Hydromorphone

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Hydromorphone
Systematic (IUPAC) name
4,5-α-epoxy-3-hydroxy-17-methyl morphinan-6-one
Identifiers
CAS number	466-99-9
ATC code	N02AA03
PubChem	5284570
DrugBank	APRD01021
ChemSpider	4447624
Chemical data
Formula	C17H19NO3
Mol. mass	285.338 g/mol
Synonyms	dihydromorphinone
Pharmacokinetic data
Bioavailability	Oral: 30–35%, Intranasal: 52–58%[1]
Protein binding	20%
Metabolism	Hepatic
Half life	2–3 hours[2]
Excretion	Renal
Therapeutic considerations
Pregnancy cat.	C
Legal status	Class A (UK), DEA Schedule II (USA)
Dependence Liability	High
Routes	oral, intramuscular, intravenous, subcutaneous, intranasal, rectal, sublingual, transmucosal, buccal, transcutaneous (experimental)

Hydromorphone, a more common synonym for dihydromorphinone and dimorphone, commonly a hydrochloride (trade names Palladone, Palladone SR, Dilaudid and numerous others) is a potent centrally-acting analgesic drug of the opioid class; it is a derivative of morphine, specifically a hydrogenated ketone thereof—therefore a semi-synthetic drug and is both medically an opiate analgesic and legally a narcotic. It should not be confused with hydromorphinol, also known as 14-hydroxydihydromorphine and RAM-320 nor dihydromorphine (Paramorfan). While all of these are strong opioids, they are indeed different drugs. Additional confusion here comes from the fact that in a handful of countries hydromorphinol is distributed under the trade name Numorphan, which is the trade name for oxymorphone in the rest of the world according to the current version of The A-Z Encyclopaedia of Alcohol & Drug Abuse and other references.

As explored below, 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.

Hydromorphone is used in medicine as an alternative to morphine and diacetylmorphine for analgesia and as a second- or third-line narcotic antitussive (cough suppressant) for cases of dry, painful, paroxysmal coughing resulting from continuing bronchial irritation after influenza and other ailments, inhalation of fungus and other causes, and is generally regarded to be the strongest of the latter class of drugs, and was developed shortly after another powerful antitussive, heroin, was removed from clinical use for this purpose in most of the world and in many countries banned outright. Part of the effectiveness of hydrocodone for this purpose may be due to part of the dose being converted to hydromorphone in the liver.

This modification of the morphine molecule 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, with the result that hydromorphone is somewhat faster-acting and about eight to ten times stronger than morphine and about three to five times stronger than heroin on a 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 from 8:1 to a little under 4:1. It is not uncommon, for example, for the 8-mg tablet to have an effect similar to 30 mg of morphine sulphate or a similar morphine preparation.

In many countries of the world, hydromorphone has become more commonly used, particularly since the well-documented gradual change in attitudes in some places about proper protocols for dealing with chronic pain of non-malignant aetiologies. In the United States, the main drugs-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.

Hydromorphone was first synthesized and researched in Germany, in 1924, and introduced to the mass market by Knoll under the brand name Dilaudid in 1926. Some authorities and publications use this name as a genericised brand name (e.g. like Kleenex, Xerox &c.) for hydromorphone and the name indicates its derivation and degree of similarity to morphine (by way of laudanum)—Cf. Dicodid (hydrocodone), Dihydrin (dihydrocodeine) and Dinarkon (oxycodone). Hydromorphone may also be known by the brand name Morphodid.

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.

Contents 1 Uses 2 Brand names and dosage forms 3 Available forms 4 Details 5 Pharmacokinetics 6 Side effects 7 Illicit Use 8 Withdrawal 9 Chemistry 10 See also 11 References 12 Notes 13 External links

[edit] Uses

Hydromorphone is used to relieve moderate to severe pain and severe, painful dry coughing. As explored in detail below, hydromorphone is becoming more popular in the treatment of chronic pain in many countries, and it is used as a substitute for heroin and morphine where one or both of these drugs are not marketed. Hydromorphone is preferred even over morphine in many cases ranging from the emergency department to the operating suite to ongoing treatment of chronic pain syndromes on account of hydromorphone's superior solubility and speed of onset and less troublesome side effect profile and lower dependence liability as compared to morphine and heroin. Hydromorphone is thought to be 8-10 times stronger than morphine, but with a lower dependence liability. However other studies have suggested hydromorphone is less than twice as potent as hydrocodone or oxycodone and therefore just over twice as strong as morphine via oral administration.^[3]

