Constantine III (Western Roman emperor)

Constantine III (Latin: Flavius Claudius Constantinus; died shortly before 18 September 411) was a common Roman soldier who was declared emperor in Roman Britain in 407 and established himself in Gaul. He was recognised as co-emperor of the Roman Empire from 409 until 411.

Constantine rose to power from within the field army of Roman Britain and was acclaimed emperor in early 407. He promptly moved to Gaul (modern France), taking all of the mobile troops from Britain, with their commander Gerontius, to confront bands of Germanic invaders who had crossed the Rhine the previous winter. With a mixture of fighting and diplomacy Constantine stabilised the situation and established control over Gaul and Hispania (modern Spain and Portugal), establishing his capital at Arles. The sitting emperor of the Western Roman Empire, Honorius, sent an army under Sarus the Goth to expel Constantine's forces. After initial victories, Sarus was repulsed. In Hispania, Honorius's relatives rose and expelled Constantine's administration. An army under the general Gerontius was sent to deal with this and Constantine's authority was re-established. In early 409 Honorius recognised Constantine as co-emperor. Constantine in turn raised his own oldest son to co-emperor as Constans II.

In 409 Gerontius rebelled, proclaimed his client Maximus emperor and incited barbarian groups in Gaul to rise up. Constans was sent to quash the revolt, but was defeated and withdrew to Arles. Meanwhile, Constantine invaded northern Italy, but his plan failed and he also pulled back to Arles. In 410 Constans was sent to Hispania again. Gerontius had strengthened his army with Germanic tribesmen and defeated Constans; the latter retreated north and was defeated again and killed at Vienne early in 411. Gerontius then besieged Constantine in Arles. Honorius appointed a new general, Flavius Constantius, who arrived at Arles while Gerontius was outside the city. Much of Gerontius's army deserted to Constantius, who took over the siege. A force attempting to relieve Constantine was ambushed. Constantine abdicated, took holy orders and – promised his life – surrendered. Constantius had lied: Constantine was killed and his head presented to Honorius on a pole.

## Background

Following the death of the Roman emperor Theodosius I in 395 the Roman Empire was divided between his two sons: Arcadius became emperor of the Eastern Roman Empire and ten-year-old Honorius of the Western. Honorius was underage and the leading general Stilicho became hugely influential and the de facto commander-in-chief of the Roman armies in the west.

During this period Roman Britain was suffering raids by the Scoti, Saxons and Picts. Sometime between 396 and 398 Stilicho is said by contemporary poet and speech writer Claudian to have ordered a campaign against the Picts, probably a naval campaign intended to suppress their seaborne raids on the east coast of Roman Britain. He may also have ordered campaigns against the Scoti and Saxons. Other interpretations suggest it went badly, or that troops defending Roman Britain defeated a Pictish invasion without external support. This is the last recorded Roman military campaign in Britain. Stilicho sent funds to strengthen the defences along Hadrian's Wall and the coastal defences at about the same time.

In 401 or 402 Stilicho needed military manpower for wars with the Visigoths and the Ostrogoths and so stripped Hadrian's Wall of troops. The year 402 is the last date from which Roman coinage is found in large quantities in Britain, suggesting the Empire was no longer paying the troops who remained. Meanwhile, the Picts, Saxons and Scoti continued their raids, which may have increased in scope. In 405 the Irish king Niall of the Nine Hostages is described as having raided along the southern coast of Britain.

Both the Eastern and Western Empires were suffering from incursions of large groups from Germanic tribes, whom the Romans referred to generically as "barbarians". In 406 a group of Alans and Goths led by Radagaisus invaded Italy. The group included women and children and is estimated to have been 90,000–100,000 strong, of whom more than 20,000 were fighting men. For six months they devastated northern Italy, capturing and sacking several cities. After concentrating his forces, Stilicho caught the Goths while they were besieging Florentia (modern Florence) and defeated them at the Battle of Faesulae; 12,000 prisoners joined the Roman army and so many captives were sold that the market in slaves collapsed. The Western Empire's problems with barbarian intruders were far from over, however.

## Life

Little is known of Flavius Claudius Constantinus before he was declared emperor and took the regnal name Constantine. His date and place of birth are unknown, as is his marital status. He had two sons, although their names prior to being given more regal-sounding ones are likewise unknown. Regarding his personal habits, one fifth-century historian described him as a glutton and another considered that his major flaw was being inconstant in his policies.

