Opioid Toxicity - Objectives Opioid Toxicity: A Poison Center and Pediatric Perspective Review Increases in Opioid-related Injuries Review the Pathophysiology of Opioid Toxicity Discuss Optimal Treatments for Opioid Toxicity Daniel E Brooks MD Medical Director; Banner Poison & Drug Information Center Center for Toxicology & Pharmacology Education and Research University of Arizona COM-Phx; Phoenix, Arizona Identify Pediatric and Unique Opioid Toxicities Greatest Increase is Exposures Greatest Increase is Exposures 1
Naloxone Use 2016 Opioid Calls to US Poison Centers Total Cases = 289,444 Increasing US Opioid Deaths Opioid Death - Case Report 2
Opioid Abuse - High School Students June, 2017 Fischbach: Cardio Young 2017 3
Case One Case One 2 YO boy is found with decreased consciousness and minimal respiratory effort. BP-60/p HR-78 RR-6 Pulse Ox-88% RA. No signs of trauma. Pupils = 1 mm. Chest - diminished effort / lungs sounds. EMTs place him on high-flow oxygen and transport. In the ER an IV is placed and he is given 2 mg of naloxone. Pt awakes immediately. 35 minutes later, he is obtunded again, receives more naloxone and then started on a naloxone infusion. 4
Case One Parents are interviewed by ED and CPS staff. The child had been in normal state of health. Case One What Happened? No illness, sick contacts or change in behavior; normal diet (breast feeding). Mother taking Tylenol #3 (acetaminophen/codeine); no pills are missing. Opiates Opiates and Opioids Naturally occurring plant alkaloids (poppy) Morphine, Codeine and Heroin Opioids = Opiates Opioids Synthetic substances (fentanyl, hydrocodone) Similar actions at opiate receptors All act on opiate receptors 5
Opiate Structures Synthetic Opiate Structures Propoxyphene Fentanyl (found in plants) Methadone Opioid Receptors Opioid Receptors Endogenous opioids (endorphins) Neuro-inhibition Separate sub-classes Opioid Type Region Effect Delta (1 and 2) Brain Central analgesia Antidepressant Dependence Kappa (1-3) К Brain Spinal Cord Spinal analgesia Sedation Miosis Chronic activation causes down regulation (tolerance, withdrawal potential) Mu (1-3) μ Brain Spinal Cord Central analgesia Hypoventilation Miosis Euphoria GI Dysmotility 6
Equivalent Opioid Doses Opioid Toxidrome Mental Status Depression Hypoventilation Miosis Opioid Complications Respiratory Depression Reduced respiratory rate and tidal volume Reduced sensitivity to hypercapnia / hypoxia Bradycardia / Hypotension (CNS, Histamine) Speedball - Sympathomimetic effects (Cocaine / Amphetamine; naloxone antagonism) Case One 2 YOM found with decreased consciousness and minimal respiratory effort. Responded to naloxone; required an infusion. Only possible exposure was mother s use of acetaminophen/codeine. 7
Codeine Toxicity Codeine Toxicity via Breastfeeding Codeine is an inactive drug that requires metabolism to an active form (morphine). There is genetic variability in a person s ability to metabolize (activate) codeine. Some people are extensive metabolizers and have abnormally high enzyme levels. Codeine Toxicity via Breastfeeding Codeine Levels After Breastfeeding Willmann et al: Nature 2009 8
Fentanyl Patch (FP) Abuse 17 YO man found unresponsive after inhaling a FP. Intubated : Pulse Ox 70% on 100% FiO 2 Vomiting and developed severe ARDS. (Hypoxic - PaO 2 ~45 on 100% FiO 2 ) Patient positioning, nitric oxide, oscillator w/o success. ECMO initiated and patient recovered on HD #9. Pizon AF, Brooks DE: Vet & Human Tox 2004 Fentanyl Patch Abuse Developed to deliver steady analgesia for 72 hrs 25 ug/hr patch contains a total of ~ 5 mg fentanyl (5,000 ug) Fentanyl remains after use 28-84% if removed early Max concentration ~ 30 hrs T ½ ~ 15 hrs Opioid Complications Hypoxic Injury Hypotension (mild) Aspiration Pneumonitis Non-cardiogenic Pulmonary Edema Withdrawal Psychosis Infection (abscess, endocarditis) 9
