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Pethidine's apparent ''[[in vitro]]'' efficacy as an "[[antispasmodic]]" is due to its local anesthetic effects. It does not have antispasmodic effects ''[[in vivo]]''.<ref>{{cite journal | last = Wagner | first = Larry E., II | coauthors = Michael Eaton, Salas S. Sabnis, Kevin J. Gingrich | title = Meperidine and Lidocaine Block of Recombinant Voltage-Dependent Na<sup>+</sup> Channels: Evidence that Meperidine is a Local Anesthetic | journal = Anesthesiology | volume = 91 | issue = 5 | pages = 1481–1490 | publisher = Lippincott Williams & Wilkins | month = November | year = 1999 | doi = 10.1097/00000542-199911000-00042 | pmid = 10551601}}</ref> Pethidine also has stimulant effects mediated by its inhibition of the [[dopamine]] [[Dopamine transporter|transporter (DAT)]] and [[norepinephrine]] [[Norepinephrine transporter|transporter (NAT)]]. Because of its DAT inhibitory action, pethidine will substitute for cocaine in animals trained to discriminate cocaine from saline.<ref name="izenwasser">{{cite journal | last = Izenwasser | first = Sari | coauthors = Amy Hauck Newman, Brian M. Cox, Jonathan L. Katz | title = The cocaine-like behavioral effects of meperidine are mediated by activity at the dopamine transporter | journal = European Journal of Pharmacology | volume = 297 | issue = 1–2 | pages = 9–17 | publisher = Elsevier | date = January/February 1996 | doi = 10.1016/0014-2999(95)00696-6 | pmid = 8851160}}</ref>
Pethidine's apparent ''[[in vitro]]'' efficacy as an "[[antispasmodic]]" is due to its local anesthetic effects. It does not have antispasmodic effects ''[[in vivo]]''.<ref>{{cite journal | last = Wagner | first = Larry E., II | coauthors = Michael Eaton, Salas S. Sabnis, Kevin J. Gingrich | title = Meperidine and Lidocaine Block of Recombinant Voltage-Dependent Na<sup>+</sup> Channels: Evidence that Meperidine is a Local Anesthetic | journal = Anesthesiology | volume = 91 | issue = 5 | pages = 1481–1490 | publisher = Lippincott Williams & Wilkins | month = November | year = 1999 | doi = 10.1097/00000542-199911000-00042 | pmid = 10551601}}</ref> Pethidine also has stimulant effects mediated by its inhibition of the [[dopamine]] [[Dopamine transporter|transporter (DAT)]] and [[norepinephrine]] [[Norepinephrine transporter|transporter (NAT)]]. Because of its DAT inhibitory action, pethidine will substitute for cocaine in animals trained to discriminate cocaine from saline.<ref name="izenwasser">{{cite journal | last = Izenwasser | first = Sari | coauthors = Amy Hauck Newman, Brian M. Cox, Jonathan L. Katz | title = The cocaine-like behavioral effects of meperidine are mediated by activity at the dopamine transporter | journal = European Journal of Pharmacology | volume = 297 | issue = 1–2 | pages = 9–17 | publisher = Elsevier | date = January/February 1996 | doi = 10.1016/0014-2999(95)00696-6 | pmid = 8851160}}</ref>