### Rise

In 406 the approximately 6,000 troops of the Roman field army based in Roman Britain were dissatisfied. They had not been paid for several years, a large contingent had left to fight on the continent four years earlier and had not returned, the coastal defences had been dismantled to form the new field army and their commander had been replaced. They revolted and determined to choose their own leader. Their first choice was a man named Marcus, whom they appointed emperor. After a short period, unhappy with his performance, they killed him and appointed Gratian. He also failed to meet the troops' expectations and was killed after four months. On 31 December 406 several tribes of barbarian invaders, including the Vandals, Sueves and Alans crossed the Rhine, perhaps near Mainz, and overran the Roman defensive works in a successful invasion of the Western Roman Empire. Hearing of the Germanic invasion the Roman military in Britain was desperate for some sense of security in a world that seemed to be rapidly falling apart. They next chose as their leader a man named after the famed emperor of the early fourth century, Constantine the Great, who had himself risen to power through a military coup in Britain. Flavius Claudius Constantinus was a common soldier, not an officer, and early in 407, possibly February, his fellows acclaimed him as emperor. The modern historian Francisco Sanz-Huesma differs and proposes that Constantine was a skilled politician who engineered the three acclamations with the (successful) intention of eventually raising himself to imperial power.

Rebellion in Roman Britain was not unusual, a contemporary described it as a "province rich in usurpers". It was on the periphery of the Empire and there was a common view that it was overlooked in terms of resources and patronage. Such revolts were usually short-lived; Constantine was uncommon in both establishing a lasting power base and in successfully exporting his rebellion to the mainland. Constantine moved quickly: he appointed two officers already in Gaul (modern France) as generals, Justinianus and Nebiogastes, instructing them to seize Arles and the passes which controlled traffic to and from Italy. He crossed the Channel at Bononia (modern Boulogne), taking with him all of the 6,000 or so mobile troops left in Britain and their commander, the general Gerontius. This denuded Roman Britain of front-line military protection and explains the disappearance of the legions in the early fifth century. Constantine travelled to Lyon, where he set up his headquarters and commenced minting coins in his own name. The Roman Army of Gaul declared for him, followed by the civilian administration in Hispania (modern Spain and Portugal). The central Roman authorities did not respond to the Germanic invasion, and Constantine's forces got the better of at least one confrontation with the Vandals. Constantine also negotiated agreements with the Germanic groupings of the Franks, Alamanni and the Burgundians, thus securing the line of the Rhine. The main Vandal force and their allies moved into northern Gaul (modern Belgium).

The Western Roman emperor, Honorius, and his commander-in-chief Stilicho were in conflict with the Eastern Roman Empire and allied to a large force of Visigoths under Alaric. The relationship with the Visigoths was shaky – they were demanding land or money for their services. An agreement was reached for a joint West Roman-Visigoth army to threaten the Eastern Empire to extort land from it which would then be given to the Visigoths. This manoeuvre was supposed to commence in May or June 407. By then the Vandals and their allies had broken into Gaul, where Constantine had control of the army and was claiming the imperial throne. Sending a large Western Roman force to the east would have left Italy open to invasion by one or both of these groups and so the offensive was cancelled. Instead a small army led by Sarus the Goth was sent west to put down Constantine's revolt while Stilicho's main army waited on events.

Sarus defeated the army commanded by Justinianus in a pitched battle, killing Justinianus. Constantine personally moved against Sarus, but was besieged in Valence. Nebiogastes attempted to negotiate and was killed by Sarus. Another army, led by Gerontius and Edobichus and largely made up of freshly recruited Franks and Almannics, arrived to relieve Valence after a week of siege. Sarus was forced to retreat into Italy. Central control had deteriorated to the extent that Sarus needed to buy his passage through the Alpine passes from the brigand Bagaudae, who controlled them. With this success Constantine established control over most of Gaul and the Alpine passes into Italy.

### Co-emperor

By May 408 Constantine had captured Arles and made it his capital, taking over the existing imperial administration and officials, and appointing Apollinaris as chief minister (with the title of praetorian prefect). Heros was installed as a pliant archbishop of Arles in spite of local opposition. Constantine commenced minting large quantities of good quality coins at Arles, possibly using bullion seized from Sarus's loot during his hasty retreat, and made a show of being an equal of both the Western and Eastern Emperors.

Constantine's oldest son had entered a monastery and was a monk at the time his father rebelled, but he was summoned to the new imperial court. Constantine appointed him to the position of caesar – a senior, formal position that also recognised him as heir apparent – and gave him the imperial-sounding name of Constans. He was swiftly married so a dynasty could be founded. Early in 408 he was sent with Gerontius into Hispania. Hispania was a stronghold of the House of Theodosius, but on Constantine's initial landing on the continent, Honorius's relatives and partisans there had been either unwilling or militarily unable to oppose his assumption of control. When Sarus seemed on the verge of ending Constantine's revolt, two members of Honorius's family – Didymus and Verinianus – rebelled and overthrew Constantine's regime in Hispania. When Sarus withdrew to Italy, the knowledge of the large new army assembling at Ticinum (modern Pavia) with the intention of shortly engaging Constantine encouraged them to persist and even to attempt to seal the Pyrenean passes. Constantine feared that Honorius's cousins would organise an attack from that direction while troops under Sarus and Stilicho attacked him from Italy in a pincer manoeuvre. He struck first, at Hispania. Constans and Gerontius's army forced a pass and was reinforced. Constans established himself at Saragossa and rebuilt the civilian administration. Gerontius took the army and decisively defeated Honorius's supporters at a battle in Lusitania where Didymus and Verinianus were captured. With Hispania back under Constantine's control Constans left his new wife at Saragossa and returned to Arles to report to his father. Didymus and Verinianus accompanied him and were executed as civilian rebels, which further soured relations with Honorius.

