Naloxone Hydrochloride

(BANM, USAN, rINNM)
Naloxone Hydrochloride Chemical formula
Synonyms: (BANM, USAN, rINNM) N-Allylnoroxymorphone Hydrochloride; Cloridrato de Naloxona; EN-15304; Hidrocloruro de naloxona; Nalokson Hidroklorür; Naloksonihydrokloridi; Naloksono hidrochloridas; Naloksonu chlorowodorek dwuwodny; Naloxone, Chlorhydrate de; Naloxone (chlorhydrate de) dihydraté; Naloxon-hidroklorid; Naloxon-hydrochlorid; Naloxonhydroklorid; Naloxoni Hydrochloridum; Naloxoni hydrochloridum dihydricum. 17-Allyl-6-deoxy-7,8-dihydro-14-hydroxy-6-oxo-17-normorphine hydrochloride dihydrate; (−)-(5R,14S)-9a-Allyl-4,5-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride dihydrate.
Cyrillic synonym: Налоксона Гидрохлорид.

💊 Chemical information

Chemical formula: C19H21NO4,HCl,2H2O = 399.9.
CAS — 465-65-6 (naloxone); 357-08-4 (anhydrous naloxone hydrochloride); 51481-60-8 (naloxone hydrochloride dihydrate).
ATC — V03AB15.
ATC Vet — QV03AB15.

Pharmacopoeias.

In Chin., Eur., Int., Jpn, and US. Forms specified may be anhydrous, dihydrate, or both.

Ph. Eur. 6.2

(Naloxone Hydrochloride Dihydrate; Naloxone Hydrochloride BP 2008). It contains two molecules of water of hydration. A white or almost white, hygroscopic, crystalline powder. Freely soluble in water; soluble in alcohol; practically insoluble in toluene. Store in airtight containers. Protect from light.

USP 31

(Naloxone Hydrochloride). It is anhydrous or contains two molecules of water of hydration. A white to slightly offwhite powder. Soluble in water, in dilute acids, and in strong alkali; slightly soluble in alcohol; practically insoluble in chloroform and in ether. Its aqueous solution is acidic. Store in airtight containers at a temperature of 25°, excursions permitted between 15° and 30°. Protect from light.

Incompatibility.

Infusions of naloxone hydrochloride should not be mixed with preparations containing bisulfite, metabisulfite, long-chain or high-molecular-weight anions, or solutions with an alkaline pH.

💊 Adverse Effects

Nausea and vomiting have occurred with naloxone. Some adverse effects may be associated with opioid withdrawal. There have been individual reports of hypotension, hypertension, cardiac arrhythmias, and pulmonary oedema, generally in patients given naloxone postoperatively. Seizures have also been reported infrequently.
However, there have also been reports in healthy patients,5,6 including some fatalities.5 Hypotension, bradycardia, and precipitation of focal seizures have been reported in patients given high-dose naloxone for acute ischaemic stroke.7 Ventricular fibrillation has been observed in an opioid addict given naloxone to reverse the effects of diamorphine.8 However, this patient was later shown to have hepatic cirrhosis and alcoholic cardiomyopathy and the National Poisons Information Service in London noted that it had never been informed of such a suspected adverse reaction despite being contacted in about 800 cases of opioid poisoning each year.9 In a later report severe adverse effects were noted in 6 of 453 subjects given naloxone to reverse diamorphine intoxication.10 The effects were: asystole (1 case), generalised convulsions (3), pulmonary oedema (1), and violent behaviour (1).
1. Tanaka GY. Hypertensive reaction to naloxone. JAMA 1974; 228: 25–6
2. Azar I, Turndorf H. Severe hypertension and multiple atrial premature contractions following naloxone administration. Anesth Analg 1979; 58: 524–5
3. Flacke JW, et al. Acute pulmonary edema following naloxone reversal of high-dose morphine anesthesia. Anesthesiology 1977; 47: 376–8
4. Michaelis LL, et al. Ventricular irritability associated with the use of naloxone hydrochloride: two case reports and laboratory assessment of the effects of the drug on cardiac excitability. Ann Thorac Surg 1974; 18: 608–14
5. Wride SRN, et al. A fatal case of pulmonary oedema in a healthy young male following naloxone administration. Anaesth Intensive Care 1989; 17: 374–7
6. Taff RH. Pulmonary edema following naloxone administration in a patient without heart disease. Anesthesiology 1983; 59: 576–7
7. Barsan WG, et al. Use of high dose naloxone in acute stroke: possible side effects. Crit Care Med 1989; 17: 762–7
8. Cuss FM, et al. Cardiac arrest after reversal of effects of opiates with naloxone. BMJ 1984; 288: 363–4
9. Barret L, et al. Cardiac arrest following naloxone. BMJ 1984; 288: 936
10. Osterwalder JJ. Naloxone—for intoxications with intravenous heroin and heroin mixtures—harmless or hazardous? A prospective clinical study. Clin Toxicol 1996; 34: 409–16.

