(-)-Nalorphine

311.37

311.37

200-546-1

U59WB2WRY2

9400

DTXSID3023348

Crystals (from diethyl ether)

V - Various

52.9

1.86

1.38g/cm3

208-209 °C

493.6ºC at 760 mmHg

252.3ºC

1.699

Sparingly soluble in ether; soluble in chloroform, dilute alkalies

1.5X10-10 mm Hg at 25 deg C (est)

Subcutaneous-rat LD50: 474 mg/kg; oral-mouse LD50: 1140 mg/kg

Flammable; burning produces toxic nitrogen oxide fumes

D25 -155.3° (c = 3 in methanol)

Henry's Law constant = 1.8X10-16 atm-cu m/mol at 25 °C (est)

pKa = 7.64

Decomp at 258-259 °C; crystals from alc; soluble in water /Nalorphine hydrobromide/|Hydroxyl radical reaction rate constant = 3.0X10-10 cu cm/molec-sec at 25 °C (est)

Treasury is ventilated, low temperature and dry; stored separately from food materials

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

Nalorphine hydrochloride injection. ... Indications for use. Respiratory and circulatory depression in dogs resulting from overdosage of, or unusual sensitivity to, morphine and certain other narcotics. Not for depression due to any other cause. ... Limitations: Successive doses of the drug gradually lose their analeptic effect and eventually induce respiratory depression equal to that of opiates. Therefore, do not exceed therapeutic dosage. Do not mix drug with meperidine solutions because the buffer will cause precipitation. Federal law restricts this drug to use by or on the order of a licensed veterinarian.|The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Nalorphine hydrochloride is included on this list. /Nalorphine hydrochloride/|Schedule III shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. Nalorphine (DEA Code Number: 9400) is included on this list.

moderately toxic

When both morphine and nalorphine were given together, intramuscularly, in varying dosages, the resulting effects on the respiration were complex: with 5 mg of morphine, increasing the dose of nalorphine produced greater depression than increasing it with 10 mg morphine. The interaction of the two drugs was regarded as an example of "competitive dualism". The antagonism by nalorphine of the respiratory depression produced by morphine was primarily related to differences in the intrinsic action of each drug, and not simply due to mutually competitive affinities for certain receptor sites.|... Resp depressant actions of nalorphine-type antagonists may add to existing resp depression produced by CNS depressants.|Nalorphine HBR reportedly enhanced depression caused by combination injection of meperidine-levallorphan in pt receiving phenelzine /and other monoamine oxidase inhibitors/ ... /Nalorphine hydrobromide/

LD50 Rat sc 474 mg/kg|LD50 Rat iv 226 mg/kg|LD50 Mouse oral 1140 mg/kg|LD50 Mouse ip 492 mg/kg|For more Non-Human Toxicity Values (Complete) data for NALORPHINE (7 total), please visit the HSDB record page.

Used to reverse opioid overdose.

Narcotic Antagonists|Nalorphine is a narcotic antagonist that is used to reverse respiratory depression from narcotic overdose. It has been used either alone or in combination with meperidine or morphine during labor to reduce neonatal /respiratory/ depression. Nalorphine has also been given to the newborn to prevent neonatal asphyxia. /Former/|Nalorphine is a narcotic antagonist with some agonist properties that reduces or abolishes the depressant actions of morphine and other narcotic substances but not those of barbiturates or other non-narcotic depressants. Nalorphine has analgesic properties but is unsuitable for use as analgesic because of its unpleasant side-effects. /Former/|MEDICATION (Vet): as pharmacological antagonist to resp depression, hypotension, depression, etc, produced by narcotics such as morphine, fentanyl, codeine, meperidine, methadone, hydromorphone, thiambutene, cyprenorphine, etorphene, etc, but not that produced by many anesthetics such as barbiturates, ether, chloral hydrate, etc. Despite fact that it is strong antagonist to most narcotic drug effects, it is synergistic with their antitussive effects, and is also antitussive by itself ... /SRP: former use/|For more Therapeutic Uses (Complete) data for NALORPHINE (7 total), please visit the HSDB record page.

In patients given narcotic antagonists who have apparently recovered from their overdose, observation must be continued for up to 48 hours as the half-life of the antagonist was generally shorter than that of the narcotic.|Some mixed agonist-antagonist drugs such as ... nalorphine, can produce severe psychotomimetic effects that are not reversible with naloxone (suggesting that these undesirable side effects are not mediated through classical opioid receptors). Also, ... nalorphine can precipatate withdrawal in opioid-tolerant patients. For these reasons, the clinical use of these mixed agonist-antagonist drugs is limited.|FDA Pregnancy Risk Category: D /POSITIVE EVIDENCE OF RISK. Studies in humans, or investigational or post-marketing data, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective./ /Former/|... After chronic admin of high dosage, abrupt discontinuation ... causes characteristic withdrawal syndrome ... One early sign is repeated brief episodes of sensation that is described by some subjects as "electric shocks to head" and by others as light-headedness or fainting spells ... not ... convulsive phenomena ...|For more Drug Warnings (Complete) data for NALORPHINE (7 total), please visit the HSDB record page.