By early 408 the Visigoths were running out of patience with Stilicho. They moved from Epirus (modern Albania) to Noricum (modern Austria) and demanded a payment of 4,000 pounds (1,800 kg) of gold on pain of their invading Italy. Honorius and the Roman Senate were prepared to resist, but Stilicho persuaded them to approve the payment, to allow him to concentrate on the situation in Gaul. He had assembled an army at Ticinum with which to do this. It is possible that the plan was for the Visigoths to accompany this force as military allies. On 1 May the emperor of the Eastern Empire, Arcadius, died, leaving a seven-year-old heir, Theodosius II. A disagreement arose between Stilicho and Honorius, who each wished to travel to Constantinople – the capital of the Eastern Empire – to represent the Western Empire's interests. Stilicho got his way: he was to leave for the east while Honorius remained in Ravenna, the capital of the Western Empire. But a rift between him and Honorius was obvious. The Roman establishment, led by the senior bureaucrat Olympius, worked to oppose Stilicho by spreading rumours that he wished to travel east to depose Theodosius and set his own son on the throne. On 13 August Honorius was formally reviewing the army about to set out from Ticinum against Constantine. With him were many of the senior officers and officials of the Western Empire. The troops mutinied, slaughtering Stilicho's supporters but respecting the person of the Emperor. Stilicho sought sanctuary, then surrendered and was executed on 22 August.

Olympius reversed the policy of making a massive payment to the Visigoths and the native parts of the Army of Italy started slaughtering Goths: especially their fellow soldiers and their wives and children. The latter, living in Italian cities, sometimes overtly as hostages for their husbands and fathers' good behaviour, were easy targets. Those Goths who could fled north and joined Alaric, greatly increasing his fighting strength. Alaric promptly crossed the Alps and headed south through Italy, devastating the countryside. He camped his army outside Rome and demanded a huge ransom. Late in 408 Constantine sent an embassy to Ravenna. Needing to placate him, Honorius acknowledged him as co-emperor and sent a purple robe as formal recognition. The pair were joint consuls in 409. At around this time, Constantine raised Constans to the position of co-emperor, theoretically equal in rank to Honorius or Theodosius, as well as to Constantine.

With the Visigoths deep in Italy and unopposed, Olympius's influence ended and a new chief minister, Jovius, entered into peace negotiations but Honorius continued to refuse to reach an agreement with Alaric. The Visigoths in retaliation continued to roam across Italy and extort vast sums from the city of Rome. Alaric elevated his own emperor, the senator Priscus Attalus, to no avail. On 24 August 410 the Visigoths entered Rome and pillaged the city for three days.

### Decline

In spring or summer 409 Apollinaris was replaced as praetorian prefect by Decimus Rusticus and Constans was sent back to Hispania. Either before Constans left Arles or while he was travelling Gerontius rebelled, proclaiming his client Maximus as emperor. Maximus was an important figure in his own right, but it was clear he was controlled by Gerontius. They set up court at Tarraco (modern Tarragona). Gerontius was concerned that he would not be able to withstand the military force Constantine could bring to bear and so attempted to incite the barbarians who had entered Gaul late in 406 against Constantine. These had been quiescent in the north of the territory, but now set off across Gaul for the rich territories of Aquitaine and Narbonensis (modern south-west and southern France). They spread devastation across these areas, much to the horror of the populace. Concentrating on the threat from Constans, Gerontius weakened his garrisons in the Pyrenean passes and in autumn 409 much of the barbarian force entered Hispania. Eventually Gerontius was able to reach a modus operandi with some of these groups whereby they supplied him with military forces, which enabled him to take the offensive against Constantine.

From 408 Saxon pirates raided Roman Britain extensively, undeterred by the totally inadequate force which Constantine had left. The locals organised their own defences, so successfully that they defeated the Saxons in 409. Distressed that Constantine had failed to defend them, the Roman inhabitants of Britain rebelled and expelled his officials, accepting that henceforth they would have to look to their own defence. Inspired by the example of Roman Britain, later that year the Bagaudae of Armorica (modern Brittany) also expelled Constantine's officials and declared independence.

