||This article needs additional citations for verification. (November 2012)|
|Systematic (IUPAC) name|
|Legal status||Controlled (S8) (AU) Class A—Non-Clinical use—and Schedule II—Clinical use (UK),
DEA Schedule II (USA)
|Routes||oral, intramuscular, intravenous, subcutaneous, intranasal, rectal, sublingual, transmucosal, buccal, transdermal (experimental)|
|Bioavailability||Oral: 30–35%, Intranasal: 52–58%|
|Formula||C17H19NO3 - HCL|
|Solubility in water||HCl: 333 mg/mL (20 °C)|
| (what is this?)
Hydromorphone, a more common synonym for dihydromorphinone, commonly a hydrochloride (brand names Palladone, Dilaudid, and numerous others) is a very potent centrally acting analgesic drug of the opioid class. It is a derivative of morphine, to be specific, a hydrogenated ketone thereof, and it can be said that hydromorphone is to morphine as hydrocodone is to codeine and, therefore, a semi-synthetic drug. It is, in medical terms, an opioid analgesic and, in legal terms, a narcotic. Hydromorphone is commonly used in the hospital setting, mostly intravenously (IV) because its bioavailability orally, rectally, and intranasally is very low. Sublingual administration is usually superior to swallowing for bioavailabilty and effects.
Hydromorphone is much more soluble in water than morphine and therefore hydromorphone solutions can be produced to deliver the drug in a smaller volume of water.
Very small quantities of hydromorphone are detected in assays of opium on rare occasions; it appears to be produced by the plant under circumstances and by processes which are not understood at this time and may include the action of bacteria. A similar process and/or other metabolic processes in the plant may very well be responsible for the very low quantities of hydrocodone also found on rare occasions in opium and alkaloid mixtures derived therefrom; dihydrocodeine, oxymorphol, oxycodone, oxymorphone, metopon and possibly other derivatives of morphine and/or hydromorphone also are found in trace amounts in opium.
Hydromorphone was first synthesized and researched[by whom?] in Germany in 1924; Knoll introduced it to the mass market in 1926 under the brand name Dilaudid, indicating its derivation and degree of similarity to morphine (by way of laudanum)—compare Dicodid (hydrocodone), Dihydrin (dihydrocodeine) and Dinarkon (oxycodone). The brand name Dilaudid is more widely known than generic term hydromorphone, and because of this, Dilaudid is often used—generically to mean any form of hydromorphone.
Hydromorphone is used to relieve moderate to severe pain and severe, painful dry coughing. Hydromorphone is becoming more popular in the treatment of chronic pain in many countries, including the United States. Hydromorphone displays superior solubility and speed of onset, a less troublesome side effect profile, and lower dependence liability as compared to morphine and diamorphine. It is thought to be 6–8 times stronger than morphine, but with a lower risk of dependency. Hydromorphone is therefore preferred over morphine in many areas ranging from the ongoing treatment of chronic pain syndromes, the emergency department to the operating suite. It is a common alternative for those tending to have hallucinations from fentanyl administered through dermal patches and other dosage forms.
Hydromorphone, a semi-synthetic μ-opioid agonist, is a hydrogenated ketone of morphine and shares the pharmacologic properties typical of opioid analgesics. Hydromorphone and related opioids produce their major effects on the central nervous system and gastrointestinal tract. These include analgesia, drowsiness, mental clouding, changes in mood, euphoria or dysphoria, respiratory depression, cough suppression, decreased gastrointestinal motility, nausea, vomiting, increased cerebrospinal fluid pressure, increased biliary pressure, pinpoint constriction of the pupils, increased parasympathetic activity and transient hyperglycemia.
The chemical modification of the morphine molecule to produce hydromorphone results in a drug with higher lipid solubility and ability to cross the blood–brain barrier and, therefore, more rapid and complete central nervous system penetration. The results shows hydromorphone to be somewhat faster-acting and about eight to ten times more potent than morphine and about three to five times more potent than heroin on a per milligram basis. The effective morphine to hydromorphone conversion ratio can vary from patient to patient by a significant amount with relative levels of some liver enzymes being the main cause; the normal human range appears to be of 8:1. It is not uncommon, for example, for the 2-mg tablet to have an effect similar to that of 30 mg of morphine sulfate or a similar morphine preparation.
