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Benzodiazepines - can they help reduce anaesthesia related side effects?


Benzodiazepines (BDZ) have been used regularly since the 1960s as anticonvulsants and as part of a balanced approach to anaesthesia.  The group of drugs are particularly useful in the more critical cases, and have several advantages over the more commonly used sedatives for this group of patients.

BDZ all have a similar basic chemical structure: a benzene ring joined with a diazepine ring.  Minor changes to the basic structure can have significant effects on the pharmacokinetics of the individual drug1


BDZ act mainly at the post-synaptic gamma amino butyric acid-A (GABAA) receptors of the cerebral cortex, with some activity in the cerebellar cortex, hypothalamus, thalamus & limbic system1

The BDZ augment the effects of GABA at the GABAA receptor2 by increasing the influx of chloride ions, with resultant hyperpolarisation and depression of neuronal transmission2,3,4,5.  This mainly results in anxiolysis, sedation and hypnosis, although in the healthy animal disinhibition (excitement, aggression) is frequently seen, and this class of drugs is not routinely used in such patients1,2,5,6.  

BDZ act at a different location on the GABAA receptor to other CNS depressants e.g. alfaxalone, propofol, ethanol3

All BDZ are highly lipid soluble and readily cross the blood-brain barrier. The highly lipophilic nature of the BDZ can result in redistribution to fatty tissues and a short duration of action1.  This is of relevance in obese patients where there is a higher volume of distribution, and shorter duration of action, than in lean animals4.  Midazolam is more lipid soluble than diazepam and has a duration of action of 1-4 hours in dogs, compared to 4-12 hours for diazepam6

BDZ are highly protein bound2,3,6,7


Both midazolam and diazepam undergo initial oxidation followed by conjugation via the cytochrome P450 system in the liver1

Diazepam is metabolised to N-desmethyldiazepam1,2,4, oxazepam & temazepam. All have some degree of clinical activity. Conjugation (glucuronidation) and subsequent excretion occur via urine and bile2,6. The active metabolites of diazepam have the potential for entero-hepatic recycling and accumulation6

Midazolam is hydroxylated to 4-hydroxymidazolam which has minimal clinical activity1.

Accumulation of BDZ metabolites can also occur in animals experiencing renal failure4, and juveniles, geriatrics and liver disease patients may experience increases in elimination half-life with resultant prolonged activity1


Retrograde amnesia1,3,4
Muscle relaxation1,3,4,5
Minimal cardiovascular effects (at clinical doses)5
Minimal respiratory effects (at clinical doses)5
Appetite stimulation in cats7
Not analgesic7

Cardiovascular effects 

At clinical doses and when administered intravenously (IV) BDZ have only minor effects on the cardiovascular system. Slight reductions in systemic vascular resistance, preload, cardiac output and blood pressure may be occasionally observed, but are well tolerated in healthy patients1.   

Respiratory effects 

At clinical doses BDZ usually have minimal effects on the respiratory system. Minor reductions in tidal volume and a mild increase in respiratory rate may be observed. However, if combined with other CNS depressants, and/or used at doses >0.2mg/kg (for both midazolam and diazepam), there may be an exacerbation of respiratory depression with a reduced ventilatory response to carbon dioxide and a slight relaxation of the intercostal muscles1,6

Muscle tone 

Muscle tone is reduced via the effects of the BDZ on dorsal horn of the spinal cord1


There is a marked difference in individual sensitivity to BDZs, particularly in healthy patients, and maximum effects may not be seen for several minutes following IV administration3

In healthy patients disinhibition, or paradoxical excitement, is commonly observed rather than anxiolysis/sedation3,8, and previously calm animals can become aggressive5,6.  Although these effects may be masked by administering BDZ together with an opioid, they are not fully eliminated and excitement can still occur5.  For this reason, BDZ are not routinely used in healthy patients for premedication or sedation5,6

Animals with a higher American Society of Anaesthesiaologists (ASA) Physical Status Classification (III or above) are more likely to be sedated following BDZ administration, with excitement being rarely seen3,5.  BDZ are useful for critically ill patients as there is minimal cardiovascular or respiratory depression at clinical doses5.  


