Naloxone

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Not to be confused with naltrexone or naloxazone.
Naloxone
Naloxone.svg
Naloxone-3D-balls.png
Systematic (IUPAC) name
(1S,5R,13R,17S)- 10,17-dihydroxy- 4-(prop-2-en-1-yl)- 12-oxa- 4-azapentacyclo [9.6.1.01,13.05,17.07,18] octadeca- 7(18),8,10-trien- 14-one
Clinical data
AHFS/Drugs.com monograph
Pregnancy cat. B1 (AU) B (US)
Legal status Prescription Only (S4) (AU)
Routes IV, IM
Pharmacokinetic data
Bioavailability 2% (Oral, 90% absorption but high first-pass metabolism)
Metabolism Liver
Half-life 1-1.5 h
Excretion Urine, Biliary
Identifiers
CAS number 465-65-6 YesY
ATC code V03AB15
PubChem CID 5284596
IUPHAR ligand 1638
DrugBank DB01183
ChemSpider 4447644 YesY
UNII 36B82AMQ7N YesY
KEGG D08249 YesY
ChEBI CHEBI:7459 N
ChEMBL CHEMBL80 YesY
Synonyms 17-allyl- 4,5α-epoxy- 3,14-dihydroxymorphinan- 6-one
Chemical data
Formula C19H21NO4 
Mol. mass 327.37 g/mol
 N (what is this?)  (verify)

Naloxone is a pure opioid antagonist[1] developed by Sankyo in the 1960s.[2][3] Unlike other opioid receptor antagonists it has no concomitant agonist properties. Naloxone is a drug used to counter the effects of opioid overdose, such as heroin or morphine specifically the life-threatening depression of the central nervous system, respiratory system, and hypotension secondary to opiate overdose. Naloxone is also experimentally used in the treatment for congenital insensitivity to pain with anhidrosis (CIPA), an extremely rare disorder (1 in 125 million) that renders one unable to feel pain, or differentiate temperatures. It is marketed under various trademarks including Narcan, Nalone, Evzio and Narcanti, and has sometimes been mistakenly called "naltrexate". It is not to be confused with naltrexone, an opioid receptor antagonist with qualitatively different effects, used for dependence treatment rather than emergency overdose treatment. It is also combined with buprenorphine in a drug called Suboxone which is used to treat opioid addiction. [4]

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[5]

In most developed countries naloxone is required to be present whenever opiates or opioids are administered intravenously to combat accidental overdose.

Medical uses[edit]

Opiate overdose[edit]

Naloxone is included as a part of emergency overdose response kits distributed to heroin and other opioid drug users, and this has been shown to reduce rates of fatal overdose.[6][7][8][9][10][11][12] Prescribing naloxone should be accompanied by standard education that includes preventing, identifying, and responding to an overdose; rescue breathing; and calling the emergency services.[13] Naloxone should be prescribed if the patient is also prescribed a high dose of opioid (>100 mg of morphine equivalence/day), is prescribed any dose of opioid accompanied by a benzodiazepine, or is suspected or known to use opioids non-medically.[14] Projects of this type are under way in many US cities, including San Francisco, Philadelphia, Baltimore, Boston, Los Angeles, Milwaukee, Chicago, and Cleveland and the states of New Mexico, New York as well as in Canada in certain cities such as Toronto.[15][16][17] CDC estimates that US programs for drug users and their caregivers prescribing take-home doses of naloxone and training on its utilization are estimated to have prevented 10,000 opioid overdose deaths.[16] Healthcare institution-based naloxone prescription programs have also helped reduce rates of opioid overdose in North Carolina, and have been replicated in the US military.[18][19] Nevertheless, scale-up of healthcare-based opioid overdose interventions is limited by providers' insufficient knowledge and negative attitudes towards prescribing take-home naloxone and by sluggish federal government response.[20][21] Programs training police and fire personnel in opioid overdose response using naloxone have also shown promise in the US and there is increasing effort to integrate opioid fatality prevention in the overall response to the overdose crisis.[21][22][23][24][25]

Pilot projects were also started in Scotland in 2006. Also in the UK, in December 2008 the Welsh Assembly Government announced intention to establish demonstration sites for 'take home' naloxone.[26] While naloxone is still the standard treatment in emergency reversal of opioid overdose, its clinical use in the long-term treatment of opioid addiction is being increasingly superseded by naltrexone. Naltrexone is structurally similar but has a slightly increased affinity for κ-opioid receptors over naloxone, can be administered orally, and has a longer duration of action.