Patients with kidney problems must exercise caution when dosing hydromorphone. In those with renal impairment, the half-life of hydromorphone can increase to as much as 40 hours. This could cause an excess buildup of the drug in the body, and result in fatality. The typical half-life of intravenous hydromorphone is 2.3 hours. Peak plasma levels usually occur between 30 and 60 minutes after oral dosing.
Hydromorphone is extensively metabolized via glucuronidation in the liver, with greater than 95% of the dose metabolized to Hydromorphone-3-glucuronide along with minor amounts of 6-hydroxy reduction metabolites.
CNS depressants, such as other opioids, anesthetics, sedatives, hypnotics, barbiturates, phenothiazines, chloral hydrate, dimenhydrinate and glutethimide may enhance the depressant effects of hydromorphone. MAO inhibitors (including procarbazine), first-generation antihistamines (brompheniramine, promethazine, diphenhydramine, chlorpheniramine), beta-blockers, and alcohol may also enhance the depressant effect of hydromorphone. When combined therapy is contemplated, the dose of one or both agents should be reduced.
Side effects 
Adverse effects of hydromorphone are similar to those of other potent opioid analgesics, such as morphine and heroin. The major hazards of hydromorphone include dose-related respiratory depression and sometimes circulatory depression. More common side effects include light-headedness, dizziness, sedation, itching, constipation, nausea, vomiting, and sweating. Massive overdoses are rarely observed in opioid-tolerant individuals, but, when they occur, they may lead to circulatory system collapse. A particular problem that may occur with hydromorphone is accidental administration in place of morphine due to a mix-up between the similar names, either at the time the prescription is written or when the drug is dispensed. This has led to several deaths and calls for hydromorphone to be distributed in distinctly different packaging from morphine to avoid confusion. The effects of overdose can be exaggerated by dose dumping if the medication is taken with alcohol or benzodiazepines.
Recreational use 
|This section does not cite any references or sources. (November 2012)|
Like other opiates, hydromorphone can be used recreationally. Mostly this can be mediated by its strong affinity to the μ-opioid receptor, inducing euphoria, sedation, and other prototypical morphinian effects . These effects it make it susceptible to abuse, but people with legitimate pain often are able to use it safely. However users of the drug likely develop a physical dependence on the drug from extended use, but that is to be expected when treating chronic pain and does not in itself signify addiction. In abusers, a strong psychological dependence, thus creating an addiction with repeated use. While physical dependence causes withdrawal, psychological dependence can create strong compulsions to use the drug which can last for a long time, even after the physical dependence is broken. However, because hydromorphone is more expensive on the streets than heroin is, while having similar characteristics, its abuse rate is lower. Opiates like hydrocodone, oxycodone, and fentanyl are typically prescribed more often than hydromorphone ,.
The short length of action of hydromorphone and other metabolic factors mean that the abstinence syndrome, or withdrawal, is brief but intense. A low dosing user of hydromorphone opting or otherwise forced to quit "cold turkey" can expect a withdrawal syndrome as intense as that of morphine but much more severe. It is compressed into a spike, peaking in 14 to 21 hours and resolving in 36 to 72 hours, provided the user is not taking other longer-acting opioids and has normal liver and kidney function. All of the effects of hydromorphone and its attendant withdrawal syndrome can be significantly lengthened by such factors. Possible but less common is the opposite: some patients require oral doses of hydromorphone as frequently as every 90 minutes, and the withdrawal syndrome can peak in as little as 9 hours. Users taking over 40 milligrams per day can experience painful withdrawal lasting up to two weeks with symptoms including constant shaking, cold sweats, diarrhea, vomiting, muscle pain, body cramps, and insomnia. Even after the withdrawal, long-term users of this drug can experience symptoms for months, even years after, however, those symptoms are usually psychological, including drug cravings, feelings of self-doubt, of "emptiness", moderate depression, mild anxiety, and sometimes slight insomnia, though these symptoms occurring after the initial withdrawal are usually much more prominent in users who use the drug (or other drugs) recreationally, likely because recreational users enjoy the effects that it has on their mood.
Hydromorphone is known in various countries around the world by the brand names Hydal, Dimorphone, Sophidone LP, Dilaudid, Hydrostat, Hydromorfan, Hydromorphan, Hymorphan, Laudicon, Opidol, Palladone, Hydromorph Contin and others. An extended-release version of hydromorphone called Palladone was available for a short time in the United States before being voluntarily withdrawn from the market after a July 2005 FDA advisory warned of a high overdose potential when taken with alcohol. As of March 2010, it is still available in the United Kingdom under the brand name Palladone SR, Nepal under the brand name Opidol, and in most other European countries.
