Naloxone

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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 an opioid antagonist[1] drug developed by Sankyo in the 1960s.[2][3] Naloxone is a drug used to counter the effects of opioid 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, 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.

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.

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,[4] although this solution is more common outside of clinical facilities.

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.[5]

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 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.[6]

Uses[edit]

Counteracting opiate overdose and addiction[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.[7][8][9][10][11][12][13][14][15] Prescribing naloxone should be accompanied by standard education that includes preventing, identifying, and responding to an overdose; rescue breathing; and calling the emergency services.[16] 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.[17] Projects of this type are under way in many US cities, including San Francisco, Philadelphia, Baltimore, Boston, Los Angeles, Milwaukee, and Chicago and the states of New Mexico, New York as well as in Canada in certain cities such as Toronto.[18][19][20] 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.[19] 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.[21][22] 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.[23][24] 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.[24][25][26][27][28]

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.[29] 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.[30]

Beyond treatment for overdose, a variant of naloxone called (+)-naloxone is showing promise as a way of treating opioid-related addiction.[31] 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. Supposedly, the naloxone would throw the user into precipated withdrawals, or at the very least, blocking buprenorphine's abusable effects. However, given that buperenorphine has a higher affinity for opioid receptors than naloxone, naloxone is not a hindrance, it neither causes precipated withdrawals nor blocks the user's 'high'. In fact, buprenorphine has a higher affinity for opioid receptors than almost all opioids including heroin.

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[edit]

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."[32]

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.[33][34]

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.[35] 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.[36]

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.[37] 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.[23][38] Naloxone distribution programs utilize licensed prescribers to distribute the drug, sometimes relying on “standing orders” mechanisms[22][39] 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."[40]

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.[19] The approximate cost of a 1 ml ampoule of naloxone in the US is estimated to be significantly higher than in most Western countries.[22]

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.

See also[edit]

References[edit]

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External links[edit]