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DEA NFLIS-Drug Category -> Narcotic Analgesics

DEA Schedule II Controlled Substance

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Synthetic Cannabinoids or Psychoactive Compounds

log Kow = 0.11

0.9

Highly soluble

In water, 1,931 mg/L at 25 °C

Freely soluble in alcohol; very soluble in chloroform

4.39e+00 g/L

Breast Feeding; Lactation; Milk, Human; Analgesics, Opioid; Narcotics; Antitussive Agents; Opiates

Pharmaceuticals

Opioid analgesics

Decomposes at 305ºC

266-267 °C

Fine white or practically white crystalline powder. Odoress. MP: 305-315 °C with decomposition (evacuated tube); specific optical rotation: -133 deg at 25 °C/D (c = 1 in water). Soluble in 3 parts water; sparingly soluble in alcohol; practically insoluble in ether. /Hydromorphone hydrochloride/

266 - 267 °C

Danger

H301 (75%): Toxic if swallowed [Danger Acute toxicity, oral]

P203, P261, P264, P270, P271, P272, P280, P301+P316, P302+P352, P304+P340, P316, P318, P319, P321, P330, P333+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 4 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

DEA schedule II controlled substance

Status: No longer Valid Update: 22-03-2018 https://echa.europa.eu/registration-dossier/-/registered-dossier/24209

Schedule II 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. Substances, vegetable origin or chemical synthesis. Unless specifically excepted or unless listed in another schedule, any of the following substances whether produced directly or indirectly by extraction from substances of vegetable origin, or independently by means of chemical synthesis, or by a combination of extraction and chemical synthesis: (1) Opium and opiate, and any salt, compound, derivative, or preparation of opium or opiate excluding apomorphine, thebaine-derived butorphanol, dextrorphan, nalbuphine, nalmefene, naloxegol, naloxone, and naltrexone, and their respective salts, but including the following. Hydromorphone (DEA Code Number: 9150) is included on this list.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl Hydromorphone hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Hydromorphone hydrochloride/

CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016; This guideline provides recommendations for primary care clinicians who are prescribing opioids for chronic pain outside of active cancer treatment, palliative care, and end-of-life care. The guideline addresses 1) when to initiate or continue opioids for chronic pain; 2) opioid selection, dosage, duration, follow-up, and discontinuation; and 3) assessing risk and addressing harms of opioid use. CDC developed the guideline using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework, and recommendations are made on the basis of a systematic review of the scientific evidence while considering benefits and harms, values and preferences, and resource allocation. CDC obtained input from experts, stakeholders, the public, peer reviewers, and a federally chartered advisory committee. It is important that patients receive appropriate pain treatment with careful consideration of the benefits and risks of treatment options. This guideline is intended to improve communication between clinicians and patients about the risks and benefits of opioid therapy for chronic pain, improve the safety and effectiveness of pain treatment, and reduce the risks associated with long-term opioid therapy, including opioid use disorder, overdose, and death.[Dowell D et al; Morbidity and Mortality Weekly Report (MMWR) 65 (1):1-49 (2016); Available from, as of March 22, 2016: http://www.cdc.gov/mmwr/volumes/65/rr/rr6501e1.htm]

DHHS/NIDA; Research Monograph Series 52: Testing Drugs for Physical Dependence Potential and Abuse Liability (1984) DHHS Pub No. (ADM)87-1332.

Steinberg SK, Kornijenko M; Can Pharm J 121: 182-6 (1988). The role of hydromorphone hydrochloride (Dilaudid) in the control of cancer pain is reviewed, including pharmacology, pharmacokinetics, adverse effects, drug interactions, dosage forms, administration, epidural use, compatibility, stability, and a comparison of properties with those of morphine.