The structure of midazolam, and its water solubility, are pH dependent: at a low pH the diazepine ring in midazolam is ionised and open producing a water-soluble formulation1,2,6.  If the surrounding pH exceeds 4 the diazepine ring closes, is no longer ionised, and the midazolam becomes lipid soluble and hydrophobic2,3,4,5.  Therefore, when administered intravenously in its water soluble, open ring, form the midazolam is subjected to a plasma pH of approximately 7.4 and the ring closes.  This produces the lipid soluble structure allowing it to cross the blood-brain barrier1. Midazolam is 95% protein bound1

As midazolam is water soluble it causes minimal pain on injection2,3,5, and is not associated with thrombophlebitis. It may be administered intramuscularly5.  

The elimination half-life of midazolam is 77-98 mins in the dog3.  It is more rapidly acting, more potent and more readily redistributed than diazepam1,4,5. Additionally, it has a shorter duration of action than diazepam (1-4 hours for midazolam compared to 4-12 hours for diazepam).   The less active metabolites of midazolam make it more suitable for infusions6

Midazolam is commonly used in animals assessed to be ASA Physical Status III or greater, or as a co-induction agent with alfaxalone, opioids, ketamine or propofol3

At doses > 0.2mg/kg midazolam may produce peripheral vasoconstriction and negative inotropy with resultant hypotension and a slight increase in heart rate6

Midazolam has powerful amnesic properties2

The only formulation registered in the United Kingdom is licenced for use in horses. 


Diazepam is hydrophobic with a high lipid solubility1,2,7 and is 95% protein bound2.  Commercial formulations of diazepam are either solubilised in propylene glycol plus ethanol1,5, or in a soya bean lipid emulsion1.  Both formulations of diazepam are poorly absorbed when given intramuscularly (IM), and are painful, therefore use should be restricted to intravenous administration5,6,7

Intravenous administration of the aqueous formulation of diazepam can cause pain and thrombophlebitis3,5 and, additionally, the propylene glycol in the aqueous formulation has been implicated in the development of cardiac arrhythmias, hypotension and heamolysis6. In cats, prolonged or repeated intravenous administration of propylene glycol has been reported to cause cardiovascular depression, and therefore midazolam is the BDZ of choice for cats7

Intravenous administration of the lipid emulsion formulation of diazepam is non-irritant and less painful than the aqueous product, therefore, in the majority of patients the emulsion is the preferred product5

Diazepam has a slower onset of action than midazolam and a longer duration of action (4-12 hours for diazepam compared to 1-4 hours for midazolam)6.  The plasma elimination half-life of diazepam is 3.2 hours in the dog3, with an even longer half-life for the active metabolite desmethyldiazepam3,4

In cats diazepam inhibits bile acid efflux resulting in bile acid accumulation in the hepatocytes. Repeated or prolonged administration may therefore contribute to feline liver injury7

Diazepam adheres to some plastics, possibly including syringes & giving sets, so injections should be prepared & immediately administered6

2 formulations are registered in the UK for cats and dogs, both 5mg/ml. 

FLUMAZENIL (antagonist)

Like midazolam, flumazenil is an imidazobenzodiazepine. Flumazenil is a competitive, potent and selective BDZ receptor antagonist1,3,4. It is 40-50% protein bound and is readily redistributed1. Flumazenil is rapidly acting, demonstrating clinical effects within 2 minutes of administration2, although the duration of action is shorter than either diazepam or midazolam. Therefore, close observation of the patient is required as the clinical effects of midazolam or diazepam can re-emerge, and supplementary doses of flumazenil may be required1,2


Sedation & anaesthesia 

BDZ are commonly used in anaesthesia for sedation, premedication2, and co-induction. The aim of co-induction is to reduce the dose of other CNS depressants, therefore minimising the potentially unwanted side-effects of the induction and maintenance agents3,4.  However, it should be remembered that in fit, healthy animals BDZ alone may not result in sedation and may in fact, cause disinhibition and excitement or aggression.  BDZ alone cannot induce anaesthesia in healthy animals and should be used in combination with other CNS depressants e.g. alfaxalone9,10

The main use of BDZ is part of a multimodal approach to anaesthesia3

a. Sedation/premedication 

BDZ may be used as a sole anxiolytic agent for severely debilitated, paediatric or geriatric patients6. The dose of either midazolam of diazepam for these patients is 0.1-0.25mg/kg IV6 starting with the lowest dose.

BDZ, in combination with an opioid, are suitable for premedication of debilitated patients in the ASA III and above category or for paediatric/geriatric animals5,6,11.

