Naloxone
Naloxone, sold under the brand name Narcan among others, is an opioid antagonist, a medication used to reverse or reduce the effects of opioids. For example, it is used to restore breathing after an opioid overdose. Effects begin within two minutes when given intravenously, five minutes when injected into a muscle, and ten minutes as a nasal spray. Naloxone blocks the effects of opioids for 30 to 90 minutes.
Administration to opioid-dependent individuals may cause symptoms of opioid withdrawal, including restlessness, agitation, nausea, vomiting, a fast heart rate, and sweating. To prevent this, small doses every few minutes can be given until the desired effect is reached. In those with previous heart disease or taking medications that negatively affect the heart, further heart problems have occurred. There is limited data on naloxone's safety during pregnancy. Naloxone is a non-selective and competitive opioid receptor antagonist. It reverses the depression of the central nervous system and respiratory system caused by opioids.
Naloxone was patented in 1961 and approved for opioid overdose in the United States in 1971. It is on the World Health Organization's List of Essential Medicines.
Medical uses
Opioid overdose
Naloxone is useful in treating both acute opioid overdose and respiratory or mental depression due to opioids. Whether it is useful in those in cardiac arrest due to an opioid overdose is unclear.It is included as a part of emergency overdose response kits distributed to heroin, fentanyl, and other opioid drug users, and to emergency responders. This has been shown to reduce rates of deaths due to overdose. A prescription for naloxone is recommended if a person is on a high dose of opioid, is prescribed any dose of opioid accompanied by a benzodiazepine, or is suspected or known to use opioids nonmedically. Prescribing naloxone should be accompanied by standard education that includes preventing, identifying, and responding to an overdose; rescue breathing; and calling emergency services.
Distribution of naloxone to individuals likely to encounter people who overdose is one aspect of harm reduction strategies.
However, with opioids that have longer half-lives, respiratory depression returns after naloxone has worn off; therefore, adequate dosing and continuous monitoring may be necessary.
Clonidine overdose
Naloxone can also be used as an antidote in an overdose of clonidine, a medication that lowers blood pressure. Clonidine overdoses are of special relevance for children, in whom even small doses can cause significant harm. However, there is controversy regarding naloxone's efficacy in treating the symptoms of clonidine overdose, namely slow heart rate, low blood pressure, and confusion/somnolence. Case reports that used doses of 0.1mg/kg repeated every 1–2 minutes have shown inconsistent benefit. As the doses used throughout the literature vary, it is difficult to form a conclusion regarding the benefit of naloxone in this setting. The mechanism for naloxone's proposed benefit in clonidine overdose is unclear. Still, it has been suggested that endogenous opioid receptors mediate the sympathetic nervous system in the brain and elsewhere in the body.Preventing recreational opioid use
Naloxone is poorly absorbed when taken orally or sublingually, so it is often added to oral or sublingual opioid preparations, including buprenorphine and pentazocine, so that when swallowed or taken sublingually, only the non-naloxone opioid has an effect. However, if the combination is injected, the naloxone is believed to block the effect of the other opioid. This combination is used to prevent non-medical use.However, SAMHSA's clinical guidelines state that if the combination of buprenorphine and naloxone is injected by a regular user of buprenorphine or buprenorphine/naloxone, then the buprenorphine would still produce an agonist effect but the naloxone would fail to produce an antagonist effect. This is because the amount of naloxone that would be required to block the buprenorphine after injection is much larger than the amount that is contained in buprenorphine/naloxone pills and strips. If someone who is not physically dependent on opioids were to inject the buprenorphine/naloxone combination, then the effects of the buprenorphine may at most be slightly lessened, but the individual would still be expected to experience euphoric effects.
Other uses
A 2003 meta-analysis of existing research showed naloxone to improve blood flow in patients with shock, including septic, cardiogenic, hemorrhagic, or spinal shock, but could not determine if this reduced patient deaths.Oral naloxone has been used for opioid-induced constipation. A 2018 meta-analysis cites 5 studies that tests it for this purpose. It found that medical treatment for OIC can be more efficacious than placebo, but did not look into the effect of individual treatments such as naloxone. As a result, no conclusion can be drawn from the study on naloxone's effectiveness for OIC.
Naloxone and other opiod antagonists have been examined as possible treatments for disassociative disorders. This use predicates on the theory that disassociative disorders cause disregulation in the bodies natural opiod pathways. A 2023 meta-analytic study found some evidence of opiod antagonists being effective against disassociative disorders, but possible publication bias and differences in testing criteria encourages additional research.
