Naloxone

Not to be confused with Naltrexone.
Naloxone
Names
Trade namesNarcan, Evzio, Nyxoid, others
Other namesEN-1530; N-Allylnoroxymorphone; 17-Allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one, naloxone hydrochloride (USAN US)
IUPAC name
  • (4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-(prop-2-en-1-yl)-2,3,4,4a,5,6-hexahydro-1H-4,12-methano[1]benzofurano[3,2-e]isoquinolin-7(7aH)-one
Clinical data
Drug classOpioid receptor antagonist[1][2]
Main usesReversal of opioids[3]
Side effectsOpioid withdrawal (restlessness, agitation, nausea, fast heart rate, sweating)[4]
Pregnancy
category
  • AU: B1[5]
  • US: (IV/IM/subcutaneously): B/C [5]
    Routes of
    use    		Endotracheal, intranasal, IV, IM, IO
    Onset of action2 min (IV), 5 min (IM)[4]
    Duration of action30–60 min[4]
    Defined daily doseNot defined[6]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa612022
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only) / S3 (Pharmacist Only Medicine)[7]
    • DE: § 48 AMG/§ 1 MPAV (Prescription only)
    • UK: POM (Prescription only) [8]
    • US: ℞-only / OTC
    • In general: ℞ (Prescription only)
    Pharmacokinetics
    Bioavailability2% (by mouth, 90% absorption but high first-pass metabolism) 50% (intranasally)
    MetabolismLiver
    Elimination half-life1–1.5 h
    ExcretionUrine, bile
    Chemical and physical data
    FormulaC19H21NO4
    Molar mass327.380 g·mol−1
    3D model (JSmol)
    SMILES
    • O=C1[C@@H]2OC3=C(O)C=CC4=C3[C@@]2([C@]5(CC1)O)CCN(CC=C)[C@@H]5C4
    InChI
    • InChI=1S/C19H21NO4/c1-2-8-20-9-7-18-15-11-3-4-12(21)16(15)24-17(18)13(22)5-6-19(18,23)14(20)10-11/h2-4,14,17,21,23H,1,5-10H2/t14-,17+,18+,19-/m1/s1 checkY
    • Key:UZHSEJADLWPNLE-GRGSLBFTSA-N checkY

    Naloxone, sold under the brand name Narcan among others, is a medication used to block the effects of opioids.[4] It is commonly used to counter decreased breathing in opioid overdose.[4] Naloxone may also be combined with an opioid (in the same pill), to decrease the risk of opioid misuse.[4] When given intravenously, effects begin within two minutes, and when injected into a muscle within five minutes.[4] Another route it can be given is by spraying it into a person's nose.[9] The effects of naloxone last from about half an hour to an hour.[10] Multiple doses may be required, as the duration of action of most opioids is greater than that of naloxone.[4]

    Administration to opioid-dependent individuals may cause symptoms of opioid withdrawal, including restlessness, agitation, nausea, vomiting, a fast heart rate, and sweating.[4] To prevent this, small doses every few minutes can be given until the desired effect is reached.[4] In those with previous heart disease or taking medications that negatively affect the heart, further heart problems have occurred.[4] It appears to be safe in pregnancy, after having been given to a limited number of women.[11] Naloxone is a non-selective and competitive opioid receptor antagonist.[1][2] It works by reversing the depression of the central nervous system and respiratory system caused by opioids.[4]

    Naloxone was patented in 1961 and approved for opioid overdose in the United States in 1971.[12][13] It is on the World Health Organization's List of Essential Medicines.[14] Naloxone is available as a generic medication.[4] Its wholesale price in developing countries is between $0.50 and $5.30 per dose.[15] Vials of naloxone are not very expensive (less than $25) in the United States.[16] As of 2020, the price for a package of two auto-injectors in the US is $178.[17][18][19] The 2018 price for the NHS in the United Kingdom is about £5 per dose.[20] In Australia, a single dose is available, without prescription, and costs AU$20; those with a prescription, five doses can bought for AU$40, amounting to a rate of eight dollars per dose.[21]