Healthy subjects given progressively larger doses of nalorphine became tolerant to its effects and were cross tolerant to the effects of cyclazocine. On withdrawal, an abstinence syndrome developed which was milder than that for morphine but similar to cyclazocine.

Agents inhibiting the effect of narcotics on the central nervous system. (See all compounds classified as Narcotic Antagonists.)

Nalorphine is poorly absorbed when given by mouth. When administered by injection, it readily passes into the brain and across the placenta. It is largely metabolised in the liver and excreted in the urine. About 2 to 6% of the dose is excreted unchanged in the urine.|... The brain/plasma ratios and degree of plasma-protein binding were significantly higher for naloxone as compared to nalorphine. The amounts of free naloxone excreted as a percentage of the dose in urine and feces 96 hours after injection of the 10 mg/kg sc dose were 4.1 and 3.9 (for nalorphine 4.7 and 8.3); conjugated drug 15.4 and 1.2 (for nalorphine 13 and 0.9); total radioactivity 43.3 and 20.9 (for nalorphine 34.8 and 19.2), respectively. ...|In this study, the elimination of nalorphine was investigated to characterize the relation between renal and hepatic excretion of organic cations. Nalorphine is excreted effectively both via kidney and liver. However, its hepatic excretion dominates in adult rats. In young, 20-day-old animals biliary nalorphine elimination is immature and the excreted amounts are significantly lower. Renal excretion of nalorphine is quite similar in rats of both ages. After bile duct ligation renal excretion of nalorphine increases significantly in adult rats whereas it remains unchanged in young ones. Remarkably, after bilateral nephrectomy hepatic elimination of nalorphine is even diminished in both age groups. In further experiments renal excretion of nalorphine could be stimulated in adult rats after repeated administration of trometamol, triiodothyronine, or dexamethasone; these treatments had no consequences on biliary secretion of nalorphine.|Following parenteral admin of nalorphine, concn in brain are 3-4 times higher than after comparable doses of morphine. Brain concn fall rapidly and only trace amt are found after 4 hr.|First-pass effect of nalorphine-HCl, about 50% of admin radioactivity was excreted in expired air (14)CO2 and urine (conjugated and unchanged nalorphine) by 48 hr after either iv or oral admin suggesting that absorption was essentially complete. /Nalorphine HCl/

Nalorphine-3-glucuronide dihydrate and nalorphine-6-glucuronide were isolated as urinary metabolites of nalorphine in dogs, and nalorphine-3-ethereal sulfate and nalorphine-3-glucuronide dihydrate were isolated in cats. ...|Nalorphine yields 2-hydroxynalorphine & nalorphine-3-beta-d-glucuronide in rabbit; yields normorphine in rat. /from table/|... Nalrophine is much more effective after parenteral than oral admin, probably because of rapid biotransformation in liver (mainly through conjugation with glucuronic acid). /SRP: former use/|First-pass effect of nalorphine-hydrogen chloride was measured in rats, major metabolic pathway for nalorphine was n-deallylation and glucuronidation. /Nalorphine HCl/

The T1/2 of naloxone and nalorphine in rat brain and plasma with 1 and 10 mg/kg sc doses was 0.4 hour.