Several [[4-Fluoromeperidine|analogues of pethidine]] have been synthesized that are potent inhibitors of the reuptake of the [[monoamine neurotransmitter]]s dopamine and [[norepinephrine]] via DAT and NET.<ref>{{cite journal | last = Lomenzo | first = Stacey A. | coauthors = Jill B. Rhoden, Sari Izzenwasser, Dean Wade, Theresa Kopajtic, Jonathan L. Katz, Mark L. Trudell | title = Synthesis and Biological Evaluation of Meperdine Analogs at Monoamine Transporters | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 5 | pages = 1336–1343 | publisher = American Chemical Society | date = 2005-03-05 | doi = 10.1021/jm0401614 | pmid = 15743177}}</ref><ref name="psrs">{{cite journal | title = Demerol: Is It the Best Analgesic? | journal = Pennsylvania Patient Safety Reporting Service Patient Safety Advisory | volume = 3 | issue = 2 | publisher = Pennsylvania Patient Safety Authority | month = June | year = 2006 | url = http://www.psa.state.pa.us/psa/lib/psa/advisories/v3n2june2006/junevol_3_no_2_article_g_demerol.pdf | accessdate = 2007-01-16|format=PDF}}</ref> It has also been associated with cases of [[serotonin syndrome]], suggesting some interaction with [[Serotonin|serotonergic neurons]], but the relationship has not been definitively demonstrated.<ref name="nsw"/><ref name="izenwasser"/><ref name="psrs"/><ref name = "Latta">{{cite journal | last = Latta | first = Kenneth S. | coauthors = Brian Ginsberg, Robert L. Barkin | title = Meperidine: A Critical Review | journal = American Journal of Therapeutics | volume = 9 | issue = 1 | pages = 53–68 | publisher = Lippincott Williams & Wilkins | date = January/February 2002 | doi = 10.1097/00045391-200201000-00010 | pmid = 11782820}}</ref> It is more lipid-soluble than morphine, resulting in a faster onset of action. Its duration of clinical effect is 120–150 minutes although it is typically administered in 4-6 hour intervals. Pethidine has been shown to be less effective than [[morphine]], [[diamorphine]] or [[hydromorphone]] at easing severe pain, or pain associated with movement or coughing.<ref name="izenwasser"/><ref name="psrs"/><ref name="Latta"/> It is also used for the treatment of [[postanesthetic shivering]].
Several [[4-Fluoromeperidine|analogues of pethidine]] have been synthesized that are potent inhibitors of the reuptake of the [[monoamine neurotransmitter]]s dopamine and [[norepinephrine]] via DAT and NET.<ref>{{cite journal | last = Lomenzo | first = Stacey A. | coauthors = Jill B. Rhoden, Sari Izzenwasser, Dean Wade, Theresa Kopajtic, Jonathan L. Katz, Mark L. Trudell | title = Synthesis and Biological Evaluation of Meperdine Analogs at Monoamine Transporters | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 5 | pages = 1336–1343 | publisher = American Chemical Society | date = 2005-03-05 | doi = 10.1021/jm0401614 | pmid = 15743177}}</ref><ref name="psrs">{{cite journal | title = Demerol: Is It the Best Analgesic? | journal = Pennsylvania Patient Safety Reporting Service Patient Safety Advisory | volume = 3 | issue = 2 | publisher = Pennsylvania Patient Safety Authority | month = June | year = 2006 | url = http://www.psa.state.pa.us/psa/lib/psa/advisories/v3n2june2006/junevol_3_no_2_article_g_demerol.pdf | accessdate = 2007-01-16|format=PDF}}</ref> It has also been associated with cases of [[serotonin syndrome]], suggesting some interaction with [[Serotonin|serotonergic neurons]], but the relationship has not been definitively demonstrated.<ref name="nsw"/><ref name="izenwasser"/><ref name="psrs"/><ref name = "Latta">{{cite journal | last = Latta | first = Kenneth S. | coauthors = Brian Ginsberg, Robert L. Barkin | title = Meperidine: A Critical Review | journal = American Journal of Therapeutics | volume = 9 | issue = 1 | pages = 53–68 | publisher = Lippincott Williams & Wilkins | date = January/February 2002 | doi = 10.1097/00045391-200201000-00010 | pmid = 11782820}}</ref>
It is more lipid-soluble than morphine, resulting in a faster onset of action. Its duration of clinical effect is 120–150 minutes although it is typically administered in 4-6 hour intervals. Pethidine has been shown to be less effective than [[morphine]], [[diamorphine]] or [[hydromorphone]] at easing severe pain, or pain associated with movement or coughing.<ref name="izenwasser"/><ref name="psrs"/><ref name="Latta"/> It is also used for the treatment of [[postanesthetic shivering]].