Opioid Complications Chest Wall Rigidity Syndrome Gastrointestinal paresis Chronic use does not result in tolerance Associated with high dose fentanyl More common in the Operating Room and during Rapid Sequence Intubation Can be treated with oral naloxone (lower doses, up to 6mg) Does not have systemic effects > 450 mcg doses Responds to naloxone Opioid Complications Chasing the Dragon - Phoenix Style 21 YOM presented to a Phoenix ED with difficulties in speech and writing for Seizures are not typically associated with opioid toxicity or withdrawal. 3-4 days. History of heroin abuse via inhalation of burning smoke: Chasing the Dragon. Alert, dysarthria, dysmetria and ataxia. Except for neonates with intra-uterine exposure Only associated with the following drugs: Brain MRI revealed gross white matter changes consistent with leukoencephalopathy. He received CoEnzyme Q-10, vitamin C and E; Propoxyphene Meperidine Tramadol Pentazocine discharged home on HD #5. 15 M F/U: improved dysarthria, ataxia remains. 10
Heroin Heroin Metabolism Semisynthetic opioid developed in 1874 Route Onset Peak IV 30 sec - 2 min 10 minutes IM or 15 minutes 30 minutes Nasal SQ 20-30 minutes 90 minutes CYP 2D6 T 1/2 ~ 6 minutes Analgesics effects can last up to 6 hrs Morphine-6-Glucuronide (active) Morphine-3-Glucuronide (inactive) Chasing the Dragon Novel Opioids Inhaling the smoke of heroin pyrolized on aluminum foil. Achieves pharmacokinetics ~ IV administration. Associated with spongiform leukoencephalopathy. Syndrome: ataxia, bradykinesia, dysarthria MRI/CT - cerebellar/cerebral white matter damage Stronger drugs are being sold on the street and internet (often mislabeled). 1970s / 80s - China white ( α-methyl fentanyl). 2006 - Get High or Die Trying (heroin/fentanyl). Recently: Carfentanil, U-47700 and m30. 11
Carfentanil Analogue of fentanyl. 1974 large animal anesthetic. 2012 Moscow theater crisis (170 deaths, 130 hostages). Nalmefene may work better than naloxone? Yong et al: Nalmefene reverses carfentanil-induced loss of righting reflex and respiratory depression in rats. EJP 2014 Opioid Potencies U-47700 Synthetic opioid developed in the 1970s ~ 8 C as potent as morphine Illicitly sold as heroin, fentanyl, Norco US deaths started to occur in April, 2016 12
U-47700 U-47700 Reportedly produces more euphoria Prince s autopsy m30 Pharmaceutical medications: oxycodone 30mg morphine SR 30mg Phoenix m30s Associated with 32 recent deaths (Phx n=18) Started ~ March 2017 Thought to originate in Mexico Illicit medications? Autopsy all found fentanyl 13
National (US) m30 Test Results Desomorphine Synthetic opioid developed in the US (1930s) Known as Krokodil in Russia Started ~ 2003; outbreak in 2010 Can be made from codeine Dermatopathology with skin bopping Purity Range: 71-97% 2 US attributed to Krokodil Meth 14
Desomorphine Associated with tissue necrosis Opioid Antagonists Naloxone (Narcan ) and Nalmefene (Revex ) Compete for binding to opioid receptors Reversal of opioid effects Naltrexone (ReVia and Vivitrol ) Very long acting antagonist (> 24 hrs) Can be given IM (q 4 weeks) Can lead to severe, prolonged withdrawal Naloxone (Narcan ) Opioid Antagonists Administered = IV, IM, or SQ (not PO) Initial Dose = 0.4 mg (dilute in 10cc, give slowly) No maximal Dose (Most patients respond to 10 mg) Onset of action = within 30 seconds Duration of Effect = ~ 45 minutes Agent Naloxone (Narcan ) Duration (maximal) Advantages 1 hr Cheap Easy to Use Disadvantages Potential for Re-dosing Nalmefene 4 hrs Longer Effect Expensive, Withdrawal Naltrexone 24 hrs Much Longer Effect Expensive, Withdrawal All work much better at μ receptors 15
