Midazolam

• 1. Introduction

  ›

  In 2014, Oklahoma prepared to execute Clayton Lockett with an untested three-drug combination that included 100 mg of midazolam, a drug far better known in hospitals than in prisons. Partway through, Lockett apparently regained consciousness and began to speak.

  Midazolam, sold under the brand name Versed among others, is a benzodiazepine. Surgeons use it to calm patients before an operation. Dentists use it to settle children. Palliative teams use it in the last hours of a life. The same chemical sits behind all of these scenes.

  How can one drug do such different jobs? What does it actually do inside the body, and where do its limits lie? And why did courts, drug makers and prison officials end up fighting over it?

  90918694

• 2. Calm Without Sleep

  ›

  Five minutes is about how long midazolam takes to start working once it enters a vein. Injected into a muscle, it can take fifteen minutes. Swallowed, it takes between 10 and 20 minutes. It can also be sprayed into the nose or placed against the cheek.

  The drug makes people sleepy, lowers anxiety and causes anterograde amnesia, which blocks memories of events after the dose. It does not make a person unconscious. It only sedates. Someone who loses memory this way usually has no sense of the gap, unless they already knew it was a possible effect.

  The GABA-A receptor explains almost all of this. Midazolam does not switch the receptor on directly. Instead it strengthens the effect of the brain's own messenger chemical, GABA, by making chloride channels open more often. That produces neural inhibition. Sedation, sleep, reduced anxiety, amnesia, muscle relaxation and protection against seizures all follow from it.

  In adults the drug is short-acting, with an elimination half-life of 1.5 to 2.5 hours. The figure is longer in the elderly, in young children and in adolescents. Swallowed midazolam is poorly absorbed, and only 50% of it reaches the bloodstream. The liver breaks it down with cytochrome P450 enzymes and by glucuronide conjugation. An active byproduct, alpha-hydroxymidazolam, contributes only 10% of the drug's biological activity.

  In samples of human liver tissue, the drug's half-life is a mere 3.3 minutes.

  44104112

• 3. The Hospital Workhorse

  ›

  In the intensive care unit, midazolam is the most popular benzodiazepine. Three traits explain why. Its elimination half-life is short, it dissolves in water, and it suits a continuous drip.

  Intravenous midazolam is used for procedural sedation, often alongside an opioid such as fentanyl. It also serves for preoperative sedation, for starting general anesthesia, and for sedating patients on ventilators. Compared with diazepam, it is better at blurring memories of endoscopy. Propofol, however, wins on recovery time and memory loss. For long sedation, lorazepam is preferred because it lasts longer. Propofol also has advantages in intensive care, including shorter weaning and earlier removal of the breathing tube.

  Newborns in neonatal intensive care sometimes receive midazolam, but with extra caution. It should not run longer than 72 hours, because of tachyphylaxis, withdrawal and neurological complications. Doctors should avoid bolus injections in newborns. Dentists also use it to ease anxiety and manage behaviour in children.

  A seizure lasting over five minutes is another use. For children, the drug can go into the cheek or the nose. Buccal and intranasal midazolam may be easier to give, and more effective, than diazepam given rectally. The weaknesses are real. Because the half-life is short, more than 50% of people treated have breakthrough seizures. Treatment fails in 14 to 18% of people with refractory status epilepticus. Tolerance to the anticonvulsant effect builds quickly, and doses may need to rise several times over, so long-term epilepsy treatment is not recommended.

  Paired with an antipsychotic, midazolam also treats acute schizophrenia marked by aggressive or out-of-control behaviour. At the end of life, low doses given under the skin ease agitation, restlessness or anxiety in the final hours or days. It is a first-line choice for palliative continuous deep sedation, and higher doses are rarely needed.

  That cheek-delivered seizure treatment would later earn a landmark approval in Europe.

  2829303139

• 4. Origins and Reach

  ›

  Walser and Fryer, working at Hoffmann-LaRoche in the United States, are credited with synthesizing midazolam in 1975. Its water solubility made it less likely than similar drugs to cause thrombophlebitis, an inflammation of the veins. The patent is dated 1974, and the drug entered medical use in 1982. It is one of about 35 benzodiazepines in current medical use.

  Its anticonvulsant properties were studied in the late 1970s. Not until the 1990s did it emerge as an effective treatment for convulsive status epilepticus. By 2010 it was the most commonly used benzodiazepine in anesthetic medicine. In acute care it overtook lorazepam and diazepam, since it is shorter lasting, more potent and less painful at the injection site. Veterinarians are using it more as well, again thanks to its water solubility.