Like other opioid drugs, pethidine has the potential to cause [[physical dependence]] or [[Substance dependence|addiction]]. Pethidine may be more likely to be abused than other prescription opioids, perhaps because of its rapid onset of action.<ref>{{cite web|url=http://www.nps.org.au/__data/assets/pdf_file/0020/17273/RADAR_Dec_05_To_print_complete.pdf |title=In Brief |accessdate=2009-12-22 |coauthors= |month=December | year=2005 |work=NPS Radar |publisher=National Prescribing Service }}</ref> When compared with [[oxycodone]], [[hydromorphone]], and [[placebo]], pethidine was consistently associated with more euphoria, difficulty concentrating, confusion, and impaired psychomotor and cognitive performance when administered to healthy volunteers.<ref>{{cite journal | last = Walker | first = Diana J. | coauthors = James P. Zacny | title = Subjective, Psychomotor, and Physiological Effects of Cumulative Doses of Opioid µ Agonists in Healthy Volunteers | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 289 | issue = 3 | pages = 1454–1464 | publisher = American Society for Pharmacology and Experimental Therapeutics | month = June | year = 1999 | pmid = 10336539}}</ref> The especially severe side effects unique to pethidine among opioids — serotonin syndrome, seizures, delirium, dysphoria, tremor — are primarily or entirely due to the action of its metabolite, [[norpethidine]].<ref name="Latta"/><ref name="psrs"/
Like other opioid drugs, pethidine has the potential to cause [[physical dependence]] or [[Substance dependence|addiction]]. Pethidine may be more likely to be abused than other prescription opioids, perhaps because of its rapid onset of action.<ref>{{cite web|url=http://www.nps.org.au/__data/assets/pdf_file/0020/17273/RADAR_Dec_05_To_print_complete.pdf |title=In Brief |accessdate=2009-12-22 |coauthors= |month=December | year=2005 |work=NPS Radar |publisher=National Prescribing Service }}</ref> When compared with [[oxycodone]], [[hydromorphone]], and [[placebo]], pethidine was consistently associated with more euphoria, difficulty concentrating, confusion, and impaired psychomotor and cognitive performance when administered to healthy volunteers.<ref>{{cite journal | last = Walker | first = Diana J. | coauthors = James P. Zacny | title = Subjective, Psychomotor, and Physiological Effects of Cumulative Doses of Opioid µ Agonists in Healthy Volunteers | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 289 | issue = 3 | pages = 1454–1464 | publisher = American Society for Pharmacology and Experimental Therapeutics | month = June | year = 1999 | pmid = 10336539}}</ref> The especially severe side effects unique to pethidine among opioids — serotonin syndrome, seizures, delirium, dysphoria, tremor — are primarily or entirely due to the action of its metabolite, [[norpethidine]].<ref name="Latta"/><ref name="psrs"/

Revision as of 04:07, 15 August 2012

Pethidine
Clinical data
Pregnancy
category
  • Category C (USA)
Dependence
liability		Moderate - High
Routes of
administration		oral, intranasal, rectal
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability50–60%
MetabolismLiver
Elimination half-life3–5 hours
ExcretionRenal
Identifiers
  • Ethyl 1-methyl-4-phenylpiperidine-4-carboxylate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.299 Edit this at Wikidata
Chemical and physical data
FormulaC15H21NO2
Molar mass247.33g/mol g·mol−1
3D model (JSmol)
  • O=C(OCC)C2(c1ccccc1)CCN(C)CC2
  • InChI=1S/C15H21NO2/c1-3-18-14(17)15(9-11-16(2)12-10-15)13-7-5-4-6-8-13/h4-8H,3,9-12H2,1-2H3 checkY=
  • Key:XADCESSVHJOZHK-UHFFFAOYSA-N checkY=
  (verify)

Pethidine (INN) or meperidine hydrochloride (USAN) (commonly referred to as Demerol[1] but also referred to as: isonipecaine; lidol; pethanol; piridosal; Algil; Alodan; Centralgin; Dispadol; Dolantin; Mialgin (in Indonesia); Petidin Dolargan (in Poland);[2] Dolestine; Dolosal; Dolsin; Mefedina) is a fast-acting opioid analgesic drug.

Pethidine was the first synthetic opioid synthesized in 1932 as a potential anti-spasmodic agent by the chemist Otto Eislib. Its analgesic properties were first recognized by Otto Schaumann working for IG Farben, Germany.[3]

Pethidine is indicated for the treatment of moderate to severe pain, and is delivered as a hydrochloride salt in tablets, as a syrup, or by intramuscular, subcutaneous or intravenous injection. For much of the 20th century, pethidine was the opioid of choice for many physicians; in 1975 60% of doctors prescribed it for acute pain and 22% for chronic severe pain.[4]

Compared to morphine, pethidine was supposed to be safer and carry less risk of addiction, and to be superior in treating the pain associated with biliary spasm or renal colic due to its putative antispasmodic effects. In fact, pethidine is no more effective than morphine at treating biliary or renal pain, and its low potency, short duration of action, and unique toxicity (i.e., seizures, delirium, other neuropsychological effects) relative to other available opioid analgesics have seen it fall out of favor in recent years for all but a very few, very specific indications.[5] Several countries, including Australia, have put strict limits on its use.[6] Nevertheless, some physicians continue to use it as a first line strong opioid.

