by Aldo Emigdio Bartolini Salinas and Jesús Daniel López Tapia
A 22-year-old male was brought to the emergency room by EMS at 7 pm. His parents arrived at the hospital and mentioned that this was not the first time their son had a similar event. The patient was lethargic upon his arrival so clinical history was difficult to obtain from the patient and the parents had no additional information to provide.
On physical examination, the patient was lethargic and slightly bradycardic with 59 bpm, his respiratory rate was 14 per minute. Body temperature was stable at 36.6°C and blood pressure was 105/80 mmHg. Oxygen saturation at room air was 94%. Bilateral pupils were miotic, but no clear measurement was obtained. On auscultation, cardiac and lung sounds were rhythmic and stable. Neurologic examination was accurate. Gastrointestinal auscultation showed hypoactive bowel sounds. When blood pressure was measured there were needle marks on both of his forearms. The rest of the systematic evaluation was normal. Electrocardiogram and laboratory studies were made to rule out other possible diagnoses.
Critical Bedside Actions and General Approach
In an emergency setting, evaluating circulation, airway, breathing and vital signs are a priority.
Attention must be paid to respiratory rate; pulse oximetry must be done to evaluate oxygen saturation while additional studies are being performed. A ventilation mask with supplementary oxygen to 100% must be given. Eyes, mental status, and skin should be examined. Miotic pupils, euphoria and skin marks are usually found in opioid-intoxicated patients.
A thorough clinical history and physical examination must be done. Further details will be discussed in this chapter.
According to the United Nations Office on Drugs and Crime, in 2010 there were more than 15 million opioid consumers worldwide. Opiates are withdrawn from the poppy plant (Papaver somniferum), these substances have psychoactive properties and are processed into natural, synthetic and semi-synthetic methods of use. These substances have been used in cultural, recreational and medicinal settings. Unfortunately, opioid derivatives such as prescription drugs and “recreational” drugs like heroin have been motive of abuse and intoxication, being the number one illicit drug on the market with more deadly outcomes due to abuse.
Opiate pharmacokinetics, toxicology, clinical manifestations, and management will be broadly discussed in this chapter.
Worldwide opioid abuse, dependence, and intoxication have been increasing in numbers. As of 2015, the United States had an approximate of 2.6 million opioid consumers and addicts. This number includes opioid addicts due to pain relievers and non-prescription opioid consumption. It is vital to consider that heroin use via injection is responsible for the transmission of HIV and hepatitis C. In Russia, Central Asia, and Ukraine, it is responsible for 60-70% of all HIV infections.
Gender distribution of opioid abuse is more common in men than women, ranging in a 3:1 (M: F ratio) for heroin and 1.5:1 for prescription opiates. The most common age of consumers is of 26 years or younger.
Pharmacokinetics and Toxicology
Opioid-related sites in the brain are hypothalamus, thalamus and the limbic system. They bind competitively to an opioid specific receptor. To this date, three specific receptors have been identified: mu (µ), delta (δ) and kappa (Κ). An opioid-receptor like-1 is still under investigation. These subtypes have a specific and different effect on the body. They are capable of producing cAMP (adenylate cyclase), closing/opening calcium and potassium channels, leading to the ability to hyperpolarize the cell and modulating neurotransmitter release.
There are three action category;
Opioids can be consumed orally, by snorting and by subcutaneous or intravenous injection. Its effects vary depending on their site of administration, dose and the type of opioid consumed. If it is taken orally, it may take about six hours to have its maximum effect (methadone) and its clinical effect may persist for 24 to 48 hours. When snorted, its peak effect is usually 30 minutes after. When injected subcutaneously, it may take just about 15 minutes. It may show an immediate effect when done intravenously.
Three main effects caused by opioid consumption are analgesia, euphoria, and anxiolysis. Analgesia occurs by inhibiting transmission from the peripheral nerve to the spinal cord. Anxiolysis happens when opioids act upon noradrenaline releasing neurons located in the locus coeruleus. Euphoria is related to the mesolimbic system dopamine increase.
Most opioids are metabolized by the liver to active metabolites and excreted by the kidneys. They have a large distribution volume of 1-10L/kg and are protein-bonded in most cases, which makes hemodialysis a problematic way for opioid clearance.
History and Physical Examination Hints
Opioids affect the body in various ways. The more consistent clinical effects of opioids are a depressed respiratory rate, changes in mental status, decreased bowel sounds and pupillary constriction (miosis). Additional findings include hypothermia, bradycardia, hyporeflexia, dermal marks.
