Naloxone

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.	B (USA) B1 (Aus)
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 Y
ATC code	V03AB15
PubChem	CID 5284596
IUPHAR ligand	1638
DrugBank	DB01183
ChemSpider	4447644 Y
UNII	36B82AMQ7N Y
KEGG	D08249 Y
ChEBI	CHEBI:7459 N
ChEMBL	CHEMBL80 Y
Synonyms	17-allyl- 4,5α-epoxy- 3,14-dihydroxymorphinan- 6-one
Chemical data
Formula	C19H21NO4
Mol. mass	327.37 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C19H21NO4/c1-2-8-20-9-7-18-15-11-3-4-12(21)16(15)24-17(18)13(22)5-6-19(18,23)14(20)10-11/h2-4,14,17,21,23H,1,5-10H2/t14-,17+,18+,19-/m1/s1 Y Key:UZHSEJADLWPNLE-GRGSLBFTSA-N Y
N (what is this?)  (verify)

Naloxone is an opioid antagonist drug developed by Sankyo in the 1960s.^[1] Naloxone is a drug used to counter the effects of opiate overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory system. 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. It is marketed under various trademarks including Narcan, Nalone, 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.

Pharmacodynamics[link]

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.

Chemistry[link]

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[link]

Naloxone is most commonly injected intravenously for fastest action. The drug generally acts within a minute, and its effects may last up to 45 minutes. It can also be administered via intramuscular or subcutaneous injection. Use of a wedge device (nasal atomizer) attached to a syringe to create a mist delivering the drug to the nasal mucosa^[2] may also be utilized, although this solution is more likely utilized outside of a clinical facility. Naloxone is used orally along with Oxycontin Controlled Release and it 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. ^[3]

Uses[link]

This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (July 2008)

Counteracting opiate overdose and addiction[link]

Naloxone has been distributed as part of emergency overdose response kits to heroin and other opioid drug users, and this has been shown to reduce rates of fatal overdose. Projects of this type are under way in many US cities, including San Francisco, New Mexico, Philadelphia, New York State, Baltimore, Boston, Los Angeles, Milwaukee, and Chicago.^[4][5] 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 reversed 10,000 opioid overdose deaths.^[6] 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.^[7][8] Nevertheless, scale-up of healthcare-based opioid overdose interventions is limited by providers' insufficient knowledge and negative attitudes towards prescribing take-home naloxone.^[9] Programs training police and fire personnel in opioid overdose response using naloxone have also shown promise in the US.^[10][11]

Pilot projects were also started in Scotland in 2006 {{(http://www.scotland.gov.uk/Topics/Justice/law/Drugs-Strategy/drugrelateddeaths/NationalNaloxone)}. Also in the UK, in December 2008 the Welsh Assembly Government announced intention to establish demonstration sites for 'take home' Naloxone.^[12] 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.^[13]

Preventing opioid abuse[link]

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 buprenorphrine. Naloxone was added to Suboxone in an effort to dissuade patients from injecting the tablets, due to naloxones ability to block opioid receptors and send the user into immediate withdrawal. Users with a high tolerance however may still be able to abuse Suboxone via injection given that buprenorphine has a higher affinity for opioid receptors than naloxone. 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.

Depersonalization disorder[link]

A 2001 Russian study has shown that naloxone can be used to treat depersonalization disorder. According to the study: "In three of 14 patients, depersonalization symptoms disappeared entirely and seven patients showed a marked improvement. The therapeutic effect of naloxone provides evidence for the role of the endogenous opioid system in the pathogenesis of depersonalization."^[14]

Side-effects[link]

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.^[15]

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.^[16] 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.^[17]

Legal status[link]

Patent status[link]

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

Prescription status[link]

In the US, naloxone is classified as a prescription medication, though it is not a controlled substance. ,^[18] Dispensing the drug by medical professionals (including physicians or other licensed prescribers) at the point of service is subject to rules that vary state to state. ^[19] Naloxone distribution programs utilize licensed prescribers to distribute the drug, sometimes relying on “standing orders” mechanisms^[20][21] to increase scale-up.

Shortage and Pricing[link]

Naloxone has been periodically under FDA shortage designation since 2001 and was recently re-verified as being in shortage due to a manufacturing delay. ^[22] Twenty-one out of 48 naloxone prescription programs surveyed in 2010 reported they had experienced challenges in obtaining naloxone in the months leading up to the survey, mainly due either to cost increases that outstripped allocated funding or the suppliers’ inability to fill orders.^[23] The approximate cost of a 1ml ampoule of naloxone in the United States is estimated to be significantly higher than in most Western countries; on average, the price for naloxone supply has increased precipitously in recent years. ^[24]

Identification[link]

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. Nalaxone

See also[link]

• (+)-Naloxone
• Naloxol

References[link]

External links[link]

• Chicago Recovery Alliance's naloxone distribution project
• Report on Naloxone and other opiate antidotes, by the International Programme on Chemical Safety