Pharmacodynamics/mechanism of action

Main article: Opioid

Like morphine, pethidine exerts its analgesic effects by acting as an agonist at the mu opioid receptor.[7] It also has a kappa opioid receptor action, which is of unknown clinical significance. It has structural similarities to atropine and other tropane alkaloids and may have some of their effects and side effects.[1] In addition to these opioidergic and anticholinergic effects, it has local anesthetic activity related to its interactions with sodium ion channels.

Pethidine's apparent in vitro efficacy as an "antispasmodic" is due to its local anesthetic effects. It does not have antispasmodic effects in vivo.[8] Pethidine also has stimulant effects mediated by its inhibition of the dopamine transporter (DAT) and norepinephrine transporter (NAT). Because of its DAT inhibitory action, pethidine will substitute for cocaine in animals trained to discriminate cocaine from saline.[9]

Several analogues of pethidine have been synthesized that are potent inhibitors of the reuptake of the monoamine neurotransmitters dopamine and norepinephrine via DAT and NET.[10][11] It has also been associated with cases of serotonin syndrome, suggesting some interaction with serotonergic neurons, but the relationship has not been definitively demonstrated.[6][9][11][12]

It is more lipid-soluble than morphine, resulting in a faster onset of action. Its duration of clinical effect is 120–150 minutes although it is typically administered in 4-6 hour intervals. Pethidine has been shown to be less effective than morphine, diamorphine or hydromorphone at easing severe pain, or pain associated with movement or coughing.[9][11][12] It is also used for the treatment of postanesthetic shivering.

Like other opioid drugs, pethidine has the potential to cause physical dependence or addiction. Pethidine may be more likely to be abused than other prescription opioids, perhaps because of its rapid onset of action.[13] When compared with oxycodone, hydromorphone, and placebo, pethidine was consistently associated with more euphoria, difficulty concentrating, confusion, and impaired psychomotor and cognitive performance when administered to healthy volunteers.[14] The especially severe side effects unique to pethidine among opioids — serotonin syndrome, seizures, delirium, dysphoria, tremor — are primarily or entirely due to the action of its metabolite, norpethidine.[12]Cite error: The <ref> tag has too many names (see the help page).); accumulating with regular administration, or in renal failure. Norpethidine is toxic and has convulsant and hallucinogenic effects. The toxic effects mediated by the metabolites cannot be countered with opioid receptor antagonists such as naloxone or naltrexone and are probably primarily due to norpethidine's anticholinergic activity probably due to its structural similarity to atropine though its pharmacology has not been thoroughly explored. The neurotoxicity of pethidine's metabolites is a unique feature of pethidine compared to other opioids. Pethidine's metabolites are further conjugated with glucuronic acid and excreted into the urine.

Interactions

Pethidine has serious interactions that can be dangerous with MAOIs (e.g., furazolidone, isocarboxazid, moclobemide, phenelzine, procarbazine, selegiline, tranylcypromine). Such patients may suffer agitation, delirium, headache, convulsions, and/or hyperthermia. Fatal interactions have been reported including the death of Libby Zion.[15] It is thought to be caused by an increase in cerebral serotonin concentrations. It is possible that pethidine can also interact with a number of other medications, including muscle relaxants, some antidepressants, benzodiazepines, and alcohol.

Pethidine is also relatively contraindicated for use when a patient is suffering from liver, or kidney disease, has a history of seizures or epilepsy, has an enlarged prostate or urinary retention problems, or suffers from hypothyroidism, asthma, or Addison's disease.

Adverse effects

The adverse effects of pethidine administration are primarily those of the opioids as a class: nausea, vomiting, sedation, dizziness, diaphoresis, urinary retention and constipation. Unlike other opioids, it does not cause miosis. Overdosage can cause muscle flaccidity, respiratory depression, obtundedness, cold and clammy skin, hypotension and coma. A narcotic antagonist such as naloxone is indicated to reverse respiratory depression. Serotonin syndrome has occurred in patients receiving concurrent antidepressant therapy with selective serotonin reuptake inhibitors or monoamine oxidase inhibitors. Convulsive seizures sometimes observed in patients receiving parenteral pethidine on a chronic basis have been attributed to accumumulation in plasma of the metabolite norpethidine (normeperidine). Fatalities have occurred following either oral or intravenous pethidine overdosage.[16][17]