Hydromorphone is most commonly detected via blood and urine testing. Hydromorphone is usually detectable via blood screen for up to 24 hours and via urine screen from 3 - 8 days. Urine screen depends on several factors such as age, frequency of use, weight and duration of use. Extremes: a 20 year old patient with a normal BMI, who is administered a small dosage <8 mg per day for <5 days) would screen positive for up to 3 day in 95% of clinical tests. Conversely, patients who are > 35 years of age and have been administered a heavy doseage (>16 mg per day) with an overweight to obese BMI tend to test positive up to 7-8 days in 85% of clinical cases.
Available forms 
- Tablets: 1 mg, 2 mg, 3 mg, 4 mg, 8 mg
- Capsules (Palladone): 1.3 mg, 2.6 mg
- Modified-Release capsules (Palladone SR): 2 mg, 4 mg, 8 mg, 16 mg, 24 mg, 30 mg, 32 mg, 52 mg
- Extended-Release (24hr) tablets (Jurnista): 4 mg, 8 mg, 16 mg, 32 mg, 64 mg
- Extended-Release Exalgo tablets—8 mg: Red Round, biconvex, printed with “EXH 8, 12 mg: Dark yellow Round, biconvex, printed with “EXH 12, 16 mg: Yellow Round, biconvex, printed with “EXH 16 white round exh 32mg
- Controlled-Release capsules (Hydromorph Contin): 3 mg, 6 mg, 9 mg, 12 mg, 18 mg, 24 mg, 30 mg
- Suppository: 3 mg, 5 mg
- Powder for injection: 250 mg (hydromorphone HCl)
- Oral liquid (HCl): 1 mg/mL (480 mL)
- Cough Syrup: 1 mg/mL and 1 mg/5 ml
- Injection (HCl): 1 mg/mL (1 mL), 2 mg/mL (1 mL, 20 mL), 4 mg/mL (1 mL),
- Dilaudid-HP: 10 mg/mL (1 mL, 5mL, 50mL)
Another option for prolonged administration is an implantable pump loaded with 90 days' worth of hydromorphone; the device consists of two small titanium tubes arranged into a piston with a semi-permeable membrane on one end which operates the pump by means of osmotic pressure, as the device is placed in areas under the skin which have a salinity gradient. Like morphine—which also has an identical molecular weight, hydromorphone can be dissolved in DMSO and applied externally to allow the body to pull the solution into the bloodstream. Hydromorphone can also be made into an emulsion for IM or SC injection which can continue to release the drug into the system in sufficient quantities to maintain therapeutic concentrations for up to a week.
Legal status 
In the United States, the main drug control agency, the Drug Enforcement Administration, reports an increase in annual aggregate production quotas of hydromorphone from 766 kilograms in 1998 to 3,300 kilograms in 2006, and an increase in prescriptions in this time of 289%, from about 470,000 to 1,830,000.
Like all opioids used for analgesia, hydromorphone is potentially habit-forming and is listed in Schedule II of the United States' Controlled Substances Act of 1970 as well as in similar levels under the drugs laws of practically all other countries and is listed in the Single Convention On Narcotic Drugs.
In the United States, the state of Ohio has approved the use of an intramuscular injection of hydromorphone and midazolam as a backup means of carrying out executions when a suitable vein cannot be found for intravenous injection.
Hydromorphone is made from morphine either by direct re-arrangement (made by reflux heating of alcoholic or acidic aqueous solution of morphine in the presence of platinum or palladium catalyst) or reduction to dihydromorphine (usually via catalytic hydrogenation), followed by oxidation with benzophenone in presence of potassium tert butoxide or aluminium tert butoxide (Oppenauer oxidation). The 6 ketone group can be replaced with a methylene group via the Wittig reaction to produce 6-Methylenedihydrodesoxymorphine, which is 80× stronger than morphine.