Color change from pale yellow to light green occurred when solutions of minocycline hydrochloride or tetracycline hydrochloride were mixed with hydromorphone hydrochloride in 5% glucose injection. Mixtures of hydromorphone hydrochloride and dexamethasone sodium phosphate exhibited concentration-dependent incompatibility. White cloudiness, haziness, or precipitation developed 4 hours after mixing thiopental sodium and hydromorphone hydrochloride. Stability of mixtures of fluorouracil and hydromorphone hydrochloride in 0.9% sodium chloride or 5% glucose depended on the concentration of fluorouracil present. Hydromorphone hydrochloride 0.5 mg/mL with fluorouracil 1 mg/mL was stable for at least 7 days at 32 °C and for at least 35 days at 23, 4, or -20 °C. When the concentration of fluorouracil was increased to 16 mg/mL, hydromorphone was noted to decompose incurring unacceptable losses after 3 days at 32 °C or after 7 days at 23 °C, but was stable for at least 35 days at 4 or -20 °C. /Hydromorphone hydrochloride/

Store in airtight containers at a temperature of 25 °C, excursions permitted between 15 and 30 °C. Protect from light. /Hydromorphone hydrochloride/

Hydromorphone hydrochloride injection should be protected from light and stored at a controlled room temperature of 20-25 °C, but may be exposed to temperatures ranging from 15-30 °C. Hydromorphone hydrochloride immediate-release tablets and oral solution should be stored in tight, light-resistant containers at 25 °C, but may be exposed to temperatures ranging from 15-30 °C. The extended-release tablets should also be stored at 25 °C, but may be exposed to temperatures ranging from 15-30 °C. /Hydromorphone hydrochloride/

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, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

In the treatment of overdosage, primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. A potentially serious oral ingestion, if recent, should be managed with gut decontamination. In unconscious patients with a secure airway, instill activated charcoal (30-100 g in adults, 1-2 g/kg in infants) via a nasogastric tube. A saline cathartic or sorbitol may be added to the first dose of activated charcoal. Supportive measures (including oxygen, vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. The opioid antagonist, naloxone, is a specific antidote against respiratory depression which may result from overdosage, or unusual sensitivity to Hydromorphone. Therefore, an appropriate dose of this antagonist should be administered, preferably by the intravenous route, simultaneously with efforts at respiratory resuscitation. Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression. (L1712)

Drugs that induce CYP-450 enzymes involved in the metabolism of hydromorphone, such as rifampin and rifabutin, result in decreased serum concentrations and clinical effect.

Patients receiving hydromorphone hydrochloride extended-release tablets should not consume alcoholic beverages or prescription or nonprescription preparations containing alcohol; intake of alcohol with the extended-release tablets may result in increased peak plasma concentrations of hydromorphone and ingestion of a potentially toxic dose of the drug. /Hydromorphone hydrochloride/

Because opiate agonists may potentiate the effects of other CNS depressants including other opiate agonists, general anesthetics, tranquilizers, sedatives and hypnotics, and alcohol, opiate agonists should be used with great caution and in reduced dosage when used in conjunction with such drugs. Some tranquilizers, especially phenothiazines, may antagonize opiate agonist analgesia. /Opiate agonists/

Opiate agonists may potentiate the effects of tricyclic antidepressants and monoamine oxidase (MAO) inhibitors, including procarbazine hydrochloride; therefore, opiate agonists should be used with great caution and in reduced dosage when used in conjunction with such drugs. Virtually all the reported incidents of opiate agonist interaction with MAO inhibitors have occurred in patients receiving meperidine. ... If an opiate agonist is required in patients receiving MAO inhibitors, a sensitivity test should be performed with small increments of morphine administered over a period of several hours while the patient is kept under close medical observation. /Opiate agonists/

For more Interactions (Complete) data for HYDROMORPHONE (10 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 2200(SRC), determined from a structure estimation method(2), indicates that hydromorphone is expected to have slight mobility in soil(SRC). The estimated pKa of the tertiary amine in hydromorphone is 8.59(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as a cation and cations do not volatilize. Hydromorphone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.9X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2016).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 2200(SRC), determined from a structure estimation method(2), indicates that hydromorphone is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of the tertiary amine in hydromorphone of 8.59(3) indicates hydromorphone will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 5(SRC), from its log Kow of 0.11(5) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2016).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), hydromorphone, which has an estimated vapor pressure of 1.9X10-9 mm Hg at 25 °C(2), is expected to exist solely in the particulate phase. Particulate-phase hydromorphone may be removed from the air by wet or dry deposition(SRC). By analogy to morphine, which exhibits a UV maximum of 285 nm in acid and 298 nm in alkali(3), hydromorphone may be susceptible to direct photolysis by sunlight(SRC).

