Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Opioid poisoning Dr Ian Cheung AED PWH General information on opioids opiates indicates natural derivatives of the poppy plant, such 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 in the world. 1973 Kosterlitz & Snyder discovered opioid receptors and endogenous opioids. General information on 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 General information on opioids 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-'neefei-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 metabolites (morphine-3-glucuronide & morphine-6glucuronide) 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 General information on opioids Tebaine extracted of Papaver bracteatum can be processed into codeine and semi-synthetic compounds (hydrocodon, oxycodon, oxymorphon) General information on opioids Codeine metabolizes into morphine in the organism however, hepatic microsomic ferment, which enables this transformation (cytochrome P450 IID6) is absent in 10% of people. General information on opioids Semi-Synthetic opioids Heroin It takes approximately ten kilograms of Opium to make one kilogram of Heroin. metabolised to morphine hydrocodone oxycodon oxymorphon General information on opioids 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 proopiomelanocortin, 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. Clinical and molecular effects of exogenous and endogenous opioids 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. Clinical and molecular effects of exogenous and endogenous opioids 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 Clinical and molecular effects of exogenous and endogenous opioids 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. Clinical and molecular effects of exogenous and endogenous opioids orphan opioid receptor has not been found to be activated by traditional opioids - hence an "orphan" receptor role of the orphan opioid receptor has not been definitively characterised Henderson G, McKnight AT (1997). The orphan opioid receptor and its endogenous ligand nociceptin/orphanin FQ. Trends Pharmacol Sci 18, 293-300. Clinical and molecular effects of exogenous and endogenous opioids 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 receptors 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); hallucination (both visual & auditory); respiratory and vasomotor stimulation; mydriasis Agonist: dextromethorphan; antagonist: haloperidol Fries, DS (2002). Opioid Analgesics. In Williams DA, Lemke TL. Foye's Principles of Medicinal Chemistry (5 ed.). Philadelphia: Lippincott Williams & Wilkins. Clinical and molecular effects of exogenous and endogenous opioids opiate receptors Several possible effects at the various receptors, but typically grouped as follows: Agonist (1, 2, ) Agonist-antagonist ( agonist, antagonist): produces withdrawal symptoms in opioid () dependent patients. Antagonist (1, 2, antagonist) Partial agonist (1, 2 partial agonist, antagonist) 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 convulsant; 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 Roles of the main types of opioid receptors µ Analgesia Supraspinal Spinal Peripheral Respiratory depression Pupil constriction Reduced GI motility Euphoria Dysphoria Sedation Physical dependence +++ ++ ++ +++ ++ ++ +++ – ++ +++ d – ++ – ++ – ++ – – – – – + ++ – + + – +++ ++ + See Rang, Dale and Ritter, p. 575 Clinical and molecular effects of exogenous and endogenous opioids • Miosis • is mediated by a mu receptor-related excitatory action at the parasympathetic nerve that innervates the pupil 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. 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 ?? Diagnosis Hoffman JR, Schriger DL, Luo JS. The empiric use of naloxone in patients with altered 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% Diagnosis Hoffman JR, Schriger DL, Luo JS. The empiric use of naloxone in patients with altered mental status: a reappraisal. Ann Emerg Med. 1991;20:246-52. 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. Diagnosis Hoffman JR, Schriger DL, Luo JS. The empiric use of naloxone in patients with altered mental status: a reappraisal. Ann Emerg Med. 1991;20:246-52. 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 • Observation alone until normal level of consciousness • If no improvement after 4 hours, consider alternative diagnosis No 1. BVM ventilation with 100% O2 2. Naloxone 0.2-0.4mg IV/SC/IM 3. Repeated dosing up to 10mg if no improvement in 2-3mins Consider intubation if 1. inability to ventilate adequately with BVM 2. poor oxygenation despite adequate ventilation 3. persistent hypoventilation after 2nd dose of naloxone 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 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-3glucuronide, 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 patient naltrexone patient get no euphoric effect from heroin so person gets 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 testing Urine 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 testing Urine 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 1889 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 receptors in the central nervous system Heroin is more lipid soluble than morphine and other opiates; thus, it crosses the bloodbrain 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 5-10 mins 20-30 mins 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. Heroin accounts for both the "rush" experienced by users and the toxicity. Peripheral tissues (blood, kidney, and liver) can also hydrolyze heroin to 6monoacetylmorphine 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 Dosages w/ no tolerance w/ heavy tolerance Common 5 - 10 mg 20 - 40 mg 8 - 15 mg 40 - 60 mg Strong Onset Duration : 10 - 20 seconds : 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 Peak Onset Peak Duration Duration : 5 - 10 seconds : 10 minutes : 5 - 6 minutes : 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 the 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 because of severe hypoxia respond in 24 to 36 hours with supportive care Benowitz NL, Rosenberg J, Becker CE. Cardiopulmonary catastrophes in drugoverdosed patients. Med Clin North Am. 1979;63:267-96 Complications Noncardiogenic pulmonary edema 61/ 64 patients with noncardiogenic pulmonary edema 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 question In [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 scenario A 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. Safe discharge of some patients who have taken an overdose of opioids may be possible after one hour Search