💊 Precautions

Naloxone should be used with caution in patients physically dependent on opioids, or who have received large doses of opioids, as an acute withdrawal syndrome may be precipitated. Naloxone crosses the placenta and a withdrawal syndrome may be precipitated in neonates of opioid-dependent mothers. Caution is required in patients with cardiac disease or those receiving cardiotoxic drugs. The duration of action of some opioids exceeds that of naloxone; patients should therefore be carefully observed after administration in case of relapse.

💊 Pharmacokinetics

Naloxone is absorbed from the gastrointestinal tract but it is subject to considerable first-pass metabolism. It is metabolised in the liver, mainly by glucuronide conjugation, and excreted in the urine. It has a plasma half-life of about 1 hour after parenteral administration. Naloxone crosses the placenta.

Pregnancy and the neonate.

A study in 30 mothers given a single intravenous dose of naloxone during the second stage of labour, indicated that naloxone rapidly crossed the placental barrier so that some therapeutic effect might be anticipated in most neonates.1 Placental transfer in 7 further mothers given naloxone intramuscularly was considered to be too variable for therapeutic purposes. In 12 neonates given naloxone hydrochloride 35 or 70 micrograms intravenously via the umbilical vein, the mean plasma half-life was 3.53 or 2.65 hours respectively.2 These halflives were 2 to 3 times longer than those reported for adults, possibly due to a diminished ability of the newborn to metabolise drugs by conjugation with glucuronic acid. Mean peak plasma concentrations of 8.2 nanograms/mL or 13.7 nanograms/mL in those given 35 or 70 micrograms respectively, were reached within 40 minutes but this time was very variable, and in 5 neonates peak concentrations were reached within 5 minutes. Naloxone hydrochloride 200 micrograms intramuscularly in 17 further neonates produced peak concentrations of 7.4 to 34.6 nanograms/mL at 0.5 to 2 hours.
1. Hibbard BM, et al. Placental transfer of naloxone. Br J Anaesth 1986; 58: 45–8
2. Moreland TA, et al. Naloxone pharmacokinetics in the newborn. Br J Clin Pharmacol 1980; 9: 609–12.