IDENTIFICATION AND USE: Hydromorphone forms as crystals from ethanol. Hydromorphone is analgesic drug and a Schedule II controlled substance. HUMAN EXPOSURE AND TOXICITY: Acute overdosage produces signs of opioid toxicity: circulatory and CNS depression, lethargy, coma, respiratory depression, and decreased GI motility with ileus. Apnea, hypotension, bradycardia, noncardiogenic pulmonary edema, seizures, dysrhythmias, and death may occur with severe poisoning. Pruritus may occur and persist during epidural hydromorphone infusion. Hydromorphone is metabolized by the liver to hydromorphone-3-glucuronide (H3G), a compound that can potentially cause neuroexcitatory phenomena with accumulation. Parenteral hydromorphone has few neuroexcitatory symptoms until H3G accumulates past a neurotoxic threshold, such as might occur with increasing dose or duration, which, when exceeded, causes neuroexcitatory symptoms to manifest. In a study of 33 deaths related to hydromorphone, fatalities due to hydromorphone occurred at 51 ng/mL and greater; however, tolerant users of this drug, as seen in the deaths attributed to natural causes, may achieve incidental concentrations that would otherwise be considered fatal. Dosage of hydromorphone hydrochloride should be reduced in patients with renal or hepatic impairment based on the degree of impairment. Hydromorphone hydrochloride extended-release tablets should not be administered to patients with any underlying condition that can result in narrowing of the GI tract. ANIMAL STUDIES: When administered intraperitoneally, hydromorphone caused a significant decrease in hepatic hepatocellular glutathione (GSH) concentrations in male mice. In mice after intrathecal (i.t.) administration hydromorphone produced both hypoglycemic and behavioral effects. Hydromorphone (0.1, 0.3, and 0.6 mg/kg) and an equivalent volume of saline (0.9% NaCl) solution (control treatment) were administered intramuscularly to kestrels in a masked randomized complete crossover study design. Hydromorphone at 0.6 mg/kg significantly increased the thermal foot withdrawal threshold, compared with the response after administration of saline solution, and hydromorphone at 0.1, 0.3, and 0.6 mg/kg significantly increased withdrawal responses compared with baseline values. Appreciable sedation was detected in 4 birds when administered 0.6 mg of hydromorphone/kg. Hydromorphone can be administered to dogs following orthopedic surgery without a clinically important risk of vomiting or regurgitation.

Hydromorphone is a fast-acting, potent opioid used for acute and chronic pain management. The drug can be substituted with other opioids and adheres to a distinct conversion scale. Hydromorphone is offered in various formulations, including injections, rectal suppositories, and oral forms, available in both immediate- and extended-release variants. Owing to the risk profile, the prescription and administration of the drug require meticulous attention, along with a comprehensive understanding of its potential adverse effects and interactions.

Hydromorphone is a narcotic analgesic; its principal therapeutic effect is relief of pain. Hydromorphone interacts predominantly with the opioid mu-receptors. These mu-binding sites are discretely distributed in the human brain, with high densities in the posterior amygdala, hypothalamus, thalamus, nucleus caudatus, putamen, and certain cortical areas. They are also found on the terminal axons of primary afferents within laminae I and II (substantia gelatinosa) of the spinal cord and in the spinal nucleus of the trigeminal nerve. In clinical settings, Hydromorphone exerts its principal pharmacological effect on the central nervous system and gastrointestinal tract. Hydromorphone also binds with kappa-receptors which are thought to mediate spinal analgesia, miosis and sedation.

