Opioid poisoning Dr Ian Cheung AED PWH. General information on opioids opiates indicates natural derivatives of the poppy plant, such as morphine and

Opioid poisoning

Dr Ian Cheung

AED PWH

General information on opioids

opiates indicates natural derivatives of the poppy plant, su

ch as morphine and codeine opioids

denote natural opiates, semi-synthetic (e.g. hydrocodone) and synthetic compounds (e.g. fentanyl), as well as endogenous opioids

The History of Opioids A 6000-year-old Sumerian tablet The Egyptians The Greeks 1000AD Arab traders introduce to China China and opium trade The Opium War of 1839 1902 Structure of morphine determined 1952 Australians were the largest heroin consumer i

n the world. 1973 Kosterlitz & Snyder discovered opioid receptor

s and endogenous opioids.


Papaver somniferum or opium poppy grows in various parts of the world sedative, anaesthetic and fixing qualities contains several active alkaloids

morphine (10%-15%) , codeine (1%-3%) and tebaine (1%-2%)

semi-synthetic drugs are produced heroin and hydromorphon


Papaver somniferum or opium poppy

Morphine was first isolated from opium in 1805 by a German pharmacist, Wilhelm Sertürner (1783-1841)

He named it morphium - after Morpheus, the Greek god of dreams

The Opium Poppy : Papaver Somniferum鴉片罌粟 The Opium Poppy: Papaver Somniferum

Common names:

White Poppy, Opium Poppy, Mawseed, Herb of Joy, Mohn, Klapper-Rosen, Mago, Magesamen, Weismagen, wilder Magen, Magensaph, Rosule, Adormidero, Hashas, Kheshkhash Abu Al Noum, O Fang, O Fu Jung, O P'Ien, Tengkoh, Ya P'Ien, Yu Mi. "

Papaver ( 罌粟科罌粟屬，發音為 pa-‘pah-ver) 。拉丁語 pappa 是食物或牛奶之意，引申形容果實所流出的白色乳汁。

somniferum ( 種名，發音為 som-'nee-fei-rum) ， somnifer ，導致睡眠的。按古希臘常用罌粟果實來裝飾睡神 Hypnos ，而羅馬睡神則稱為 Somnus 。罌粟屬約 50 種，本種可供製作鴉片，可稱為鴉片罌粟 ( 英文是 opium poppy) 。

Pharmacokinetics

absorption readily absorbed from GI tract, nasal mucosa, lung

subcutaneous, intramuscular, and intravenous route bound free morphine accumulates in kidney, lung, liver,

and spleen CNS is primary site of action (analgesia/sedation)

Pharmacokinetics

metabolism/excretion metabolic transformation in liver conjugation with glucuronic acid to water-soluble metabolit

es (morphine-3-glucuronide & morphine-6- glucuronide) excreted by kidney half life is 2.5 to 3 hours (does not persist in body tissue) morphine 3 glucuronide in main excretion product lose 90% in first day duration of 10 mg dose is 3 to 5 hours


Tebaine extracted of Papaver bracteatum can be processed into codeine and semi-synthetic

compounds (hydrocodon, oxycodon, oxymorphon)


Codeine metabolizes into morphine in the organism however, hepatic microsomic ferment, which enab

les this transformation (cytochrome P450 IID6) is absent in 10% of people.


Semi-Synthetic opioids Heroin

It takes approximately ten kilograms of Opium to make one kilogram of Heroin.

metabolised to morphine hydrocodone oxycodon oxymorphon


Synthetic opioids pethidine, methadone, pentazocine, fentanyl, dextropropoxyphen, propoxyphene…

Clinical and molecular effects of exogenous and endogenous opioids

A lot of new information appeared during the last 20 years

The endogenous peptides with opiate-like activity. The three major classes currently recognized are the

ENKEPHALINS, the DYNORPHINS, and the ENDORPHINS.

Each of these families derives from different precursors, proenkephalin, prodynorphin, and pro-opiomelanocortin, respectively.

There are also at least three classes of opioid receptors, but the peptide families do not map to the receptors in a simple way.


opiate receptors present in both the central and the peripheral nervous systems Mu (μ)-receptors: 2 subtypes – Mu1 and Mu2

Mu1-receptors responsible for most of the supraspinal and peripheral analgesic effects and euphoria

Mu2-receptors responsible for respiratory depression, delayed gastrointestinal motility, miosis, pruritus and physical dependence

has high affinity for enkephalins and beta-endorphin but low affinity for dynorphins

activate by morphine, codeine, and methadone

Schwartz M. Opiates and narcotics. In: Haddad LM, Shannon MW, Winchester JF, eds. Clinical Management of Poisoning and Drug Overdose. 3d ed. Philadelphia: WB Saunders; 1998:505-22.