Several techniques are described: 

  • Premedication with opioid followed by BDZ co-induction of anaesthesia

Premedication with an opioid administered intramuscularly and allow a suitable period of time to reach peak effect.

The BDZ, midazolam or diazepam, is administered by slow intravenous injection immediately followed by the IV induction agent, to effect.  This will allow a reduced dose of induction agent.

The induction agent should be administered immediately following the BDZ as, if too much time is allowed to elapse, excitement may occur.

This protocol is not ideally suited to difficult patients as the opioid premedicant may not provide a suitable degree of sedation5.

Suggested BDZ doses are 0.2-0.5mg/kg5,7.

  • Opioid + BDZ premedication followed by induction agent

Premedication with an opioid plus BDZ and sufficient time allowed for the drugs to reach peak effect.

Induction as normal with a the same degree of dose sparing as one would expect from the use of acepromazine as a premedicant.

In healthy patients this protocol produces unpredictable results: the level of sedation following opioid + BDZ premedication ranging from none to profound5.

In the sicker patient sedation tends to be more reliable and predictable5.

Suggested BDZ doses vary:

Midazolam IM 0.2mg/kg from plus an opioid IM5
BDZ 0.1-0.25mg/kg IV plus an opioid6;
Midazolam 0.3-0.4mg/kg plus opioid IM or IV12.

  • BDZ plus opioid co-administration for induction

In poor anaesthetic risk patients it may be possible to induce anaesthesia with a co-administered opioid and BDZ.

This type of protocol results in good cardiovascular stability, but should be reserved for the sicker patient3,5,13.

If the BDZ/opioid combination fails to achieve stage III anaesthesia it will still have produced a significant dose sparing effect on the actual induction agent with a resultant reduction in cardiorespiratory side-effects5.

BDZ are not induction agents and the opioid/BDZ combination is rarely effective for induction of anaesthesia in the healthy patient5.

  • Severely debilitated animals 

 BDZ alone may be sufficient to provide anxiolysis/sedation in these patients6.

b. BDZ with ketamine 

BDZ may reduce hallucinations when used prior to, or in combination with, dissociative anaesthetics e.g. ketamine3. Midazolam (usually) may also be used in combo with ketamine to offset muscle rigidity produced by the ketamine and to improve CNS depression5.

Suggested BDZ doses are: 0.1-0.25mg/kg IV6

c. Reducing restlessness during anaesthetic recovery or for intensive care patients 

Midazolam or diazepam are useful for reducing restlessness during anaesthetic recovery (0.25-0.4mg/kg IV) but respiratory depression can occur6

Midazolam is the preferred drug of many anaesthetists for the critical care patient: It is water soluble, has a short duration of action and a short elimination half-life11

Midazolam may be administered to reduce anxiety and restlessness in intensive care patients: Provided adequate analgesia has been administered and the patient checked to ensure the bladder is empty 6, small doses of BDZ (0.1-0.2mg/kg5) will assist in calming distressed patients. Midazolam infusions can be titrated to effect8 and will provide longer term sedation (0.2mg/kg/hour IV5).  It should be noted however, that long-term infusions may result in dysphoria although this can be treated with the antagonist flumazenil 

Appetite stimulation 

In cats small doses of intravenous diazepam (0.4mg/kg) administered every 24 hours have been used for the management of anorexia. Although the mode of action is unclear5 it may be related to increased attraction to tastes11. If used for this indication food should be readily available following administration as the response will occur in seconds8. Cats treated with diazepam should be closely observed and the food/water removed immediately sedation occurs to avoid aspiration. 

Blocked cats 

Urethral relaxation following intravenous BDZ may be useful for “blocked cats” (0.5-1mg/kg IV)6

Treatment of convulsions/status epilepticus. 

For the initial treatment of convulsions up to 0.5mg/kg of midazolam or diazepam may be administered IV and repeated every 10 mins for up to 3 doses. If an infusion is necessary midazolam is the better choice as it does not adhere to plastics (diazepam in both aqueous & emulsion version can adhere to plastics), is less cumulative, and has a low risk of thrombophlebitis6.  Suggested midazolam infusion rate: 0.4µg/kg/min IV6.