💊 Uses and Administration

Naloxone is a specific opioid antagonist that acts competitively at opioid receptors. It is an effective antagonist of opioids that possess agonist or mixed agonistantagonist activity although larger doses may be needed for compounds with the latter activity. It is used to reverse opioid central depression, including respiratory depression, induced by natural or synthetic opioids in the treatment of known or suspected opioid overdosage, postoperatively after the use of opioids during surgery, and in neonates when opioid analgesics have been given to the mother during labour. Naloxone hydrochloride is usually given intravenously for a rapid onset of action, which occurs within 2 minutes. The onset of action is only slightly less rapid when it is given intramuscularly or subcutaneously. Other routes, including the endotracheal, have also been used. The duration of action of naloxone is dependent on the dose and route; it is usually reported to be several hours, but may be much shorter, in the region of 1 hour or less. In the treatment of known or suspected opioid overdosage, the initial dose of naloxone hydrochloride is 0.4 to 2 mg given intravenously and repeated if necessary at intervals of 2 to 3 minutes. If no response has been seen after a total dose of 10 mg then the diagnosis of overdosage with drugs other than opioids should be considered. If the patient is suspected of being physically dependent on opioids the dose may be reduced to 100 to 200 micrograms to avoid precipitating withdrawal symptoms. If the intravenous route is not feasible the intramuscular or subcutaneous route can be used. Naloxone hydrochloride may also be used postoperatively to reverse central depression resulting from the use of opioids during surgery. For adults, a dose of 100 to 200 micrograms may be given intravenously at intervals of 2 to 3 minutes, titrated for each patient in order to obtain an optimum respiratory response while maintaining adequate analgesia. All patients receiving naloxone should be closely observed as the duration of action of many opioids exceeds that of naloxone and repeated doses may be required. Alternatively, to sustain opioid antagonism, an intravenous infusion may be used. Dosage regimens have not been well established, and the rate of infusion must be titrated according to the patient’s response. Some have recommended an infusion of 60% of the initial dose per hour, diluted to a concentration of 200 micrograms/mL in glucose. Others have suggested an initial intravenous loading dose of 400 micrograms, followed by a continuous infusion at an initial rate of 400 micrograms/hour. Alternatively, an intravenous loading dose of 5 micrograms/kg has been suggested, followed by a continuous infusion of 2.5 micrograms/kg per hour. For doses in children, see Administration in Children, below. Some opioid analgesics have been formulated with naloxone hydrochloride to reduce their potential for parenteral abuse, or as a substitution treatment for opioid dependence. Naloxone hydrochloride has also been used cautiously in small doses to diagnose opioid dependence by precipitating the withdrawal syndrome.

Administration in children.

In the treatment of known or suspected opioid overdosage in children, licensed product information recommends an initial dose of naloxone hydrochloride of 10 micrograms/kg intravenously, followed, if necessary, by a larger dose of 100 micrograms/kg. If the intravenous route is not feasible the intramuscular or subcutaneous route can be used. For acute respiratory depression induced by opioids the Committee on Drugs of the American Academy of Pediatrics has recommended a dose for naloxone of 100 micrograms/kg by the intramuscular, intravenous, or intratracheal routes for neonates, including premature infants, to the age of 5 years or 20 kg bodyweight; absorption may be erratic after intramuscular use. They advocated that children over 5 years or 20 kg should be given a minimum of 2 mg. These doses may be repeated as necessary to maintain opioid reversal.1,2 The Committee noted that these higher dose recommendations were based partly on the concern that 10 micrograms/kg might not provide optimal opiate reversal in some infants, and that it was felt that the higher doses posed no increased risk.3 The American Heart Association guidelines for paediatric advanced life support gave the same doses as the Committee for children to the age of 5 years or 20 kg bodyweight, but stated that those aged over 5 years or 20 kg be given a dose of 2 mg, without specifying this as a minimum.4 The use of injections containing 20 micrograms/mL of naloxone hydrochloride is no longer recommended because of the fluid load involved at these doses, especially in small neonates.1 It has been noted that specialists differ in their dosage of naloxone;5 a study in the USA found that paediatric intensive care and emergency medicine physicians tended to use 100 micrograms/kg up to a maximum initial dose of 2 mg. In contrast, anaesthesiologists have tended to use initial doses of 10 to 20 micrograms naloxone, regardless of body-weight;5 the American Academy of Pediatrics states that lower initial doses of 10 micrograms/kg may be considered for other clinical situations such as respiratory depression during pain management.2 Licensed product information states that for postoperative use, initial doses of 5 to 10 micrograms may be given intravenously at 2 to 3 minute intervals until the desired response is obtained. Opioid-induced depression in neonates resulting from the use of opioid analgesics in the mother during labour may be reversed by giving naloxone hydrochloride 10 micrograms/kg to the infant by intravenous, intramuscular, or subcutaneous injection, repeated at intervals of 2 to 3 minutes if necessary. Alternatively, a single intramuscular dose of about 60 micrograms/kg may be given at birth for a more prolonged action. Naloxone should be given with caution to the infants of opioid dependent mothers since withdrawal symptoms can result.
1. American Academy of Pediatrics. Emergency drug doses for infants and children and naloxone use in newborns: clarification. Pediatrics 1989; 83: 803
2. Committee on Drugs. Drugs for pediatric emergencies. Abstract: Pediatrics 1998; 101: e13. Full version: http:// pediatrics.aappublications.org/cgi/reprint/101/1/e13.pdf (accessed 30/06/06
3. American Academy of Pediatrics. Naloxone dosage and route of administration for infants and children: addendum to emergency drug doses for infants and children. Pediatrics 1990; 86: 484–5
4. American Heart Association. 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 12: Pediatric Advanced Life Support. Circulation 2005; 112 (suppl): IV-167–IV-187. Also available at: http://circ.ahajournals.org/cgi/reprint/112/24_suppl/IV-1.pdf (accessed 05/02/08
5. Hasan RA, et al. Cardiorespiratory effects of naloxone in children. Ann Pharmacother 2003; 37: 1587–92.