opiate receptors Kappa (κ)-receptors: 3 subtypes – Kappa 1, 2 & 3

activated by other endogenous opioids (for example, dinomorphine)

produce spinal (κ1) and supraspinal (κ3) analgesia separately from receptor function

play a part in miosis (κ1), respiratory depression, nausea and dysphoria (κ2)

endogenous ligands are the dynorphins


opiate receptors Delta(δ) receptors :

mediate spinal analgesia but are also found in cortical regions

Modulation of receptors function and dopaminergic neurons

endogenous ligands for the δ receptor are the enkephalins

Some research suggests that they may also be related to seizures

Reisine T, Pasternak G. Opioid analgesics and antagonists. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman A, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York: McGraw-Hill; 1996:521-55.


orphan opioid receptor has not been found to be activated by traditional opioi

ds - hence an "orphan" receptor role of the orphan opioid receptor has not been definiti

vely characterised

Henderson G, McKnight AT (1997). The orphan opioid receptor and its endogenous ligand - nociceptin/orphanin FQ. Trends Pharmacol Sci 18, 293-300.


opiate receptors Sigma (σ) receptors : 2 subtypes – Sigma 1 & 2

once thought to be a type of opioid receptor However, pharmacological testing indicated that the sigma r

eceptors were activated by drugs completely unrelated to the opioids, and their function was unrelated to the function of the opioid receptors.

designated as a separate class of receptors associate with dysphoria (opposite of euphoria); hallucinatio

n (both visual & auditory); respiratory and vasomotor stimulation; mydriasis

Agonist: dextromethorphan; antagonist: haloperidolFries, DS (2002). Opioid Analgesics. In Williams DA, Lemke TL. Foye's Principles of Medicinal Chemistry (5 ed.). Philadelphia: Lippincott Williams & Wilkins.


opiate receptors Several possible effects at the various receptors,

but typically grouped as follows: Agonist (1, 2, ) Agonist-antagonist ( agonist, antagonist): prod

uces withdrawal symptoms in opioid () dependent patients.

Antagonist (1, 2, antagonist) Partial agonist (1, 2 partial agonist, antagonis

t)

Common Opioid Agonists and Antagonists Codeine: naturally occurring agonist; often combined with acetaminophen; antitussive;

needs metabolism to morphine for analgesic effect (not everyone capable of this metabolism)

Dextromethorphan (Robitussin DM, Coricidin): semisynthetic agonist; antitussive, nonanalgesic; abused for psychotomimetic effects

Diphenoxylate (Lomotil): synthetic agonist; combined with atropine as antidiarrheal agent

Fentanyl (Sublimaze): synthetic agonist; very high potency and short acting Heroin: semisynthetic agonist; derived from morphine (diacetylmorphine) Loperamide (Imodium): synthetic agonist; antidiarrheal agent Meperidine (Demerol): synthetic agonist; also called pethidine; metabolite is a convulsa

nt; serotonin syndrome (see clinical effects) Methadone (Dolophine): synthetic agonist; very long acting; opioid substitution therapy Morphine: naturally occurring; the gold standard Naloxone (Narcan): semisynthetic antagonist; short acting Naltrexone (Trexan): semisynthetic antagonist; very long acting Pentazocine (Talwin): semisynthetic agonist-antagonist; psychotomimetic Propoxyphene (Darvon): synthetic agonist; seizures, cardiac dysrhythmias in overdose Tramadol (Ultram): synthetic agonist; seizures may occur at therapeutic doses

Analgesia

Supraspinal

Spinal

Peripheral

Respiratory depression

Pupil constriction

Reduced GI motility

Euphoria

Dysphoria

Sedation

Physical dependence

+++

++

++

+++

++

++

+++

–

++

+++

–

++

–

++

–

++

–

–

–

–

–

+

++

–

+

+

–

+++

++

+

µ

Roles of the main types of opioid receptors

See Rang, Dale and Ritter, p. 575


Reisine T, Pasternak G. Opioid analgesics and antagonists. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman A, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York: McGraw-Hill; 1996:521-55.

• Miosis • is mediated by a mu receptor-related excitatory action at the parasympathetic nerve that innervates the pupil

CLINICAL PRESENTATION

Pinpoint pupils Respiratory depression Bradycardia Hypotension Hypothermia Pulmonary edema Seizures

Diagnosis

Altered Mental states (GCS<12)plus one of the following:

1. RR <12 breaths/min

2. miotic pupils

3. circumferential evidence or history of opioid use

The opioid toxidrome was first described in the 1970s as a triad of depressed level of consciousness, miotic pupils, and decreased respiration

Khantzian EJ, McKenna GJ. Acute toxic and withdrawal reactions associated with drug use and abuse. Ann Intern Med. 1979;90:361-72.

