Naloxone

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
Identifiers
CAS number	465-65-6
ATC code	V03AB15
PubChem	CID 4425
DrugBank	DB01183
ChemSpider	4447644
Chemical data
Formula	C19H21NO4
Mol. mass	327.27 g/mol
Synonyms	17-allyl- 4,5α-epoxy- 3,14-dihydroxymorphinan- 6-one
Pharmacokinetic data
Bioavailability	2% (90% absorption but high first-pass metabolism)
Metabolism	Liver
Half-life	1-1.5 h
Excretion	Urine, Biliary
Therapeutic considerations
Pregnancy cat.	B (USA) B1 (Aus)
Legal status	Prescription Only (S4) (AU)
Routes	IV, IM
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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. 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

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

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

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^[1] may also be utilized, although this solution is more likely utilized outside of a clinical facility.

Uses

Counteracting opiate overdose and addiction

Naloxone has been distributed as part of emergency kits to heroin users, and this has been shown to reduce rates of fatal overdose. Projects of this type are under way in San Francisco, New Mexico, Philadelphia, New York State, Baltimore, Boston, Los Angeles, Milwaukee, and Chicago, with pilot projects started in Scotland in 2006. While naloxone is still often used in emergency treatments for 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 treatment of opioid-induced constipation under the trade name Targin and in the Netherlands under Targinact.^[2]

Preventing opioid abuse

Naloxone is used as a secondary chemical in the drug Suboxone. Suboxone and Subutex were created to help opiate-addicted patients detoxify. 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 grinding it up for abuse in combination with opiates. Intravenously administered naloxone is supposed to block the effects of any opiates and cause the user to go into immediate withdrawal. 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 is often begun with Suboxone's sister drug, Subutex, which does not contain the naloxone.

Depersonalization disorder

A recent Russian study has shown that naloxone can be used to successfully 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."[1]

Side-effects

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.^[3]

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.^[4] 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.^[5]

Legal status

The patent for Naloxone has expired and the drug is currently available in various generic forms.

Identification

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.

References

• British National Formulary 55, March 2008; ISBN 9780853697763

External links

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