Eating disorders.

Endogenous opioids may have a role in the pathophysiology of eating disorders,1 thus opioid antagonists such as naloxone and naltrexone have been tried in their management. However, their role appears to be limited and they do not form part of the usual management of these conditions.
1. de Zwaan M, Mitchell JE. Opiate antagonists and eating behavior in humans: a review. J Clin Pharmacol 1992; 32; 1060–72.

Non-opioid overdosage.

Naloxone antagonises the action of exogenous and endogenous opioids. This may explain the varying responses reported to naloxone used in the treatment of overdosage with non-opioids, some of which may modulate endogenous opioids. Benefit has been reported1 with naloxone in valproate overdosage, although the evidence is based on case reports. There have also been case reports suggesting benefit in overdosage with camylofin,2 chlorpromazine,3 and ibuprofen.4 A study5 with midazolam in healthy subjects found that naloxone did not reverse respiratory depression, although there had been earlier reports of benefit in coma due to benzodiazepines. Naloxone has been used for clonidine intoxication, but retrospective reviews6,7 have concluded that responses are inconsistent, and there have been reports of hypertension. A lack of response has also been reported8 in brimonidine overdosage. There has been a report9 of the successful use of naloxone after captopril overdosage. Naloxone may also be of benefit in overdosage with drugs that are structurally related to opioids, including apomorphine,10 dextromethorphan,11 and loperamide.12
1. Roberge RJ, Francis EH. Use of naloxone in valproic acid overdose: case report and review. J Emerg Med 2002; 22: 67–70
2. Schvartsman S, et al. Camylofin intoxication reversed by naloxone. Lancet 1988; ii: 1246
3. Chandavasu O, Chatkupt S. Central nervous system depression from chlorpromazine poisoning: successful treatment with naloxone. J Pediatr 1985; 106: 515–6
4. Easley RB, Altemeier WA. Central nervous system manifestations of an ibuprofen overdose reversed by naloxone. Pediatr Emerg Care 2000; 16: 39–41
5. Forster A, et al. Respiratory depressant effects of different doses of midazolam and lack of reversal with naloxone—a doubleblind randomized study. Anesth Analg 1983; 62: 920–4
6. Fiser DH, et al. Critical care for clonidine poisoning in toddlers. Crit Care Med 1990; 18: 1124–8
7. Wiley JF, et al. Clonidine poisoning in young children. J Pediatr 1990; 116: 654–8
8. Sztajnbok J. Failure of naloxone to reverse brimonidine-induced coma in an infant. J Pediatr 2002; 140: 485–6
9. Varon J, Duncan SR. Naloxone reversal of hypotension due to captopril overdose. Ann Emerg Med 1991; 20: 1125–7
10. Bonuccelli U, et al. Naloxone partly counteracts apomorphine side effects. Clin Neuropharmacol 1991; 14: 442–9
11. Schneider SM, et al. Dextromethorphan poisoning reversed by naloxone. Am J Emerg Med 1991; 9: 237–8
12. Friedli G, Haenggeli C-A. Loperamide overdose managed by naloxone. Lancet 1980; i: 1413.

