Naloxone

Not to be confused with Naltrexone.
Naloxone
Clinical data
Trade names Narcan, Evzio
AHFS/Drugs.com Monograph
Pregnancy
category
  • AU: B1
  • US: C (Risk not ruled out) [1]
Routes of
administration		 Endotracheal, intranasal, IV, IM
ATC code V03AB15 (WHO)
Legal status
Legal status
  • AU: S3 (Pharmacist only) [2]
  • UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability 2% (Oral, 90% absorption but high first-pass metabolism)
Metabolism Liver
Onset of action 2 min (IV), 5 min (IM)[1]
Biological half-life 1–1.5 h
Duration of action 30 to 60 min[1]
Excretion Urine, Biliary
Identifiers
Synonyms 17-allyl- 4,5α-epoxy- 3,14-dihydroxymorphinan- 6-one
CAS Number 465-65-6 YesY
PubChem (CID) 5284596
IUPHAR/BPS 1638
DrugBank DB01183 YesY
ChemSpider 4447644 YesY
UNII 36B82AMQ7N YesY
KEGG D08249 YesY
ChEBI CHEBI:7459 N
ChEMBL CHEMBL80 YesY
Chemical and physical data
Formula C19H21NO4
Molar mass 327.38 g·mol−1
3D model (Jmol) Interactive image
 NYesY (what is this?)  (verify)

Naloxone, sold under the brandname Narcan among others, is a medication used to block the effects of opioids, especially in overdose.[1] Naloxone may be combined within the same pill as an opioid to decrease the risk of misuse. When given intravenously, it works within two minutes, and when injected into a muscle, it works within five minutes.[1] The medication may also be used in the nose.[3] The effects of naloxone last about half an hour to an hour.[4] Multiple doses may be required, as the duration of action of most opioids is greater than that of naloxone.[1]

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.[1] It appears to be safe in pregnancy, after having been given to a limited number of women.[5] Naloxone is a pure opioid antagonist. It works by reversing the depression of the central nervous system and respiratory system caused by opioids.[1]

Naloxone was patented in 1961 by Jack Fishman, Mozes J. Lewenstein, and the company Sankyo. The drug was approved for opioid overdose by the Food and Drug Administration in 1971.[6] Naloxone is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[7] Naloxone is available as a generic medication and is not very expensive.[1][8] Its wholesale price in the developing world is between US$0.50 and 5.30 per dose.[9]

Medical uses

Opiate overdose

A naloxone kits as distributed in British Columbia, Canada

Naloxone is useful both in acute opioid overdose and in reducing respiratory or mental depression due to opioids.[1] Whether it is useful in those in cardiac arrest due to an opioid overdose is unclear.[10]

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.[11] A prescription for naloxone 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.[12] Prescribing naloxone should be accompanied by standard education that includes preventing, identifying, and responding to an overdose; rescue breathing; and calling emergency services.[13]

Preventing opioid abuse

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 orally, just the opioid has an effect, but if misused by injecting, the naloxone blocks the effect of the opioid.[1][14] This combination is used in an effort to prevent abuse.[14]

Other

In a meta-analysis of people with shock, including septic, cardiogenic, hemorrhagic, or spinal shock, those who received naloxone had improved blood flow. The importance of this is unclear.[15]

Naloxone is also experimentally used in the treatment for congenital insensitivity to pain with anhidrosis, an extremely rare disorder (one in 125 million) that renders one unable to feel pain or differentiate temperatures.

Naloxone can also be used as an antidote in overdose of clonidine, a medication that lowers blood pressure.[16]

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.[17][18]

Naloxone has been shown to block the action of pain-lowering endorphins which 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, both in clinical and experimental pain, if the placebo is administered together with a hidden or blind injection of naloxone.[19] 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.

Special populations

Pregnancy and breast feeding

Naloxone is pregnancy category B or C in the United States.[1] 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 only be used during pregnancy if it is a medical necessity.[20]

If naloxone is excreted in breast milk is unknown.