Hydromorphone's side effect profile is closer to that of dihydromorphine than to that of morphine or heroin and importantly produces less nausea and vomiting and fewer histamine-related side effects (itching, redness of skin, &c.) than morphine as a result. In cases where significant doses are anticipated, hydromorphone may be easier to titrate to the needed dose for this and other related reasons. Like all other opioid analgesics, tolerance develops with repeated administration and there is no true maximum dose, although requirements for pain relief can often remain more or less constant for extended periods after initial titration and tolerance does indeed commonly follow a course of plateaus of this type interspersed with comparatively infrequent escalations of varying intensity and in some cases the opportunity to titrate downwards as well.

The above-mentioned properties account for hydromorphone being a useful agent for chronic pain. Many chronic pain patients find that hydromorphone has a spectrum of actions which suit them just as well as morphine, and better than synthetics like methadone, piritramide, fentanyl, or levorphanol in alleviating suffering, as contrasted with simple pain of equal objective intensity. Hydromorphone is a common alternative for those who tend to have hallucinations from fentanyl in the form of skin plasters and other dosage forms. Hydromorphone also lacks the toxic metabolites of many opioids related to pethidine and some of the methadone class. Hydromorphone also tends to cause less nausea than morphine.

In the United States and some other countries, hydromorphone has long been only available as instant release oral formulations (viz. Hydal, Sophidone, Dilaudid and numerous generic hydromorphone formulations) for breakthrough pain or taken continuously by the clock every 1½ to 4 hours during the day; this is unlike morphine, oxycodone, and oxymorphone, which have both extended and immediate release oral versions. But since the release of Palladone SR, Hydal Retard, Morphodid, HydromorphContin, and the like, hydromorphone can also be used more effectively for chronic pain. HydromorphContin is the Canadian version, whilst Palladone SR is available in other countries and Hydal Retard is the continental European version and the oldest of the three.

Jurnista, the first 24-hour extended-release preparation of hydromorphone, uses the OROS Push-Pull system to deliver a consistent level of the opioid over a 24-hour period. Developed by ALZA Corporation, Jurnista is used in Europe and elsewhere to treat chronic pain and sometimes as a substitute for methadone in opioid substitution maintenance treatment programs when a person suffers serious side effects from the substitute opioid he/she is receiving, or when treatment with methadone or other opioids has failed. There is increasingly widespread usage of hydromorphone as a substitute for illegal opioids in maintenance treatment programs around the world, mostly because it offers a better quality of life to addicts, and lacks some of methadone's more troublesome side effects. Currently, Jurnista is not approved in the USA.

Another recent development, a hydromorphone polymer implant, which is designed to be implanted subcutaneously, could offer an alternative to methadone maintenance treatment, as well as pain management for both cancer patients and chronic pain sufferers. The device, after being implanted in a patient, releases a near constant dosage of hydromorphone for an extended period of time -- at least one month. For those involved in methadone maintenance treatment, the hydromorphone polymer implant could offer several advantages to both patients and program managers: 1) daily clinic visits are unnecessary; 2) treatment costs and time are both reduced; 3) risk of the illegal diversion of a controlled substance is greatly reduced, if not eliminated; 4) convenience could increase patient compliance; and 5) the cost, time, and convenience advantages could lead to increased treatment capacity and success. One further advantage, for anyone with a hydromorphone polymer implant would be greater freedom to travel, especially internationally, without the need to consider local laws and restrictions on hydromorphone and other opioids.

United States manufacturers are currently producing more hydromorphone than in the recent past and many now make 8-mg tablets as the drug has become more popular for chronic pain, reducing or eliminating the inventory problems that would have plagued pharmacies in the past such as a long-term chronic pain patient on Dilaudid as the sole or central agent. This scenario, uncommon but indeed observed in the past, could happen where such patients could require monthly prescription fill quantities in the low quadruple figures over a prolonged period during which the dose is likely to escalate or at least remain constant, depleting supplies at the regional warehouse or distributor level after a few months after the beginning of the year because of the Schedule II annual production quotas and restrictions on movement of inventory imposed by the state and federal governments.

