Naloxone

Overview
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. 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, another 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 injected, usually initially intravenously for fastest action. The drug acts after about two minutes, and its effects may last about 45 minutes. Other routes, including intramuscular injection, subcutaneous,endo-tracheal tube,and intranasal injection (use of a wedge device attached to the syringe to create a mist delivering the drug to the nasal mucosa) may also be utilized, although these are more likely in the prehospital setting.

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 and Chicago, with pilot projects started in Scotland in 2006.

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. In one experiment, women treated with naloxone reported higher pain levels during childbirth than women not so treated. 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.

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.

The effect of the hallucinogenic plant Salvia Divinorum and its primary active chemical Salvinorin-A, a κ-opioid agonist, can be inhibited by the pre-administration of naloxone. Naloxone has similar inhibitory effects on PCP, ketamine, and dextromethorphan.

Naloxone is also being used as a secondary chemical in the 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 4 parts Buprenorphine and 1 part Naloxone, while Subutex contains only Buprenorphrine.

Naloxone was added to Suboxone 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 their 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. 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 desireability 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. Like methadone, buprenorphine has only recently been approved for use in the management of pain, and likely restrictions on prescribing authority will be eased over time as buprenorphine sees wider use and acceptance by the medical profession, and concerns over diversion and abuse lessen.

The addition of naloxone to bruprenorphine 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, pain in the abdomen, back pain, withdrawal syndrome, vasodilation, constipation, diarrhea, nausea, vomiting, insomnia, and sweating. 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 is Suboxone.

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 has CAS 51481-60-8.