-ingestion of other CNS depressants, which act synergistically to increase toxicity. In the case of single-agent diazepam overdose, symptoms manifest as CNS depression and are very rarely fatal. In mild cases, lethargy, drowsiness, and confusion are common symptoms. In cases of severe overdose, symptoms manifest as ataxia, diminished reflexes, hypotonia, hypotension, respiratory depression, coma (rarely), and death (very rarely).[8]

 

Treatment of benzodiazepine overdose involves protection of the airway, fluid resuscitation, and the use of flumazenil if indicated. Flumazenil works via competitive antagonism at the benzodiazepine receptor and can rapidly reverse coma. However, in patients with benzodiazepine tolerance, the use of flumazenil can precipitate acute withdrawal symptoms, autonomic instability, and seizures.

 

Potential for Diazepam Abuse and Dependence

 

Diazepam is a Schedule IV controlled substance with the potential for abuse. Development of dependence and tolerance can occur in those who are addiction-prone, on long-term treatment, or in those patients taking high doses. Thus, these individuals should be under careful supervision. Once an individual develops dependence, the risk of developing withdrawal symptoms increases. Signs of benzodiazepine withdrawal include tremor, rebound anxiety, perceptual disturbances, dysphoria, psychosis, agitation, irritability, restlessness, sweating, headache, confusion, myalgias, abdominal pain, and vomiting. In cases of long-term use and abrupt cessation, there is potential for hallucinations and epileptic seizures to occur.[14]

 

Propylene Glycol Toxicity

 

Propylene glycol toxicity is a rare toxidrome associated with the parenteral use of diazepam. Propylene glycol is a common diluent used in the suspension of IV diazepam. Large doses or long-term infusions of IV diazepam can cause accumulation of propylene glycol and subsequent anion gap metabolic acidosis. Signs of the propylene glycol poisoning include the development of serum hyperosmolality, hemolysis, cardiac dysrhythmias, hypotension, lactic acidosis, seizure, acute kidney injury, and multisystem organ failure.[15]

 

Enhancing Healthcare Team Outcomes

 

Diazepam is a fast-acting potent anxiolytic popular in use due to its broad therapeutic index, low toxicity, and improved safety profile. Nonetheless, diazepam is still a drug with high potential for use disorder associated with severe adverse/toxic effects. Managing patients on benzodiazepines requires an interdisciplinary team approach consisting of physicians, nurses, and pharmacists. Further, prescribing physicians should be responsible for making use of state and federal controlled substance databases to monitor for possible use disorder, diversion, and improper drug use.

 

 

Thanks for posting.

 

This part was very interesting

 

“Propylene Glycol Toxicity

 

Propylene glycol toxicity is a rare toxidrome associated with the parenteral use of diazepam. Propylene glycol is a common diluent used in the suspension of IV diazepam. Large doses or long-term infusions of IV diazepam can cause accumulation of propylene glycol and subsequent anion gap metabolic acidosis. Signs of the propylene glycol poisoning include the development of serum hyperosmolality, hemolysis, cardiac dysrhythmias, hypotension, lactic acidosis, seizure, acute kidney injury, and multisystem organ failure.[15]”

I found this part very interesting.  Might be one piece of the puzzle as to who/how/why some develop withdrawal symptoms whereas others don't.

 

 

Potential for Diazepam Abuse and Dependence

 

Diazepam is a Schedule IV controlled substance with the potential for abuse. Development of dependence and tolerance can occur in those who are addiction-prone, on long-term treatment, or in those patients taking high doses. Thus, these individuals should be under careful supervision. Once an individual develops dependence, the risk of developing withdrawal symptoms increases. Signs of benzodiazepine withdrawal include tremor, rebound anxiety, perceptual disturbances, dysphoria, psychosis, agitation, irritability, restlessness, sweating, headache, confusion, myalgias, abdominal pain, and vomiting. In cases of long-term use and abrupt cessation, there is potential for hallucinations and epileptic seizures to occur.[14]

And presumably, the time it takes to develop tolerance in people is somewhat variable. I wonder if any doctor takes the time to discuss that or monitor a patient for it. They'd have to see the patient weekly or something, wouldn't they? Is there a moment in time when that happens?