Since, as noted above, there is not currently a hydromorphone analogue of MS-Contin or OxyContin on the market in the United States, the similarity in effects of hydromorphone and oxymorphone (which does come in an extended-release form, Opana) is particularly important to note at this time since high-dose maintenance regimens of hydromorphone for chronic pain can present the aforementioned logistical problems for pharmacists and patients. Clinical experience with oxymorphone for chronic pain generally shows it to be very similar to hydromorphone in its effects for most patients, with nausea and itching being even less common than with hydromorphone by a small percentage as shown in the clinical trials for the Opana series.

Furthermore, many authorities believe that the cross-tolerance between morphine and hydromorphone is incomplete, making alternating morphine and hydromorphone or adding the two drugs to a rotation of three or more agents a strategy worthy of consideration in a case of chronic pain or other afflictions requiring use of centrally-acting analgesics for an extended period. In addition, hydromorphone is similar to other opioids and semi-synthetics in particular as having its effectiveness possibly impacted by levels of liver enzymes, kidney issues, and other drugs being taken. This is especially the case when the drug is being given by mouth and careful titration which has control of pain as its objective is particularly important and it is quite possible that the amount of hydromorphone taken per 24 hours and single-dose quantities could vary significantly—in either direction—from the averages predicted by equianalgesic dose tables from one patient to the next.

Hydromorphone is also an important agent for use against moderate chronic pain, sub-chronic pain from severe injury, and acute pain requiring rapidly escalating doses of narcotic analgesics in countries where the majority or all of mid-level narcotic analgesics are mixed with paracetamol, aspirin, ibuprofen, naproxen, diclofenac and the like. The effects on the liver of paracetamol are particularly dangerous in such situations, and since hydrocodone and dihydrocodeine are not available for compounding prescriptions in the United States, for example, the choices left for these cases are oxycodone in pure form, morphine, levorphanol, possibly methadone, and hydromorphone. Of the above, the agents which cause intolerable side effects in the lowest percentage of users are levorphanol and hydromorphone. In such near borderline cases, the difficulty and/or time frame of titrating the available forms of fentanyl and mitigating side effects may make that agent a less than perfect choice as well.

In addition to the above, hydromorphone usually proves to be the first alternative of choice to morphine and fentanyl in severe chronic pain situations because the other commonly available agent in the United States, Canada, and various other countries is oxycodone, which a large percentage of chronic pain specialists do not rank high on the list of analgesics for maintenance treatment of most chronic pain syndromes (although a subgroup of patients do in fact respond particularly well to it, making its continued availability for this purpose very important nonetheless) for reasons ranging from stigma to regulatory and legal barriers limiting availability and/or willingness of physicians and pharmacists to deal with it, to the fact that many patients do have a very different reaction to oxycodone including a higher dependence and abuse liability than hydromorphone or most other opioids, a liability that some experts rate as uniquely combining the codeine, morphine, and cocaine types.^{[citation needed]}

[edit] Brand names and dosage forms

Hydromorphone is known in various countries around the world by the trade names Hydal, Sophidone, Hydrostat, Hydromorfan, Hydromorphan, Laudicon, Hymorphan, Opidol, Palladone and others (Warning: The brand names are inconsistent from country to country.). 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 an FDA advisory released in July 2005 warned of a high overdose potential when taken with alcohol; it is still available in the United Kingdom under the brand name Palladone SR as of March 2007, and in most other European countries. Another extended-release version called Hydromorph Contin, manufactured as controlled release capsules, continues to be produced and distributed in Canada by Purdue Pharma Inc. in Pickering, Ontario. In addition to Purdue-Frederick, other manufacturers of hydromorphone products include Ethex, Knoll, Abbott, Endo, Mallinkroft, Merck, Mundipharma, and Lannacher amongst others.

Hydromorphone hydrochloride (anhydrous) is the salt used in virtually all hydromorphone products and in prescription compounding at this time. The free base conversion ratio of this salt is 0.887. Other salts which are used rarely are the sulphate (conversion factor 0.853) and the terephtalate (conversion factor 0.638), with the bitartrate, tartrate, and hydroiodide having been in some use prior to 1955.

Combination products are uncommon but do exist, such as Dilaudid-Atropin, which contains atropine and in the past a hydromorphone combination for the induction of Twilight Sleep was available, i.e. hydromorphone and scopolamine. The reasons for adding atropine to hydromorphone tablets or other formulations are twofold: one, the fact that anticholinergics help opioids combat neuropathic pain, and two, to discourage deliberate overdose. For the latter reason atropine is added to diphenoxylate for anti-diarrhoeal products like Lomotil and tablets of morphine, tilidine and methadone for pain.