Pupillary constriction (miosis) is frequent in opioid intoxication. However, normal pupils or mydriasis (pupil dilation) are possible when the patient takes a stimulant simultaneously or when the in case of extended respiratory depression. Therefore, normal pupil examination does not exclude the possibility of intoxication. A thorough and careful examination is a must.
Check respiratory rate to evaluate a suspected opioid-intoxication. A respiratory rate below 12 bpm is a great predictor of toxicity. The pulse oximeter shows oxygen saturation, but a normal reading does not exclude hypercapnia. Monitoring respiratory ventilation via end-tidal CO2 monitoring and capnography helps to assess diagnosis and possible complications.
Noncardiogenic pulmonary edema is frequent in opioid intoxication. The symptoms include cyanosis, pink bronchial secretions, and rales (with all the additional symptomatology of intoxication). It is usually resolved once a normal respiratory rate and ventilation are obtained. Cardiovascular changes, mostly bradycardia and hypotension is due to an increase in parasympathetic activity and release of histamine. Lethal ventricular tachyarrythmias might occur.
Gastrointestinal changes include decreased bowel sounds, peristalsis, and constipation. Additionally, renal changes, particularly renal failure due to rhabdomyolysis may be present (from heroin and methadone abuse). Skin marks due to “skin popping” may be present secondary to subcutaneous injection. Changes in the reproductive system include changes in menstrual cycles, infertility, abnormal prolactin secretion, and decreased libido.
Generally, clinical manifestation is enough for diagnosis. When in doubt, laboratory and imaging findings may be helpful. The most common differential diagnoses are the following.
- Drug-induced toxicity
- Ethanol toxicity produces none or little miosis and no gastrointestinal changes. Withdrawal produces hyperthermia and seizures.
- Sedative-Hypnotics toxicity causes less respiratory depression and ataxia in children. Withdrawal produces hyperthermia and seizures.
- Clonidine toxicity causes miosis, hypotension, bradycardia and no gastrointestinal changes.
- Hypoglycemic agents
- Organophosphate toxicity causes miosis, vomiting, diarrhea, bradycardia, hypotension or tachycardia and hypertension.
- Any medical condition that causes coma.
Emergency Diagnostic Tests and Interpretation
History and physical examination are generally sufficient to make a diagnosis. In some complicated cases, laboratory studies, urine screening tests and cardiac screening are recommended.
- Serum or finger-stick glucose measurement (to rule out hypoglycemia)
- Serum acetaminophen concentration (in case of suspected concurrent use with opioids, to rule out suicidal attempt with acetaminophen)
- Serum creatine phosphokinase, blood urea nitrogen, creatinine, urinalysis and serum electrolytes (to rule out rhabdomyolysis).
- Serum ethanol level (to rule out intoxication)
- Blood gas measurement.
- Basic metabolic panel
Urine toxicologic screenings
- Opioids can be detected in urine samples in a maximum period of two days.
- Routine urine toxicologic screens are not recommended. They confirm recent abuse, but not acute toxicity.
- They can report many false positive results.
- Electrocardiographic (ECG) evaluation is strongly recommended in patients who present palpitations, syncope, chest pain and dysrhythmias.
- If the initial ECG is normal, a control ECG should be repeated 4-6 hours after.
- If the initial ECG shows abnormalities such as QT or QRS prolongation, cardiac monitoring should be done until a normal rhythm.
- Some specific cardiac disturbances are presented in the following abused substances:
- Methadone: torsade de pointes, QT prolongation.
- Loperamide: QT or QRS prolongation, ventricular tachycardia.
- Oxycodone: QT prolongation.
- Plain chest X-rays are reserved for patients who present with symptoms of aspiration pneumonia, respiratory distress syndrome, uncorrected hypoxia or abnormal sounds during lung auscultation.
Emergency Treatment Options
In an emergency setting, evaluating circulation, airway, breathing and vital signs are a priority. Ventilatory support should be given with a bag mask and 100% oxygen to patients with respiratory distress or when the proper respiratory function has been jeopardized. If the patient has oxygen saturation above 90% and more than 12 breaths per minute at room air, observation is adequate. However, if oxygen saturation drops below 90%, supplemental oxygen, bag mask and 0.05 mg intravenous naloxone must be administered to restore normal ventilation. If the blood glucose is 60mg/dl or less, administer glucose intravenously.
The first line treatment is Naloxone, a lipophilic, short-acting opioid antagonist, that can effectively reverse opiate-related symptoms. Full patient history is essential to determine whether the patient is a long-term or short-term opioid user, the type of opioid consumed, time of administration and dosage.