Constantine sent a further embassy to Ravenna, which achieved little, but Constantine's emissary, Jovius, did suborn one of Honorius's senior generals, Allobich. In spring 410 Constantine led an army into northern Italy. It is possible that he claimed he intended to assist Honorius against the Visigoths. It is also likely he was counting on support from Allobich. When he reached the River Po he heard, wrongly, that Allobich was dead, which caused him to abandon his mission and withdraw to Arles.

Meanwhile, Constans, with an army commanded by a general named Justus, attempted to subdue Gerontius. He failed, although no details are known, and returned to Arles in spring 410. At about the same time Constantine returned from his abortive invasion of Italy. Given the difficulties the Visigoths were creating in Italy, Gerontius was considered a greater threat than Honorius. Edobichus was again sent north to raise troops from the Franks while Constans returned to confront Gerontius with a fresh army. Events are again unclear, but it seems likely that Gerontius was simultaneously advancing on Arles. The two armies clashed and Constans was defeated. He fell back to the north with what was left of his command, hoping to be reinforced by Edobichus. But Gerontius caught him at Vienne, probably early in 411, defeated his army and killed Constans. Gerontius's army then marched on Arles and besieged Constantine.

### Fall

In 411 Honorius appointed a new general, Flavius Constantius, who took the Army of Italy over the Alps into Gaul in another attempt to suppress Constantine. Constantius arrived at Arles while Gerontius was outside the city. Many of Gerontius's troops deserted to Constantius and Gerontius retreated to Hispania with the remainder. There, in a hopeless position, Gerontius committed suicide. Constantius's army took over the siege. Meanwhile Edobichus raised troops in northern Gaul among the Franks and Alamanni, combined them with those of the Army of Gaul still loyal to Constantine and marched to Constantine's assistance. Constantius defeated this force in an ambush. Constantine, his hopes fading after the troops guarding the Rhine abandoned him to support yet another claimant to the imperial throne, the Gallo-Roman Jovinus, surrendered to Constantius along with his surviving son Julian. Despite a promise of safe passage, and Constantine's assumption of clerical office, Constantius imprisoned the former soldier and had him and Julian beheaded in either August or September 411. His head was mounted on a pole and presented to Emperor Honorius on 18 September. It was later displayed outside Carthage, as was that of Julian.

## Aftermath

Constantius withdrew in the face of Jovinus's forces. The modern historian Peter Heather describes the Roman Army of Gaul as emerging from Constantine's wars "in tatters". In 413 a Visigoth army under Athaulf, who was now allied with Honorius, suppressed Jovinus's revolt. Constantius took over Stilicho's role as the main power in the Western Empire and generalissimo. He was broadly able to recover the situation for the central authorities and to enable reconstruction. Gaul was pacified, the rebellion in Armorica was quashed and the area brought back under Roman control, the barbarians in Hispania were in large part subdued and the Visigoths were settled on land in Aquitaine as Roman allies. Roman rule never returned to Britain after Constantine stripped its defences. In 417 Constantius married Honorius's sister, Galla Placidia. On 8 February 421, Honorius made Constantius co-emperor under himself. Constantius reigned only seven months, dying on 2 September. Honorius then ruled alone until his death in 423, whereupon Constantius's son, Valentinian III, assumed the throne.

## Legend

Constantine III is also known as Constantine II of Britain. He has been associated with the Constantine found in Geoffrey of Monmouth's popular and imaginative Historia Regum Britanniae, who comes to power following Gracianus Municeps's reign. Geoffrey's Constantine, through his son Uther Pendragon, becomes the grandfather of the legendary King Arthur. Other sources explicitly state that Constantine III is the grandfather of Arthur.

## Notes, citations and sources

Roman emperor from 407 to 411


Midazolam

Midazolam, sold under the brand name Versed among others, is a benzodiazepine medication used for anesthesia and procedural sedation, and to treat severe agitation. It works by inducing sleepiness, decreasing anxiety, and causing a loss of ability to create new memories. Like other benzodiazepines, it works by increasing the activity of the GABA neurotransmitter in the brain.

The drug does not cause an individual to become unconscious, merely to be sedated. It is also useful for the treatment of prolonged (lasting over 5 minutes) seizures. Midazolam can be given by mouth, intravenously, by injection into a muscle, by spraying into the nose, or through the cheek. When given intravenously, it typically begins working within five minutes; when injected into a muscle, it can take fifteen minutes to begin working. Effects last between one and six hours.

Side effects can include a decrease in efforts to breathe, low blood pressure, and sleepiness. Tolerance to its effects and withdrawal syndrome may occur following long-term use. Paradoxical effects, such as increased activity, can occur especially in children and older people. There is evidence of risk when used during pregnancy but no evidence of harm with a single dose during breastfeeding.

Midazolam was patented in 1974 and came into medical use in 1982. It is on the World Health Organization's List of Essential Medicines. Midazolam is available as a generic medication. In many countries, it is a controlled substance.