Some brands of hydromorphone tablets contain small amounts of sulphites. Hydromorphone's oral to intravenous effectiveness ratio is 5:1 and equinalgesia conversion ratio (hydromorphone HCl to anhydrous morphine sulfate, IV, SC, or IM) is 8:1 and is about 4:1 orally. This means that 30 mg of immediate-release morphine by mouth is similar in analgesic effect to 7.5 mg of hydromorphone by mouth, 10 mg of morphine by injection, and 1.5 mg of hydromorphone by injection. These doses also correspond to about 30 mg of hydrocodone, 24 mg of oxycodone, 200 mg of codeine, 135 mg of dihydrocodeine, 20 mg of dihydromorphine, 15 mg of nicomorphine, 12 mg of heroin, 34 mg of piritramide, circa or about 18 mg of ketobemidone, and 8 mg of dextromoramide by the default routes of administration and 60 mg of extended-release morphine via the oral route. These figures can vary from person to person, especially with oral administration, on account of such things as relative and absolute levels of some liver enzymes, system pH, and others. This is especially the case with methadone, levomethadone and phenadoxone, which require extra steps in the conversion and titration process.

At this point in time, the tablets and capsules with the highest immediate-release dose of hydromorphone are 8-mg tablets; however, 16-mg (quarter-grain), 32-mg (half-grain) and 64-mg (one grain) tablets were available at least through the late 1950s in some countries, and 24-, 36-, and 48-mg tablets less commonly. As was the case with many other medications, including most of the centrally-acting analgesics, hypodermic tablets for preparing injections were made in the past, as well, and the tablets for oral administration were in fact low- or zero-residue multi-purpose tablets which could replace the "Solvets", as the hypodermic tablets were called, in times of emergency. In western countries, inexpensive ampoules of sterile solution for injection have largely replaced the hypodermic tablets that were so common in past decades.

True to its indication of complete interchangeability with morphine, hydromorphone is often used with other drugs such as scopolamine and other anticholinergics for neuropathic pain, with the admixed, simultaneous, or near-simultaneous administration of hydromorphone, orphenadrine and an NSAID being a common protocol for severe musculo-skeletal conditions.

The 32-mg extended-release Palladone SR capsule, 500-mg (10 mg/ml * 50 ml) vial of Dilaudid HP injection, and 5-mg suppositories are the units with the largest doses in their respective categories at this time. The hydromorphone analogue of Roxanol (liquid for oral, sublingual, or buccal administration via a calibrated dropper—not to be confused with Dilaudid Cough Syrup, which is more dilute and contains a number of other ingredients including peach flavouring) of 1 mg per ml is available in 480 ml bottles, and the 250-mg phial of lipophilised powder for preparing injections with 1000-mg and 1/8-oz. phials available in the past.

Oral formulations of hydromorphone can also be administered under the tongue and between the lower jaw and cheek; these routes increase the effectiveness of the tablets by putting hydromorphone into the bloodstream prior to passing through the liver. A liquid formulation is commonly available and recommended specifically for these routes, and uncoated low-residue oral formulations are available in some countries to take advantage of this fact. However, all tablets potentially can be used in this fashion although they dissolve more slowly than purpose-made sublingual, buccal, and orally disintegrating tablets of other drugs like nitroglycerine, morphine, fentanyl, ondansetron, and others. Some tablets work better in this fashion if the coating on the tablet is first removed by sucking on it for a short time.

As with many other drugs, oral and soluble forms of hydromorphone such as the oral liquid, cough syrup, soluble tablets, &c., can be mixed with water or fruit juice if so desired; carbonated beverages and effervescent medications like Alka-Seltzer have the added advantage of driving the medication through the stomach wall more rapidly. Hydromorphone has a characteristic taste which is somewhat bitter but with a slight sweet component characteristic of ketones in general; it is not as bitter as morphine.

Hydromorphone is generally believed to be the second most common agent, after morphine, used in patient-controlled analgesia (PCA) units worldwide. The injectable forms of hydromorphone are suitable for outpatient use in a fashion similar to insulin once the patient and/or caretakers have been instructed on injection technique and such related matters as aspirating before IM or SC injection to make certain that the dose is not going to be accidentally injected directly into a vein or artery. Dilution of the injection fluid with saline or distilled water is common is such cases and especially when the drug is administered intravenously. Pre-loaded syringes are available in some countries or can of course be prepared by a doctor, nurse, or compounding pharmacy.