Get your copy of the downloadable Benzodiazepines Summary & Suggested Dose Table here

Article by
Dr. Karen Heskin

Originally published: Thursday, 29th November 2018


  1. Smith T, Pinnock C, Lin T & Jones R (2009). Fundamental of anaesthesia, 3rd edition. Cambridge University Press.
  2. Peck T, Hills S & Williams M (2008). Pharmacology and Anaesthesia for Intensive Care, 3rd edition. Cambridge University Press.
  3. Clarke KW, Trim CM, Hall LW (2014). Veterinary Anaesthesia, 11th edition. Saunders Elsevier.
  4. Hemmings HC & Hopkins PM (2005). Foundations of Anaesthesia. Basic Sciences for Clinical Practice. Elsevier
  5. Welsh L (2009). Anaesthesia for Veterinary Nurses. Wiley & Sons
  6. Dugdale A (2010). Veterinary Anaesthesia: Principles to Practice. Blackwell Publishing Ltd.
  7. Steagal P, Robertson S & Taylor P (2018). Feline Anaesthesia and Pain Management. Wiley Blackwell.
  8. Covey-Crump GL & Murrison PJ (2008). Fentanyl or midazolam for co-induction of anaesthesia with propofol in dogs. Veterinary Anaesthesia and Analgesia, 35, 463-472
  9. Italiano M & Robinson R (2018). Effect of benzodiazepines on the dose of alfaxalone needed for endotracheal intubation in healthy dogs. Veterinary anaesthesia and Analgesia, 45, 720-728
  10. Zapata A, Laredo FG, Escobar M, Agut A, Soler M & Belda E (2018). Effects of midazolam before or after alfaxalone for co-induction of anaesthesia in healthy dogs. Veterinary Anaesthesia and Analgesia, 45, 609-617
  11. Silverstein DC & Hopper K (2015). Small Animal Critical Care Medicine, Saunders Elsevier
  12. Duke-Novakovski T, de Vries M & Seymour C (2016). BSAVA Manual of Canine and Feline Anaesthesia and Analgesia.
  13. Psatha E, Alibhai HIK, Jiminez-Lozano A, Armitage-Chan E & Broadbelt DC (2011). Clinical efficacy and cardiorespiratory effects of alfaxalone, or diazepam/fentanyl for induction of anaesthesia in dogs that are poor anaesthetic risk. Veterinary Anesthesia and Analgesia, 38, 24-36


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AceSedate®, Our New Acepromazine, Available Now.

We have extended our anaesthesia and analgesia portfolio with the launch of AceSedate®. Containing the tried and trusted, long-acting sedative agent acepromazine as its active ingredient, AceSedate can be used for the premedication, sedation and tranquilisation of cats and dogs.

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Time: is 30 minutes long enough?

This recent study examined whether the application of EMLA cream, for 30 or 60 minutes, would be a useful tool to improve patient compliance prior to intravenous cannula placement in the veterinary clinical practice setting.

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Caesarean Section Survival Guide. Part 2: Anaesthetic Protocol Selection & Peri-operative Considerations.

In this second instalment of the 2-part article, we explore premedication, induction, maintenance & monitoring, recovery and analgesia for the Caesarean section patient.

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Buprenorphine: it’s not all static in rabbits

Opioids are well known for causing gastrointestinal stasis in mammalian species. This recent paper examined the effects of a single high dose of buprenorphine on the rabbit gastrointestinal tract using non-invasive imaging techniques.

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Caesarean Section Survival Guide. Part 1: Physiology & Pre-anaesthetic Considerations.

In the first instalment of this 2-part review Karen examines the physiological changes that occur during pregnancy and how those adjustments can affect the selection of anaesthetic protocols for the increasingly common Caesarean section.

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No leeway for the spay: A comparison between methadone and buprenorphine for perioperative analgesia in dogs undergoing ovariohysterectomy.

This recent paper compares post-operative pain scores and requirement for rescue analgesia following premedication with methadone or buprenorphine, in combination with acepromazine or medetomidine, in 80 bitches undergoing ovariohysterectomy.

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Cardiac arrest - the human factor

Cardiac arrest in dogs and cats is, thankfully, relatively rare. However, when it does happen it can have devastating consequences for the animal, owner and the veterinary team. This study examined the common causalities leading up to a cardiac arrest with the aim of changing protocols to improve outcomes.

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Are you Using Safety Checklists in your Practice?