## Medical uses

### Seizures

Midazolam is sometimes used for the acute management of prolonged seizures. Long-term use for the management of epilepsy is not recommended due to the significant risk of tolerance (which renders midazolam and other benzodiazepines ineffective) and the significant side effect of sedation. A benefit of midazolam is that in children it can be given in the cheek or in the nose for acute seizures, including status epilepticus. Midazolam is effective for status epilepticus or when intravenous access cannot be obtained, and has advantages of being water-soluble, having a rapid onset of action and not causing metabolic acidosis from the propylene glycol vehicle (which is not required due to its solubility in water), which occurs with other benzodiazepines.

Drawbacks include a high degree of breakthrough seizures—due to the short half-life of midazolam—in over 50% of people treated, as well as treatment failure in 14–18% of people with refractory status epilepticus. Tolerance develops rapidly to the anticonvulsant effect, and the dose may need to be increased by several times to maintain anticonvulsant therapeutic effects. With prolonged use, tolerance and tachyphylaxis can occur and the elimination half-life may increase, up to days. Buccal and intranasal midazolam may be both easier to administer and more effective than rectally administered diazepam in the emergency control of seizures.

### Procedural sedation

Intravenous midazolam is indicated for procedural sedation (often in combination with an opioid, such as fentanyl), preoperative sedation, for the induction of general anesthesia, and for sedation of people who are ventilated in critical care units. Midazolam is superior to diazepam in impairing memory of endoscopy procedures, but propofol has a quicker recovery time and a better memory-impairing effect. It is the most popular benzodiazepine in the intensive care unit (ICU) because of its short elimination half-life, combined with its water solubility and its suitability for continuous infusion. However, for long-term sedation, lorazepam is preferred due to its long duration of action, and propofol has advantages over midazolam when used in the ICU for sedation, such as shorter weaning time and earlier tracheal extubation.

Midazolam is sometimes used in neonatal intensive care units. When used, additional caution is required in newborns; midazolam should not be used for longer than 72 hours due to risks of tachyphylaxis, and the possibility of development of a benzodiazepine withdrawal syndrome, as well as neurological complications. Bolus injections should be avoided due to the increased risk of cardiovascular depression, as well as neurological complications. Midazolam is also sometimes used in newborns who are receiving mechanical ventilation, although morphine is preferred, owing to its better safety profile for this indication.

Sedation using midazolam can be used to relieve anxiety and manage behaviour in children undergoing dental treatment.

### Agitation

Midazolam, in combination with an antipsychotic drug, is indicated for the acute management of schizophrenia when it is associated with aggressive or out-of-control behaviour.

### End of life care

In the final stages of end-of-life care, midazolam is routinely used at low doses via subcutaneous injection to help with agitation, restlessness or anxiety in the last hours or days of life. At higher doses during the last weeks of life, midazolam is considered a first line agent in palliative continuous deep sedation therapy when it is necessary to alleviate intolerable suffering not responsive to other treatments, but the need for this is rare.

## Administration

Routes of administration of midazolam can be oral, intranasal, buccal, intravenous, and intramuscular.

## Contraindications

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, in alcohol- or other drug-dependent individuals or those with comorbid psychiatric disorders. Additional caution is required in critically ill patients, as accumulation of midazolam and its active metabolites may occur. Kidney or liver impairments may slow down the elimination of midazolam leading to prolonged and enhanced effects. Contraindications include hypersensitivity, acute narrow-angle glaucoma, shock, hypotension, or head injury. Most are relative contraindications.

## Side effects

Side effects of midazolam in the elderly are listed above. People experiencing amnesia as a side effect of midazolam are generally unaware their memory is impaired, unless they had previously known it as a side effect.

Long-term use of benzodiazepines has been associated with long-lasting deficits in memory, and show only partial recovery six months after stopping benzodiazepines. It is unclear whether full recovery occurs after longer periods of abstinence. Benzodiazepines can cause or worsen depression. Paradoxical excitement occasionally occurs with benzodiazepines, including a worsening of seizures. Children and elderly individuals or those with a history of excessive alcohol use and individuals with a history of aggressive behavior or anger are at increased risk of paradoxical effects. Paradoxical reactions are particularly associated with intravenous administration. After nighttime administration of midazolam, residual 'hangover' effects, such as sleepiness and impaired psychomotor and cognitive functions, may persist into the next day. This may impair the ability of users to drive safely and may increase the risk of falls and hip fractures. Sedation, respiratory depression and hypotension due to a reduction in systematic vascular resistance, and an increase in heart rate can occur. If intravenous midazolam is given too quickly, hypotension may occur. A "midazolam infusion syndrome" may result from high doses, is characterised by delayed arousal hours to days after discontinuation of midazolam, and may lead to an increase in the length of ventilatory support needed.