The Kappa-3 opioid receptor subtype is found throughout the brain and participates in supraspinal analgesia. This receptor is primarily responsible for the action of nalorphine, an agonist-antagonist opioid. ... All opioid receptor subtypes are members of a family of a superfamily of membrane bound receptors that are coupled to G proteins. The G proteins are responsible for signaling the cell that the receptor has been activated and for initiating the the desired cellular effects. /Opioids/|Agonists selective for kappa receptors produce analgesia that has been shown in animal to be mediated primarily at spinal sites. Respiratory depressin and miosis may be less severe with kappa agonists. Instead of euphoria (/as with mu-receptors/), kappa receptor agonist produce dysphoric and psychotomimetic effects.|The effects of graded doses of nalorphine and morphine were studied in nondependent chronic spinal dogs. Morphine and low doses of nalorphine produced behavioral changes characterized by indifference, whereas the largest dose of nalorphine produced canine delirium indistinguishable from that produced by SKF-10, 047 or cyclazocine. Nalorphine depressed the flexor reflex; however, a plateau was observed. The data suggest that nalorphine is a partial agonist of the kappa type and a sigma agonist in addition to being a competitive antagonist at the mu receptor, and further, that the dysphoric and hallucinogenic effects of nalorphine-like drugs are due to their sigma activity.|Intracellular microelectrode studies were conducted to investigate the actions of the partial agonist-antagonist nalorphine at an opiate receptor on functional frog skeletal muscle fiber membranes. In high bath concentrations (greater than or equal to 10(-4) M), nalorphine alone produces agonist actions similar to the "full" opiate agonists. These actions were (i) to depress both the sodium and potassium (gNa and gK) conductance increases due to electrical stimulation by a nonspecific local anestheticlike mechanism and (ii) to depress gNa by a specific opiate receptor mediated mechanism. In a much lower bath concentration (1 X 10(-8) M) nalorphine acts to antagonize the specific opiate receptor mediated depression of gNa produced by the "full" agonist meperidine. Thus in this preparation nalorphine, "the partial antagonist," has the same actions as naloxone, which is often considered to be a full antagonist. ...|For more Mechanism of Action (Complete) data for NALORPHINE (6 total), please visit the HSDB record page.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ The effects of nalorphine 5 mg im, a partial opiate antagonist, on circulating levels of PRL, GH, TSH, LH, FSH and cortisol were studied in six healthy men. Nalorphine produced a produced a prompt and sharp increase in serum PRL and a small, delayed rise in serum GH. Serum LH and cortisol decreased after drug administration and no change in serum FSH and TSH was observed.|/HUMAN EXPOSURE STUDIES/ The comparative study of 2 narcotic antagonists, naloxone and nalorphine, was performed in healthy volunteers. The influence of these drugs on the respiratory and cicularoty systems and on the psychical state was compared. The study was carried out in a double-blind, cross-over manner. Increasing doses of naloxone and placebo or nalorphine and placebo, were administered intravenously. Naloxone, even in very high doses, caused no changes in cardivascular system, acid-base balance, sensitivity of respiratory centre to carbon dioxide and psychical state of volunteers. After the administration of nalorphine, even in very small doses, changes in psychical state in all examined subjects were observed. Nalorphine caused /a/ significant change in the ventilatory response to CO2. ...|/HUMAN EXPOSURE STUDIES/ In the control trials on near-term pregnant women before tyhe onset of labor, nalorphine was found to cause a mild respiratory acidosis in the mother and metabolic acidosis in the fetus. ...|/SIGNS AND SYMPTOMS/ Significant percentage experience unpleasant reactions that range from anxiety, "crazy feelings," and vivid, disturbing, "unreal" daydreams to frank hallucinations.|For more Human Toxicity Excerpts (Complete) data for NALORPHINE (8 total), please visit the HSDB record page.

Allylnormorphine

Nalorphine|Nalline|9400|Schedule III - Substances in the DEA Schedule III have a potential for abuse less than substances in Schedules I or II and abuse may lead to moderate or low physical dependence or high psychological dependence.|Yes

Allorphine|Anarcon|Anthorphine|Antofin|For more Formulations/Preparations (Complete) data for NALORPHINE (19 total), please visit the HSDB record page.

Nalorphine is listed in schedule iii of controlled substances act.|... allyl derivative of morphine. ... able to "antagonize" or neutralize most of the effects of narcotic drugs (morphine, codeine), but not those of other types of depressants|Nalorphine ... no longer available in the United States.

Analyte: nalorphine hydrochloride; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards /Nalorphine hydrochloride /|Analyte: nalorphine hydrochloride; matrix: chemical identification; procedure: ultraviolet absorption spectrophotometry with comparison to standards /Nalorphine hydrochloride /|Analyte: nalorphine hydrochloride; matrix: chemical purity; procedure: ultraviolet absorption spectrophotometry at 285 nm with comparison to standards /Nalorphine hydrochloride /|AMPEROMETRIC HIGH PERFORMANCE LIQ CHROMATOGRAPHIC METHOD FOR DETECTION OF NALORPHINE.|Chemiluminescence detection was used in combination with flow injection analysis to determine > or = 1 fmol of morphine by its reaction with MnO4- in an acidic tetraphosphate soln. Structurally similar narcotics can also be determined by the same procedure. A mechanism for the chemiluminescent reaction is suggested.

Analyte: nalorphine hydrochloride; matrix: pharmaceutical preparation (injection solution); procedure: thin-layer chromatography with comparison to standards (chemical identification) /Nalorphine hydrochloride /|Analyte: nalorphine hydrochloride; matrix: pharmaceutical preparation (injection solution); procedure: ultraviolet detection spectrophotometry at 285 nm with comparison to standards (chemical purity) /Nalorphine hydrochloride /|Analyte: nalorphine; matrix: pharmaceutical preparation (solution); procedure: high-performance liquid chromatography with ultraviolet detection at 214 nm; limit of detection: 3.1 ng/mL|Analyte: nalorphine; matrix: urine; procedure: high-performance liquid chromatography with electrochemical detection and ultraviolet detection at 210 nm; limit of detection 40 ng/mL|For more Clinical Laboratory Methods (Complete) data for NALORPHINE (10 total), please visit the HSDB record page.

Pharmaceuticals