Hydromorphone is a schedule II narcotic which can lead to physical dependence or addiction. High doses lead to respiratory depression, nausea, and vomiting. Overdoses lead to extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of hydromorphone can be estimated to be 2200(SRC). According to a classification scheme(2), this estimated Koc value suggests that hydromorphone is expected to have slight mobility in soil. The estimated pKa of the tertiary amine in hydromorphone is 8.59(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/HUMAN EXPOSURE STUDIES/ Pain is one the most common symptoms experienced by palliative care patients. The treatment of pain involves the use of strong opioids such as hydromorphone, morphine, methadone, fentanyl, oxycodone, oxymorphone, or levorphanol for moderate to severe pain. Hydromorphone is metabolized by the liver to hydromorphone-3-glucuronide (H3G), a compound that can potentially cause neuroexcitatory phenomena with accumulation. Pharmacokinetic studies have shown that H3G levels in patients with renal insufficiency are 4 times as high as those with normal renal function; however, reports have been conflicting as to whether or not it is safe to use hydromorphone in renal insufficiency. In this study we sought to determine the prevalence of neuroexcitation in patients with renal insufficiency who were given hydromorphone, as measured by the glomerular filtration rate (GFR), and to investigate factors associated with increased risk of neuroexcitation in this patient group. For the 12- month period from June 2007 through June 2008, charts of inpatient hospice patients that showed a glomerular filtration rate of <60 (mL/min/1.73 sq m) and hydromorphone administration for pain control via continuous infusion were reviewed for the occurrence of neuroexcitatory effects, including tremor, myoclonus, agitation, cognitive dysfunction, and seizures. Overall prevalence of neuroexcitatory effects were: tremor 11 (20%), myoclonus 11 (20%), agitation 26 (48%), and cognitive dysfunction 21 (39%). No seizures were observed. No neuroexcitatory effects were observed for the lowest quartile of dose or duration of hydromorphone. There was a strong and graded increase in neuroexcitatory effects with increasing quartile of dose or duration of hydromorphone for agitation (dose, p<0.0001; duration, p<0.0001) and cognitive dysfunction (dose, p<0.0002; duration, p<0.002). Consistent but weaker trends were observed for tremor and myoclonus. Parenteral hydromorphone has few neuroexcitatory symptoms until H3G accumulates past a neurotoxic threshold, such as might occur with increasing dose or duration, which, when exceeded, causes neuroexcitatory symptoms to manifest.

/HUMAN EXPOSURE STUDIES/ To investigate effects of extended-release (ER) hydromorphone dosing time (morning, QAM; evening, QPM) on sleep physiology in patients with chronic low back pain. Design: Randomized, double-blind, placebo-controlled, crossover trial. Setting: Clinical research site. Patients: Fifteen patients with moderate-to-severe chronic low back pain requiring long-term opioid analgesia. Following an open-label immediate-release (IR) hydromorphone titration phase, patients received once-daily ER hydromorphone QAM or QPM for at least 14 days and then crossed over to the alternate regimen. Overnight polysomnographic sleep studies were performed at baseline, following IR hydromorphone titration, and following each ER hydromorphone dosing period. The primary outcome measure was prevalence of nocturnal apnea-hypopnea index (AHI). Other evaluations included central apnea index and obstructive apnea index; Short-Form McGill Pain Questionnaire; a modified Medical Outcomes Study sleep scale, patient responses in a daily diary, and adverse event safety profiles. Mean AHI scores were lower following QAM rather than QPM dosing, but not significantly (12.9 vs. 17.1, P>0.05). Secondarily, QAM dosing resulted in numerically fewer apnea episodes and improvements in pulse oximetry measures; however, these differences were not significant (P>0.05). Sleep quality/quantity and pain measures were improved with opioid therapy overall, particularly QPM dosing, without significantly compromising safety. ER hydromorphone QAM dosing may be preferred if sleep-disordered breathing associated with ongoing opioid therapy is of concern; however, QPM dosing may be advantageous in terms of pain relief and quality/quantity of sleep. Further research is recommended to provide more definitive clinical guidance.