Enteral naloxone has been successfully used in the reduction of gastritis and esophagitis associated with opioid therapy in mechanically ventilated acute care patients.

The combination oxycodone/naloxone is used for the prophylaxis of opioid-induced constipation in patients requiring strong opioid therapy under the trade name Targin and in the Netherlands under Targinact.[27]

Beyond treatment for overdose, a variant of naloxone called (+)-naloxone is showing promise as a way of treating opioid-related addiction.[28] By binding to the body's TLR4 immune receptors, substances like heroin no longer produce the dopamine needed to generate substance addiction yet retains the pain-relieving effect of these drugs. This means that if both morphine and (+)-naloxone are taken simultaneously, a patient will receive the necessary analgesic effect of the morphine but avoid the potential for addiction. Such usage is still awaiting clinical testing.

Preventing opioid abuse[edit]

Naloxone is used as a secondary chemical in the drug Suboxone. Suboxone and Subutex were created to help opiate-addicted patients detox. 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 injecting the tablets. When taken orally as prescribed the naloxone within the drug has no noticeable physiologic effect, however when injected the naloxone within the combination drug can precipitate withdrawal symptoms reducing the potential for suboxone to be abused. This makes it a useful adjunct in the treatment of opioid addiction.[29] It has also been used in the treatment of protracted and chronic pain in patients with a known history of drug abuse.

Oral or sublingual administration affects only the gastrointestinal tract, and has the added benefit of helping to reverse constipation and lowered bowel motility caused by chronic medical use, or abuse, of a variety of opioids. Because of possible side effects of naloxone in some patients, chemical detox can begin with Suboxone's sister drug, Subutex, which does not contain naloxone. It is common for Suboxone film to be used in all cases unless pregnancy is a concern.

Septic Shock[edit]

Studies show that to give this to a person in severe pain would be unethical and inhumane. Some studies have looked at the effect of naloxone on blood pressure in patients with septic shock. Results have been mixed as there is an apparent benefit in some patients while others show an association with adverse effects. Despite the apparent pressor response that can be seen there does not yet appear to be an improvement in patient survival. Current studies aim to clarify the possible role of naloxone in this setting.[30]

Special populations[edit]

Pregnancy and breast feeding[edit]

Naloxone is Pregnancy Category C. Studies in rodents given a daily maximum dose of 10mg naloxone showed no harmful effects to the fetus although human studies are lacking and the drug does cross the placenta which may lead to the precipitation of withdrawal in the fetus. In this setting further research is needed before safety can be assured therefore naloxone should only be used during pregnancy if it is a medical necessity.[31]

It is currently unknown if naloxone is excreted in breast milk.

Kidney and liver dysfunction[edit]

There are currently no established clinical trials in patients with renal insufficiency or hepatic disease and as such these patients should be monitored closely if naloxone is clinically indicated.

Side-effects[edit]

Possible side effects include: change in mood, increased sweating, nausea, nervousness, restlessness, trembling, vomiting, allergic reactions such as rash or swelling, dizziness, fainting, fast or irregular pulse, flushing, headache, heart rhythm changes, seizures, sudden chest pain, and pulmonary edema.[32][33]

Naloxone has been shown to block the action of pain-lowering endorphins which the body produces naturally. The likely reason for this is that these endorphins operate on the same opioid receptors that naloxone blocks. Naloxone is capable of blocking a placebo pain-lowering response, both in clinical and experimental pain, if the placebo is administered together with a hidden or blind injection of naloxone.[34] Other studies have found that placebo alone can activate the body's μ-opioid endorphin system, delivering pain relief via the same receptor mechanism as morphine.[35]

Pharmacodynamics[edit]

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 κ- and δ-opioid receptors. Unlike other opioid receptor antagonists naloxone is essentially a pure antagonist with no agonist properties. If administered in the absence of concomitant opioid usage there will be functionally no pharmacologic activity (except the inability for the body to combat pain naturally), in contrast to direct opiate agonists which will elicit opiate withdrawal symptoms of both opiate-tolerant and opiate-naive patients. There is no evidence of the development of tolerance or dependence on naloxone. The mechanism of action is not completely understood however studies suggest that it functions to produce withdrawal symptoms by competing for opiate receptor sites within the CNS (a competitive antagonist, not a direct agonist), thereby preventing the action of both endogenous and xenobiotic opiates on these receptors without directly producing any effects itself.[36]

Pharmacokinetics[edit]

When administered parenterally, as is most common, naloxone has a rapid distribution throughout the body. The mean serum half life has been shown to range from 30 to 81 minutes, shorter than the average half life of some opiates necessitating repeat dosing if you must stop opioid receptors from triggering for an extended period, unnecessary in a emergency clinical sense. Naloxone is primarily metabolized by the liver. Its major metabolite is naloxone-3-glucuronide which is excreted in the urine.[37]

Chemistry[edit]

Naloxone is synthesized from thebaine. The chemical structure of naloxone resembles that of oxymorphone, the only difference being the substitution of the N-methyl group with an allyl (prop-2-enyl) group. The name naloxone has been derived from N-allyl and oxymorphone.

