Naxolone

Also known as

Narcan, nalone, evzio

Classification

Opioid, opiate antagonist

Overview

Naloxone is a drug that reverses the effects of opioids among dependent individuals . Naloxone blocks or reverses the effects of opioid medication, including extreme drowsiness, slowed breathing, or loss of consciousness.

Naloxone is used to treat a narcotic overdose in an emergency situation. This medicine should not be used in place of emergency medical care for an overdose .

A specific opiate antagonist that has no agonist activity. It is a competitive antagonist at mu, delta, and kappa opioid receptors.

For the complete or partial reversal of narcotic depression, including respiratory depression, induced by opioids including natural and synthetic narcotics, propoxyphene, methadone and the narcotic-antagonist analgesics: nalbuphine, pentazocine and butorphanol. It is also indicated for the diagnosis of suspected acute opioid overdose. It may also be used as an adjunctive agent to increase blood pressure in the management of septic shock .

Medical usage

Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory system. It is not to be confused with Naltrexone, an opioid receptor antagonist, used for dependence treatment rather than emergency overdose treatment .

What does it look like?

Colourless liquid, usually in a vial or within an auto-injector .

Source

Naloxone is derived from Thebaine. Thebaine (paramorphine) is a naturally occurring chemical of Opium, but has stimulatory rather than depressant effects .

Dosage

Therapeutic

• intramuscular - commonly - 0.4 - 2 mg,
• insufflated - commonly - 1 - 4 mg .

What are the different forms?

• injection,
• autoinjectable,
• nasal spray.

How long do its effects last?

Onset of effects

• intramuscular - 0 - 5 minutes,
• insufflated - 0 - 10 minutes .

Duration of effects

• intramuscular - 30 - 60 minutes,
• insufflated - 30 - 60 minutes .

Pharmacology

Naloxone has an extremely high affinity for μ-opioid receptors in the central nervous system. Naloxone is a μ-opioid receptor competitive antagonist, and its rapid blockade of those receptors often produces rapid onset of withdrawal symptoms. Naloxone also has an antagonist action, though with a lower affinity, at k and δ-opioid receptors.

There have been community Naloxone distribution via peer group networks in the UK for some years. There are currently plans to introduce a more family/relative friendly buccal spray, as some families and carers have reported time consuming difficulties in locating and using Narcan - filled syringes.

Naloxone is used as a secondary chemical in the drug Suboxone. Suboxone and Subutex are NICE licenced treatments for opioid dependence in the UK. Suboxone contains four parts buprenorphine and one part naloxone, while Subutex contains only buprenorphine. Naloxone was added to Suboxone in an effort to dissuade patients from crushing and snorting or injecting the tablets (sub-linguals).

Like Naltrexone, Naloxone has been shown to block the action of pain-lowering endorphins/dynorphins which the body produces naturally. The reason for this is that these endorphins operate on the same opioid receptors that naloxone blocks, hence the low mood and irritability that often affects people on Nalorex tablets .

Naloxone acts as a potent μ-opioid receptor inverse agonist. Because of its high affinity for the μ-opioid receptor, it knocks other ligands out of the receptor. Naloxone also has a lower affinity as an antagonism at the κ-opioid and δ-opioid receptors. If naloxone is administered without previous administration of opioids, it has few biological effects, notably a lower pain threshold. Naloxone has two isomers, (+)naloxone and (-)naloxone, with the latter being active. The liver metabolises naloxone. It has very low oral bioavailability which is why it is administered intravenously, intramuscularly or intranasally. Small amounts of naloxone are often added to opioids like buprenorphine and pentazocine to prevent abuse. Naloxone has been noted to block a placebo based analgesic effect. For example, if an individual has been administered something that they were told was morphine and had a analgesic response to it, naloxone will block that response , .