In this article, Carl focuses on the benefits of introducing a safety checklist in practice to reduce patient morbidity, mortality and to improve communication between members of the veterinary team. The article contains links to the AVA safety checklist as well as a link to a customisable list that you can adapt to your practice needs. 

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The Big Chill - Temperature Management in Sedated and Anaesthetised Patients

The effects of hypothermia are very far reaching throughout the peri-anaesthetic process. In this article, James takes us through the interesting mechanisms of body cooling and warming, the clinical relevance of hypothermia and what we can do to prevent it.

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Keeping the Finger on the Pulse -  Nuances in CV Monitoring

All patients are exposed to the risks associated with general anaesthesia. Continuously monitoring anaesthetised patients maximises patients safety and wellbeing. In this article, Dan takes us through the common monitoring techniques that provide information about the cardiovascular status of your patient. 

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Effect of Maropitant on Isoflurane Requirements & Postoperative Nausea & Vomiting

Despite being widely recognized in humans, postoperative nausea and vomiting (PONV), and the role of maropitant in reducing inhalational anaesthetic requirements have been poorly documented in dogs. This recent study evaluates PONV and isoflurane requirements after maropitant administration during routine ovariectomy in bitches.

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New! Alfaxan® Multidose Now Available

We are happy to announce we have enhanced our anaesthesia and analgesia portfolio with the introduction of Alfaxan®Multidose for dogs, cats and pet rabbits.

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Sevoflurane requirement in dogs premedicated with medetomidine and butorphanol

Little information is available about the effect that different doses of medetomidine and butorphanol may have when using sevoflurane for maintenance of anaesthesia in dogs. This recent study evaluates heart rate and median sevoflurane concentration required at different dose rates.

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Capnography II - What happened to the elephants? A summary of abnormal traces

In this second article of the capnography series, James provides a guide to a few of the most common traces that you will encounter during surgery. Scroll to the end of the article to download a printable capnography cheatsheet. 

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Pain, what a Pain! (Part 2) – Practical Tips On How To Perform Dental Nerve Blocks In Companion Animal Practice

In this second article of the Pain, what a Pain! series, Dan takes us through the LRA techniques associated with dental and oral surgery. In this article, you will find practical tips and pictures on common dental nerve blocks as well as safety concerns to consider.

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​Peri-anaesthetic mortality and nonfatal gastrointestinal complications in pet rabbits

This recent retrospective study looks at the cases of 185 pet rabbits admitted for sedation or general anaesthetic and evaluates the incidence and risk factors contributing to peri-anaesthetic mortality and gastrointestinal complications.

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Pain, what a Pain! How Locoregional Anaesthesia can Improve the Outcome and Welfare of Veterinary Patients (Part 1)

In this first article out of a series of two, Dan takes us through an introduction and practical tips for appropriate local anaesthesia delivery. Find out why these anaesthesia techniques, that are well recognised in human medicine, have seen an increase in popularity in veterinary medicine over the recent years

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Perspectives on Premeds – Opioids

Perspectives on Premeds is a series of articles touching on different pharmacological, physiological and clinical aspects of pre-anaesthetic medication. This second article aims to provide a refresher on opioids.

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Effects of Dexmedetomidine with Different Opioid Combinations in Dogs

Read the highlights of a recently published research paper that evaluates cardiorespiratory, sedative and antinociceptive effects of dexmedetomidine alone and in combination with morphine, methadone, meperidine, butorphanol, nalbuphine and tramadol. 

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Preoxygenation Study Highlights

This study evaluates the effectiveness of two methods of preoxygenation in healthy yet sedated dogs and the impact of these methods on time taken to reach a predetermined haemoglobin desaturation point (haemoglobin saturation (SpO2) of 90%) during an experimentally induced period of apnoea.

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Capnography – Not Just a Load of Hot Air

Capnography is the measurement of inhaled and exhaled carbon dioxide (CO2) concentration. The graphical illustration of CO2 within respired gases versus times is known as the capnogram.

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Perspectives on Premeds – Alpha-2 Agonists

Perspectives on Premeds is a series of articles touching on different pharmacological, physiological and clinical aspects of pre-anaesthetic medication. This first article aims to provide a refresher on α2 agonists.

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Alfaxan - now licensed for use in pet rabbits

Jurox Animal Health is delighted to announce that Alfaxan is now licensed for cats, dogs and pet rabbits. This is an exciting advance and could change the way rabbits are anaesthetised in the U.K.

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