1. Opioid overdose can occur from both prescription and illicit opioid use. Common opioids involved include morphine, heroin, fentanyl, oxycodone, and hydrocodone.
2. Symptoms of opioid overdose include respiratory depression, sedation, small pupils, nausea, vomiting, and decreased heart rate. Naloxone is used as an antidote to reverse the effects of opioid overdose.
3. Treatment of opioid overdose focuses on supporting breathing, administering naloxone, monitoring for complications, and managing withdrawal symptoms which can include restlessness, nausea, and drug craving. Prevention strategies aim to reduce opioid misuse and increase access to treatment.
2. Overview
Opioids - all natural, synthetic, and semisynthetic agents with morphine-like actions.
Opiates – naturally occurring opioids.
Opium (Gk) juice in reference to poppy juice from opium poppy (Papaver sp)
Morphine (prototype) – isolated by Sertürner in 1803 and named it after Morpheus
Profound analgesia, sedation and euphoria
Endorphin - endogenous opioid peptides -endomorphins, dynorphins, enkephalin
Narcotic - refers to any agent that induces sleep(nonspecific)
4. Pharmacokinetics
Absorption
Well absorbed enterally or parenterally.
Transdermal patches, Rectal suppositories, buccal transmucosal (lozenges)
Oral route – 1st pass effect
Serum therapeutic doses reached 1 to 2hrs after oral ingestion
Heroine –IV (1 min) inhalation (3 -5 min) or SC (10 min)
Distribution
High volume of distribution – can cross BBB
Predilection for highly perfused tissues (brain, lungs, liver, kidneys, and spleen)
Adipose tissues – poorly perfused but serve as reservoirs
5. Pharmacokinetics
Metabolism and Excretion
All opioids undergo hepatic metabolism and renal elimination
The more polar the less the CNS effects and the more excretable
Renal impairments increases the risk of toxicity
1. Morphine undergo glucuronidation
morphine-3-glucuronide (M3G) - neuroexcitatory properties
morphine-6-glucuronide (M6G) – 4-6 times more potent analgesia
2. Heroin (diacetylmorphine) is hydrolyzed to morphine.
3. Pethidine, fentanyl – hepatic oxidation
6. Pharmacokinetics
Cytochrome P45O enzyme
Codeine and Tramadol (met by CYP2D6) → Morphine & O-desmethyltramadol resp
oxycodone (met by CYP2D6) – less active metabolites
Fentanyl (CYP3A5) – inert metabolites
Polymorphism of receptor genes and Cytochrome P450 enzyme
Interindividual variability and drug interactions.
7. Pharmacodynamics
3 types of opioid receptors – mu-(µ), kappa-(κ) and delta –(δ)
CNS - Dorsal horn of spinal cord, areas of nociception, resp centre and euphoria.
Systemic – Sensory nerves, GIT, Endothelial of CVS, Immune cells.
Cellular effects on neurons
1. close voltage-gated Ca2+ channels on presynaptic nerve to reduce transmitter release.
Nociceptive nerve – glutamate, acetylcholine, norepinephrine, serotonin, and substance P.
2. Hyperpolarize postsynaptic neurons by opening K+ channels
Activation of descending inhibitory pathways that inhibit pain transmission neurons.
8. Clinical Application
Analgesia – MI, renal colic, cancer patient, obstetrics
Antidiarrheal effects – loperamide, lomotil
Antitussives – codeine in cough mixtures
Anti-Shivering – pethidine
Anaesthesia – pre-medicant due the sedative, anxiolytic, and analgesic effects.
Main anaesthetic medication
Adjunct with other agents intra-operatively
Regional anaesthesia – epidural or subarachnoid space
9. Epidemiology
United Nations Office on Drug and Crime (UNODC)
The global prevalence of opiate (heroin, morphine, and opium) - 0.4% of the population aged 15-64 years.
The global number of opiate users increased from 17.7 million in 2015 to 19.4 million in 2016
70,000-100,000 people die from opioid overdose each year
40 million pills of counterfeit tramadol were seized at the port of Cotonou, Benin in 2016 – INCB.
Benin, Nigeria, Ghana, Togo, Niger, Sierra Leone, Cameroon and Cote d’Ivoire – Tramadol
CDC in the US in 2010
enough opioid analgesics were sold to medicate every American adult with a typical dose of 5 mg of
hydrocodone every 4 hours for 1 month
10. Street Names
Morphine – M, Miss Emma, Monkey, China Girl, Murder-8 etc
Heroine - The Dragon, Snowball, Tar, White, White Nurse.