The recommended naloxone dose is 0.4 mg for most patients, including those with methadone abuse. It should be diluted in 10 mL of normal saline to reach 0.04mg/ml dilution. Administer 1 ml separate boluses to improve the patients’ respiratory rate above eight breaths per minute. Its clinical effects last up to approximately 70 minutes.
In patients that have abused fentanyl or other synthetic opioids, an increased dosage is recommended. No established dosing is available, but some recommend increasing naloxone dose every 2-3 minutes, starting with 0.5mg -2mg-4mg-10mg and administering a maximum dose of 15mg. Another suggested method of use is by administering naloxone every 2-3 minutes starting with 0.04mg-0.08mg-0.16mg. If respiratory rate is not improved after maximum dose, a different diagnosis must be considered.
Naloxone might be administered intravenously, nebulized and intranasally. A summary of dosage and administration route is discussed in Table.
|Intravenous Naloxone||Nebulized Naloxone||Intranasal Naloxone|
|Recommended Dosage||0.4 mg in 10 mL of normal saline (0.04mg/ml). Administration in separate boluses of 1ml.||2 mg in 3ml normal saline solution with a standard face mask.||1 mg/ml per naris
(total dose: 2mg)
|Pros.||A gentle method of opioid intoxication reversal, no acute withdrawal symptoms||Easy titration, lower risk of withdrawal symptoms.||Can be used in a patient with complicated intravenous access.|
|Cons.||Close monitoring is recommended.||No clinical data is available.||It might be difficult to titrate because of unknown absorption rates and bioavailability in humans.|
Li, K., et al (2018). Annals of Emergency Medicine, 72(1), 9–11., Stolbach, A., & Hoffman, R. (2018, April 18). Acute Opioid Intoxication in Adults. Retrieved from UpToDate: www.uptodate.com, and Yin, S. (2018, January 10). Opioid Intoxication in Children and Adolescents. Retrieved from UpToDate: www.uptodate.com
After naloxone administration, observation is recommended because symptoms may reappear in the first hour.
Pediatric, Geriatric, Pregnant patient, and other Considerations
Morphine and fentanyl might be used for moderate pain in children under 12 years of age and infants, although respiratory depression is frequent. Codeine and tramadol may be used in children older than 12 years old.
The treatment of opioid intoxication is dependent on children’s weight. 0.1 mg/kg IV naloxone (max.2mg per dose) should be administered below 20 kg. 2 mg IV naloxone is recommended over 20 kg.
Most opioids are category C and teratogenic, especially in the first trimester. If used for an extended period or during delivery (except for pethidine), opioids may cause respiratory depression in both the mother and the neonate. For chronic pain, opioids should only be given as a last resort. The safer opioids for pregnant women are codeine, morphine, pethidine, and propoxyphene. In lactation, morphine can be administered, but it must be interrupted every 4 to 6 hours. Buprenorphine and fentanyl are not recommended due to their high concentration in breast milk.
Opioid intoxication during pregnancy can result in severe respiratory distress in both the mother and the neonate. Opioid abuse causes neonatal abstinence syndrome characterized by low birth weight, CNS hyperirritability, myoclonus, hyperreflexia, sweating, vomiting, diarrhea, death, and others. Opioid intoxication during pregnancy requires a neonatologist in the team.
Geriatric population may be particularly vulnerable to opioid side effects or toxicity. Lowered doses must and well-established times and days are recommended. Caretakers should be capable and adequately knowledgeable about medication administration. In case of toxicity or abuse, care must be done by a geriatrician or addictionologist.
Respiratory or Hepatic pathology
Opioid use should be avoided. If used, close monitoring is of importance.
- Opioid overdoses with short-acting agents may be treated in the emergency department.
- Opioid overdoses with a long-acting (ex. methadone) agents or combinations must be admitted to the ICU.
- A psychiatric evaluation is recommended once the patients’ mental status and respiration rate become normal.
- Naloxone should not be administered 2-3 hours before discharge.
- In case of intentional opioid overdose (as a suicide attempt or drug addiction), the patient must be referred to a psychiatric evaluation or rehabilitation facility.
References and Further Reading
- Aghajanian, G., & Wang, Y. (1987). Common alpha 2- and opiate effector mechanisms in the locus coeruleus: intracellular studies in brain slices. Neuropharmacology, 793.
- Berling, I., Whyte, I., & Isbister, G. (2013). Oxycodone overdose causes naloxone responsive coma and QT prolongation. An International Journal of Medicine, 35-41.
- Bruneau, J., Goyer, M., Ahamad, K., Poulin, G., Selby, P., Fischer, B., . . . Wood, E. (2018). Management of opioid use disorders: a national clinical practice guideline. Canadian Medical Association Journal, 247-257.