/SIGNS AND SYMPTOMS/ Tapentadol is a novel analgesic that activates mu-opioid receptors and blocks norepinephrine reuptake. There is very little information available regarding the non-analgesic pharmacodynamic effects of tapentadol. This outpatient study evaluated the physiological, subject-rated, and performance effects of therapeutic doses of tapentadol compared to two control drugs in humans. This double-blind, within-subject study examined the effects of oral placebo, tapentadol (25, 50, and 75 mg), tramadol (50, 100, and 150 mg), and hydromorphone (2, 4, and 6 mg). Nine occasional opioid users completed the study. Pharmacodynamic drug effects were measured before and for 6 hr after drug administration. All three doses of the tested drugs produced comparable, time-dependent decreases in pupil diameter, but the effects were generally not dose dependent. The high dose of tapentadol, as well as all three doses of tramadol and hydromorphone, increased positive subject-rated effects (e.g., "Good Effects" and "Like the Drug") as a function of time. Only tramadol increased negative subject-rated effects (e.g., "Bad Effects" and "Nauseous"); however, these were of low magnitude. The highest tested dose of tapentadol produced a profile of positive effects comparable to that of hydromorphone, whereas tramadol produced positive and negative subject-rated effects. The mixed findings for tramadol are consistent with previous findings indicating that it has a distinct profile of effects relative to prototypic opioids. Future research should examine the effects of higher tapentadol doses, as well as the factors contributing to the different subject-rated profile of effects observed for tramadol relative to tapentadol and hydromorphone.

/SIGNS AND SYMPTOMS/ Acute overdosage produced signs of opioid toxicity: circulatory and CNS depression, lethargy, coma, respiratory depression, and decreased GI motility with ileus. Miosis is a variable finding, depending on the particular opioid; coingestants; and secondary effects, such as hypoxia. Apnea, hypotension, bradycardia, noncardiogenic pulmonary edema, seizures, dysrhythmias, and death may occur with severe poisoning.

For more Human Toxicity Excerpts (Complete) data for HYDROMORPHONE (18 total), please visit the HSDB record page.

Schedule II 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. Substances, vegetable origin or chemical synthesis. Unless specifically excepted or unless listed in another schedule, any of the following substances whether produced directly or indirectly by extraction from substances of vegetable origin, or independently by means of chemical synthesis, or by a combination of extraction and chemical synthesis: (1) Opium and opiate, and any salt, compound, derivative, or preparation of opium or opiate excluding apomorphine, thebaine-derived butorphanol, dextrorphan, nalbuphine, nalmefene, naloxegol, naloxone, and naltrexone, and their respective salts, but including the following. Hydromorphone (DEA Code Number: 9150) is included on this list.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl Hydromorphone hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Hydromorphone hydrochloride/

N02AA03

N - Nervous system

QN - Nervous system

In clinical trials, hydromorphone has been shown to be suitable for pain relief in patients that do not tolerate the side effects of [morphine] or that suffer from renal failure or asthma. It has been shown to be 5-7 times more potent than morphine with a shorter duration of analgesia. Some of the observed effects of the consumption of hydromorphone for acute pain are complete and longlasting pain relief when compared to other pain relief agents such as [meperidine], [morphine], [diamorphine], [bupivacaine], [indomethacin], and [fentanyl]. On the same trials, hydromorphone was shown to produce respiratory depression, lower cognitive function, miosis, mydriasis, constipation, hypotension, and vertigo but to present a reduced incidence of pruritus (which indicates a lower release of histamine) and nausea. The respiratory depression is known to be caused by the effect on the brain stem respiratory centers as well as to a reduction in the responsiveness of this brain stems to increase carbon dioxide tension.

Hydromorphone is an opioid agonist that can bind to different types of opioid receptors. Its analgesic effect is suggested to be related to the effect on the mu-opioid receptors. It has been reported to also have a minor affinity for the delta and kappa receptor. On the other hand, it is known to act at the level of the medulla which allows it to depress the respiratory drive and suppress cough. The onset of action of the immediate release form of hydromorphone is achieved in 15-20 minutes and having a lasting effect for 3-4 hours while the extended-release form onset of action is of 6 hours lasting for about 13 hours.

/Accumulation of the active morphine-3-glucuronide (M3G) and hydromorphone-3-glucuronide (H3G) metabolites is one proposed mechanism for the development of neuroexcitatory effects including allodynia and opioid-induced hyperalgesia (OIH).

The half-life of hydromorphone immediate-release is of 2-3 hour while the extended release can range from 8-15 hours.

The parent drug has a half-life of elimination of 2.5 hours.