In rare susceptible individuals, midazolam has been known to cause a paradoxical reaction, a well-documented complication with benzodiazepines. When this occurs, the individual may experience anxiety, involuntary movements, aggressive or violent behavior, uncontrollable crying or verbalization, and other similar effects. This seems to be related to the altered state of consciousness or disinhibition produced by the drug. Paradoxical behavior is often not recalled by the patient due to the amnesia-producing properties of the drug. In extreme situations, flumazenil can be administered to inhibit or reverse the effects of midazolam. Antipsychotic medications, such as haloperidol, have also been used for this purpose.

Midazolam is known to cause respiratory depression. In healthy humans, 0.15 mg/kg of midazolam may cause respiratory depression, which is postulated to be a central nervous system (CNS) effect. When midazolam is administered in combination with fentanyl, the incidence of hypoxemia or apnea becomes more likely.

Although the incidence of respiratory depression/arrest is low (0.1–0.5%) when midazolam is administered alone at normal doses, the concomitant use with CNS acting drugs, mainly analgesic opiates, may increase the possibility of hypotension, respiratory depression, respiratory arrest, and death, even at therapeutic doses. Potential drug interactions involving at least one CNS depressant were observed for 84% of midazolam users who were subsequently required to receive the benzodiazepine antagonist flumazenil. Therefore, efforts directed toward monitoring drug interactions and preventing injuries from midazolam administration are expected to have a substantial impact on the safe use of this drug.

### Pregnancy and breastfeeding

Midazolam, when taken during the third trimester of pregnancy, may cause risk to the neonate, including benzodiazepine withdrawal syndrome, with possible symptoms including hypotonia, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Symptoms of hypotonia and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth. Other neonatal withdrawal symptoms include hyperexcitability, tremor, and gastrointestinal upset (diarrhea or vomiting). Breastfeeding by mothers using midazolam is not recommended.

### Elderly

Additional caution is required in the elderly, as they are more sensitive to the pharmacological effects of benzodiazepines, metabolise them more slowly, and are more prone to adverse effects, including drowsiness, amnesia (especially anterograde amnesia), ataxia, hangover effects, confusion, and falls.

### Tolerance, dependence, and withdrawal

A benzodiazepine dependence occurs in about one-third of individuals who are treated with benzodiazepines for longer than 4 weeks, which typically results in tolerance and benzodiazepine withdrawal syndrome when the dose is reduced too rapidly. Midazolam infusions may induce tolerance and a withdrawal syndrome in a matter of days. The risk factors for dependence include dependent personality, use of a benzodiazepine that is short-acting, high potency and long-term use of benzodiazepines. Withdrawal symptoms from midazolam can range from insomnia and anxiety to seizures and psychosis. Withdrawal symptoms can sometimes resemble a person's underlying condition. Gradual reduction of midazolam after regular use can minimise withdrawal and rebound effects. Tolerance and the resultant withdrawal syndrome may be due to receptor down-regulation and GABAA receptor alterations in gene expression, which causes long-term changes in the function of the GABAergic neuronal system.

Chronic users of benzodiazepine medication who are given midazolam experience reduced therapeutic effects of midazolam, due to tolerance to benzodiazepines. Prolonged infusions with midazolam results in the development of tolerance; if midazolam is given for a few days or more a withdrawal syndrome can occur. Therefore, preventing a withdrawal syndrome requires that a prolonged infusion be gradually withdrawn, and sometimes, continued tapering of dose with an oral long-acting benzodiazepine such as clorazepate dipotassium. When signs of tolerance to midazolam occur during intensive care unit sedation the addition of an opioid or propofol is recommended. Withdrawal symptoms can include irritability, abnormal reflexes, tremors, clonus, hypertonicity, delirium and seizures, nausea, vomiting, diarrhea, tachycardia, hypertension, and tachypnea. In those with significant dependence, sudden discontinuation may result in withdrawal symptoms such as status epilepticus.

### Overdose

A midazolam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. Benzodiazepine overdose in healthy individuals is rarely life-threatening with proper medical support; however, the toxicity of benzodiazepines increases when they are combined with other CNS depressants such as alcohol, opioids, or tricyclic antidepressants. The toxicity of benzodiazepine overdose and the risk of death are also increased in the elderly and those with obstructive pulmonary disease or when used intravenously. Treatment is supportive; activated charcoal can be used within an hour of the overdose. The antidote for an overdose of midazolam (or any other benzodiazepine) is flumazenil. While effective in reversing the effects of benzodiazepines it is not used in most cases as it may trigger seizures in mixed overdoses and benzodiazepine dependent individuals.