Naloxone

as a diagnostic tool ??

DiagnosisHoffman JR, Schriger DL, Luo JS. The empiric use of naloxone in patients with alter

ed mental status: a reappraisal. Ann Emerg Med. 1991;20:246-52.

• examined the usefulness of clinical criteria to predict a final diagnosis of opiate overdose (N=730)

• clinical criteria alone:

sensitivity of 92% and specificity of 76%

• a complete naloxone response + clinical criteria

sensitivity of 86% and specificity of 97%



Major conclusion:

1. most patients with undifferentiated abnormal mental status and no clinical signs of opiate intoxication would not benefit from naloxone

2. no occult opiate intoxications would be missed if this drug was not given.



Implications:

1. The utility of naloxone as a diagnostic aid is questionable;

2. the drug should be used only to treat life-threatening respiratory depression.

3. addition of naloxone only worsened the sensitivity for making this diagnosis

4. not every patient who responds to naloxone has an opiate overdose

Assessment of suspected sole opioid poisoning

Adequate ventilation?

Yes No

• Observation alone until normal level of consciousness• If no improvement after 4 hours, consider alternative diagnosis

1. BVM ventilation with 100% O22. Naloxone 0.2-0.4mg IV/SC/IM3. Repeated dosing up to 10mg

if no improvement in 2-3mins

Complete naxolone response:• Observation for 2-3 hours for complication or resedation• Repeated naloxone ONLY for clinical significant hypoventilation• Consider naloxone drip for long-acting opioid, like methadone, body packer (2/3 of the effective reversal dose per hour)• CXR for patients with respiratory symptoms• Appropriate substances abuse referral

Consider intubation if 1. inability to ventilate adequately with BVM2. poor oxygenation despite adequate ventilation3. persistent hypoventilation after 2nd dose of naloxone

Incomplete diagnosis:• higher doses of naloxone for opioid like proproxyphene, fentanyl.• consider alternative diagnosis

Naloxone

Naloxone is a potent antagonist at the mu, kappa, and delta receptors that is devoid of agonist activity

It is readily absorbed intravenously intramuscularly, and via endotracheal tube.

In its oral form, naloxone undergoes extensive hepatic metabolism and is inactive.

Because of its high lipid solubility, it rapidly enters the central nervous system and has a rapid onset of action.

Naloxone

Peak brain levels of naloxone occur within 15 minutes and decline by 50% within the first hour.

After intravenous injection, the effects of naloxone occur in 1 to 2 minutes and last 45 to 90 minutes.

Naloxone is hepatically metabolized to naloxone-3-glucuronide, an inactive compound that is renally excreted.

Naloxone• Naloxone 0.2-0.4mg IV/SC/IM

• Repeated dosing up to 10mg if no improvement in 2-3mins

• Lower starting doses can be used for obvious heroin abuser as long as ventilatory support is adequate

• Higher naloxone doses may be necessary to reverse the effects of synthetic oral opiates e.g. propoxyphene, fentanyl, body packer.

Moore RA et al. Naloxone: underdosage after narcotic poisoning. Am J Dis Child 1980:134(2): 156-8

Naloxone(Children)

The initial dose in children is 10 to 30 microgram per kg, followed by a dose of 100 microgram per kg if there is no response.

Infusion should be at a rate of 30 microgram per kg

per hour.

Infusion may be recommended in the case of opioids with a long half-life (e.g. methadone, dextropropoxyphene, body packer).

Naltrexone

same effect of naloxone except it is used orally so can't use it if for person with acute toxicity

long duration of activity single dose block action of heroin effects for 24 hours used for emergency treatment, once stabilized, give p

atient naltrexone patient get no euphoric effect from heroin so person g

ets off heroin (negative reinforcement) approved for use by the FDA also used for treatment of alcoholism

Laboratory and bedside testing

based on the medical history and physical examination

H’sitx, SaO2, ABG, ECG, Temp APAP and ASA level CXR for respiratory symptoms or hypoxia

Laboratory and bedside testingUrine drug screens:

Immunoassay assess for morphine as a screen for heroin

common false –ve: synthetic opioids that are structurally unlike morphine but have significant opioids toxicity, examples are methadone, propoxyphene, fentanyl, pethidine, dextromethophan

methadone will show up on its own assay

Laboratory and bedside testingUrine drug screens:

Unexpected false positives occassionally, such as fluoroquinolones, quinolone antibiotics, rifampicin

Dextromethorphan may cause false positive PCP screen

+ve test implies recent exposure to opioid

Jennifer L Zacher. False-positive urine opiate screening assoicated with fluoroquinolone use. Ann Pharmacother 2004; 38:1525-8

Laboratory and bedside testing

Comment from YC: (quoted without prior permission)

In summary, opioids immunoassay has limited (if any) role in the acute management of suspected opioids poisoned patients simply because of the false +ve and –ve. We still have to back to our clinical toxidrome and the responsiveness to naloxone in deciding our management.