Tramadol – Chill pill, Tramal Lite, Trammies,
Super Tramadol-X 200 brand are known in Cameroon as ‘tomatoes’
13. Diagnostic Strategies - History
People at risk of opioid overdose
1. People with opioid dependence
Reduced tolerance ( after incarceration or rehab)
2. People on prescribed opioids
3. Combined with other sedatives
4. Other co-morbidities --- lung disease, liver or renal impairment
5. Household members of people in possession of strong opioids (children)
14. Diagnostic Strategies - History
People likely to witness an overdose (Source of history)
1. People at risk of an opioid overdose, their friends and families
2. people whose work brings them into contact with people who overdose
health care workers and the police,
Emergency service workers,
People providing accommodation to people who use drugs,
Peer education and outreach workers
3. Time of ingestion, quantity, and co-ingestants.
4. Pill bottles, drug paraphernalia, or eyewitness accounts may assist in the diagnosis
15. Clinical Features
Opioid Toxidrome --- CNS depression, Resp depression, and Pupillary miosis
Needle track are sometimes evident
Skin-popping (SC) and Mainlining (IV)
Powdery substances may be seen on around the nose.
Pruritus, flushed skin, and urticaria
Febrile – (co-infections OR co-ingestants – cocaine OR adulterants – scopolamine)
Physical injuries
18. Clinical Features
Gastrointestinal
Nausea & Vomiting
Constipation and in severe cases paralytic ileus (absent bowel sounds)
Kidneys and urinary tract
urinary retention from urethral sphincter spasm and decreased detrusor tone
Heroine nephropathy
19. Clinical Features
Nervous system
Reduced GCS, Euphoria, analgesia and reduced mentation (drowsiness)
Seizures – pethidine, propoxyphene, tramadol
Acute psychosis anxiety, agitation and dysphoria – less frequent
Miosis in overdose (sometimes a red eye)
Mydriasis -Morphine, pethidne, diphenoxylate/atropine (Lomotil), propoxyphene and CNS hypoxia
Hearing loss
Hypertonicity, myoclonus, and seizures – pethidine and propoxyphene
20. Special CNS Features
Parkinsonian symptoms – Bradykinesia, rest tremors, rigidity, and postural instability
Pethidine produced in street labs - MPTP metabolites
Focal lesions in Substantia nigra.
Heroine Associated Spongiform leukoencephalopathy (HASL)
psychomotor retardation, dysarthria, ataxia, tremor etc
Chasing the dragon
Serotonin Syndrome
Caused by ingesting 2 or more serotonergic drugs (MAOI, SSRI, TCA etc)
Pethidine, Tramadol, fentanyl, oxycodone, hydrocodone.
21.
22. Diagnostic Strategies - Investigations
Biochemistries: RBS, BUE and Cr
SPO2 monitoring
Arterial blood gases
A 12-lead ECG – propoxyphene or methadone
QRS widening, QT prolongation or torsades de pointes.
Chest X-ray - hypoxemia and coarse crackles (rales)
Abdominal X-rays – Body packers/mule.
Urine toxicology screen - positive for days after last use
Serum acetaminophen and salicylate concentrations
24. Supportive Treatment
Supplemental Oxygen – Bag and mask, Endotracheal tube
Correction of dehydration and/or electrolyte imbalance – IV RL or NS
Correction of Hypoglycaemia
Abortion of any seizures - Diazepam
GIT Decontamination
Body packer, multi-drug ingestion or opioid combination products
whole-bowel irrigation and activated charcoal
Continuous cardio-resp monitoring
Dialysis cannot clear opioids
25. Treatment: Antidote
Antidote – Naloxone*, Nalmefene
Indicated in case of significant cns and resp depression
Naloxone
Onset (1 – 2)min; Maximal effect (5-10)min; Duration of action (1 to 2hrs)
IV Naloxone (0.4 to 2 mg ) for adults
IV Naloxone ( 0.1 mg/kg in the children < 5yrs ) OR (0.1-2mg/dose in children >5yrs)
0.1-0.4 mg of IV aliquots every 1-2 minute until ventilation is adequate
Chronic users - 0.04 to 0.2 mg and then slowly titrated up gradually (avoids acute withdrawal)
IM Naloxone – 2mg stat
Intranasal spray (Narcan Nasal Spray) – 0.4mg/spray.
Reconsider the diagnosis if the patient fails to respond after 10 mg.
27. Admission and Discharge Criteria
Asymptomatic adults – observed for at least 4hrs
Asymptomatic children – at least 24hrs
Adults with resp depression – admitted for 12-24hrs
Length of detention – dependent on opioid half life.