Because of its potency in very small quantities, the significance of the advantage of avoiding or reducing first-pass hepatic metabolism, rapid action and short metabolic and elimination half-life and other chemical characteristics including high lipid solubility and relatively moderate to low molecular weight (identical to morphine) - hydromorphone, along with its even stronger relative oxymorphone, is amongst drugs mentioned as the possible analgesic agents in new formulations and methods of delivery. Some of the products said to be in development or under discussion in the pharmaceutical industries of Europe, the United States, Canada, China, and/or various Pacific Rim contries as of February 2008 are:

1. Nasal sprays and drops (the former is the most commonly-used version of butorphanol in many places in the world. A related method, that of nebulising the drug for inhalation, is often used for morphine to get near-instantaneous pain relief in some pain disorders and painful lung problems (phials and cartridges for respective nebulisers are currently available, with the rule of thumb being that 2 mg of nebulised morphine is equal to 10 mg injected by the subcutaneous, intramuscular, and intravenous route and 1 mg via the various intraspinal routes) and since hydromorphone has an identical molecular weight, higher milligram potency, and superior lipid solubility, this method works well and is possible to implement with equipment and drug formulations currently on the market.
2. An injectable formulation which contains the drug in liposomes in an appropriate vehicle which can continue to release the active agent in sufficient quantities to maintain therapeutic concentrations in the system for up to a week following a deep intramuscular depot injection (recently introduced for morphine; has been in use for a while with other drugs for unrelated conditions, e.g. Depo-Provera)
3. New variations on the oral, sublingual, buccal and/or rectal routes of administration.
4. A transdermal/transcutaneous delivery system somewhat similar to extant transdermal drug delivery systems for fentanyl, sufentanil, lidocaine, clonidine, scopolamine, nicotine
5. An electrophoretic transdermal delivery system—a variant of the fentanyl patch which contains electrical components to aid delivery of the drug. There is some question as to whether electrophoresis is a sine qua non for a transdermal system based on opioids outside the fentanyl family. Hydromorphone and chemically-related drugs with similar molecular weight and lipid solubiilty can theoretically be delivered transdermally to an extent which is superior to morphine but most likely less than that of most of the fentanyls. Other possible candidates for this route of delivery would seem to include oxymorphone, dihydroetorphine, metopon, desomorphine, acetylmorphone, diamorphine, diacetyldihydromorphine, dihydromorphine, and some other semi-synthetics.
6. A conventional skin plaster (using ingredients in the carrier liquid/gel to change local skin characteristics to improve absorption) which delivers both a narcotic analgesic and local anaesthetic such as lidocaine, mepivacaine, bupivicaine, ropivacaine &c. (most likely from a separate reservoir and skin-contact areas within the patch rather than mixing the local anaesthetic with the narcotic) for use against low back pain from sciatica, shingles, radiculopathy, other primary neuropathic pain conditions and chronic severe pain secondary to lumbago and other degenerative connective-tissue diseases of the spinal column. Many transdermal drug delivery systems use ethanol as the main solvent since it also promotes skin permeability for drug transfer with minimal skin irritation. and yes
7. An implantable osmotic pump similar to that being developed by a consortium including Durect, ALZA, and others—a pump based on a piston powered by osmotic pressure which pumps drug/s into the body over an extended period. The unit is implanted under the skin and has no external or protruding parts. This pump was specifically developed as a hydromorphone delivery system and it is unclear whether is would be suitable or superior for drugs which are effective in much smaller quantities such as the fentanyls or Bentley Compounds like dihydroetorphine.

[edit] Available forms

• Tablets - 0.5 mg, 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
• Controlled Release capsules (Hydromorph Contin) - 3 mg, 6 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/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)

[edit] Details

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.

Several different parameters explored in detail below can impact hydromorphone's Absorption, Distribution, Metabolism & Elimination profile, with the result that the normal range of the morphine:hydromorphone potency ratio can be from half to double that published via the oral route and a bit less parenterally.

CNS depressants, such as other opioids, anesthetics, sedatives, hypnotics, barbiturates, phenothiazines, chloral hydrate 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.