Naloxone (Narcan ) Adverse Effects Withdrawal Re-sedation Hypertension / Tachycardia Non-cardiogenic Pulmonary Edema? Non-cardiogenic Pulmonary Edema Naloxone-induced catecholamine surge that impairs diastolic relaxation Increased pco 2 -induced BP and HR MÜller Effect - inspiration against a closed glottis produces negative intrathoracic pressure Naloxone Drip When to Use - if the patient requires multiple doses, or a very large dose Initial Dose = 2/3 of effect dose per hour If a patient requires a total dose of 3 mg to wake up, start naloxone drip at 2 mg/hr Stopping the Naloxone Drip Clinical examination most important Vitals and Pulse Oximetry Can slowly wean the infusion or Turn off the drip and observe the patient for 3 hours 16
Treating Opiate Withdrawal It is not as dangerous as alcohol withdrawal. It is not life-threatening. Involves pain, depression and anxiety. Opiate Withdrawal Not life threatening (neonates can seize - rare). Depends on substance / amount abused. Substances with longer T ½ have later onset of withdrawal symptoms. Methadone = 24 hrs vs. Heroin = 6 hrs. Opiate Withdrawal Signs and Symptoms Opiate Withdrawal Patients Best To Try To Anticipate Nausea Pain/Discomfort Diarrhea Piloerection Vomiting Anxiety Yawning Insomnia Patients often have multiple pain-related issues that can complicate treatment. Acute Medical Issue (why was pt admitted) Chronic pain Substance Abuse Underlying psychiatric issues 17
Treating Opiate Withdrawal Minimize symptoms with antiemetic, clonidine Treat nausea and vomiting Rehydrate with IVFs (follow PO intake) Clonidine (partial agonist at opiate receptors) Start 0.1 mg PO TID (up to 25 ug/kg/d) Long-acting Therapeutic Opiate Agents Morphine sulfate (MS Contin) SR, oral > parental Oxycodone (OxyContin) SR, shorter acting Methadone Oral > parenteral Buprenorphine National Methadone and Buprenorphine Data Buprenorphine (Buprenex, Subutex ) long-acting partial opioid agonist Buprenorphine and naloxone (Suboxone ) agonist - antagonist Boyer et al: Amer J Addictions 2009 18
Pediatric (< 6YO) ED Visits for Buprenorphine Arizona Opioid Assistance and Referral Line OAR Line 888-688-4222 Soft Start Date: Friday, February 23, 2018 (0700) Advertised Go-Live Date: March 20, 2018 (tentative) Partnership: Arizona Department of Health Service and Arizona s two Poison & Drug Information Centers Budnitz et al: MMWR 10/21/16 Take Home Points Take Home Points Opioid-related Injuries are Increasing (acute toxicity, adverse effects) Opioid-related Deaths are Increasing Increase in Opioid Dependence/Withdrawal Opiate Toxidrome CNS Depression Respiratory Depression Miosis (small pupils) 19
Take Home Points Acute Opioid Toxicity Focus on the Airway Ventilation AND Oxygenation Consider a Naloxone Drip Take Home Points Opiate Complications Tolerance and Dependence (increases in dosing) Withdrawal Treatment (MAT, behavioral health) Infections (abscess, endocarditis) Take Home Points Opiate Withdrawal is Not Life Threatening (except in neonates) QUESTIONS? (additional slides) Focus on Objective Symptoms Methadone 20mg PO QD Will Control Vast Physiological Withdrawal OAR Line 888-688-4222 daniel.brooks@bannerhealth.com 20