Hazardous use, harmful use, dependence, and diversion

In data from the U.S. Drug Abuse Warning Network, mentions of hazardous or harmful use of pethidine declined between 1997 and 2002, in contrast to increases for fentanyl, hydromorphone, morphine, and oxycodone.[18] The number of dosage units of pethidine that were reported lost or stolen in the U.S. increased 16.2% between 2000 and 2003, from 32,447 to 37,687.[19]

Notes

This article uses the terms "hazardous use", "harmful use", and "dependence" in accordance with Lexicon of alcohol and drug terms published by the World Health Organization (WHO) in 1994.[20] In WHO usage, the first two terms replace the term "abuse" and the third term replaces the term "addiction".[20]

http://pubs.acs.org/doi/suppl/10.1021/jm0401614/suppl_file/jm0401614_s.pdf

The first QSAR focused on exploring how changing the nature of the aromatic substituents alters monoamine reuptake inhibitor affinities.[21][22]

File:Meperidine.gif
Pethidine
Nitrile Precursors → Pethidine/Analogs Ki & IC50, μM
Ar [3H]Pax [3H]CFT [3H]Dop
Ph ? → 0.413 ? → 17.8 ? → 12.6
p-F 10.1 → 0.308 45% → 10.7 8% → 47%
p-Cl 5.11 → 0.277 22.0 → 4.10 36% → 26.9
p-I 0.430 → 0.0211 8.34 → 3.25 36.7 → 11.1
p-Me 13.7 → 1.61 41.8 → 12.4 22% → 76.2
m,p-Cl2 0.805 → 0.0187 2.67 → 0.125 11.1 → 1.40
β-Naph 0.125 → 0.0072 2.36 → 1.14 21.8 → 11.6
Mean ± SEM of 3 experiments in triplicate. % inhibition @ 100μM

Particular emphasis needs to be placed on the ↑ D/S of the p-iodo and β-Naph analogs.

  • p-I, D/S = 155
  • BN, D/S = 158

In behavioral activity studies, none of the compounds would substitute for cocaine in mice, and they were also inactive as LMA stimulants.

This is in direct contrast to the methylphenidate analogs which more convincingly displayed cocaine-like traits.

The aryl moiety can be modified depending on whether DAT affinity is actually desirable or SERT affinity is wanted.

(J. Rhoden et, al.)[23]

Meperidine was initially found to be selective for the SERT over the DAT.

All the further analogs in the second QSAR study are based around the m,p-Cl2 phenyl substitution pattern.

m,p-Cl2 Meperidine esters
R CFT nM Para nM Ratio
Et12518.76.7
Me38315.425
n-Pr44916.427
i-Pr27143.36.3
n-Bu86416.054
n-Pen28344.36.4

The N-demethyl metabolite of meperidine is toxic and accumulates upon repeat dosing.

Also, the ester in meperidine is readily hydrolyzed.

The above picture is of "UCB" a SRI/NK1 antagonist currently under development by Astra Zeneca.[24]