[edit] Pharmacokinetics

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.^[4] Peak plasma levels usually occur between 30 and 60 minutes after oral dosing.^[5]

[edit] Side effects

Adverse effects of hydromorphone are similar to those of other opioid analgesics, such as morphine. The major hazards of hydromorphone include dose-related respiratory depression and sometimes circulatory depression.^[6] More common side effects include light-headedness, dizziness, sedation, constipation, nausea, vomiting, and sweating.^[6] 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 instead 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 to morphine to avoid confusion.^[7][8] The effects of overdose can be exaggerated by dose dumping if the medication is taken with alcohol or benzodiazepines.^[9]

A possible and likely side effect associated with hydromorphone is euphoria, achieved dually through a perceived effect from the transition of a state of pain to a state of pain-relief induced through opioids, or through direct stimulation of the μ opioid receptor (μ₁ and μ₂) [of which hydromorphone, related to the morphine molecule, is a primary μ agonist]. Although this can lead to addiction and reward-seeking behavior, it has been demonstrated that when opioids are taken for pain relief, patients are very unlikely to misuse the drug (see Opioids). Nevertheless, there is a certain risk of abuse and dependence among patients prescribed any opioid, including hydromorphone.^[10] A question long debated in medicine has been whether or not addiction potential and analgesia are separable; the existence of drugs such as cyclazocine and other benzomorphans may point to the con side of the debate yet it is easy to understand why a drug which acts against all components of pain in the way that opioids would generate a seek orientation, morbid or not, in any organism under consideration, from fish to frogs to rats to monkeys to people.

[edit] Illicit Use

Hydromorphone appears on the street to an extent, with more than 99% sourced from patients selling prescriptions, armed robbery, and burglary of pharmacies. Slang terms for it include D, dilly, dillies, dill, k4, k1, k2, k3, k8, M8, Big D, Super 8, Hydro, M-80s, white triangle, moose, hospital heroin, drugstore heroin, shake & bake, peaches, and others. The equipotency of price to dosage ranks hydromorphone among the highest priced of all opioids for sale on the street. Both licit and illicit users as well as older pharmacists and doctors refer to hydromorphone tablets by their hydromorphone content in fractions of a grain (e.g. a "sixteenth" is a 4 mg tablet, an "eighth" is 8 mg, a "thirty-second" is 2 mg, 1 mg tablets are "sixty-fourths", the 3 mg tablet is a "three sixty-fourth" and long term Dilaudid users both licit and illicit as well as pharmacists may remember quarter-grain (16 mg) tablets back in the day.

Capsules of up to 36 mg hydromorphone are also available on the street. Despite this large dose, they are not highly sought after when there is a choice between them and the traditional 2, 4, and 8 milligram tablets. The capsules are large and brightly colored (yellow for 18 mg, red for 30 mg), and within they contain tiny beads which are maddeningly hard, which no amount of cooking will break apart. The only way to break them to a powder is by brute force, with a heavy mortar, stories are heard of coffee grinders. The beads are not like those found in many pharmaceuticals which melt or break apart easily, but are closer to those found in Kadian brand 100 mg morphine capsules. Although this prevents easy injection, it seems likely that the true intent of the manufacturer was to ensure the slow dissolution of a large dose of narcotics in the patients stomach.

The clandestine production of hydromorphone is an only moderately difficult proposition which calls for equipment and other tools readily available (although expensive in the case of Column VII catalysts like Platina Black or collodial platinum) and it is possible via catalytic hydrogenation of morphine or demethylation of hydrocodone. One sticking point: purified hydrocodone or starting quantities on the order of 3 grammes or more of morphine are required. The details for the former case are available in German patents from the middle 1930s op. cit. which show several methods of creating dihydromorphinone class semi-synthetics; some of the methods which do not require hydrogen gas have yields of upwards of 70 per cent.

The aforementioned increase in licit use has, with time, led to downward price pressure both from changes in the simple supply and demand equation that governs all commerce and the fact that the low bioavailability of hydromorphone as compared to oxycodone means that a given reseller's clientele will usually have a large contingent of non-needle-using customers who may have tried hydromorphone by mouth and been disappointed and who want oxycodone, hydrocodone, and to a lesser extent codeine and dihydrocodeine, therefore affecting the demand side of the equation as well.

[edit] Withdrawal

The short length of action of hydromorphone and other metabolic factors mean that the abstinence syndrome (withdrawal) is brief but intense; a heavy and/or long-term 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 in that it is compressed into a spike which will peak in 14 to 21 hours and resolve in 36 to 72 hours, provided they were not taking other longer-acting opioids, or have abnormalities in drug metabolism and/or liver or 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 would compress into an even more violent spike which can peak in as little as 9 hours.