    Medical uses

    Opioid overdose

    A naloxone kit as distributed in British Columbia, Canada

    Naloxone is useful to treat opioid overdose resulting in respiratory or mental depression.[4] Whether it is useful in those in cardiac arrest due to an opioid overdose is unclear.[22] Its use is recommended in those with a respiratory rate of less than 8 breaths per minute or oxygen levels less than 85%.[23]

    If minimal or no response is observed within 2–3 minutes, dosing may be repeated every 2 minutes until the maximum dose of 10 mg has been reached. If no response occurs at this time, alternative diagnosis and treatment should be pursued. Depending on the severity of overdose, a high dose exceeding 10 mg may be needed.[24] The effects of naloxone may wear off before those of the opioids, and they may require repeat dosing at a later time. Patients experiencing effects should be monitored for respiratory rate, heart rate, blood pressure, temperature, ABGs and level of consciousness. Those with a greater risk for respiratory depression should be identified prior to administration and watched closely.[25]

    It is included as a part of emergency overdose response kits distributed to heroin and other opioid drug users and emergency responders. This has been shown to reduce rates of deaths due to overdose.[26][27] A prescription is recommended if a person is on 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 nonmedically.[28] Prescribing naloxone should be accompanied by standard education that includes preventing, identifying, and responding to an overdose; rescue breathing; and calling emergency services.[29]

    For people 65 years and older, unclear if there is a difference in response. However, older people often have decreased liver and kidney function that may lead to an increased level of naloxone in their body.[30]

    Clonidine overdose

    Naloxone can also be used as an antidote in overdose of clonidine, a medication that lowers blood pressure.[31] Clonidine overdoses are of special relevance for children, in whom even small doses can cause significant harm.[32] 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.[32] Case reports that used doses of 0.1 mg/kg (maximum of 2 mg/dose) repeated every 1–2 minutes (10 mg total dose) have shown inconsistent benefit.[32] As the doses used throughout the literature vary, it is difficult to form a conclusion regarding the benefit of naloxone in this setting.[33] The mechanism for naloxone's proposed benefit in clonidine overdose is unclear, but it has been suggested that endogenous opioid receptors mediate the sympathetic nervous system in the brain and elsewhere in the body.[33] Some poison control centers recommend naloxone in the setting of clonidine overdose, including intravenous bolus doses of up to 10 mg naloxone.[34][35]

    Opioid misuse

    Naloxone is poorly absorbed when taken by mouth, so it is commonly combined with a number of oral opioid preparations, including buprenorphine and pentazocine, so that when taken by mouth, only the opioid has an effect.[4][36] However, if the opioid and naloxone combination is injected, the naloxone blocks the effect of the opioid.[4][36] This combination is used in an effort to prevent abuse.[36]

    Other uses

    In people with shock, including septic, cardiogenic, hemorrhagic, or spinal shock, those who received naloxone had improved blood flow. The importance of this is unclear.[37]

    Naloxone is also experimentally used in the treatment for congenital insensitivity to pain with anhidrosis,[38] an extremely rare disorder that renders one unable to feel pain or differentiate temperatures.[39]

    Naloxone can also be used to treat itchiness brought on by opioid use,[40] as well as opioid-induced constipation.[41]

    Children

    Naloxone can be used in babies 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.[42] 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.[43][44]

    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 is not established.[45]

    Dosage

    In adults the typical dose is 1 to 3 micrograms per kg (0.2 mg) intravenously.[3] In children 5 to 10 micrograms per kg intravenously may be used.[3] If after 2 to 3 minutes there is insufficient benefit the dose may be repeated.[3]

    The intravenous route is preferred over the IM route.[3] The defined daily dose is not defined.[6]

    Side effects

    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.[46][47]

    Besides the side effects listed above, naloxone also has other adverse events, such as other cardiovascular effects (hypertension, hypotension, tachycardia, ventricular fibrillation, ventricular tachycardia) and central nervous system effects, such as agitation, body pain, brain disease, and coma. In addition to these adverse effects, naloxone is also contraindicated in people with hypersensitivity to naloxone or any of its formulation components.[48]