Symptoms of midazolam overdose can include:

- Ataxia
- Dysarthria
- Nystagmus
- Slurred speech
- Somnolence (difficulty staying awake)
- Mental confusion
- Hypotension
- Respiratory arrest
- Vasomotor collapse

- Impaired motor functions
  - Impaired reflexes
  - Impaired coordination
  - Impaired balance
  - Dizziness
- Coma
- Death

### Detection in body fluids

Concentrations of midazolam or its major metabolite, 1-hydroxymidazolam glucuronide, may be measured in plasma, serum, or whole blood to monitor for safety in those receiving the drug therapeutically, to confirm a diagnosis of poisoning in hospitalized patients, or to assist in a forensic investigation of a case of fatal overdosage. Patients with renal dysfunction may exhibit prolongation of elimination half-life for both the parent drug and its active metabolite, with accumulation of these two substances in the bloodstream and the appearance of adverse depressant effects.

## Interactions

Protease inhibitors, nefazodone, sertraline, grapefruit, fluoxetine, erythromycin, diltiazem, clarithromycin inhibit the metabolism of midazolam, leading to a prolonged action. St John's wort, rifapentine, rifampin, rifabutin, phenytoin enhance the metabolism of midazolam leading to a reduced action. Sedating antidepressants, antiepileptic drugs such as phenobarbital, phenytoin and carbamazepine, sedative antihistamines, opioids, antipsychotics and alcohol enhance the sedative effects of midazolam. Midazolam is metabolized almost completely by cytochrome P450-3A4. Atorvastatin administration along with midazolam results in a reduced elimination rate of midazolam. St John's wort decreases the blood levels of midazolam. Grapefruit juice reduces intestinal 3A4 and results in less metabolism and higher plasma concentrations.

## Pharmacology

Midazolam is a short-acting benzodiazepine in adults with an elimination half-life of 1.5–2.5 hours. In the elderly, as well as young children and adolescents, the elimination half-life is longer. Midazolam is metabolised into an active metabolite alpha1-hydroxymidazolam. Age-related deficits, renal and liver status affect the pharmacokinetic factors of midazolam as well as its active metabolite. However, the active metabolite of midazolam is minor and contributes to only 10 percent of biological activity of midazolam. Midazolam is poorly absorbed orally, with only 50 percent of the drug reaching the bloodstream. Midazolam is metabolised by cytochrome P450 (CYP) enzymes and by glucuronide conjugation. Oxidation of midazolam is the major metabolite in human liver microsome (HLM). The half life (T1/2) of midazolam in HLM is 3.3 min. The therapeutic as well as adverse effects of midazolam are due to its effects on the GABAA receptors; midazolam does not activate GABAA receptors directly but, as with other benzodiazepines, it enhances the effect of the neurotransmitter GABA on the GABAA receptors (↑ frequency of Cl− channel opening) resulting in neural inhibition. Almost all of the properties can be explained by the actions of benzodiazepines on GABAA receptors. This results in the following pharmacological properties being produced: sedation, induction of sleep, reduction in anxiety, anterograde amnesia, muscle relaxation and anticonvulsant effects.

## History

Midazolam is among about 35 benzodiazepines currently used medically, and was synthesized in 1975 by Walser and Fryer at Hoffmann-LaRoche, Inc in the United States. Owing to its water solubility, it was found to be less likely to cause thrombophlebitis than similar drugs. The anticonvulsant properties of midazolam were studied in the late 1970s, but not until the 1990s did it emerge as an effective treatment for convulsive status epilepticus. As of 2010, it is the most commonly used benzodiazepine in anesthetic medicine. In acute medicine, midazolam has become more popular than other benzodiazepines, such as lorazepam and diazepam, because it is shorter lasting, is more potent, and causes less pain at the injection site. Midazolam is also becoming increasingly popular in veterinary medicine due to its water solubility. In 2018 it was revealed the CIA considered using Midazolam as a "truth serum" on terrorist suspects in project "Medication".

## Society and culture

### Cost

Midazolam is available as a generic medication.

### Availability

Midazolam is available in the United States as a syrup or as an injectable solution.

Dormicum brand midazolam is marketed by Roche as white, oval, 7.5-mg tablets in boxes of two or three blister strips of 10 tablets, and as blue, oval, 15-mg tablets in boxes of two (Dormonid 3x) blister strips of 10 tablets. The tablets are imprinted with "Roche" on one side and the dose of the tablet on the other side. Dormicum is also available as 1-, 3-, and 10-ml ampoules at a concentration of 5 mg/ml. Another manufacturer, Novell Pharmaceutical Laboratories, makes it available as Miloz in 3- and 5-ml ampoules. Midazolam is the only water-soluble benzodiazepine available. Another maker is Roxane Laboratories; the product in an oral solution, Midazolam HCl Syrup, 2 mg/ml clear, in a red to purplish-red syrup, cherry in flavor. It becomes soluble when the injectable solution is buffered to a pH of 2.9–3.7. Midazolam is also available in liquid form. It can be administered intramuscularly, intravenously, intrathecally, intranasally, buccally, or orally.