Kidney and liver dysfunction

Currently, no established clinical trials have been conducted in person with insufficient kidney function or liver disease, and as such, these people should be monitored closely if naloxone is clinically indicated.

Pharmacodynamics

Naloxone has an extremely high affinity for μ-opioid receptors in the central nervous system (CNS). Naloxone is a μ-opioid receptor (MOR) inverse agonist,[21] 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- (KOR) and δ-opioid receptors (DOR). If 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.[22]

The Ki affinity values of (−)-naloxone for the MOR, KOR, and DOR have been reported as 0.559 nM, 4.91 nM, and 36.5 nM, respectively, whereas for (+)-naloxone, 3,550 nM, 8,950 nM, and 122,000 nM, respectively, have been reported.[23] As such, (−)-naloxone appears to be the active isomer.[23] Moreover, these data suggest that naloxone binds to the MOR with approximately 9-fold greater affinity relative to the KOR and around 60-fold greater affinity relative to the DOR.[23]

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.[22]

Administration

Naloxone is most commonly injected intravenously for fastest action, which usually causes the drug to act within a minute, and lasts up to 45 minutes. It can also be administered via intramuscular, subcutaneous injection, or nasal spray.[24] There is a pre packaged nasal spray that does not require assembly and delivers a consistent dose. It can be repeated if necessary.[25] A non-FDA approved wedge device (nasal atomizer) attached to a syringe may be used to create a mist that delivers the drug to the nasal mucosa.[26] It is more common outside of facilities where the majority of overdoses occur.[27][28]

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. If people show a response, they should remain under close monitoring; the effects of naloxone may wear off before those of the opioids, and they may require repeat dosing at a later time.

In April 2014, the US Food and Drug Administration (FDA) approved a hand-held automatic injector naloxone product that is pocket-sized and can be used in nonmedical settings such as in the home.[29] 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.[30] The approval process was fast-tracked as one initiative to reduce the death toll caused by opiate overdoses. At the time of approval, an estimated 16,000 annual deaths were attributed to prescription opioid overdoses in the US.[31]

Naloxone can be used along with oxycontin controlled release and may help reduce constipation associated with opioids. By mouth administration of naloxone blocks opioid action at the intestinal receptor level, but has low systemic bioavailability due to hepatic first pass metabolism.[32]

Society and culture

Names

The patent for naloxone has expired. It is available in generic medication. Trade names include: Narcan, Nalone, Evzio, Prenoxad Injection, Narcanti, Narcotan, and others.

In the United States, naloxone is classified as a prescription medication, though it is not a controlled substance.[33] While it is legal to prescribe naloxone in every state, dispensing the drug by medical professionals (including physicians or other licensed prescribers) at the point of service is subject to rules that vary by jurisdiction.

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 carry naloxone to quickly respond to opioid overdoses.[34]

In Australia, as of February 1, 2016, naloxone is now available "over the counter" in pharmacies without a prescription.[35] It comes in single use filled syringe similar to law enforcement kits.

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 and plans to remove it in 2016, allowing naloxone to be more accessible.[36][37] Due to the rising drug deaths across the country, the Canadian Public Health ministry proposed a change to make naloxone more widely available to Canadians in support of efforts to address the growing number of opioid overdoses.[38] Some pharmacies are now (as of February 2016) allowed to distribute take-home naloxone kits.[39]

Prehospital access

Laws in many jurisdictions have been changed in recent years to allow wider distribution of naloxone.[40][41] Several states have also moved to permit pharmacies to dispense the medication without the person first seeing a physician or other non-pharmacist professional.[42] Over 200 naloxone distribution programs utilize licensed prescribers to distribute the drug, often through the use of standing medication orders [43][44] whereby the medication is distributed under the medical authority of a physician or other prescriber (such as a pharmacist under California's AB1535).