    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.[49] 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.[50][51]

    Naloxone should be used with caution in people with cardiovascular disease as well as those that are currently taking medications that could have adverse effects on the cardiovascular system such as causing low blood pressure, fluid accumulation in the lungs (pulmonary edema), and abnormal heart rhythms. There have been reports of abrupt reversals with opioid antagonists leading to pulmonary edema and ventricular fibrillation.[52]

    Hypersensitivities

    Naloxone preparations may contain methylparaben and propylparaben and is inappropriate for use by people with a paraben hypersensitivity. If a person is sensitive to nalmefene or naltrexone, naloxone should be used with caution as these three medications are structurally similar. Cross-sensitivity among these drugs is unknown.[53] Preservative-free preparations are available for those with paraben hypersensitivities.

    Pregnancy and breastfeeding

    Naloxone is pregnancy category B or C in the United States.[4] Risks of untreated insufficient breathing; however, are likely greater than the risks of naloxone.[3]

    Studies in rodents given a daily maximum dose of 10 mg naloxone showed no harmful effects to the fetus, although human studies are lacking and the drug does cross the placenta, which may lead to the precipitation of withdrawal in the fetus. In this setting, further research is needed before safety can be assured, so naloxone should be used during pregnancy only if it is a medical necessity.[54]

    Whether naloxone is excreted in breast milk is unknown, however, it is not active when taken by mouth and therefore is unlikely to affect a breastfeeding infant.[55]

    Pharmacology

    Pharmacodynamics

    Naloxone at opioid receptors
    CompoundAffinities (Ki)RatioRef
    MORDORKORMOR:DOR:KOR
    Naloxone1.1 nM16 nM12 nM1:15:11[56]
    (−)-Naloxone0.559 nM
    0.93 nM    		36.5 nM
    17 nM    		4.91 nM
    2.3 nM    		1:65:9
    1:18:2    		[57]
    [58]
    (+)-Naloxone3,550 nM
    1,000 nM    		122,000 nM
    1,000 nM    		8,950 nM
    1,000 nM    		1:34:3
    ND    		[57]
    [58]

    Naloxone is a lipophilic compound that acts as a non-selective and competitive opioid receptor antagonist.[1][2] The pharmacologically active isomer of naloxone is (−)-naloxone.[57][59] Naloxone's binding affinity is highest for the μ-opioid receptor, then the δ-opioid receptor, and lowest for the κ-opioid receptor;[1] naloxone has negligible affinity for the nociceptin receptor.[60]

    If naloxone is administered in the absence of concomitant opioid use, no functional pharmacological activity occurs, except the inability for the body to combat pain naturally. In contrast to direct opiate agonists, which elicit opiate withdrawal symptoms when discontinued in opiate-tolerant people, no evidence indicates the development of tolerance or dependence on naloxone. The mechanism of action is not completely understood, but studies suggest it functions to produce withdrawal symptoms by competing for opiate receptor sites within the CNS (a competitive antagonist, not a direct agonist), thereby preventing the action of both endogenous and xenobiotic opiates on these receptors without directly producing any effects itself.[61]

    Pharmacokinetics

    When administered parenterally (nonorally or nonrectally, e.g. intravenously or by injection), as is most common, naloxone has a rapid distribution throughout the body. The mean serum half life has been shown to range from 30 to 81 minutes, shorter than the average half life of some opiates, necessitating repeat dosing if opioid receptors must be stopped from triggering for an extended period. Naloxone is primarily metabolized by the liver. Its major metabolite is naloxone-3-glucuronide, which is excreted in the urine.[61] For people with liver diseases such as alcoholic liver disease or hepatitis, naloxone usage has not been shown to increase serum liver enzyme levels.[62]

    Naloxone has low systemic bioavailability when taken by mouth due to hepatic first pass metabolism, but it does block opioid receptors that are located in the intestine.[41]