  In 2011, the European Medicines Agency granted a marketing authorisation for a buccal form sold as Buccolam. It was first approved for prolonged, acute, convulsive seizures in people from three months to under 18 years of age. The agency described it as the first use of a paediatric-use marketing authorisation.

  On pharmacy shelves, the drug takes several forms. Roche markets Dormicum as white, oval 7.5 mg tablets and blue, oval 15 mg tablets, each stamped with "Roche". Dormicum also comes in ampoules of 1, 3 and 10 mL at 5 mg/mL. Novell Pharmaceutical Laboratories sells ampoules as Miloz. Roxane Laboratories makes a cherry-flavored oral syrup at 2 mg/mL. Midazolam is the only water-soluble benzodiazepine available.

  The World Health Organization lists it as an essential medicine, and generic versions exist. The law treats it as a controlled drug nearly everywhere. In the Netherlands it is a List II drug of the Opium Law. The Convention on Psychotropic Substances puts it in Schedule IV. The United Kingdom classes it as Schedule 3 and Class C. In the United States it carries DEA number 2884 and sits in Schedule IV as a non-narcotic agent with low potential for abuse.

  In 2018 it came out that the CIA had considered using midazolam as a "truth serum" on terrorist suspects, in a project called "Medication".

  1769858444

• 5. When Sedation Goes Wrong

  ›

  A dose of 0.15 mg/kg can slow breathing in healthy people, an effect thought to start in the central nervous system. On its own at normal doses, respiratory depression or arrest is uncommon, at 0.1 to 0.5%. Adding other central nervous system drugs, especially opioid painkillers, raises the odds of low blood pressure, stopped breathing and death, even at therapeutic doses. Fentanyl makes low blood oxygen or apnea more likely.

  Among midazolam users who later needed the antagonist flumazenil, 84% had a potential interaction involving at least one depressant of the central nervous system. Other medicines and foods also change how long the drug lasts. Protease inhibitors, nefazodone, sertraline, fluoxetine, erythromycin, diltiazem, clarithromycin and grapefruit slow its breakdown, so its action is prolonged. St John's wort, rifapentine, rifampin, rifabutin and phenytoin speed it up, so it works less. Atorvastatin also slows elimination. Grapefruit juice lowers the 3A4 enzyme in the gut, so more drug reaches the blood.

  Children and older people face a higher risk of paradoxical effects, in which the drug excites instead of calms. So do people with a history of heavy drinking or of aggressive behavior. Reactions are linked especially to intravenous use. A patient may feel anxiety, make involuntary movements, behave violently or aggressively, or cry and talk uncontrollably. The cause seems tied to the disinhibition the drug produces. Because of the amnesia, patients often cannot recall the episode. In extreme cases flumazenil can reverse the effects, and antipsychotics such as haloperidol have also been used.

  After a nighttime dose, a hangover may carry into the next day, with sleepiness and impaired thinking and movement. That can make driving unsafe and raises the risk of falls and hip fractures. Giving intravenous midazolam too quickly can drop blood pressure. High doses can cause a "midazolam infusion syndrome", in which waking is delayed by hours or days and ventilator support lasts longer.

  Memory deficits from long-term benzodiazepine use recover only partly six months after stopping.

  4546504348

• 6. Dependence and Overdose

  ›

  About one-third of people treated with benzodiazepines for longer than 4 weeks become dependent. Risk factors include a dependent personality, a short-acting drug, high potency and long use. Midazolam infusions can produce tolerance and withdrawal within days, which is unusually fast.

  Withdrawal symptoms range from insomnia and anxiety to seizures and psychosis, and they can mimic the condition being treated. ICU withdrawal can include irritability, tremors, delirium, vomiting, a fast heartbeat and high blood pressure. The remedy is slow reduction. A prolonged infusion is tapered gradually, sometimes with an oral long-acting benzodiazepine, clorazepate dipotassium. If tolerance appears during intensive care sedation, adding an opioid or propofol is recommended. Researchers link tolerance to receptor down-regulation and changes in how GABA-A receptor genes are expressed.