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".[45] Emergency Medical Service Providers (EMS) routinely administer naloxone, except where basic Emergency Medical Technicians are prohibited by policy or by state law.[46]

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.[47] The approximate cost of a 1 ml ampoule of naloxone in the US is estimated to be significantly higher than in most Western countries.[43]

Projects of this type are under way in many North American cities.[47][48][49] 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.[47] 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.[43][50] 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.[51][52][53][54][55]

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.[56]

As of February 2016, Pharmacies across Alberta and some other Canadian jurisdictions are allowed to distribute take-home naloxone kits. This is as part of the government's plan to tackle a growing fentanyl drug crisis.[39]

Identification

Naloxone is the INN, BAN, USAN for the medication.

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.

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.[57]

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 "Naloxone Hydrochloride". The American Society of Health-System Pharmacists. Retrieved Jan 2, 2015.
  2. ↑ Melissa Davey (29 January 2016). "Selling opioid overdose antidote Naloxone over counter 'will save lives'". The Guardian.
  3. ↑ Roberts, James R. (2014). Roberts and Hedges' clinical procedures in emergency medicine (6 ed.). London: Elsevier Health Sciences. p. 476. ISBN 9781455748594.
  4. ↑ Bosack, Robert (2015). Anesthesia Complications in the Dental Office. John Wiley & Sons. p. 191. ISBN 9781118828625.
  5. ↑ "Prescribing medicines in pregnancy database". Australian Government. 3 March 2014. Retrieved 22 April 2014.
  6. ↑ Yardley, William (14 December 2013). "Jack Fishman Dies at 83; Saved Many From Overdose". New York Times. Retrieved 2015-07-06.
  7. ↑ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  8. ↑ Hamilton, Richard J. (2013). Tarascon pocket pharmacopoeia : 2014 classic shirt-pocket edition (28 ed.). Sudbury: Jones & Bartlett Learning. p. 174. ISBN 9781284053982.
  9. ↑ "Naloxone HCL". International Drug Price Indicator Guide. Retrieved 13 August 2015.
  10. ↑ Lavonas, EJ; Drennan, IR; Gabrielli, A; Heffner, AC; Hoyte, CO; Orkin, AM; Sawyer, KN; Donnino, MW (3 November 2015). "Part 10: Special Circumstances of Resuscitation: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.". Circulation. 132 (18 Suppl 2): S501–18. PMID 26472998.
  11. ↑ Maxwell S, Bigg D, Stanczykiewicz K, Carlberg-Racich S (2006). "Prescribing naloxone to actively injecting heroin users: a program to reduce heroin overdose deaths". J Addict Dis. 25 (3): 89–96. doi:10.1300/J069v25n03_11. PMID 16956873.
  12. ↑ Lazarus P (2007). "Project Lazarus, Wilkes County, North Carolina: Policy Briefing Document Prepared for the North Carolina Medical Board in Advance of the Public Hearing Regarding Prescription Naloxone". Raleigh, NC.
  13. ↑ Bowman S, Eiserman J, Beletsky L, Stancliff S, Bruce RD (July 2013). "Reducing the health consequences of opioid addiction in primary care". Am. J. Med. 126 (7): 565–71. doi:10.1016/j.amjmed.2012.11.031. PMID 23664112.
  14. 1 2 Orman, JS; Keating, GM (2009). "Buprenorphine/naloxone: a review of its use in the treatment of opioid dependence.". Drugs. 69 (5): 577–607. doi:10.2165/00003495-200969050-00006. PMID 19368419.
