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====Pump====
====Pump====
Intrathecal drug delivery systems are implanted for chronic pain when other options - such as surgery and traditional pharmacotherapy - are ruled out, and the patient in question is considered a suitable fit, in terms of any contraindications, both physiologically and psychologically.<ref>{{Cite journal|url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2080496/pdf/CroatMedJ_48_0022.pdf|title = Implantable Intrathecal Pumps for Chronic Pain: Highlights and Updates|last = Knight|first = Karen H.|date = Feb 2007|journal = Croatian Medical Journal|doi = |pmid = PMC2080496|access-date = 19/03/2015}}</ref> Intrathecal pumps are battery-operated
{{unreferenced section|date=January 2014}}

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 [[Dimethyl sulfoxide|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.
The three medications approved by the FDA for use with an intrathecal pump are [[Ziconotide]], [[Morphine]], and [[Baclofen]]. Hydromorphone is, however, often used as a second-line therapy, with a recommended starting dosage of 0.02-0.5mg/day.<ref>{{Cite journal|url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227625/pdf/jpr-7-615.pdf|title = Current Perspectives on Intrathecal Drug Delivery|last = Bottros|first = Michael M.|date = 6/11/2014|journal = Journal of Pain Research|doi = |pmid = PMC4227625|access-date = }}</ref>


== Legal status ==
== Legal status ==

Revision as of 16:51, 19 March 2015

[1]

Hydromorphone
Clinical data
Other namesdihydromorphinone
AHFS/Drugs.comMonograph
MedlinePlusa682013
Pregnancy
category
  • AU: C
Dependence
liability		High
Routes of
administration		oral, intramuscular, intravenous, subcutaneous, intranasal, rectal, sublingual, transmucosal, buccal, transdermal (experimental)
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityOral: 30–35%, Intranasal: 52–58%[2]
Protein binding20%
MetabolismHepatic
Elimination half-life2–3 hours[3]
ExcretionRenal
Identifiers
  • 4,5-α-epoxy-3-hydroxy-17-methyl morphinan-6-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.006.713 Edit this at Wikidata
Chemical and physical data
FormulaC17H19NO3
Molar mass285.3g/mol g·mol−1
3D model (JSmol)
Solubility in waterHCl: 333 mg/mL (20 °C)
  • O=C4[C@@H]5Oc1c2c(ccc1O)C[C@H]3N(CC[C@]25[C@H]3CC4)C
  • InChI=1S/C17H19NO3/c1-18-7-6-17-10-3-5-13(20)16(17)21-15-12(19)4-2-9(14(15)17)8-11(10)18/h2,4,10-11,16,19H,3,5-8H2,1H3/t10-,11+,16-,17-/m0/s1 checkY
  • Key:WVLOADHCBXTIJK-YNHQPCIGSA-N checkY
  (verify)

Hydromorphone, a more common synonym for dihydromorphinone (not to be confused with dihydromorphine, which is a different derivative of the morphine family), 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 comparatively, 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(under the tongue) is usually superior to swallowing for bioavailability and effects, however Hydromorphone, like most opiates, is bitter and hydrophilic, not lipophilic, so is absorbed poorly/slowly through mouth membranes.[4]

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. The hydrochloride salt is soluble in three parts of water whereas a gram of morphine hydrochloride dissolves in 16 ml of water; for all common purposes the pure powder for hospital use can be used to produce solutions of virtually arbitrary concentration. When the powder has appeared on the street, this very small volume of powder needed for a dose means that overdoses are likely for those who mistake it for heroin or other powdered narcotics, especially those that have been cut or 'stepped on' already.

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.

History

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,[5] 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 the generic term hydromorphone, and because of this, Dilaudid is often used generically to mean any form of hydromorphone.

Pharmacology

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.

Pharmacokinetics

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 show 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.[citation needed] 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 4-8:1. It is not uncommon, for example, for a 2-mg tablet to have an effect similar to that of 30 mg of morphine sulfate or a similar morphine preparation, whereas other patients may need 8 mg for a similar effect.

Patients with renal abnormalities 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 resulting in fatality. The typical half-life of intravenous hydromorphone is 2.3 hours.[6] Peak plasma levels usually occur between 30 and 60 minutes after oral dosing.[7]

Metabolism

Hydromorphone is metabolized to hydromorphone-3-glucoronide which has no analgesic effects. Like the morphine metabolite, morphine-3-glucoronide, if levels of hm-3-glucoronide build up in one's system, it can produce excitatory neurotoxic effects such as restlessness, myoclonus and hyperalgesia. Metabolite build up can occur in patients with compromised kidney function, or sometimes in older patients.[8]

Interactions

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.[9]

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.[10] More common side effects include light-headedness, dizziness, sedation, itching, constipation, nausea, vomiting, and sweating.[10] Patients should take care when taking benzodiazepines (such as diazepam) in conjunction with hydromorphone, as this may increase side effects such as dizziness and difficulty concentrating.[11]

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.[12][13]

Massive overdoses are rarely observed in opioid-tolerant individuals, but, when they occur, they may lead to circulatory system collapse. The effects of overdose can be exaggerated by dose dumping if the medication is taken with alcohol.[14]

Sugar cravings associated with hydromorphone use are the result of a glucose crash after transient hyperglycemia following injection or a less profound lowering of blood sugar over a period of hours, in common with morphine, heroin, codeine, and other opiates.