Diphenoxylate-atropine (Lomotil) – has long T1/2
Asymptomatic Body packers – discharged after passing out all packets
Psychiatric evaluation or drug abuse counseling
Discharge to a stable social setting
30. Withdrawal
CNS excitation, (Restlessness, agitation, anxiety and mydriasis).
Cognition and mental status are unaffected.
Dysphoria and drug craving may be severe and prolonged
Nausea, vomiting, diarrhea, and abdominal cramps
High BP and pulse, tachypnea
Onset depends on drug meperidine (8-12 hrs) and methadone (2-4 days)
Symptoms peak between 36 and 48 hours and subside after 72 hours
Treatment is symptomatic
Clonidine
Avoid using opioid routinely
31. New York Time – Opiophobia has left Africa in Agony
Despite that risk, under no circumstances should adequate pain relief ever be withheld simply
because an opioid exhibits potential for abuse or because legislative controls complicate the
process of prescribing narcotics .
(Katzung Basic Pharmacology)
32. References
Rosen Emergency Medicine 8th Edition, Opioids
Medscape, Opioid toxicity
Nelson Textbook of Paediatrics 20th Edition, 2015
Katzung Basic Clinical Pharmacology 12 Edition
WHO Critical Review Report : Tramadol 2018
WHO Community management of opioid overdose 2014
Editor's Notes
Opioid is more precise and is the correct medical term for the agents that act on opiate receptors in the body
Methadone - Tolerance and physical dependence develop more slowly and withdrawal effects are milder
Opioids - Available alone or in combination with other agents (e.g., acetaminophen and salicylates).
However, because of the first-pass effect, the oral dose of the opioid (eg, morphine) may need to be much higher than the parenteral dose to elicit a therapeutic effect.
Very important, particularly after frequent high-dose administration or continuous infusion of highly lipophilic opioids that are slowly metabolized, eg, fentanyl
The opioids are converted in large part to polar metabolites (mostly glucuronides), which are then readily excreted by the kidneys.
Some of the opioid are rendered inerts by the liver and excreted by the kidneys.
Others like tramadol, codeine and small amounts of morphine are converted to more potent analgesics
30% of individuals of European descent and 50% of Asian descent,8 which is associated with increased dosage requirements for pain control
This spinal action has been exploited clinically by direct application of opioid agonists to the spinal cord, which provides a regional analgesic effect while reducing the unwanted respiratory depression, nausea and vomiting, and sedation that may occur from the supraspinal actions of systemically administered opioids.
Diminished largely because a number of effective synthetic compounds have been developed that are neither analgesic nor addictive.
Non-infective diarrhoea
Direct toxic effects are extensions of their acute pharmacologic actions.
Acute lung injury - Acute lung injury is a disorder of acute inflammation that causes disruption of the lung endothelial and epithelial barriers. The alveolar–capillary membrane is comprised of the microvascular endothelium, interstitium, and alveolar epithelium.
Condition in which fluid collects in the air sacs of the lungs, depriving organs of oxygen
Mechanisms include opioid-induced delayed gastric emptying, direct stimulation of the chemoreceptor trigger zone, and vestibular stimulation
Dysphoria is a state of generalized unhappiness, restlessness, dissatisfaction, or frustration
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyri-dine) - a side product during synthesis of a meperidine analogue
Psychomotor retardation involves a slowing-down of thought and a reduction of physical movements in an individua
Heroine Associated Spongiform leukoencephalopathy (HASL) rare condition that is characterized by progressive damage (-pathy) to white matter (-leuko-) in the brain (-encephalo-), particularly myelin
twisting of peaks"), is a specific type of abnormal heart rhythm that can lead to sudden cardiac death. It is a polymorphic ventricular tachycardia that exhibits distinct characteristics on the electrocardiogram
The differential diagnosis encompasses all causes of depressed mental status
coexistence of miosis and respiratory depression greatly narrows the possibilities.
1. activated charcoal (1 g/kg in children and 50-100 gin adults)
2. Abortion of any seizures - Correction of hypoxia, hypoglycaemia or electrolyte imbalance.
Competitive antagonists and and can reverse all the receptor-mediated actions of opioids.
Naloxone - Excellent safety profile
Nalmefene – longer T1/2 (8 to 11)hrs = IV 0.5 to 1.5 mg (stop when clinical response has been achieved)
IM or intranasal naloxone. Clinical reversal occurs within 5-10 minute
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Although opioid withdrawal can be uncomfortable, it is not life-threatening