Administration[edit]

Naloxone is most commonly injected intravenously for fastest action, which usually causes the drug to act within a minute, and last up to 45 minutes. It can also be administered via intramuscular or subcutaneous injection. Finally, a wedge device (nasal atomizer) attached to a syringe may be used to create a mist which delivers the drug to the nasal mucosa,[38] although this solution is more common outside of clinical facilities.

The individual is closely monitored for signs of improvement in respiratory function and mental status. If minimal or no response is observed within 2-3 minutes dosing may be repeated every 2 minutes until the maximum dose of 10 mg has been reached. If there is no response at this time alternative diagnosis and treatment should be pursued. If patients do show a response they should remain under close monitoring as the effects of naloxone may wear off before those of the opioids and they may require repeat dosing at a later time.

Naloxone is used orally along with Oxycontin Controlled Release, and helps in reducing the constipation associated with opioids. Enteral administration of naloxone blocks opioid action at the intestinal receptor level, but has low systemic bioavailability due to marked hepatic first pass metabolism.[39]

In March/April 2014, the US Food and Drug Administration (FDA) approved a hand-held automatic injector naloxone product that, when activated, assists the user with spoken instructions by Eric Stoltz and is pocket-sized. The approval process was fast-tracked as one initiative to reduce the death toll caused by opiate overdoses in the US. At the time of approval, an estimated 16,000 annual deaths were attributed to prescription opioid overdoses in the US.[40]

Legal status[edit]

Patent status[edit]

The patent for naloxone has expired. It is available in generic forms.

Prescription status[edit]

United States[edit]

In the US, naloxone is classified as a prescription medication, though it is not a controlled substance.[41] While it is legal to prescribe naloxone in every state, dispensing the drug by medical professionals (including physicians or other licensed prescribers) at the point of service is subject to rules that vary by jurisdiction.[20][42] Naloxone distribution programs utilize licensed prescribers to distribute the drug, sometimes relying on “standing orders” mechanisms[19][43] to increase scale-up.

Officers in Quincy, Massachusetts began carrying the nasal spray form of the drug in October 2010, following the completion of a Department of Public Health pilot program, in which naloxone was distributed to friends and families of opiate users, in 2007. Quincy officers have administered the drug 221 times and reversed 211 overdoses since the commencement of the initiative. Espanola Valley, New Mexico and Ocean County, New Jersey police officers then followed the Quincy example in 2013. Quincy mayor Thomas Koch explained in early 2014: "It's easy for the cynical person to say, 'Oh, they're druggies, they're junkies, let them die. But when you put a name and a face and a family to that, then it's a different story. Some people who go down this road will never come back, but if we can bring them back, there's always hope."[44]

Law in many states have been changed in recent years to allow wider distribution of opioid antagonists.[45] Pharmacy distribution is a new mechanism being used to get the life saving antidote in the hands of more people. [46]

A survey of US naloxone prescription programs in 2010 revealed that 21 out of 48 programs reported challenges in obtaining naloxone in the months leading up to the survey, due mainly to either cost increases that outstripped allocated funding, or the suppliers' inability to fill orders.[16] The approximate cost of a 1 ml ampoule of naloxone in the US is estimated to be significantly higher than in most Western countries.[19]

Following the use of the nasal spray device by police officers on Staten Island in New York, an additional 20,000 police officers will begin carrying naloxone in mid-2014. The state's Office of the Attorney General will provide US$1.2 million to supply nearly 20,000 kits and Police Commissioner William Bratton said: "Naloxone gives individuals a second chance to get help".[47]

Identification[edit]

The CAS number of naloxone is 465-65-6; the anhydrous hydrochloride salt has CAS 357-08-4 and the hydrochloride salt with 2 molecules of water, hydrochloride dihydrate, has CAS 51481-60-8.

Media[edit]

2013 documentary film Reach for Me: Fighting to End the American Drug Overdose Epidemic interviews people involved in naloxone programs aiming to bring naloxone available to opioid users and pain patients.[48]

See also[edit]

References[edit]

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External links[edit]