The Road to H by Isadore Chein and colleagues(1964)

‘H’ is for heaven ‘H’ is for hell ‘H’ is for heroin

Heroin

Heroin is named after the German word for hero, heroisch.

In 1993, heroin was implicated in more than 3805 deaths nationwide

Relatively easily synthesize from morphine and acetic anhydride

Heroin Abuse in the United States. Rockville, MD: U.S. Department of Health and Human Services; 1997

Heroin also known as diacetylmorphine first synthesized by the Bayer Company in 18

89 as a "less addicting morphine substitute" It takes approximately ten kilograms of Opium

to make one kilogram of Heroin

de Ridder M. Heroin: new facts about an old myth. J Psychoactive Drugs. 1994;26:65-8

Heroin an agonist on the mu, kappa, and delta recept

ors in the central nervous system

Heroin is more lipid soluble than morphine and other opiates; thus, it crosses the blood-brain barrier within 15 to 20 seconds and achieves relatively high brain levels

Way EL, Kemp JW, Young JM, Grassetti DR. The pharmacologic effects of heroin in relationship to its rate of biotransformation. J Pharmacol Exp Ther. 1960;129:144-54

68%via ivi <5%

via ivi

Oldendorf WH, Hyman S, Braun L, Oldendorf SZ. Blood-brain barrier: penetration of morphine, codeine, heroin, and methadone after carotid injection. Science. 1972;178:984-6.

5-10 mins 20-30 mins

Heroin accounts for both the "rush" experienced by

users and the toxicity. Peripheral tissues (blood, kidney, and liver)

can also hydrolyze heroin to 6-monoacetylmorphine and then to morphine

Way EL, Kemp JW, Young JM, Grassetti DR. The pharmacologic effects of heroin in relationship to its rate of biotransformation. J Pharmacol Exp Ther. 1960;129:144-54

Intra-venous Heroin Dosagesw/ no tolerance w/ heavy tolerance

Common 5 - 10 mg 20 - 40 mg

Strong 8 - 15 mg 40 - 60 mg

Onset : 10 - 20 secondsDuration : 4 - 5 hours

REMARKS: The charts above shows intraveinous (IV) dosages in milligrams (mg) for individuals with different levels of tolerance. Because people quickly develop tolerance to the effects of heroin, and because batches of heroin vary from extremely low (2-3%) to extremely high (98%) purity, dosages will vary dramatically depending on whether an individual has been using regularly, and for how long. The numbers on this page are approximations only and should not be used to determine actual dosages.

Smoked Heroin Dosages

Common 15 - 25 mg

Strong 20 - 30 mg

Onset : 5 - 10 seconds

Peak Onset : 10 minutes

Peak Duration : 5 - 6 minutes

Duration : 3 - 5 hours

Heroin The route of heroin administration also strongly affects

the drug's potential to cause death or overdose. Most fatal and nonfatal heroin overdoses occur when t

he drug is administered intravenously. intramuscular and subcutaneous routes accounted for

only 0.3% and 0.5% of nonfatal heroin overdoses, respectively. (Sporer KA, Firestone J, Isaacs SM. Out-of-hospital treatment of opioid overdoses in an urban setting. Acad Emerg Med. 1996;3:660-7)

These routes allow extensive peripheral hydrolysis and therefore limit toxicity

Only one death from oral heroin administration has been reported (Rop PP, Fornaris M, Salmon T, Burle J, Bresson M. Concentrations of heroin, 06-monoacetylmorphine, and morphine in a lethal case following an oral heroin overdose. J Anal Toxicol. 1997;21:232-5)

Heroin Combinations

Pure heroin is a white powder. (No.4) Heroin is usually “cut” (diluted) with lactose. When heroin first enters the U.S., it may be 95%

pure, by the time it is sold, it is 3 to 5% pure. Heroin has a bitter taste and is often cut with

quinine. Heroin combined with cocaine is called

“speedballing.”

Complications

hospitalization rate among patients with treated heroin overdoses: 3% to 7%

admission diagnosis: non-cardiogenic pulmonary edema (1% to 2.4%)

pneumonia (0.5%)

possible endocarditis (0.25%)

persistent altered mental status or respiratory depression (0.7% to 4%)

Smith DA, Leake L, Loflin JR, Yealy DM. Is admission after intravenous heroin overdose necessary? Ann Emerg Med. 1992;21:1326-30.