    Chemistry

    Naloxone, also known as N-allylnoroxymorphone or as 17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one, is a synthetic morphinan derivative and was derived from oxymorphone (14-hydroxydihydromorphinone), an opioid analgesic.[63][64][65] Oxymorphone, in turn, was derived from morphine, an opioid analgesic and naturally occurring constituent of the opium poppy.[66] Naloxone is a racemic mixture of two enantiomers, (–)-naloxone (levonaloxone) and (+)-naloxone (dextronaloxone), only the former of which is active at opioid receptors.[67][68] The drug is a highly lipophilic, allowing it to rapidly penetrate the brain and to achieve a far greater brain to serum ratio than that of morphine.[63] Opioid antagonists related to naloxone include cyprodime, nalmefene, nalodeine, naloxol, and naltrexone.[69]

    The chemical half-life of naloxone is such that injection and nasal forms have been marketed with 24-month and 18-month shelf-lives, respectively.[70] A 2018 study noted that the nasal and injection forms presented as chemically stable to 36- and 28-months, respectively, which prompted an as yet incomplete five year stability study to be initiated.[70] This suggests that expired caches of material in community and healthcare settings may still be efficacious substantially beyond their labeled expiration dates.[70]

    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

    History

    Naloxone was patented in 1961 by Mozes J. Lewenstein, Jack Fishman, and the company Sankyo.[12] It was approved for opioid abuse treatment in the United States in 1971,[71] with opioid abuse kits being distributed by many states to medically untrained people beginning in 1996. From the period of 1996 to 2014, the CDC estimates over 26,000 cases of opioid overdose have been reversed using the kits.[72]

    Naloxone (Nyxoid) was approved for use in the European Union in September 2017.[73]

    Society and culture

    Names

    Naloxone is the generic name of the medication and its INN, BAN, DCF, DCIT, and JAN, while naloxone hydrochloride is its USAN and BANM.[74][75][76][77]

    The patent has expired and it is available as a generic medication. Brand names of naloxone include Narcan, Nalone, Evzio, Prenoxad Injection, Narcanti, Narcotan, among others.

    Routes of administration

    Intravenous

    Naloxone is commonly injected intravenously, with an onset of 1–2 minutes and a duration of up to 45 minutes.[78] While the onset is achieved fastest through IV than through other routes of administration, it may be difficult to obtain venous access in patients who use IV drugs chronically. This may be an issue under emergency conditions.[79]

    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.[80] Naloxone administered intramuscularly are provided through pre-filled syringes, vials, and auto-injector. Evzio is the only auto-injector on the market and can be used both intramuscularly and subcutaneously. It is pocket-sized and can be used in non-medical settings such as in the home.[22] 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.[81] 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.[18]

    Intranasal

    Naloxone intranasally may also be used in people who are unconscious or unresponsive.[80] While the onset of action is slightly delayed in this method of administration, the ease of use and portability are what make naloxone nasal sprays useful.[78][80] Naloxone nasal spray was approved in the United States 2015.[82] It was prepackaged, requires no assembly, and delivered a consistent dose.[83] It was developed in a partnership between LightLake Therapeutics and the National Institute on Drug Abuse.[84] The approval process was fast-tracked.[85] A generic version of the nasal spray was approved in the United States in 2019.[86]

    However, a wedge device (nasal atomizer) can also be attached to a syringe that may also be used to create a mist to deliver the drug to the nasal mucosa.[87] This is useful near facilities where many overdoses occur that already stock injectors.[88]

    Storage

    Naloxone should be stored at room temperature and protected from light. For the auto-injector, naloxone should be stored in the outer case provided.[89] If the product is cloudy, discolored, or contains particulate matter, use is not recommended.[53]