Changing morphine into hydromorphone increases its activity and, therefore, makes hydromorphone about eight times stronger than morphine on a weight basis, all other things being equal. Changed also is lipid solubility, contributing to hydromorphone's having a more rapid onset of action and alterations to the overall absorption, distribution, metabolism, and elimination profile as well as the side effect profile (in general, less nausea and itching) versus that of morphine. The semi-synthetic opiates, of which hydromorphone and its codeine analogue hydrocodone are among the best-known and oldest, include a huge number of drugs of varying strengths and with differences among themselves both subtle and stark, allowing for many different options for treatment.
Endogenous production 
Hydromorphone is made from morphine via catalytic hydrogenation and is also produced in trace amounts by human and other mammalian metabolism of morphine and occasionally appears in assays of opium latex in very small quantities, apparently forming in the plant in an unknown percentage of cases under poorly understood conditions.
Some bacteria have been shown to be able to turn morphine into closely related drugs including hydromorphone and dihydromorphine among others. The bacterium Pseudomonas putida serotype M10 produces a naturally occurring NADH-dependent morphinone reductase that can work on unsaturated 7,8 bonds, with result that, when these bacteria are living in an aqueous solution containing morphine, significant amounts of hydromorphone form, as it is an intermediary metabolite in this process; the same goes for codeine being turned into hydrocodone.
The process gave rise to various concentrations of hydromorphone, dihydromorphine, hydromorphinol, and oxymorphone during the experiments. Three paths were found: from morphine to hydromorphone with dihydromorphine as the penultimate step, from morphine to hydromorphone with morphinone as the penultimate step, and from morphine to hydromorphinol to hydromorphone.
See also 
- 6-MDDM—substitution derivative of hydromorphone's 6-ketone for 6-methylene that is extremely potent and of high efficacy
- Acetylmorphone—an acetyl ester of hydromorphone
- Chronic pain
- Dose dumping
- Hydrocodone—a hepatic prodrug of hydromorphone
- Oxymorphol—a metabolite of oxymorphone and an intermediate in the creation of hydromorphone
- Patient-controlled analgesia
- Recreational drug use
- Coda BA, Rudy AC, Archer SM, Wermeling DP (July 2003). "Pharmacokinetics and bioavailability of single-dose intranasal hydromorphone hydrochloride in healthy volunteers". Anesth. Analg. 97 (1): 117–23, table of contents. doi:10.1213/01.ANE.0000066311.40978.4F. PMID 12818953.
- Vallner JJ, Stewart JT, Kotzan JA, Kirsten EB, Honigberg IL (April 1981). "Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to human subjects". J Clin Pharmacol 21 (4): 152–6. PMID 6165742.
- Felden, L.; C. Walter; S. Harder; R.-D. Treede; H. Kayser; D. Drover; G. Geisslinger; J. Lötsch (22). "Comparative Clinical Effects of Hydromorphone and Morphine". British Journal of Anaesthesia 107 (3): 319–328. doi:10.1093/bja/aer232. PMID 21841049. Retrieved 10 March 2012.
- That's Poppycock - Hydromorphone
- Dilaudid Clinical Pharmacology
- Hydromorphone CLINICAL PHARMACOLOGY - Metabolism
- Hydromorphone Monograph (Side Effects & Drug Interactions)
- Cohen MR (June 1992). "Doctor was thinking of the wrong drug". Nursing 22 (6): 25. PMID 1377371.
- Tuohy N, Paparella S (December 2005). "Look-alike and sound-alike drugs: errors just waiting to happen". J Emerg Nurs 31 (6): 569–71. doi:10.1016/j.jen.2005.07.012. PMID 16308048.
- Palladone Pain Drug Pulled Off the Market.
- Ohio Prisons Director Announces Changes to Ohio’s Execution Process
- PHA 4220 - Neurology Pharmacotherapeutics[dead link]
- Long MT, Hailes AM, Kirby GW, Bruce NC (October 1995). "Transformations of morphine alkaloids by Pseudomonas putida M10". Appl. Environ. Microbiol. 61 (10): 3645–9. PMC 167664. PMID 7487001.
- Hydromorphone Consumer Drug Information Drugs.com.
- Exalgo: full prescribing information
- Article Discussing Withdrawal of Extended-Release Hyrdromorphone from the U.S. Market
- painCare.ca and Patient Information about Opioid Analgesics
- Dihydromorphinones From Morphine & Analogues
- United States DEA's perspective, including statistics on manufacture and prescription levels from 1998 to 2006[dead link]
- "When Is a Pain Doctor a Drug Pusher?", The New York Times, 6-17-2007