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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 4425
DrugBank APRD00025
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 hours
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.

Contents

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

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.[citation needed]

The drug also blocks 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. 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.[2] This is unsurprising, as 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.[3]

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 oesophagitis associated with opioid therapy in mechanically-ventilated acute care patients.

Naloxone is also being used as a secondary chemical in the U.S. Food and Drug Administration (FDA)-approved medicine Suboxone. Suboxone and Subutex were created as part of a detox program to help opiate addicted patients stop using opiates. Suboxone contains four parts buprenorphine and one part naloxone, while Subutex contains only buprenorphrine.

Naloxone was added to buprenorphine in an effort to dissuade patients from grinding up the Suboxone tablet and using it as part of a combination of opiates that the user would inject into his body. Intravenously administered naloxone is supposed to block the effects of any opiates and cause the user to go into immediate withdrawal. However, buprenorphine has a higher affinity for the opiate receptors, and many users have reported that Suboxone is injectable without inducing withdrawal effects.[citation needed] Oral or sublingual administration affects only the gastronintestinal 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. Buprenorphine itself has less of an effect on the central nervous system and produces far less euphoria than other opioid drugs, while still being effective in the treatment of pain. For this reason, buprenorphine is gaining acceptance in the treatment of chronic pain, as well as opioid addiction withdrawal, since it produces fewer side effects and less sedation. On the whole, it is a drug moderately useful in pain management that is further attractive due to its relative lack of desirability to opioid abusers. Currently, only certified addictionologists (physicians specializing in the treatment of drug addiction and dependence) are legally permitted to prescribe Suboxone or other drugs containing buprenorphine for the treatment of addiction in the US, although suboxone or other drugs containing buprenorphine can be prescribed for any purpose other than addiction or maintenance by any licensed physician. Buprenorphine was originally approved for use in the management of pain as Buprenex, but its use is not very common. This will likely change as medical professionals obtain more experience in its use as an analgesic in chronic pain management.

The addition of naloxone to buprenorphine in Suboxone tablets is intended to prevent misuse and abuse by injection. However, the naloxone in Suboxone does cause side effects in some people. These side effects include, but are not limited to, asthenia, chills, headache, infection, pain, abdominal pain, back pain, withdrawal syndrome, vasodilation, constipation, diarrhea, nausea, vomiting, insomnia, and sweating.[citation needed] Because of these side effects, the FDA recommends that doctors begin any chemical detox using Subutex, which does not contain any naloxone. In this way, if for some reason the doctor moves the patient to Suboxone and the patient begins having side effects related to naloxone, the doctor can easily move the patient back to Subutex.

For these reasons and others, it has been reported that Subutex is easier to withdraw from than Suboxone.

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]

Interestingly, research into the placebo effect has shown that naloxone significantly reduces placebo-induced pain relief - evidence that part of the placebo effect is mediated via endogenous production of compounds that activate opiate receptors [Sauro MD. J Psychosom Res 2005;58:115-120].

The combination oxycodone/naloxone is used for the treatment of opioid-induced constipation under the trade name Targin and in the Netherlands under Targinact.[4]

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








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