The terminal elimination half-life of hydromorphone after IV administration is about 2.3 hours. /Hydromorphone hydrochloride/

/In beagle dogs/, the serum half-life after SC hydromorphone at 0.1 mg kg(-1) and 0.5 mg kg(-1) was 0.66 hours and 1.11 hours, respectively. Hydromorphone has a short half-life, suggesting that frequent dosing intervals are needed. Based on pharmacokinetic parameters calculated in this study, 0.1 mg kg(-1) IV or SC q 2 hours or a constant rate infusion of hydromorphone at 0.03 mg kg(-1) hour(-1) are suggested for future studies to assess the analgesic effect of hydromorphone.

The purpose of this study was to determine the pharmacokinetics of hydrocodone and its active metabolite hydromorphone in six healthy Greyhound dogs. Hydrocodone bitartrate was administered at a targeted dose of 0.5 mg/kg PO. ... The mean hydromorphone CMAX was 5.2 ng/mL at 1.37 hr with a terminal half-life of 3.07 hr. ...

For more Biological Half-Life (Complete) data for HYDROMORPHONE (6 total), please visit the HSDB record page.

The metabolism of hydromorphone is mainly hepatic and it is represented by the generation of hydromorphone-3-glucuronide through glucuronidation reactions. This primary metabolic pathway is done by the activity of the UDP-glucuronosyltransferase-2B7. The first-pass hepatic metabolism is so large that it represents 62% of the initial administered dose. On the other hand, hydromorphone is also characterized by the presence of minor metabolic pathways such as the CYP3A4- and CYP2C9-driven generation of norhydromorphone.

Metabolism is primarily via the liver, with metabolites and unchanged drug excreted in the urine.

Hydromorphone is metabolized primarily in the liver where it undergoes conjugation with glucuronic acid and is excreted principally in the urine as the glucuronide conjugate. /Hydromorphone hydrochloride/

Pain is one the most common symptoms experienced by palliative care patients. The treatment of pain involves the use of strong opioids such as hydromorphone, morphine, methadone, fentanyl, oxycodone, oxymorphone, or levorphanol for moderate to severe pain. Hydromorphone is metabolized by the liver to hydromorphone-3-glucuronide (H3G), a compound that can potentially cause neuroexcitatory phenomena with accumulation. Pharmacokinetic studies have shown that H3G levels in patients with renal insufficiency are 4 times as high as those with normal renal function; however, reports have been conflicting as to whether or not it is safe to use hydromorphone in renal insufficiency.

Morphine is one of several opioids used to treat chronic pain. Because of its high abuse potential, urine drug tests can confirm "consistency with prescribed medications." Hydromorphone is a recently described minor metabolite of morphine, but few data exist on the characteristics of this metabolic pathway or the relationship of morphine and hydromorphone between and within subjects. Part I of this retrospective study shows that formation of hydromorphone from morphine is concentration-dependent and possibly saturated at high concentrations of morphine. In addition, the percentage of ultra-rapid metabolizers and poor metabolizers can be determined using the lower asymptote of a sigmoidal mathematical fit and are estimated to be 0.63 and 4.0%, respectively. Expected limits of morphine and hydromorphone (as a result of morphine metabolism) concentrations in the urine were established. Part II of this study used the metabolic ratio (hydromorphone-morphine) to determine the inter-patient and intra-patient variability in morphine metabolism to hydromorphone. Metabolic ratio values varied over a large range; 25-fold and 7-fold, respectively. The expected limits established in this study can assist in assessing the cause for possible variances in metabolism, such as drug interactions. The wide variability between and within subjects may explain unpredictable, adverse effects.

For more Metabolism/Metabolites (Complete) data for HYDROMORPHONE (8 total), please visit the HSDB record page.

Q812464R06

HYDROMORPHONE

Mechanisms of Action [MoA] - Full Opioid Agonists

Established Pharmacologic Class [EPC] - Opioid Agonist

Hydromorphone is an Opioid Agonist. The mechanism of action of hydromorphone is as a Full Opioid Agonist.

Compounds with activity like OPIATE ALKALOIDS, acting at OPIOID RECEPTORS. Properties include induction of ANALGESIA or NARCOSIS.

Agents that induce NARCOSIS. Narcotics include agents that cause somnolence or induced sleep (STUPOR); natural or synthetic derivatives of OPIUM or MORPHINE or any substance that has such effects. They are potent inducers of ANALGESIA and OPIOID-RELATED DISORDERS.