Pharmacodynamics

Naloxone is an opiate antagonist and prevents or reverses the effects of opioids including respiratory depression, sedation and hypotension. Also, it can reverse the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine. Naloxone is an essentially pure narcotic antagonist, i.e., it does not possess the "agonistic" or morphine-like properties characteristic of other narcotic antagonists; naloxone does not produce respiratory depression, psychotomimetic effects or pupillary constriction. In the absence of narcotics or agonistic effects of other narcotic antagonists, it exhibits essentially no pharmacologic activity. When given intravenously, the onset of action is apparent within 2 minutes. The onset of action is slower if given subcutaneously or intramuscularly. The duration of action also differs between sites of injection and dose .

Route of administration

• injection,
• autoinjectable,
• nasal spray.

Absorption

Well absorbed following intramuscular injection .

Volume of distribution

Following parenteral administration naloxone hydrochloride is rapidly distributed in the body. Naloxone is also very lipophillic and easily crosses the blood-brain-barrier. It can also cross the placenta .

Metabolism

Naloxone is hepatically metabolised and primarily undergoes glucuronidation to form naloxone-3-glucuronide .

Half-life

Adults = 30 - 81 minutes .

Elimination

Urine (25% - 40% is excreted as metabolites within 6 hours) .

Lethal dosage

LD50 IV administration - mouse = 150 ± 5 mg/kg, LD50 IV administration - rat = 109 ± 4 mg/kg .

Mechanism of action

While the mechanism of action of naloxone is not fully understood, the preponderance of evidence suggests that naloxone antagonizes the opioid effects by competing for the same receptor sites, especially the opioid mu receptor. Recently, naloxone has been shown to bind all three opioid receptors (mu, kappa and gamma) but the strongest binding is to the mu receptor .

Mode of use

• injected - Naloxone may be given by injection into a vein, muscle or under the skin, or via a drip into a vein .

Effects

Physical effects

• sedation .

Cognitive effects

• emotionality suppression .

Major effects

Incidence not known

• abdominal or stomach cramps,
• body aches,
• convulsions,
• diarrhoea,
• difficult or troubled breathing,
• excessive crying,
• fast, pounding, or irregular heartbeat or pulse,
• fever,
• goose-bumps,
• increased blood pressure,
• increased or excessive unconscious or jerking movements,
• irregular, fast or slow, or shallow breathing,
• irritability,
• nausea,
• vomiting,
• nervousness,
• cyanosis,
• restlessness,
• runny nose,
• shivering,
• sneezing,
• sweating,
• trembling,
• weakness,
• yawning .

Side-effects

• nausea,
• vomiting,
• sweating,
• increased heart rate,
• hyperventilation,
• increased blood pressure,
• reversal of pain relief if larger than necessary doses are given,
• irregular heart beat,
• low blood pressure ,
• chest tightness,
• intense rash with itching,
• seizures,
• acute allergic reaction with swelling of the face, lips, tongue and throat , .

Harm reduction

Some specialist services do an overdose prevention training protocol that includes naloxone. Find out if you can get you or a family member involved if there is a risk of an opiate overdose.

Some overdoses are the result of mixing opioids and benzos, resulting in acute respiratory depression, where this is the case a benzodiazepine antagonist (Flumazenil) would be indicated.

In many cases where people come round from an emergency Narcan shot, they will be in withdrawal. It is wise to exercise some caution before trying to dispel the condition with a normal dose of opiate. Narcan is active for about 45+ minutes in the body. This means that if you give someone Narcan to reverse an opioid overdose, the Narcan may wear off before the effects of the opioids wear off and to use on top of this can be very dangerous. If the Narcan is still active at the receptor the opiate will not be felt, causing frustration and perhaps leading to the situation outlined above by the time the user has sorted out the next 'hit' .

History

Naloxone was first synthesised in 1960 by Jack Fishman, an assistant at the Sloan Kettering Institute for Cancer Research, New York and developed by Harold Blumberg, a director at Endo Laboratories, NY. A British patent for naloxone was applied for by the Japanese company Sankyo Pharmaceuticals in March 1962 and issued in October 1963 .

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