strategy Medline 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 outcome 194 papers were found of which only 5 were relevant to the setting. Safe discharge of some patients who have taken an overdose of opioids may be possible after one hour Relevant paper(s) Author, date and country Patient group Smith DA et al, 1992, USA 124 patients presenting to an ED with a heroin overdose Osterwalder JJ, 1995, Switzerland 192 patients attending an ED with clinical suspicion of opioid od Study type (level of evidence) Observational Observational Outcomes Key results Study weaknesses 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 Further treatment after discharge None Time to decision 15 mins No attempt was made to compare the outcomes of different treatment modes Reattendance if discharged 1 patient died The period of observation in the ED was not recorded Follow-up was poor so it is possible that patients who sought further treatment or who died elsewhere would have been missed Relevant paper(s) (con’t) Author, date and country Patient group Watson WA et al, 1998, USA 84 patients attending an ED who had been given naloxone for a presumed opioid od 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 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 Study type (level of evidence) Observational Observational Observational Outcomes Key results Subsequent recurrence of opioid toxicity Patients who have taken a longacting opioid are more likely to experience a recurrence of toxicity Death No patients treated with naloxone died Reattendence of the ambulance within 12 hours Nil 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 1020/min, heart rate 50100/min, temperature 35-37.5 C, GCS 15/15 Study weaknesses 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 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 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) Safe discharge of some patients who have taken an overdose of opioids may be possible after one hour 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 line The evidence suggests that if a patient remains well one hour after administration of naloxone, then it is safe to discharge them. Safe discharge of some patients who have taken an overdose of opioids may be possible after one hour Level of evidence Level 3 – Small numbers of small studies or great heterogeneity or very different population. References 1. 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);1836. 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 HO CH3 O CH3CH2 C N CH3 HO C O Morphine Methadone CH2 CH CH3 N CH3 Dextromethorphan Common ingredient of cough preparations and other OTC 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 GIT Onset is rapid: 15-30 mins after ingestion Half-life approx. 2-4 hours in normal people metabolized in liver extensively to dextrorphan (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 Fentanyl (Sublimaze) 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 times more potent than fentanyl) for use in heart surgery. Today, fentanyls are extensively used for anesthesia and analgesia. HO Fentanyl (Sublimaze) O N CH3 HO Morphine H 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 O N CH2CH2 CH3CH2C N Fentanyl highly abused ,known as “China White” in Pittsburgh; “Tango & Cash” in New York City as street name Fentanyl (Sublimaze) 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. Actiq® "Perc-O-Pop's" or "Lollipop's" are street terms for Actiq®, (raspberry-flavored lozenge attached to a handle) a form of fentanyl. Fentanyl (Sublimaze) 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 Fentanyl (Sublimaze) 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 normal doses Source: DEA Tramadol (Tramal™) a novel synthetic analgesic agent dual mechanism of action: both opioid and monoaminergic 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 Tramadol (Tramal™) 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 while 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 Tramadol (Tramal™) 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 question In [patients suspected of internal drug carriage ('Body-Packers', 'Body-Stuffers')] is [plain abdominal radiography] of [diagnostic utility]? Clinical scenario A 26 year old male in custody is brought to the emergency department with abdominal pain. He claims to have ingested a large amount of 'drugfilled packages'. He is tachycardic. Examination is otherwise normal. You wonder if plain abdominal xray is indicated. Abdominal radiography in 'Body Packers'. Search strategy Medline 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 outcome Altogether 12 papers were found of which 2 were relevant to the topic of interest. Abdominal radiography in 'Body Packers'. Relevant paper(s) Author, date and country Patient group Study type (level of evidence) Outcomes Karhunen PJ et al, 1992, Finland 82 patients suspected of internal drug carriage Prospective observational series Detection of internal drug packages using abdominal radiography 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 Key results Study weaknesses Sensitivity 90% Small numbers Specificity 97% No blinding 7 out of 12 cases detected Small study Questionable 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. Abdominal radiography in 'Body Packers'. 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.” CT 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 question In [patients with opioid poisoning] does [delayed administration of activated charcoal] [reduce absorption of the poison?] Clinical scenario A 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. Delayed activated charcoal in opioid poisoning Search strategy Medline 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 outcome 34 papers were identified, of which only one was relevant to the question. Delayed activated charcoal in opioid poisoning Relevant paper(s) Author, date and country Patient group Laine K, Kivisto KT et al 1997 Finland 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 Study type (level of evidence) Outcomes Key results Absorption of pholcodeine Significant reduction when given at 0 and 2 hours Maximum serum pholcodeine level Significantly lower when given immediately; lower but not significant in 2hour group PRCT Study weaknesses Small numbers (32 patients in total) 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, cocodamol 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. Delayed activated charcoal in opioid poisoning Clinical bottom line Delayed 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. References Laine 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.