The immediate release version of hydromorphone reaches its peak concentration after 30-60 minutes while the extended-release version reaches the peak concentration after 9 hours. When administered orally, hydromorphone is absorbed mainly in the upper small intestine with a bioavailability of 60% due to intensive first-pass metabolism. In the controlled-release version of hydromorphone, the absorption follows a biphasic pharmacokinetic profile. However, even though there are clear distinctions in the absorption pathway of hydromorphone, the AUC of both versions is reported to be of 34 ng.h/ml which indicates an equivalence. The parenteral administration of hydromorphone, which is the most common pathway, presents an almost immediate absorption as observed by the presence of peak plasma concentration almost immediately. This peak plasma concentration declines rapidly due to fast redistribution into liver, spleen, kidney and skeletal muscle. In the parenteral route, the pharmacokinetic profile is log-linear and dose-dependent and to present a higher bioavailability of 78%. Other administration routes such as rectal, nasal, intraspinal and transdermal present lower bioavailability and changes in their pharmacokinetic profile.

The main elimination route of hydromorphone is through the urine in the form of the main metabolite hydromorphone-3-glucuronide. The elimination of the parent compound represents 7% of the urine elimination and 1% of the fecal elimination.

The volume of distribution of hydromorphone is reported to be of 4 L/kg.

The mean plasma clearance of hydromorphone is reported to be of 105.7 ml/min. The systemic clearance is reported to be of 1.96 L/min.

Hydromorphone hydrochloride is rapidly but incompletely absorbed from the gastrointestinal tract after oral doses; peak plasma concentrations occur within 0.5 to 1 hour. Oral bioavailability is about 50% as it undergoes extensive first-pass metabolism. Hydromorphone is about 8 to 19% bound to plasma proteins. A plasma elimination half-life of about 2.5 hours has been reported after oral or intravenous doses. Hydromorphone appears to be widely distributed in the tissues; it crosses the placenta and is distributed into breast milk. It is extensively metabolized by glucuronidation in the liver and excreted in the urine mainly as conjugated hydromorphone, dihydroisomorphine, and dihydromorphine. /Hydromorphone hydrochloride/

Hydromorphone hydrochloride is well absorbed following oral, rectal, or parenteral administration. Hydromorphone has a more rapid onset and may have a shorter duration of action than does morphine. The onset of action of hydromorphone with conventional (immediate-release) preparations is usually 15-30 minutes and analgesia is maintained for 4-5 hours, depending on the route of administration. /Hydromorphone hydrochloride/

Analgesics, Opioid; Narcotics

Hydromorphone (DEA Code Number: 9150) is a Schedule II controlled substance.

Schedule II Controlled Substance: (A) The drug or other substance has a high potential for abuse; (B) The drug or other substance has a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions; and (C) Abuse of the drug or other substances may lead to severe psychological or physical dependence.

Analgesic drug

MEDICATION

Use (kg; approx.) in Germany (2009): >250

4,5alpha:4',5'alpha-diepoxy-3,3'-dihydroxy-17,17'-dimethyl-2,2'-bimorphinanyl-6,6'-dione (pseudohydromorphone); 4,5alpha-epoxy-3-hydroxy-17-methylmorphinan-6-one 17-oxide (hydromorphone N-oxide); morphine; 4,5alpha-epoxy-17-methylmorphinan-3,6alpha-diol (dihydromorphine)

Hydromorphone can be prepared by catalytic rearrangement of morphine or by oxidation of the aliphatic hydroxyl group of dihydromorphine.

Morphine is hydrogenated over a palladium catalyst, and the resulting dihydromorphine is oxidized with benzophenone and potassium tert-butoxide. Alternative oxidants are cyclohexanone with aluminum tri(tert-butoxide) or aluminum triphenoxide.

Preparation from morphine: German patent 365683; German patent 623821 (1922, 1936 both to Knoll); by oxidation of dihydromorphine.

Hydromorphone is commercially available as the hydrochloride salt. /Hydromorphone hydrochloride/

Dilaudid, Jurnista; Opidol; Palladon; Palladone; Sophidone. /Hydromorphone hydrochloride/

Laudicon /Hydromorphone hydrochloride/

Common street names: D, Dillies, Dust, Footballs, Juice, and Smack.