Pruritus.

For reference to the use of opioid antagonists, including naloxone, in the management of pruritus, see under Nalmefene

Reversal of opioid effects.

Naloxone is used postoperatively to reverse central depression resulting from the use of opioids during surgery. However, the beneficial analgesic effects of the opioids may also be reversed, and the increasing use of shortacting intravenous opioid analgesics should reduce the need for its use. In patients receiving longer-term opioids, naloxone has been reported to alleviate some of their adverse effects without loss of therapeutic efficacy. Naloxone reversed respiratory depression in a patient given intrathecal morphine,1 and urinary retention in 3 patients after epidural morphine,2 without reversing analgesia. However, a study3 in patients receiving extradural fentanyl found that naloxone failed to relieve urinary retention whereas pain scores rapidly increased. Naloxone given intravenously has been shown to reverse the delay in gastric emptying induced by opioid analgesics in healthy subjects4 and in women during labour.5Continuous intravenous infusion of naloxone reduced the incidence of adverse effects in patients receiving morphine by patient-controlled analgesia for postoperative pain.6 Pain control was not compromised and the lower dose of naloxone used (250 nanograms/kg hourly as opposed to 1 microgram/kg hourly) appeared to have an opioid-sparing effect. In patients receiving long-term opioids, oral naloxone in a daily dose equivalent to 20 to 40% of the daily opioid dose relieved opioid-induced constipation without compromising analgesic control.7,8 Doses equivalent to 10% or less of the opioid dose were ineffective.9However, other studies10 have found adverse effects even at low doses of naloxone, and the optimum dose remains unclear. Methylnaltrexone, a related opioid antagonist is also used for the reversal of opioid-induced constipation.
1. Jones RDM, Jones JG. Intrathecal morphine: naloxone reverses respiratory depression but not analgesia. BMJ 1980; 281: 645–6
2. Rawal N, et al. Naloxone reversal of urinary retention after epidural morphine. Lancet 1981; ii: 1411.
3. Wang J, et al. Low-dose naloxone in the treatment of urinary retention during extradural fentanyl causes excessive reversal of analgesia. Br J Anaesth 1998; 80: 565–6
4. Nimmo WS, et al. Reversal of narcotic-induced delay in gastric emptying and paracetamol absorption by naloxone. BMJ 1979; 2: 1189
5. Frame WT, et al. Effect of naloxone on gastric emptying during labour. Br J Anaesth 1984; 56: 263–5
6. Gan TJ, et al. Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate. Anesthesiology 1997; 87: 1075–81
7. Sykes NP. Oral naloxone in opioid-associated constipation. Lancet 1991; 337: 1475
8. Sykes NP. Oral naloxone in opioid-associated constipation. Lancet 1991; 338: 582
9. Robinson BA, et al. Oral naloxone in opioid-associated constipation. Lancet 1991; 338: 581–2
10. Thomas MC, Erstad BL. Safety of enteral naloxone and i.v. neostigmine when used to relieve constipation. Am J Health-Syst Pharm 2003; 60: 1264–7.
DIAGNOSTIC USE. Naloxone is used to reverse opioid effects in the diagnosis of opioid overdose, although some workers have recommended that it should only be used in patients with clinical signs of opioid overdose.1 Naloxone has also been used in the diagnosis of opioid dependence. It has been given intravenously to precipitate withdrawal symptoms, but methods that do not induce acute withdrawal have also been investigated. Pupillary dilatation in response to topical naloxone solution (naloxone eye drops) has been suggested as a useful method, but varying results have been reported depending on the strength of the solution used. A study2 using naloxone hydrochloride solution 1 mg/mL distinguished patients with a physical dependence from non-dependent patients who had received opioids on a single occasion as pre-operative medication, but this response was not confirmed in another study3using naloxone 400 micrograms/mL solution. Another study4 reported that a 2 mg/mL solution of naloxone hydrochloride gave useful results in an outpatient setting. However, there has been a report5 of withdrawal syndrome and pupillary dilatation in 4 opioid dependent subjects after instillation of naloxone solution 40 mg/mL.
1. Hoffman JR, et al. The empiric use of naloxone in patients with altered mental status: a reappraisal. Ann Emerg Med 1991; 20: 246–52
2. Creighton FJ, Ghodse AH. Naloxone applied to conjunctiva as a test for physical opiate dependence. Lancet 1989; i: 748–50
3. Loimer N, et al. Conjunctival naloxone is no decision aid in opioid addiction. Lancet 1990; 335: 1107–8
4. Ghodse AH, et al. Evaluation of the opioid addiction test in an out-patient drug dependency unit. Br J Psychiatry 1999; 175: 158–62
5. Sanchez-Ramos JR, Senay EC. Ophthalmic naloxone elicits abstinence in opioid-dependent subjects. Br J Addict 1987; 82: 313–15.
OPIOID OVERDOSAGE. Naloxone is usually given intravenously in opioid overdosage but may also be given intramuscularly if intravenous access is not available. Alternative routes have also been tried; a study1 using intranasal naloxone found that it was effective for prehospital management of suspected opioid overdosage, although response was slower than with intramuscular injection.
1. Kelly A-M, et al. Randomised trial of intranasal versus intramuscular naloxone in prehospital treatment for suspected opioid overdose. Med J Aust 2005; 182: 24–7.