Special populations
Pregnancy and breastfeeding
There are no adequate and well-controlled studies of the naloxone's use in pregnant women, much of the information on naloxone in pregnancy comes from studies on the use of naloxone and buprenorphine together, rather than the study of naloxone on its own. Although one study showed a possible link to preterm labor and low birth weight, but once again this study was done on women with opioid use disorder who were taking Suboxone, no studies have been done to see if treatment with naloxone for an opioid overdose can increase the chance of pregnancy-related problems.Naloxone is able to cross the placental barrier and may precipitate neonatal withdrawal, as such it is important for women taking opioids during pregnancy to inform their baby's healthcare providers so that they can check for symptoms of withdrawal, especially if they are taking medications for OUD.
Small amounts of naloxone are excreted in breast milk, however, as naloxone is poorly absorbed orally it is not orally bioavailable and therefore is unlikely to affect a breastfeeding infant.
Children
Naloxone can be used on infants who were exposed to intrauterine opiates administered to mothers during delivery. However, there is insufficient evidence for the use of naloxone to lower cardiorespiratory and neurological depression in these infants. Infants exposed to high concentrations of opiates during pregnancy may have CNS damage in the setting of perinatal asphyxia. Naloxone has been studied to improve outcomes in this population, however the evidence is currently weak.Intravenous, intramuscular, or subcutaneous administration of naloxone can be given to children and neonates to reverse opiate effects. The American Academy of Pediatrics recommends only intravenous administration as the other two forms can cause unpredictable absorption. After a dose is given, the child should be monitored for at least 24 hours. For children with low blood pressure due to septic shock, naloxone safety and effectiveness are not established.
Geriatric use
For patients 65 years and older, it is unclear if there is a difference in response. However, older people often have decreased liver and kidney function which may lead to an increased level of naloxone in their body.Available forms
Intravenous
In hospital settings, naloxone is injected intravenously, with an onset of 1–2 minutes and a duration of up to 45 minutes.Intramuscular or subcutaneous
Naloxone can also be administered via intramuscular or subcutaneous injection. The onset of naloxone provided through this route is 2 to 5 minutes with a duration of around 30–120min. Naloxone administered intramuscularly are provided through pre-filled syringes, vials, and auto-injector. A hand-held auto-injector is pocket-sized and can be used in non-medical settings such as in the home. It is designed for use by laypersons, including family members and caregivers of opioid users at risk for an opioid emergency, such as an overdose. According to the FDA's National Drug Code Directory, a generic version of the auto-injector began to be marketed at the end of 2019.Intranasal
Narcan nasal spray was approved in the US in 2015 and is the first FDA-approved nasal spray for emergency treatment or suspected overdose. It was developed in a partnership between LightLake Therapeutics and the National Institute on Drug Abuse. The approval process was fast-tracked. A generic version of the nasal spray was approved in the United States in 2019, though did not come to market until 2021.In 2021, the FDA approved Kloxxado, an 8mg dose of intranasal naloxone developed by Hikma Pharmaceuticals. Citing the frequent need for multiple 4mg doses of Narcan to successfully reverse overdose, packs of Kloxxado Nasal Spray contain two pre-packaged nasal spray devices, each containing 8mg of naloxone.
However, a wedge device can also be attached to a syringe that may also be used to create a mist to deliver the drug to the nasalmucosa. This is useful near facilities where many overdoses occur that already stock injectors.
Side effects
Administration of naloxone to somebody who has used opioids may cause rapid-onset opioid withdrawal.Naloxone has little to no effect if opioids are not present. In people with opioids in their system, it may cause increased sweating, nausea, restlessness, trembling, vomiting, flushing, and headache, and has in rare cases been associated with heart rhythm changes, seizures, and pulmonary edema.
Naloxone has been shown to block the action of pain-lowering endorphins the body produces naturally. These endorphins likely operate on the same opioid receptors that naloxone blocks. It is capable of blocking a placebo pain-lowering response if the placebo is administered together with a hidden or blind injection of naloxone. Other studies have found that placebo alone can activate the body's μ-opioid endorphin system, delivering pain relief by the same receptor mechanism as morphine.
Naloxone should be used with caution in people with cardiovascular disease as well as those who are currently taking medications that could have adverse effects on the cardiovascular system such as causing low blood pressure, fluid accumulation in the lungs, and abnormal heart rhythms. There have been reports of abrupt reversals with opioid antagonists leading to pulmonary edema and ventricular fibrillation.
Use of naloxone to treat people who have been using opioids recreationally may cause acute opioid withdrawal with distressing physiological symptoms such as shivering, tachycardia, and nausea; these in turn may lead to aggression and reluctance to receive further treatment.