  15. ↑ Boef, B; Poirier V; Gauvin F; Guerguerian AM; Roy C; Farrell CA; Lacroix J (2003). "Naloxone for shock.". Cochrane Database Syst Rev. (4): CD004443. doi:10.1002/14651858.CD004443. PMID 14584016.
  16. ↑ Niemann, JT; Getzug, T; Murphy, W (October 1986). "Reversal of clonidine toxicity by naloxone.". Annals of Emergency Medicine. 15 (10): 1229–31. doi:10.1016/s0196-0644(86)80874-5. PMID 3752658.
  17. ↑ "Naloxone Side Effects in Detail". Drugs.com. Retrieved 5 May 2015.
  18. ↑ Schwartz JA, Koenigsberg MD (November 1987). "Naloxone-induced pulmonary edema". Ann Emerg Med. 16 (11): 1294–6. doi:10.1016/S0196-0644(87)80244-5. PMID 3662194.
  19. ↑ Sauro MD, Greenberg RP (February 2005). "Endogenous opiates and the placebo effect: a meta-analytic review". J Psychosom Res. 58 (2): 115–20. doi:10.1016/j.jpsychores.2004.07.001. PMID 15820838.
  20. ↑ Sobor, M; Timar, J.; Riba, P.; Kiraly, KP. (2013). "Behavioural studies during the gestational-lactation period in morphine treated rats". Neuropsychopharmacol Hung. 15 (4): 239–251. PMID 24380965.
  21. ↑ Sirohi, S.; Dighe, S. V.; Madia, P. A.; Yoburn, B. C. (12 May 2009). "The Relative Potency of Inverse Opioid Agonists and a Neutral Opioid Antagonist in Precipitated Withdrawal and Antagonism of Analgesia and Toxicity". Journal of Pharmacology and Experimental Therapeutics. 330 (2): 513–519. doi:10.1124/jpet.109.152678. PMC 2713087Freely accessible. PMID 19435929.
  22. 1 2 "NALOXONE HYDROCHLORIDE injection, solution". Daily Med. Retrieved 21 April 2014.
  23. 1 2 3 Codd EE, Shank RP, Schupsky JJ, Raffa RB (September 1995). "Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception". J. Pharmacol. Exp. Ther. 274 (3): 1263–70. PMID 7562497.
  24. ↑ "DailyMed - NARCAN- naloxone hydrochloride spray". dailymed.nlm.nih.gov. Retrieved 2016-01-22.
  25. ↑ "Press Announcements - FDA moves quickly to approve easy-to-use nasal spray to treat opioid overdose". www.fda.gov. Retrieved 2016-01-22.  This article incorporates text from this source, which is in the public domain.
  26. ↑ Wolfe TR, Bernstone T (April 2004). "Intranasal drug delivery: an alternative to intravenous administration in selected emergency cases". J Emerg Nurs. 30 (2): 141–7. doi:10.1016/j.jen.2004.01.006. PMID 15039670.
  27. ↑ Fiore, Kristina. "On-Label Nasal Naloxone in the Works". MedPage Today. Retrieved 2015-07-20.
  28. ↑ "FDA Approves Narcan Nasal Spray". www.jems.com. Retrieved 2015-11-21.
  29. ↑ Lavonas, EJ; Drennan, IR; Gabrielli, A; Heffner, AC; Hoyte, CO; Orkin, AM; Sawyer, KN; Donnino, MW (3 November 2015). "Part 10: Special Circumstances of Resuscitation: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.". Circulation. 132 (18 Suppl 2): S501–18. PMID 26472998.
  30. ↑ FDA News Release. "FDA approves new hand-held auto-injector to reverse opioid overdose". FDA.gov. Retrieved 2015-07-20.
  31. ↑ Brady Dennis (3 April 2014). "FDA approves device to combat opioid drug overdose". The Washington Post. Retrieved 8 April 2014.
  32. ↑ Meissner W, Schmidt U, Hartmann M, Kath R, Reinhart K (January 2000). "Oral naloxone reverses opioid-associated constipation". Pain. 84 (1): 105–9. doi:10.1016/S0304-3959(99)00185-2. PMID 10601678.
  33. ↑ 21 U.S.C.A. §§801-904; see e.g., LA Rev Stat. Ann. §40:964 (specifically excluding Naloxone from the schedule of controlled substances.)
  34. ↑ "US Law Enforcement Who Carry Naloxone". North Carolina Harm Reduction Coalition. Retrieved 12 July 2015.
  35. ↑ "Why the 'heroin antidote' naloxone is now available in pharmacies". ABC. Retrieved 1 February 2016.