Complications

Noncardiogenic pulmonary edema exact mechanism is unknown associated with both heroin and naloxone usually clinically apparent immediately or within 2

hours of administration of the drug Most patients require mechanical ventilation beca

use of severe hypoxia respond in 24 to 36 hours with supportive care

Benowitz NL, Rosenberg J, Becker CE. Cardiopulmonary catastrophes in drug-overdosed patients. Med Clin North Am. 1979;63:267-96

Complications

Noncardiogenic pulmonary edema 61/ 64 patients with noncardiogenic pulmonary ed

ema reported in the literature had significant symptoms at arrival in the emergency department or within 2 hours of arrival

Only 3 patients have had delayed symptom onset while under medical observation

Complications

Pneumonia (aspiration), Rhabdomyolysis, Compartment syndrome, Endocarditis, and Wound botulism co-ingestion trauma

Safe discharge of some patients who have taken an overdose of opioids may be possible after one hour

Three part questionIn [patients given naloxone for the treatment of opioid overdose] is [a lack of recurrence of symptoms after one hour] a sensitive predictor for [the patient being able to be safely discharged from the department]?

Clinical scenarioA 30 year old opioid addict is brought to the emergency department having overdosed on heroin. He is successfully treated with a titrated bolus of naloxone. You wonder when it will be safe to discharge the patient.


Search strategyMedline 1966-02/02 using the OVID interface.[{exp narcotics OR opioid.mp OR opiate.mp OR morphine.mp OR buprenorphine.mp OR codeine.mp OR dextromoramide.mp OR diphenoxylate.mp OR dipipanone.mp OR dextropropoxyphene.mp OR diamorphine.mp OR heroin.mp OR alfentanil.mp OR fentanyl.mp OR remifentanil.mp OR meptazinol.mp OR methadone.mp OR nalbuphine.mp OR oxycodone.mp OR pentazocine.mp OR pethidine.mp OR phenazocine.mp OR tramadol.mp} AND {exp overdose OR overdos$.mp OR exp poisons OR poison$.mp OR "acute intoxic$".mp OR "acute toxic$".mp} AND {exp patient admission OR admission.mp OR exp patient discharge OR discharge.mp OR observ$.mp OR monitor$.mp OR predict$.mp}] LIMIT to human AND English.

Search outcome194 papers were found of which only 5 were relevant to the setting.


Relevant paper(s)

Author, date and country

Patient groupStudy type

(level of evidence)

Outcomes Key results Study weaknesses

Smith DA et al,1992,USA

124 patients presenting to an ED with a heroin overdose

Observational

Time to decision 20 mins Treatments given were neither standardised nor randomised so analysis of outcome could not be performed in relation to mode of treatment

Follow-up was poor so it is possible that patients who sought further treatment or who died elsewhere would have been missed

Further treatment after discharge

None

Osterwalder JJ,1995,Switzerland

192 patients attending an ED with clinical suspicion of opioid od

Observational

Time to decision 15 mins No attempt was made to compare the outcomes of different treatment modes

The period of observation in the ED was not recorded

Reattendance if discharged

1 patient died

Author, date and country

Patient groupStudy type

(level of evidence)


Watson WA et al,1998,USA

84 patients attending an ED who had been given naloxone for a presumed opioid od

ObservationalSubsequent recurrence of opioid toxicity

Patients who have taken a longacting opioid are more likely to experience a recurrence of toxicity

No follow-up of patients was attempted after admission to hospital/discharge from the ED to assess the incidence of late complications

The period of observation in the ED was not recorded

Vilke GM et al,1999,USA

317 patients with a clinical suspicion of opioid od who refused to be transported to the ED after being given naloxone by the paramedics

Observational

DeathNo patients treated with naloxone died

Variable doses and routes of administration of naloxone were used

No follow-up of patients was attempted to ascertain if they received subsequent treatment or died in another area or attended the ED by other means of transport

Reattendence of the ambulance within 12 hours

Nil

Christenson J et al,2000,Canada

573 patients attending an ED with clinical evidence of opioid intoxication who had been given naloxone either in the prehospital setting or ED

Observational

Clinical prediction rule to predict safe discharge

Patients can be safely discharged one hour after administration of naloxone if they have normal mobility, SpO2 >92%, respiratory rate 10-20/min, heart rate 50-100/min, temperature 35-37.5 C, GCS 15/15

The rule has not been validated yet

The pattern of drug abuse in Vancouver is different from other cities, so there are concerns about whether these results can be applied to different populations (eg those that misuse a higher proportion of longer acting agents)

Relevant paper(s) (con’t)


Comment(s)The evidence consists of observational studies, three of which are retrospective reviews of medical records and thus there are concerns regarding the reliability of the data collected. In addition, only Christenson's study attempts to apply a "rule-out" strategy by attempting to identify the clinical variables that predict a low risk of delayed complications from the opioid overdose. Futher work is required to validate the rule in different populations by further prospective studies. Also, comparative trials need to be undertaken to assess the validity of the rule for different opiod overdoses.