### Legal status

In the Netherlands, midazolam is a List II drug of the Opium Law. Midazolam is a Schedule IV drug under the Convention on Psychotropic Substances. In the United Kingdom, midazolam is a Schedule 3/Class C controlled drug. In the United States, midazolam (DEA number 2884) is on the Schedule IV list of the Controlled Substances Act as a non-narcotic agent with low potential for abuse.

### Marketing authorization

In 2011, the European Medicines Agency (EMA) granted a marketing authorisation for a buccal application form of midazolam, sold under the brand name Buccolam. Buccolam was initially approved for the treatment of prolonged, acute, convulsive seizures in people from three months to less than 18 years of age. This was the first application of a paediatric-use marketing authorisation.

### Use in executions

The drug has been introduced for use in executions by lethal injection in certain jurisdictions in the United States in combination with other drugs. It was introduced to replace pentobarbital after the latter's manufacturer disallowed that drug's use for executions. Midazolam acts as a sedative but will fail to render the condemned prisoner unconscious, at which time vecuronium bromide and potassium chloride are administered, stopping the prisoner's breathing and heart, respectively. Since the condemned prisoner is not rendered unconscious but is merely sedated, the administration of vecuronium bromide and potassium chloride can cause extreme pain and panic in the person being executed.

Midazolam has been used as part of a three-drug cocktail, with vecuronium bromide and potassium chloride, in Florida and Oklahoma prisons. Midazolam has also been used along with hydromorphone in a two-drug protocol in Ohio and Arizona.

#### Notable incidents

The state of Florida used midazolam to execute William Frederick Happ in October 2013.

The state of Ohio used midazolam in the execution of Dennis McGuire in January 2014; it took McGuire 24 minutes to die after the procedure started, and he gasped and appeared to be choking during that time, leading to questions about the dosing and timing of the drug administration, as well as the choice of drugs.

The usage of midazolam in executions became controversial after condemned inmate Clayton Lockett apparently regained consciousness and started speaking midway through his 2014 execution when the state of Oklahoma attempted to execute him with an untested three-drug lethal injection combination using 100 mg of midazolam. Prison officials reportedly discussed taking him to a hospital before he was pronounced dead of a heart attack 40 minutes after the execution began. An observing doctor stated that Lockett's vein had ruptured. It is not clear whether his death was caused by one or more of the drugs or by a problem in the administration procedure, nor is it clear what quantities of vecuronium bromide and potassium chloride were released to his system before the execution was cancelled.

According to news reports, the execution of Ronald Bert Smith in the state of Alabama on 8 December 2016 went awry soon after midazolam was administered, again putting the effectiveness of the drug in question.

In October 2016, the state of Ohio announced that it would resume executions in January 2017, using a formulation of midazolam, vecuronium bromide, and potassium chloride, but this was blocked by a federal judge. On 26 July 2017, Ronald Phillips was executed with a three-drug cocktail including midazolam after the Supreme Court refused to grant a stay. Prior to this, the last execution in Ohio had been that of Dennis McGuire. Murderer Gary Otte's lawyers unsuccessfully challenged his Ohio execution, arguing that midazolam might not protect him from serious pain when the other drugs are administered. He died without incident in about 14 minutes on 13 September 2017.

On 24 April 2017, the state of Arkansas carried out a double-execution, of Jack Harold Jones, 52, and Marcel Williams, 46. Arkansas attempted to execute eight people before its supply of midazolam expired on 30 April 2017. Two of them were granted a stay of execution, and another, Ledell T. Lee, 51, was executed on 20 April 2017.

On 28 October 2021, the state of Oklahoma executed inmate John Marion Grant, 60, using midazolam as part of its three-drug cocktail hours after the U.S. Supreme Court ruled to lift a stay of execution for Oklahoma death row inmates. The execution was the state's first since 2015. Witnesses to the execution said that when the first drug, midazolam, began to flow at 4:09 p.m., Grant started convulsing about two dozen times and vomited. Grant continued breathing, and a member of the execution team wiped the vomit off his face. At 4:15 p.m., officials said Grant was unconscious, and he was pronounced dead at 4:21 p.m.

#### Legal challenges

In Glossip v. Gross, attorneys for three Oklahoma inmates argued that midazolam could not achieve the level of unconsciousness required for surgery, meaning severe pain and suffering was likely. They argued that midazolam was cruel and unusual punishment and thus contrary to the Eighth Amendment to the United States Constitution. In June 2015, the U.S. Supreme Court ruled that they had failed to prove that midazolam was cruel and unusual when compared to known, available alternatives.

The state of Nevada is also known to use midazolam in execution procedures. In July 2018, one of the manufacturers accused state officials of obtaining the medication under pretences. This incident was the first time a drug company successfully, though temporarily, halted an execution. A previous attempt in 2017, to halt an execution in the state of Arizona by another drug manufacturer was not successful.

Benzodiazepine used for anesthesia and procedural sedation

Chemical substances for emergency medicine

GABAA receptor positive allosteric modulators

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World Health Organization essential medicines