 

Anyway....if prescriptions are kept VERY short (as they should be), then tolerance is much less likely to happen.

I found this part very interesting.  Might be one piece of the puzzle as to who/how/why some develop withdrawal symptoms whereas others don't.

 

 

Potential for Diazepam Abuse and Dependence

 

Diazepam is a Schedule IV controlled substance with the potential for abuse. Development of dependence and tolerance can occur in those who are addiction-prone, on long-term treatment, or in those patients taking high doses. Thus, these individuals should be under careful supervision. Once an individual develops dependence, the risk of developing withdrawal symptoms increases. Signs of benzodiazepine withdrawal include tremor, rebound anxiety, perceptual disturbances, dysphoria, psychosis, agitation, irritability, restlessness, sweating, headache, confusion, myalgias, abdominal pain, and vomiting. In cases of long-term use and abrupt cessation, there is potential for hallucinations and epileptic seizures to occur.[14]

 

How do they know who's "addiction prone"?  I've also wondered if this happens across drugs.  So if someone's developed dependence on benzos and they get off and later on they go on a pain med for example, are they more likely to become dependent on the pain med and experience w/d symptoms because of their history of benzo dependence?

 

Edit:  And the bolded part.  Isn't the definition of dependence, experiencing w/d symptoms?

And presumably, the time it takes to develop tolerance in people is somewhat variable. I wonder if any doctor takes the time to discuss that or monitor a patient for it. They'd have to see the patient weekly or something, wouldn't they? Is there a moment in time when that happens?

 

Anyway....if prescriptions are kept VERY short (as they should be), then tolerance is much less likely to happen.

I Imagine dose escalation would be most Drs first indicator... But then most would assume an addiction model and try to address non compliance rather than a developing tolerance... Well. Thats my guess anyways...

 

 

Here's the thing: Many medications -- not just benzos -- create a physiological dependency and require tapering. One example is corticosteroids, such as Prednisone. People don't become Prednisone "addicts". Their bodies adjust to the presence of the medication, because that's how they work. Same with benzos. I shared a medical journal article on this topic quite some time ago, and it was really interesting. These medications need to be carefully monitored while a person is on them, and then carefully tapered when the person needs to come off them or they will experience withdrawal symptoms -- sometimes, rather serious ones.

 

Addiction involves other behaviours, and....now we're back to the addiction vs. dependency discussion. I know we've gone over it a million times around here, so I won't do it again. Suffice to say, they're not the same.

Here's the thing: Many medications -- not just benzos -- create a physiological dependency and require tapering. One example is corticosteroids, such as Prednisone. People don't become Prednisone "addicts". Their bodies adjust to the presence of the medication, because that's how they work. Same with benzos. I shared a medical journal article on this topic quite some time ago, and it was really interesting. These medications need to be carefully monitored while a person is on them, and then carefully tapered when the person needs to come off them or they will experience withdrawal symptoms -- sometimes, rather serious ones.

 

Addiction involves other behaviours, and....now we're back to the addiction vs. dependency discussion. I know we've gone over it a million times around here, so I won't do it again. Suffice to say, they're not the same.

well I didnt bring it up to play word games..  Nor to say what was right... -Just what I imagined would happen if people (Drs) werent properly informed with whateva medications reality... If a Dr is expecting tolerance, -I guess he would increase the dose as per howeva its done... -Or taper the medication as per how its done..

I just presented a common guage for the less monitored meds, -Dose esculation..  Then a common reaction if its not understood...

 

So yeah, we know other meds have issues, as do benzos... The question is, Do the Drs know this?? If so, no problem..!! But If there are problems outside of that meds guidelines what do you expect to happen..??

If they are not calling it these bad things (addiction or dependancy), whats happening..?? Diagnosing a new condition perhaps...?? Pre-existing..?? Telling us its in our heads..??

Yes, some meds need routine monitoring... One of mine was bloods several times a week, and adjust as per.. Others similar, I think the heparin was daily..??...  Is that what you were wondering..?? But what im thinking of here is effective level monitoring, not tolerance to a med itself... I guess it depends on the med, the Dr, and the person... But history seems to say.....If its not understood, patient blame first... Well thats my opinion too...