References

  1. ^ Demerol RxList. Retrieved 19 Jun. 2006.
  2. ^ "Lekopedia - Dolargan". jestemchory.pl. Retrieved 2006-08-01.
  3. ^ Michaelis, Martin; Schölkens, Bernward; Rudolphi, Karl (2007). "An anthology from Naunyn-Schmiedeberg's archives of pharmacology". Naunyn-Schmiedeberg's Archives of Pharmacology. 375 (2). Springer Berlin: 81–84. doi:10.1007/s00210-007-0136-z. PMID 17310263. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  4. ^ Kaiko, Robert F. (1983). "Central Nervous System Excitatory Effects of Meperidine in Cancer Patients". Annals of Neurology. 13 (2). Wiley Interscience: 180–185. doi:10.1002/ana.410130213. PMID 6187275. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  5. ^ Donna Wong (2002-03-15). "Notes on Meperidine". Wong on Web Papers. Elsevier. Retrieved 2007-04-13.
  6. ^ a b Davis, Sharon (2004). "Use of pethidine for pain management in the emergency department: a position statement of the NSW Therapeutic Advisory Group" (PDF). New South Wales Therapeutic Advisory Group. Retrieved 2007-01-17. {{cite web}}: Unknown parameter |month= ignored (help)
  7. ^ Bronwen Bryant and Kathleen Knights (2010). Pharmacology for Health Professionals, 3rd Edition. Chatswood: Mosby Australia. ISBN 978-0-7295-3929-6.
  8. ^ Wagner, Larry E., II (1999). "Meperidine and Lidocaine Block of Recombinant Voltage-Dependent Na+ Channels: Evidence that Meperidine is a Local Anesthetic". Anesthesiology. 91 (5). Lippincott Williams & Wilkins: 1481–1490. doi:10.1097/00000542-199911000-00042. PMID 10551601. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ a b c Izenwasser, Sari (January/February 1996). "The cocaine-like behavioral effects of meperidine are mediated by activity at the dopamine transporter". European Journal of Pharmacology. 297 (1–2). Elsevier: 9–17. doi:10.1016/0014-2999(95)00696-6. PMID 8851160. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  10. ^ Lomenzo, Stacey A. (2005-03-05). "Synthesis and Biological Evaluation of Meperdine Analogs at Monoamine Transporters". Journal of Medicinal Chemistry. 48 (5). American Chemical Society: 1336–1343. doi:10.1021/jm0401614. PMID 15743177. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  11. ^ a b c "Demerol: Is It the Best Analgesic?" (PDF). Pennsylvania Patient Safety Reporting Service Patient Safety Advisory. 3 (2). Pennsylvania Patient Safety Authority. 2006. Retrieved 2007-01-16. {{cite journal}}: Unknown parameter |month= ignored (help)
  12. ^ a b c Latta, Kenneth S. (January/February 2002). "Meperidine: A Critical Review". American Journal of Therapeutics. 9 (1). Lippincott Williams & Wilkins: 53–68. doi:10.1097/00045391-200201000-00010. PMID 11782820. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  13. ^ "In Brief" (PDF). NPS Radar. National Prescribing Service. 2005. Retrieved 2009-12-22. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help); Unknown parameter |month= ignored (help)
  14. ^ Walker, Diana J. (1999). "Subjective, Psychomotor, and Physiological Effects of Cumulative Doses of Opioid µ Agonists in Healthy Volunteers". The Journal of Pharmacology and Experimental Therapeutics. 289 (3). American Society for Pharmacology and Experimental Therapeutics: 1454–1464. PMID 10336539. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  15. ^ Brody, Jane (February 27, 2007). "A Mix of Medicines That Can Be Lethal". New York Times. Retrieved 2009-02-13. The death of Libby Zion, an 18-year-old college student, in a New York hospital on March 5, 1984, led to a highly publicized court battle and created a cause célèbre over the lack of supervision of inexperienced and overworked young doctors. But only much later did experts zero in on the preventable disorder that apparently led to Ms. Zion's death: a form of drug poisoning called serotonin syndrome. {{cite news}}: Cite has empty unknown parameter: |coauthors= (help)
  16. ^ Baselt, R. (2008). Disposition of Toxic Drugs and Chemicals in Man (8 ed.). Foster City, CA: Biomedical Publications. pp. 911-914.
  17. ^ Package insert for meperidine hydrochloride, Boehringer Ingelheim, Ridgefield, CT, 2005.
  18. ^ Gilson AM, Ryan KM, Joranson DE, Dahl JL (2004). "A reassessment of trends in the medical use and abuse of opioid analgesics and implications for diversion control: 1997-2002" (PDF). J Pain Symptom Manage. 28 (2): 176–188. doi:10.1016/j.jpainsymman.2004.01.003. PMID 15276196.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ^ Joranson DE, Gilson AM (2005). "Drug crime is a source of abused pain medications in the United States" (PDF). J Pain Symptom Manage. 30 (4): 299–301. doi:10.1016/j.jpainsymman.2005.09.001. PMID 16256890.
  20. ^ a b Babor T, et al., compilers (1994). Lexicon of alcohol and drug terms (PDF). Geneva: World Health Organization. ISBN 92-4-154468-6.{{cite book}}: CS1 maint: multiple names: authors list (link)
  21. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1021/jm0401614, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1021/jm0401614 instead.
  22. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/S0960-894X(99)00606-X, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/S0960-894X(99)00606-X instead.
  23. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/j.bmc.2005.05.025, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/j.bmc.2005.05.025 instead.
  24. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19110199, please use {{cite journal}} with |pmid=19110199 instead.

References

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