- Degenhardt, L., Charlson, F., Vos, T., & Mathers, B. (2014). The global epidemiology and burden of opioid dependence: Results from the Global Burden of Disease 2010 study. Addiction, 1320-1330.
- Dobiesz, V., & Robinson, D. (2018). Drug Therapy in Pregnancy. In R. Walls, R. Hockberger, & M. Gausche, Rosen’s Emergency Medicine: Concepts and Clinical Practice (pp. 2277-2295). Philadelphia: Elsevier.
- Ghuran, N. (2000). Recreational drug misuse: issues for the cardiologist. Heart, 627.
- Glick, C., Evans, O., & Parks, B. (1996). Muscle rigidity due to fentanyl infusion in the pediatric patient. Southern Medical Journal, 1119-1120.
- Hoffman, J., Schriger, D., & Luo, J. (1991). The empiric use of naloxone in patients with altered mental status: a reappraisal. Annals of Emergency Medicine, 246.
- Johnson, S. (2010). Pain Management: The Use of Opioids for Chronic Pain. In M. Miller, & J. H. Macknight, Essential Orthopaedics (pp. 127-130). Philadelphia: Saunders Elsevier.
- Li, K., Armenian, P., Mason, J., & Grock, A. (2018). Narcan or Nar-can’t: Tips and Tricks to Safely Reversing Opioid Toxicity. Annals of Emergency Medicine, 72(1), 9–11. https://doi.org/10.1016/j.annemergmed.2018.05.010
- Manini, A., Stimmel, B., & Vlahov, D. (2014). Racial susceptibility for QT prolongation in acute drug overdoses. Journal of Electrocardiology, 244-250.
- Marraffa, J., Holland, M., Sullivan, R., Morgan, B., Oakes, J., Wiegand, T., & Hodgman, M. (2014). Cardiac conduction disturbance after loperamide abuse. Clinical Toxicology Journal, 952-957.
- Morales, L., González, C., & Cámara, M. (2012). Analgesia. In B. Somoza, V. Cano, & P. Guerra, Farmacología en Enfermería: Casos clínicos (pp. 91-98). Madrid: Editorial Médica Panamericana.
- Nordt, S. (1998). “DXM”: a new drug of abuse? Annals of Emergency Medicine, 794-795.
- Organización Mundial de la Salud. (2005). Opioids. In O. M. Salud, Neurociencia del Consumo y Dependencia de Sustancias Psicoactivas (pp. 79-81). Washington: Organización Panamericana de la Salud.
- Perez, A., Scribano, P., & Perry, H. (2004). An intentional opiate intoxication of an infant: when medical toxicology and child maltreatment services merge. Pediatric Emergency Care, 769-772.
- Stolbach, A., & Hoffman, R. (2017, November 29). Opioid Withdrawal in the Emergency Setting. Retrieved from UpToDate: www.uptodate.com
- Stolbach, A., & Hoffman, R. (2018, April 18). Acute Opioid Intoxication in Adults. Retrieved from UpToDate: www.uptodate.com
- U.S. Department of Health and Human Services. (2016). Facing addiction in America: The surgeon general’s report on alcohol, drugs, and health. Washington: U.S. Department of Health and Human Services.
- United Nations Office on Drugs and Crime. (2010). World Drug Report. Vienna: United Nations on Drugs and Crime.
- Viglino, D., Bourez, D., Collomb-Muret, R., Schwebel, C., Tazarourte, K., Dumanoir, P., . . . Maigna, M. (2016). Noninvasive End Tidal CO2 Is Unhelpful in the Prediction of Complications in Deliberate Drug Poisoning. Annals of Emergency Medicine, 62-68.
- Waldhoer, M., Barlett, S., & JL, W. (2004). Opioid Receptors. Annual Review of Biochemistry, 953-990.
- Yin, S. (2018, January 10). Opioid Intoxication in Children and Adolescents. Retrieved from UpToDate: www.uptodate.com
- Department of Mental Health and Addiction Services. (2018, 8 8). Prescription Drugs and Heroin Prevention & Treatment General Resources. Retrieved from Department of Mental Health and Addiction Services: http://www.ct.gov/dmhas/cwp/view.asp?a=2902&q=560348
- The following video will give you a broad perspective about opioid abuse, general practice and treatment guidelines:
- Department of Mental Health and Addiction Services. (2018, 8 8). Prescription Drugs and Heroin Prevention & Treatment General Resources. Retrieved from Department of Mental Health and Addiction Services: https://www.youtube.com/watch?v=u2sA5rwa1zM