Hormone imbalance

Main article: Opioid § Hormone_imbalance

As with other opioids, hydromorphone (particularly during heavy chronic use) often causes temporary hypogonadism or hormone imbalance.[15]

Neurotoxicity

In the setting of prolonged use, high dosage, and/or kidney dysfunction, hydromorphone has been associated with neuroexcitatory symptoms such as tremor, myoclonus, agitation, and cognitive dysfunction.[9][16][17] This toxicity is less than that associated with other classes of opioids such as the pethidine class of synthetics in particular.

Recreational use

Like other opiates, hydromorphone can be used recreationally. Its reinforcing effects are mediated via its strong affinity for the μ-opioid receptor, inducing euphoria, sedation, reduced anxiety, respiratory depression, and other prototypical morphinian effects. Although such effects make it particularly susceptible to abuse, many patients using it for analgesia are able to use it for extended periods of time without developing drug-seeking behavior. In abusers, there can be 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 persist for days or weeks after the physical dependence is broken, and has been known to induce anxiety, insomnia, depression, and a range of other persistent mental illnesses. For this reason, psychotherapy is often included in detox programs, sometimes augmented with pharmacological therapies. Despite producing similar effects, hydromorphone is more expensive on the illicit market than heroin is,[citation needed] causing the abuse rates of hydromorphone to be lower than heroin and similar opiates in many areas. Even in the medical community, hydromorphone is quite scarce; opiates like hydrocodone, oxycodone, and fentanyl are typically prescribed more often, due in part to the fact that most doctors are more familiar with those medications and the side effects and interactions thereof.[citation needed]

Withdrawal

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 the withdrawal syndrome to be at least as intense as morphine if not 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", severe depression, extreme anxiety, and sometimes 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.

Opiate withdrawal is almost never life-threatening in and of itself although it can result in behaviors which make a sufferer a danger to themselves and others. For this reason, enduring withdrawal is safer when under the care of a qualified physician. Mild psychological issues can be treated with therapy, while more severe symptoms of psychological distress (incessant crying, suicidal/homicidal thoughts/actions, severe mood swings, etc.) may be treated with antidepressants and/or anxiolytics. If (and only if) a patient is experiencing intense physical withdrawal symptoms such as hyperalgesia, diarrhea, and photosensitivity, doctors may consider prescribing a long acting opiate substitute (such as methadone) and then slowly tapering down the dose (usually over a period of days or weeks) until the patient is on a low enough dose to discontinue the drug completely. Even after quitting the drug completely, most doctors will recommend that the patient continue to attend therapy and take all other prescribed medicines as instructed until the root cause of the patients drug abuse is identified and addressed, and the recovering addict has developed a healthy support network to prevent relapse.

Formulations

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.

There is currently a newer extended-release (once-daily) version of Hydromorphone available (in the United States), marketed under the brand name EXALGO. EXALGO was FDA-approved for marketing in March, 2010. EXALGO is available in 8, 12, 16 and 32 mg controlled-release tablets. According to the distributor,[18] Mallinckrodt Inc., EXALGO does not have the same issue with 'Dose Dumping' as did Palladone SR and "Consuming alcohol does not significantly alter the release of EXALGO into the bloodstream. However, patients should not consume alcohol while taking EXALGO due to CNS depressant effect."[19]
An identical once-daily formulation, under the trade name JURNISTA, has been launched in several countries by Janssen-Cilag. JURNISTA was first launched in Germany in August 2006.
EXALGO and JURNISTA both employ the OROS PUSH-PULL osmotic delivery system designed to release hydromorphone at a controlled rate over an extended period of time allowing for once-daily administration.[18]
Hydromorphone HCI Extended Release Tablets are now available in a generic formulation.[20]

Testing

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 to 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 days in 95% of clinical tests. Conversely, patients who are >35 years of age and have been administered a heavy dosage (>16 mg per day) with an overweight to obese BMI tend to test positive up to 7 to 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 (24 hr) 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 32 mg
  • 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, 2 mg), 4 mg/mL (1 mL),
  • Dilaudid-HP: 10 mg/mL (1 mL, 5mL, 50mL)

Pump

Intrathecal drug delivery systems are implanted for chronic pain when other options - such as surgery and traditional pharmacotherapy - are ruled out, and the patient in question is considered a suitable fit, in terms of any contraindications, both physiologically and psychologically.[21] Intrathecal pumps are battery-operated

The three medications approved by the FDA for use with an intrathecal pump are Ziconotide, Morphine, and Baclofen. Hydromorphone is, however, often used as a second-line therapy, with a recommended starting dosage of 0.02-0.5mg/day.[22]

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. The 2013 production quota was 5968.75 kilogrammes.[23]

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. The DEA ACSCN for hydromorphone is 9150.