    Labeling

    The opioid crisis in the US points out the necessity for an increase in the availability of the opioid antagonist naloxone as administered in overdose situations. In May 2020, the FDA reported on its creation of a “model drug facts label” that would enable average consumers with little or no specific training to comprehend the major components in effective, safe administration of naloxone. The agency used two prescription products in its test: the prefilled auto-injector Evzio and the nasal spray Narcan, both approved for community use in 2016. Working with experts on addiction, FDA researchers condensed the clinical information on naloxone (6,300 words over 18 pages) to eight “primary end points” providing essential data on usage in a crisis overdose emergency. The trial consisted of interviews with 710 adolescents and adults, including 430 opioid users, along with their family and friends. Results indicated that those being interviewed sufficiently understood six of the eight primary end points, and “came close” on the remaining two. The agency concluded the model label was adequate for use on naloxone sold over the counter. FDA also reported that if individuals comprehend instructions, administer naloxone and call 911, “…many lives will be saved.” They also recommended that manufacturers highlight “Call 911” on package labels.[90]

    In the United States, naloxone is available without a prescription in every state with the exception of Hawaii.[91][92] However, not all pharmacies stock or dispense naloxone.[93][94] Depending on the pharmacy, a pharmacist may have to write a prescription or not be able to give naloxone to comply with accounting rules regarding prescription medications, as naloxone is still considered a prescription only medication under FDA rules.

    While paramedics have carried naloxone for decades, law enforcement officers in many states throughout the country carry naloxone to reverse the effects of heroin overdoses when reaching the location prior to paramedics. As of July 12, 2015, law enforcement departments in 28 states are allowed to or required to carry naloxone to quickly respond to opioid overdoses.[95]

    In Australia, as of February 1, 2016, some forms of naloxone are available "over the counter" in pharmacies without a prescription.[7][96][97] It comes in single-use filled syringe similar to law enforcement kits. A single dose costs AU$20; for those with a prescription, five doses can bought for AU$40, amounting to a rate of eight dollars per dose (2019).[98]

    In Canada, naloxone single-use syringe kits are distributed and available at various clinics and emergency rooms. Alberta Health Services is increasing the distribution points for naloxone kits at all emergency rooms, and various pharmacies and clinics province-wide. Also in Alberta, take-home naloxone kits are available and commonly distributed in most drug treatment or rehabilitation centres, as well as in pharmacies where pharmacists can distribute single-use take-home naloxone kits or prescribe the drug to addicts. All Edmonton Police Service and Calgary Police Service patrol cars carry an emergency single-use naloxone syringe kit. Some Royal Canadian Mounted Police patrol vehicles also carry the drug, occasionally in excess to help distribute naloxone among users and concerned family/friends. Nurses, paramedics, medical technicians, and emergency medical responders can also prescribe and distribute the drug.

    Following Alberta Health Services, Health Canada reviewed the prescription-only status of naloxone, resulting in plans to remove it in 2016, allowing naloxone to be more accessible.[99][100] Due to the rising number of drug deaths across the country, Health Canada proposed a change to make naloxone more widely available to Canadians in support of efforts to address the growing number of opioid overdoses.[101] In March 2016, Health Canada did change the prescription status of naloxone, as "pharmacies are now able to proactively give out naloxone to those who might experience or witness an opioid overdose."[102]

    Prehospital access

    Laws in many jurisdictions have been changed in recent years to allow wider distribution of naloxone.[103][104] Several states have also moved to permit pharmacies to dispense the medication without the person first seeing a physician or other non-pharmacist professional.[105] Over 200 naloxone distribution programs utilize licensed prescribers to distribute the drug, often through the use of standing medication orders [106][107] whereby the medication is distributed under the medical authority of a physician or other prescriber (such as a pharmacist under California's AB1535). Additionally, 36 states have passed laws that provide naloxone prescribers with immunity against both civil and criminal liabilities.[108] Third-party prescriptions are also available for people, such as family and friends of people at risk for an overdose, who may find themselves in a situation that requires them to administer naloxone. Local schools, government agencies, and nonprofit organizations hold training programs to educate laypeople on proper use of naloxone. It is estimated that programs like these have helped to reverse more than 26,000 overdoses.[108]