[edit] Chemistry

Commercially, 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 80x stronger than morphine.^[11]

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 having a more rapid onset of action and alterations to the overall Absorption, Distribution, Metabolism & Elimination profile as well as the side effect profile (generally less nausea and itching) versus that of morphine. The semi-synthetic opiates, of which hydromorphone and its codeine analogue hydrocodone are amongst the best-known and oldest, include a huge number of drugs of varying strengths and with differences amongst themselves both subtle and stark, allowing for many different options for treatment.

The human liver produces hydromorphone when processing hydrocodone using the cytochrome p450 II-D-6 enzyme pathway (CYP2D6). This is the same route that is used to convert many different opiate prodrugs into the active form. The proportion of drug that is converted into the stronger form is around 10% on average although this varies markedly between individuals. Drugs that are bioactivated in this way include codeine into morphine, oxycodone to oxymorphone and dihydrocodeine to dihydromorphine.

Some bacteria have been shown to be able to turn morphine into closely related drugs including hydromorphone and dihydromorphine amongst others. As reported in the July 1993 issue of Applied Environmental Bacteriology (PDF available at http://aem.asm.org/cgi/reprint/61/10/3645.pdf), the bacterium Pseudomonas putida, serotype M10 produces a naturally occurring NADH-dependent morphinone reductase which can work on unsaturated 7,8 bonds—with result that when these bacteria are living in an aqueous solution containing morphine, significant amounts of hydromophone 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, 14β-hydroxymorphine, and 14β-hydroxymorphone during the experiments and there were two paths from morphine to hydromorphine, one having dihydromorphine as the penultimate step, and another in which it was morphinone. A third path was from morphine to 14β-hydroxymorphine to hydromorphone

The same method subtituting oxymorphone as the starting drug yields oxymorphol.

At this time no information has been published indicating whether or not this process can change dihydromorphine into metopon or acetylated morphine derivatives into the respective ketones of the acetylmorphone series.

Exposure to light will cause solutions of hydromorphone to darken to an amber colour—reportedly this does not affect the potency of the drug. Of course, any ampoules or phials containing sediment or cloudiness should be discarded.

[edit] See also

• Opioids
• Oxymorphone
• Hydrocodone
• Dihydromorphine
• Hydromorphinol
• Morphine
• Chronic pain
• Patient-controlled analgesia
• Recreational drug use

[edit] References

• Hydromorphone Consumer Drug Information Drugs.com.
• 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

[edit] Notes

1. ^ Coda BA, Rudy AC, Archer SM, Wermeling DP. "Pharmacokinetics and Bioavailability of Single-Dose Intranasal Hydromorphone Hydrochloride in Healthy Volunteers." Anesthesia Analgesia. 2003 Jul;97(1):117-23. PMID 12818953 Fulltext
2. ^ Vallner JJ, Stewart JT, Kotzan JA, Kirsten EB, Honigberg IL. "Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to human subjects." Journal of Clinical Pharmacology. 1981 Apr;21(4):152-6. PMID 6165742 Fulltext
3. ^ http://www.ncbi.nlm.nih.gov/pubmed/18606504 'The relative abuse liability of oral oxycodone, hydrocodone and hydromorphone assessed in prescription opioid abusers. shit'
4. ^ That's Poppycock - Hydromorphone
5. ^ Dilaudid Clinical Pharmacology
6. ^ ^{a b} http://www.rxlist.com/cgi/generic/hydromorphone_ad.htm Hydromorphone Monograph (Side Effects & Drug Interactions)
7. ^ Cohen MR. Doctor was thinking of the wrong drug. Nursing. 1992 Jun;22(6):25. PMID 1377371
8. ^ Tuohy N, Paparella S. Look-alike and sound-alike drugs: errors just waiting to happen. Journal of Emergency Nursing. 2005 Dec;31(6):569-71. PMID 16308048
9. ^ Palladone Pain Drug Pulled Off the Market.
10. ^ http://www.rxlist.com/cgi/generic/hydromorphone_ids.htm Hydromorphone Monograph (Drug Abuse and Dependence)
11. ^ PHA 4220 - Neurology Pharmacotherapeutics

[edit] External links

• "When Is a Pain Doctor a Drug Pusher?' New York Times 6-17-2007

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