 

I simply took your question to mean.. For anyone in the real world, ie. not the presidents son, etc, -how would Drs likely monitor for dependancy...  And what might be the effect of that...

 

I dont know about the steroids..?? I guess someone said there werent lyrica or gabapentin addicts once too...  Sorry, I just dont know..?? -Is it a serious life threatening or changing dependance like benzos can be..??

 

 

Hi Cantfly,

I hope my post didn't come across badly. I was just explaining how certain meds work in the body, in that some create a physiological dependence. Doctors and pharmacists should know which meds those are and monitor people who take them -- especially when it comes time for the person to get off the medication.

 

For example, I had to take Prednisone for a short course, and there was a very strict schedule to follow in order to get off it. The repercussions of taking it improperly can be quite serious, I understand. It would have been good to have been followed so closely with the benzodiazepines, but of course, that's not how things went.

 

Caffeine also creates a dependency in the body. So when people take it regularly (e.g. in the form of coffee), and then suddenly stop, they get withdrawal symptoms.

 

I just found the article I was thinking about. It's from 2011, and it's called "Drug Discontinuation Effects Are Part of the Pharmacology of a Drug". Check it out here:

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3200000/

 

Hi Cantfly,

I hope my post didn't come across badly. I was just explaining how certain meds work in the body, in that some create a physiological dependence. Doctors and pharmacists should know which meds those are and monitor people who take them -- especially when it comes time for the person to get off the medication.

 

For example, I had to take Prednisone for a short course, and there was a very strict schedule to follow in order to get off it. The repercussions of taking it improperly can be quite serious, I understand. It would have been good to have been followed so closely with the benzodiazepines, but of course, that's not how things went.

 

Caffeine also creates a dependency in the body. So when people take it regularly (e.g. in the form of coffee), and then suddenly stop, they get withdrawal symptoms.

 

I just found the article I was thinking about. It's from 2011, and it's called "Drug Discontinuation Effects Are Part of the Pharmacology of a Drug". Check it out here:

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3200000/

Dont mind me, -I am a tad irritated atm.. Probs related to medication discontinuation, and/or teenagers   Sorry, its not yours to bear...

 

Anyways, im pretty sure we are talking about the same thing, just you from a what should be perspective, and me, more a what is standpoint...?? -Maybe..

 

I think one of the aspects of the care/monitoring discrepancy is cost or "through-put" constraints...

-Time and Effort vs the Percieved Risk.. (the endless "how many" have significant problems??)

 

-Another issue is obviously Dr education and awareness... I was always told that opiates and benzos had a limited viable period of use, and needed a tapering proticol..  Asides things conspiring against me trauma wise, the problem was when I didnt respond well or as expected to the percieved "normal"... No one was going to force me off, but they didnt know how to best respond either..

So while they were monitoring and aware of the existing and potential problems, it wasnt enough..

 

Am in full accord with linked article.. **(thank god she says..)

I like to think the wheels are slowly turning, sadly very late, and reluctantly.. It kinda shocked me to read that many of you can still be benzo scripted for many months at a time, with no in-person Dr "face time"..!! (Which makes your point in itself)

 

So I guess what my brain fog is saying, is that I think that these problematic meds are often (not always) loosely monitored too, Just not nearly effectively enough to cater for everyone, and more, response to a problem can be poor, to say the least...

Waiting for dose esculation (or tolerance, etc) to indicate a problem is like shutting the gate after the horse has bolted...

I understand others have a very different experience to mine, one of pure neglect, mis-management, blame and disbelief...  Im not deminishing that..

 

Forgive my pondering and "clunky" texting...

There is no doubt more needs to be done...!!

 

Like what has been said all along about Flumazenil...

 

Treatment of benzodiazepine overdose involves protection of the airway, fluid resuscitation, and the use of flumazenil if indicated. Flumazenil works via competitive antagonism at the benzodiazepine receptor and can rapidly reverse coma. However, in patients with benzodiazepine tolerance, the use of flumazenil can precipitate acute withdrawal symptoms, autonomic instability, and seizures.

I wanted to know if Valium could cause urinary retention.  The pubmed article posted at the beginning of this thread states that urinary retention can be an adverse effect.  So there I have it!