    Following the use of the nasal spray device by police officers on Staten Island in New York, an additional 20,000 police officers will begin carrying naloxone in mid-2014. The state's Office of the Attorney General will provide US$1.2 million to supply nearly 20,000 kits. Police Commissioner William Bratton said: "Naloxone gives individuals a second chance to get help".[109] Emergency Medical Service Providers (EMS) routinely administer naloxone, except where basic Emergency Medical Technicians are prohibited by policy or by state law.[110] In efforts to encourage citizens to seek help for possible opioid overdoses, many states have adopted Good Samaritan laws that provide immunity against certain criminal liabilities for anybody who, in good faith, seeks emergency medical care for either themselves or someone around them who may be experiencing an opioid overdose.[111]

    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.[112] The approximate cost of a 1 ml ampoule of naloxone in the US is estimated to be significantly higher than in most Western countries.[106]

    Projects of this type are under way in many North American cities.[112][113] CDC estimates that the US programs for drug users and their caregivers prescribing take-home doses of naloxone and training on its use have prevented 10,000 opioid overdose deaths.[112] States including Vermont and Virginia have developed programs that mandate the prescription of naloxone when a prescription has exceeded a certain level of morphine milliequivalents per day as preventative measures against overdose.[114] 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.[106][115] Programs training police and fire personnel in opioid overdose response using naloxone have also shown promise in the US, and effort is increasing to integrate opioid fatality prevention in the overall response to the overdose crisis.[116][117][118][119]

    Pilot projects were also started in Scotland in 2006. Also in the UK, in December 2008, the Welsh Assembly government announced its intention to establish demonstration sites for take-home naloxone.[120]

    As of February 2016, Pharmacies across Alberta and some other Canadian jurisdictions are allowed to distribute take-home naloxone kits. Additionally, the Minister of Health issued an order to change basic life support provider's medical scope, within EMS, to administer naloxone in the event of a suspected narcotic overdose. These are part of the government's plan to tackle a growing fentanyl drug crisis.[121]

    In 2018, a maker of naloxone announced it would provide a free kit including two doses of the nasal spray, as well as educational materials, to each of the 16,568 public libraries and 2,700 YMCAs in the U.S.[122]

    Media

    The 2013 documentary film Reach for Me: Fighting to End the American Drug Overdose Epidemic interviews people involved in naloxone programs aiming to make naloxone available to opioid users and people with chronic pain.[123]

    See also

    References

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    11. ↑ "Prescribing medicines in pregnancy database". Australian Government. 3 March 2014. Archived from the original on 8 April 2014. Retrieved 22 April 2014.
    12. 1 2 Yardley, William (14 December 2013). "Jack Fishman Dies at 83; Saved Many From Overdose". New York Times. Archived from the original on 15 December 2013. Retrieved 2015-07-06.
    13. ↑ US patent 3493657, Jack Fishman & Mozes Juda Lewenstein, "Therapeutic compositions of n-allyl-14-hydroxy - dihydronormorphinane and morphine", published 1970-02-03, issued 1970-02-03, assigned to Mozes Juda Lewenstein 
    14. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
    15. ↑ "Naloxone HCL". International Drug Price Indicator Guide. Archived from the original on 22 January 2018. Retrieved 13 August 2015.
    16. ↑ Hamilton, Richard J. (2013). Tarascon pocket pharmacopoeia : 2014 classic shirt-pocket edition (28 ed.). Sudbury: Jones & Bartlett Learning. p. 174. ISBN 9781284053982. Archived from the original on 2017-09-08.
    17. ↑ "Evzio Authorized Generic Soon to Be Available". MPR. 2018-12-12. Archived from the original on 2019-10-23. Retrieved 2019-10-23.
    18. 1 2 "NDC 72853-051-02 Naloxone Hydrochloride Auto-injector". NDClist.com. Archived from the original on 2020-03-21. Retrieved 2020-03-21.
    19. ↑ "National Drug Code Directory". U.S. Food and Drug Administration (FDA). Archived from the original on 2016-05-27. Retrieved 2020-03-21.
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