Shock.

Endogenous opioids may have a role in the pathophysiology of shock but studies investigating naloxone for the treatment of shock have produced contradictory results. A systematic review1 concluded that naloxone does increase blood pressure in various forms of shock, but no significant effect on mortality was shown. US licensed product information has noted that the optimal dose and duration of therapy with naloxone have not been established, and that caution should be exercised before its use, particularly in patients with underlying pain or who have previously received opioids and may have developed opioid tolerance.
1. Boeuf B, et al. Naloxone for shock. Available in The Cochrane Database of Systematic Reviews; Issu
3. Chichester: John Wiley; 2003 (accessed 04/10/05).

💊 Preparations

BP 2008: Naloxone Injection; Neonatal Naloxone Injection; USP 31: Naloxone Hydrochloride Injection; Pentazocine and Naloxone Ta b l e t s .

Proprietary Preparations

Arg.: Antiopiaz; Grayxona; Narcanti; Narxona; Austral.: Narcan; Austria: Narcanti; Belg.: Narcan†; Braz.: Narcan; Canad.: Narcan†; Cz.: Intrenon; Narcanti†; Denm.: Narcanti; Fin.: Narcanti; Fr.: Nalone†; Narcan†; Ger.: Naloselect†; Narcanti; Gr.: Narcan; Hong Kong: Mapin; Narcan†; Hung.: Narcanti†; India: Narcotan; Indon.: Nokoba; Irl.: Narcan; Israel: Narcan†; Ital.: Narcan; Malaysia: Mapin; Narcan†; Mex.: Narcanti†; Norw.: Narcanti; NZ: Narcan; Port.: Narcan†; Naxan; Naxolan; Rus.: Naloxon (Налоксон); S.Afr.: Narcan†; Zynox; Singapore: Narcan†; Swed.: Narcanti; Switz.: Narcan; Thai.: Narcan; UK: Narcan†; USA: Narcan†; Venez.: Narcan; Oxogina. Used as an adjunct in: Belg.: Tinalox; Valtran; Cz.: Suboxone; Fr.: Suboxone; Ger.: Andolor; Celldolor; Findol N†; Gruntin Tropfen†; Nalidin; Tili Comp; Tili-Puren; Tili†; Tilicomp; Tilidalor†; Tilidin comp; Tilidin N; Tilidin plus; Tilidin-saar; Tilidura; Tiligetic†; Tilimerck†; Tilnalox; Valoron N; Israel: Talwin NX†; Malaysia: Suboxone; NZ: Suboxone; Port.: Suboxone; UK: Suboxone; USA: Suboxone; Talwin NX.
Published December 07, 2018.