  36. ↑ http://www.cbc.ca/beta/news/health/naloxone-s-prescription-only-status-to-get-health-canada-review-1.3166867
  37. ↑ http://www.health.alberta.ca/health-info/AMH-Naloxone-Take-home.html
  38. ↑ Health Canada Statement on Change in Federal Prescription Status of Naloxone. Retrieved 29 February 2016.
  39. 1 2 Naloxone kits now available at drug stores as province battles fentanyl crisis - Injection drug can temporarily reverse overdoses. Retrieved 29 February 2016.
  40. ↑ Corey Davis. "Legal interventions to reduce overdose mortality: Naloxone access and overdose good samaritan laws" (PDF). Network for Public Health Law.
  41. ↑ Davis CS, Webb D, Burris SC (2013). "Changing Law from Barrier to Facilitator of Opioid Overdose Prevention". Journal of Law, Medicine and Ethics.
  42. ↑ Ryan Oftebro, "Kelley-Ross Pharmacy provides Take-Home Naloxone to prevent opioid overdose", Kelley-Ross, August 20, 2013
  43. 1 2 3 Beletsky L, Burris SC, Kral AH (2009). "Closing Death's Door: Action Steps to Facilitate Emergency Opioid Drug Overdose Reversal in the United States". SSRN Electronic Journal. doi:10.2139/ssrn.1437163.
  44. ↑ Burris SC, Beletsky L, Castagna CA, Coyle C, Crowe C, McLaughlin JM (2009). "Stopping an Invisible Epidemic: Legal Issues in the Provision of Naloxone to Prevent Opioid Overdose". SSRN Electronic Journal. doi:10.2139/ssrn.1434381.
  45. ↑ Jessica Durando (27 May 2014). "NYPD officers to carry heroin antidote". USA Today. Retrieved 30 May 2014.
  46. ↑ Faul M, Dailey MW, Sugerman DE, Sasser SM, Levy B, Paulozzi LJ (2015). "Disparity in Naloxone Administration by Emergency Medical Service Providers and the Burden of Drug Overdose in US Rural Communities". American Journal of Public Health. doi:10.2105/AJPH.2014.302520.
  47. 1 2 3 "Community-Based Opioid Overdose Prevention Programs Providing Naloxone — United States, 2010". Centers for Disease Control and Prevention. 61 (6): 101–5. December 2010. PMID 22337174.
  48. ↑ "OD Prevention Program Locator". Overdose Prevention Alliance. Retrieved 15 May 2012.
  49. ↑ Karissa Donkin (9 September 2012). "Toronto naloxone program reduces drug overdoses among addicts". The Toronto Star. Retrieved 5 May 2015.
  50. ↑ Albert S, Brason FW, Sanford CK, Dasgupta N, Graham J, Lovette B (June 2011). "Project Lazarus: community-based overdose prevention in rural North Carolina". Pain Med. 12 Suppl 2: S77–85. doi:10.1111/j.1526-4637.2011.01128.x. PMID 21668761.
  51. ↑ Beletsky L, Rich JD, Walley AY (November 2012). "Prevention of fatal opioid overdose". JAMA. 308 (18): 1863–4. doi:10.1001/jama.2012.14205. PMC 3551246Freely accessible. PMID 23150005.
  52. ↑ Beletsky L, Moroz E. "The Quincy Police Department: Pioneering Naloxone Among First Responders.". Overdose Prevention Alliance. Retrieved 15 May 2012.
  53. ↑ Lavoie D (April 2012). "Naloxone: Drug-Overdose Antidote Is Put In Addicts' Hands". Huffington Post.
  54. ↑ Davis CS, Beletsky L (2009). "Bundling occupational safety with harm reduction information as a feasible method for improving police receptiveness to syringe access programs: evidence from three U.S. cities". Harm Reduct J. 6 (1): 16. doi:10.1186/1477-7517-6-16. PMC 2716314Freely accessible. PMID 19602236.
  55. ↑ "2013 National drug control strategy" (PDF). 2013.
  56. ↑ "IHRA 21st International Conference Liverpool, 26th April 2010 - Introducing 'take home' Naloxone in Wales" (PDF). Retrieved 9 March 2011.
  57. ↑ Reach for Me: Fighting to End the American Drug Overdose Epidemic
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