Clinical bottom lineThe evidence suggests that if a patient remains well one hour after administration of naloxone, then it is safe to discharge them.


Level of evidenceLevel 3 – Small numbers of small studies or great heterogeneity or very different population.

References1. Smith DA, Leake L, Loflin JR et al. Is admission after intravenous heroin overdose

necessary? Ann Emerg Med 1992;21(11);1326-30. 2. Osterwalder JJ. Patients intoxicated with heroin or heroin mixtures: how long should they

be monitored? Eur J Emerg Med 1995;2(2);97-101. 3. Watson WA, Steele MT, Muelleman RL, et al. Opioid toxicity recurrence after an initial

response to naloxone. J Toxicol Clin Toxicol 1998;36(1-2);11-17. 4. Vilke GM, Buchanan J, Dunford JV et al. Are heroin overdose deaths related to patient

release after prehospital treatment with naloxone? Prehospital Emerg Care 1999;3(3);183-6.

5. Christenson J, Etherington J, Grafstein E, et al. Early discharge of patients with presumed opioid overdose: development of a clinical prediction rule. Acad Emerg Med 2000;7(10);1110-18.

Optimal observation period

Aim: guarantee that most or all cases of delayed complications (e.g.noncardiogenic pulmonary edema) would occur during medical observation

If rate of noncardiogenic pulmonary edema is 2x the rate reported in recent series (5%)

and extrapolate from published reports: 95% of cases would occur within the first 2 hours of observation

Optimal observation period

A patient with a heroin overdose: 4.75% chance of developing noncardiogenic

pulmonary edema during a 2-hour observation period and

0.25% chance of developing late-appearing symptoms

acceptable risk?

Methadone

pharmacological activity similar to morphine, same potency as morphine

long duration of activity absorbed well orally 16 to 20 hour duration of action powerful pain reliever used in maintenance program for narcotic treatment

Methadone

CH3CH2 C C CH2 CH

CH3

NCH3

CH3O

O

N

HO

HO

CH3

Morphine

Dextromethorphan Common ingredient of cough preparations and other OT

C preparations; pure forms available over the internet

Referred to by proper name, also called DM, Robo, Robo shots, Robitussin DM; abuse is widespread in some parts of the US; middle and high-school and college students

A semisynthetic opioid agent, but it operates primarily at the receptor; chemical structure similar to phencyclidine and urine tests may be falsely positive for phencyclidine.

INGREDIENTS: per teaspoon (5ml) : Guaifenesin, USP 200mg and Dextromethorphan Hydrobromide, USP 10 mg.

DM (Dexromethorphan HBr)非麻醉性鎮咳劑，作用於延腦的咳嗽中樞，能有效抑制嚴重咳嗽，減少咳嗽次數。特別適用於乾咳。療效與 codeine （可待因）相當，但無抑制呼吸、睡眠或誘發成癮之副作用。 .

Dextromethorphan

Well absorbed from GITOnset is rapid: 15-30 mins after ingestionHalf-life approx. 2-4 hours in normal peo

plemetabolized in liver extensively to dextror

phan (active metabolite)excreted via kidney.

Dextromethorphan

Produces central nervous system depression with less respiratory effect than other opioids unless massive doses are ingested.

Has some serotonergic effects and is implicated as causative of the serotonin syndrome in patients using monoamine oxidase inhibitors.

Choreoathetosis and other bizarre movements may be noted, particularly in children.

Care is supportive including sedation for dysphoria.

Sandra M. Schneider. Dextromethorphan poisoning reversed by Naloxone. Am J Emerg Med. 1991;9:237-8

Propoxyphene

is extensively metabolized in liver, where it is oxidized to nor-propoxyphene (1/4 to ½ as active an analgesic as propoxyphene)

Half-life for propoxyphene in young averages 13 hrs; for its metabolites approx. 22.2 hrs

Mainly excrete by kidney

Propoxyphene

Produces fast sodium-channel blockade causing wide-complex cardiac dysrhythmias

Cardiac toxicity is responsive to sodium bicarbonate and lidocaine, but not naloxone

Higher doses of naloxone is needed for opioid toxicity

Moore RA et al. Naloxone: underdosage after narcotic poisoning. Am J Dis Child 1980:134(2): 156-8

First synthesized in Belgium in the late 1950s, fentanyl, with an analgesic potency of about 80 times that of morphine, was introduced into medical practice in the 1960s as an intravenous anesthetic under the trade name of Sublimaze®.