Hydromorphone is listed under the German Betäubungsmittelgesetz as a Suchtgift in the most restricted schedule for medicinal drugs; it is similarly controlled in Austria under the SMG and the Swiss BetmG. The Misuse of Drugs Act 1971 (UK) and its French, Canadian, Australian, Italian, Czech, Croatian, Slovenian, Swedish, Polish, Spanish, Greek, Russian, and other laws similarly control it, as do virtually all other countries.

Use in executions

In 2009, Ohio approved the use of an intramuscular injection of 500 mg of hydromorphone and a supratherapeutic dose of midazolam as a backup means of carrying out executions when a suitable vein cannot be found for intravenous injection.[24]

Hydromorphone and midazolam was injected intravenously to execute double-murderer Joseph Wood in Arizona on July 24, 2014. Wood was heavily sedated (Stage 3 "Surgical anasthesia") within 4 minutes from start but took almost two hours to transition to stage 4 (cessation of respiration) and death.[25]

Chemistry

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.[26]

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.[citation needed] 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.

Bacteria

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.[27]

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

References

  1. ^ http://www.drugs.com/pro/hydromorphone.html
  2. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ 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. doi:10.1002/j.1552-4604.1981.tb05693.x. PMID 6165742.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ http://www.drugs.com/pro/hydromorphone.html
  5. ^ Felden, L; Walter first2=C; Harder, S; et al. (22 September 2011). "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. {{cite journal}}: Cite has empty unknown parameter: |1= (help); Missing pipe in: |last2= (help); Missing pipe in: |last4= (help)CS1 maint: numeric names: authors list (link)
  6. ^ "Hydromorphone". That's Poppycock!. 19 Feb 2009.
  7. ^ Dilaudid Clinical Pharmacology
  8. ^ http://www.painweek.org/../292-50.pdf
  9. ^ a b Thwaites, D; McCann, S; Broderick, P (Aug 2004). "Hydromorphone neuroexcitation". Journal of palliative medicine. 7 (4): 545–50. doi:10.1089/1096621041838362. PMID 15353098.
  10. ^ a b Hydromorphone Monograph (Side Effects & Drug Interactions)
  11. ^ "Drug interactions between Dilaudid and Valium". Retrieved 19 November 2014.
  12. ^ Cohen, MR (June 1992). "Doctor was thinking of the wrong drug". Nursing. 22 (6): 25. PMID 1377371.
  13. ^ 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.
  14. ^ Palladone Pain Drug Pulled Off the Market.
  15. ^ Brennan, MJ (2013). "The effect of opioid therapy on endocrine function". The American Journal of Medicine. 126 (3 Suppl 1): S12–8. doi:10.1016/j.amjmed.2012.12.001. PMID 23414717.
  16. ^ Gagnon, DJ; Jwo, K (2013). "Tremors and agitation following low-dose intravenous hydromorphone administration in a patient with kidney dysfunction". Annals of Pharmacotherapy. 47 (7–8): e34. doi:10.1345/aph.1R784. PMID 23715067.
  17. ^ Rapp, SE; Egan, KJ; Ross, BK; et al. (May 1996). "A multidimensional comparison of morphine and hydromorphone patient-controlled analgesia". Anesth Analg. 82 (5): 1043–8. PMID 8610865.
  18. ^ a b Exalgo | Zalicus
  19. ^ EXALGO safety profile
  20. ^ "Actavis Receives Final Approval for Generic Version of Exalgo®" (Press release). Actavis. 13 May 2014.
  21. ^ Knight, Karen H. (Feb 2007). "Implantable Intrathecal Pumps for Chronic Pain: Highlights and Updates" (PDF). Croatian Medical Journal. PMID PMC2080496. Retrieved 19/03/2015. {{cite journal}}: Check |pmid= value (help); Check date values in: |access-date= (help)
  22. ^ Bottros, Michael M. (6/11/2014). "Current Perspectives on Intrathecal Drug Delivery" (PDF). Journal of Pain Research. PMID PMC4227625. {{cite journal}}: Check |pmid= value (help); Check date values in: |date= (help)
  23. ^ "Proposed Adjustments to the Aggregate Production Quotas for Schedule I and II Controlled Substances and Assessment of Annual Needs for the List I Chemicals Ephedrine, Pseudoephedrine, and Phenylpropanolamine for 2013". Drug Enforcement Administration (DEA), Department of Justice. 20 June 2014. Retrieved 2014-07-26.
  24. ^ "Ohio Prisons Director Announces Changes to Ohio's Execution Process". Ohio Department of Rehabilitation and Correction. November 13, 2009. Retrieved 2014-01-17.
  25. ^ "Arizona execution takes two hours". BBC News. July 24, 2014. Retrieved 2014-07-24.
  26. ^ PHA 4220 - Neurology Pharmacotherapeutics[dead link]
  27. ^ 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.
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