  Elderly patients metabolise benzodiazepines more slowly and are more sensitive to them. They are prone to drowsiness, amnesia, ataxia, confusion and falls. Midazolam taken in the third trimester of pregnancy can put a newborn at risk of withdrawal, with floppy muscle tone, pauses in breathing, a bluish skin color and poor responses to cold stress. Hypotonia and withdrawal symptoms have been reported to persist from hours to months after birth. Breastfeeding advice is mixed. There is no evidence of harm from a single dose, yet breastfeeding by mothers using midazolam is not recommended.

  An overdose is a medical emergency. In healthy people with proper support, a benzodiazepine overdose is rarely life-threatening. Alcohol, opioids or tricyclic antidepressants make it far more dangerous, as do old age, obstructive pulmonary disease and intravenous use. Treatment is supportive, and activated charcoal can be used within an hour. Signs include slurred speech, involuntary eye movements, confusion, low blood pressure, coma and death.

  The antidote is flumazenil, but doctors seldom use it, since it can trigger seizures in mixed overdoses and in dependent patients. Blood tests can track 1-hydroxymidazolam glucuronide, the drug's major metabolite, to confirm poisoning or to assist a forensic investigation of a fatal overdose.

  38545558

• 7. A Drug in the Death Chamber

  ›

  Pentobarbital's manufacturer disallowed its use in executions, and some jurisdictions in the United States turned to midazolam as a replacement. In a lethal injection, midazolam acts as a sedative and is meant to leave the prisoner in a state of deep anesthesia comparable to that of surgery. One or more other drugs then stop the heart.

  Florida and Oklahoma paired it with vecuronium bromide and potassium chloride in a three-drug cocktail. Ohio and Arizona used a two-drug protocol with hydromorphone.

  Florida used midazolam to execute William Frederick Happ in October 2013. In January 2014 Ohio used it on Dennis McGuire. He was heavily anesthetized and unconscious within 4 minutes. Another 20 minutes passed before he was declared dead. Reporters present said he gasped and appeared to choke, which raised questions about the dosing, the timing and the choice of drugs.

  Forty minutes after Clayton Lockett's execution began, he was pronounced dead of a heart attack. Prison officials reportedly discussed taking him to a hospital first. An observing doctor said his vein had ruptured. It remains unclear whether the drugs or the way they were delivered caused his death. It is also unclear how much vecuronium bromide and potassium chloride reached him before officials cancelled the execution.

  On the 8th of December 2016, Alabama executed Ronald Bert Smith. News reports said he moved soon after the midazolam was injected. Prison staff had confirmed twice that he was unconscious before the two fatal drugs went in. The case revived public concern about whether the drug works as intended.

  In October 2021, Oklahoma executed John Marion Grant, aged 60, in its first execution since 2015. The U.S. Supreme Court had lifted a stay hours earlier. When midazolam began to flow at 4:09 p.m., witnesses said Grant convulsed about two dozen times and vomited. He kept breathing, and a member of the team wiped his face. Officials said he was unconscious at 4:15 p.m. He was pronounced dead at 4:21 p.m.

  8889909192

• 8. Courts and Suppliers

  ›

  In Glossip v. Gross, attorneys for three Oklahoma inmates argued that midazolam could not reach the level of unconsciousness needed for surgery. Severe pain and suffering were therefore likely, they said, and that amounted to cruel and unusual punishment under the Eighth Amendment. In June 2015, the U.S. Supreme Court ruled that the inmates had failed to prove midazolam was cruel and unusual compared with known, available alternatives.

  In October 2016, Ohio announced that it would resume executions in January 2017 with midazolam, vecuronium bromide and potassium chloride. A federal judge blocked the plan. On the 26th of July 2017, Ronald Phillips was executed with a three-drug cocktail including midazolam, after the Supreme Court refused to grant a stay. The last execution in Ohio before his had been McGuire's.

  On the 13th of September 2017, Ohio executed Gary Otte. His lawyers had unsuccessfully argued that midazolam might not shield him from serious pain once the other drugs were given. He was pronounced dead without incident in about 14 minutes.

  In April 2017, Arkansas carried out a double execution, of Jack Harold Jones, 52, and Marcel Williams, 46. The state had tried to execute eight people before its supply of midazolam expired on the 30th of April 2017. Two received stays. Another, Ledell Lee, 51, was executed on the 20th of April 2017.

  In July 2018, one of the manufacturers accused Nevada state officials of obtaining the medication under pretences. It was the first time a drug company successfully, though temporarily, halted an execution. A similar attempt in Arizona in 2017, by another manufacturer, had failed.

  10093959698