Thereafter; two other fentanyl analogues were introduced; alfentanil (Alfenta®), an ultra-short (5-10 minutes) acting analgesic,

and sufentanil (Sufenta®), an exceptionally potent analgesic (5 to 10 ti

mes more potent than fentanyl) for use in heart surgery.

Today, fentanyls are extensively used for anesthesia and analgesia.

Fentanyl (Sublimaze)


synthetic drug different structure than morphine 80 to 100 times more potent than morphine very short acting opioid (30-45 min) used as preoperative medication onset of action is 5 minutes highly abused ,known as “China White” in Pittsburgh;

“Tango & Cash” in New York City as street name

Fentanyl

NH

CH2CH2

NCH3CH2C

O

O

N

HO

HO

CH3

Morphine


Duragesic®, for example, is a fentanyl transdermal patch used in chronic pain management, and

Actiq® is a solid formulation of fentanyl citrate on a stick that dissolves slowly in the mouth for transmucosal absorption.

Actiq® is intended for opiate-tolerant individuals and is effective in treating breakthrough pain in cancer patients.

Carfentanil (Wildnil®) is an analogue of fentanyl with an analgesic potency 10,000 times that of morphine and is used in veterinary practice to immobilize certain large animals.

"Perc-O-Pop's" or "Lollipop's" are street terms for Actiq®, (raspberry-flavored lozenge attached to a handle) a form of fentanyl.

Actiq®


Illicit use of pharmaceutical fentanyls first appeared in the mid-1970s in the medical community and continues to be a problem in the United States.

The biological effects of the fentanyls are indistinguishable from those of heroin, with the exception that the fentanyls may be hundreds of times more potent. Source: DEA


Fentanyls are most commonly used by intravenous administration, but like heroin, they may also be smoked or snorted.

associated with muscle rigidity

respond to naloxone, but may require higher than nor

mal doses

Source: DEA

Tramadol (Tramal™)

a novel synthetic analgesic agent dual mechanism of action: both opioid and m

onoaminergic only weakly bind to mu receptors (agonist) appear to inhibit reuptake of biogenic amines:

serotonin (5-HT) and norepinephrine (NE); and stimulating 5-HT release

Bamigbade TA, et al. Actions of tramadol, its enantiomers and principal metabolite, 0-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus. Br J Anaes 1997;79:352-6


Respiratory depression is less pronounced, and occurs less often but can occur, in particular with overdose (as described in children) or with impaired renal function, possibly due to retention of the active metabolite M1.

Barnung SK, Treschow M, Borgbjerg FM. Respiratory depression following oral tramadol in a patient with impaired renal function. Pain 1997;71:111-2.

Tramadol (Tramal™) In overdose, it can also cause seizures and coma whi

le cardiovascular toxicity seems to be limited to mild tachycardia and hypertension.

When seizures do occur, they are commonly of short duration and are easily treatable.

In one reported case of a seizure, the convulsions were induced by naloxone administration. Hence, although respiratory depression in overdose can be treated with the naloxone, low doses should be used to avoid rebound effects including pain, hypertension, tachycardia and seizures.

Spiller H, Gorman S, Villalobos D, Benson B, Ruskosky D, Stancavage M, et al. Prospective multicenter evaluation of tramadol exposure. Clinical Toxicology 1997;35:361-364


Caution in epileptics & those on tricyclics, SSRIs, high dose opioids (seizure threshold-lowering medication)

Contraindicated in patients on MAOIs, because of the risk of developing serotonin syndrome.

Kesavan S, Sobala GM. Serotonin syndrome with fluoxetine plus tramadol. J R Soc Med 1999;92:474-5.

Abdominal radiography in 'Body Packers'.

Three part questionIn [patients suspected of internal drug carriage ('Body-Packers', 'Body-Stuffers')] is [plain abdominal radiography] of [diagnostic utility]?

Clinical scenarioA 26 year old male in custody is brought to the emergency department with abdominal pain. He claims to have ingested a large amount of 'drug-filled packages'. He is tachycardic. Examination is otherwise normal. You wonder if plain abdominal x-ray is indicated.


Search strategyMedline 1966-03/04 using the Ovid interface.[(Exp Radiography, Abdominal OR abdominal radiography.mp OR abdominal x-ray.mp OR plain abdominal x-ray.mp OR plain film abdomen.mp) AND (body packers.mp OR body stuffers.mp OR body pack$.mp OR body stuff$.mp)] LIMIT to Human AND English.

Search outcomeAltogether 12 papers were found of which 2 were relevant to the topic of interest.


Relevant paper(s)Author, date and

countryPatient group

Study type (level of evidence)


Karhunen PJ et al,1992,Finland

82 patients suspected of internal drug carriage

Prospective observational series

Detection of internal drug packages using abdominal radiography

Sensitivity 90%

Specificity 97%

Small numbers

No blinding

Heirholzer J et al,1995,Germany

12 patients suspected of internal drug carriage

Prospective observational series

Detection of internal drug packages using abdominal radiography and ultrasound

7 out of 12 cases detected

Small studyQuestionable gold standard applied

Comment(s)The possibility of internal carriage of drugs is an increasingly frequent presentation to urban emergency departments. A diagnostic dilemma is usual owing to credibility of the presentation. It is important, therefore, that clinicians understand the utility of any investigations used. In particular the failure to appreciate the possibility of a false negative result might prove fatal.

Clinical bottom line

A single abdominal radiograph is insufficiently sensitive to rule-out abdominal drug carriage. However, specificity is high and a positive finding is diagnostic. (R/in but NOT R/out)

References Karhunen PJ, Suoranta H, Penttila A, et al. Pitfalls in the diagnosis of

drug smuggler's abdomen. J Forensic Sci 1991;36(2):397-402. Hierholzer J, Cordes M, Tantow H, et al. Drug smuggling by ingested

cocaine-filled packages: conventional x-ray and ultrasound. Abdom Imaging 1995;20(4):333-8.


Suggested algorithm for the management of “body packers.” C

T indicates computed tomography; IV, intravenous; NG, nasogastric; and PO, by mouth. From: Traub: Arch Pediatr Adolesc Med, Volume 157(2).February 2003.174–177

Delayed activated charcoal in opioid poisoning

Three part questionIn [patients with opioid poisoning] does [delayed administration of activated charcoal] [reduce absorption of the poison?]

Clinical scenarioA twenty year-old lady presents to the Emergency Department claiming to have taken 100 co-codamol tablets two hours ago. The guidelines suggest that activated charcoal is of no benefit at this stage. However, you are aware that opioids encourage gastric stasis and wonder if there is any evidence that activated charcoal is still of benefit to this patient.


Search strategyMedline using OVID interface 1966 - June 2003[exp Narcotics OR opioid.mp OR opiate.mp OR co-proxamol.mp OR co-codamol.mp] AND [exp charcoal OR activated charcoal.mp] limit to (human and english language)

Search outcome34 papers were identified, of which only one was relevant to the question.


Relevant paper(s)Author, date and

countryPatient group

Study type (level of evidence)


Laine K, Kivisto KT et al1997Finland

32 healthy volunteers, each receiving 100mg pholcodeine, randomised into four groups to receive no activated charcoal, 25g immediately, 25g at 2 hours or 25g at 5 hours. The 5-hours group also received a further 10g activated charcoal every 12 hours for 84 hours

PRCT

Absorption of pholcodeine

Significant reduction when given at 0 and 2 hours

Small numbers (32 patients in total)

Maximum serum pholcodeine level

Significantly lower when given immediately; lower but not significant in 2-hour group

Delayed activated charcoal in opioid poisoning Comment(s)

There is a paucity of evidence with regard to this topic and no clinical trials have looked at codeine, dextropropoxyphene, co-codamol or co-proxamol overdose and delayed activated charcoal administration. The only clinical trial to be done in this area used pholcodine, a weak opioid. This trial demonstrated a reduction in absorption when charcoal was administered after 2 hours.

Reduction of absorption of the poison may be particularly desirable in cases involving preparations containing opioid and paracetamol, as such overdoses are more likely to lead to significant harm. Dextropropoxyphene (as in co-proxamol), taken in relatively small doses may lead to cardiotoxicity, convulsions and death. Any reduction in the absorption of this poison by delayed activated charcoal would be particularly desirable.


Clinical bottom lineDelayed activated charcoal should be considered in the case of pholcodine overdose.

Although there is no direct evidence for the efficacy of delayed activated charcoal with other opioids, the available evidence does suggest that it should also be considered in oral overdose.

ReferencesLaine K, Kivisto KT, Ojala-Karlsson P, Neuvonen PJ. Effect of Activated Charcoal on the Pharmacokinetics of Pholcodine, with Special Reference to Delayed Charcoal Ingestion. Therapeutic Drug Monitoring 1997;19(1):46-50..

Oral Heroin Dosages

Common 50 - 70 mg

Although oral use of heroin is uncommon among party and weekend users, it is sometimes used this way as a pain medication, by field workers, and by addicts trying to ween themselves off.

Documents

Opioid poisoning Dr Ian Cheung AED PWH. General information on opioids opiates indicates natural derivatives of the poppy plant, such as morphine and