Fentanyl and Novel Psychoactive Substances 2023 PDF

Fentanyl and related opioids Graham R. Jones, Ph.D. Former Chief Toxicologist Office of the Chief Medical Examiner and Clinical Professor, Faculty of Medicine and Dentistry [email protected] Opiate vs. Opioid Opioid Refers to any chemical that activates mu-receptors (mainly in the spinal cord...

Fentanyl and related opioids Graham R. Jones, Ph.D. Former Chief Toxicologist Office of the Chief Medical Examiner and Clinical Professor, Faculty of Medicine and Dentistry [email protected] Opiate vs. Opioid Opioid Refers to any chemical that activates mu-receptors (mainly in the spinal cord and brain) • Endogenous neuropeptides • e.g. endorphins (endogenous ‘morphine’) • Opiates • Opium-derived, found naturally in opium poppy (e.g. morphine, codeine) • Semi-synthetic opioids • Derived from thebaine (from opium poppy), but not naturally occurring • e.g. hydromorphone, hydrocodone, oxycodone, oxymorphone • Synthetic opioids • Not usually structurally related to morphine • Fentanyl, methadone, tramadol, meperidine Opioid Tolerance Tolerance • The ability to withstand increasing doses with static or decreasing side effects • Tolerance can enable a person to take doses of an opioid that would kill most non-tolerant persons • Tolerance is “relative” (i.e. dose related), not absolute • Applies to any opioid • Cross-tolerance from one opioid to another occurs • e.g. if a person develops tolerance to heroin, they will also have a degree of tolerance to fentanyl • The degree of cross-tolerance can be difficult to predict Reversing Agents: Naloxone • Most common is naloxone (trade name Narcan) • Competitive antagonist binds the mu-receptor, displacing opioids that are already bound there, without activating the receptors (i.e. no analgesia) N F N F N N N N N N N Binds to mu-receptor but no activation Reversing Agents: Naloxone Naloxone half-life (t1/2) ranges from 30 to 80 minutes • Fentanyl t1/2 = 3-12 hours, so repeat naloxone injection often required • If minimal or no response within 2–3 minutes, dosing may be repeated every 2 mins to a maximum 10 mg • (e.g. 0.4 mg per injection  25 injections for 10mg) Minimal toxicity if opioids not present • (i.e. very low risk for repeat administration) Medical administration intravenous or intramuscular • Intra-nasal formulation has been available for ‘public’ use • Orally – very poor oral bioavailability, takes too long to act Are some opioids tolerant to naloxone? • Probably not… • Effectiveness depends on the dose of naloxone administered versus potency and dose of the opioid • Highly tolerant abusers using high doses will require higher doses of naloxone to reverse a coma • Some newer opioids may be more dangerous because users are not familiar to the ‘right’ dose and potency of the specific batch being trafficked • Benzodiazepines will increase CNS depression (e.g. etizolam) • Benzodiazepines NOT reversed by naloxone Medical uses of fentanyl • Short term anesthesia • Acute surgical procedures such as intubation (i.e. inserting an airway) • 50 – 200 ug intravenous • Induction of anesthesia • Often with midazolam • Adjunct to anesthesia in longer surgical procedures • Dose depends on type of surgery • Airway must be supported for higher doses and longer surgeries • Transdermal patches for long-term chronic pain • 12.5, 25, 50 and 100 ug/hour • NOT for acute or post-surgery pain • Sublingual lozenge for breakthrough pain • Dose 0.1 – 1.6 mg *Fentanyl is not “new” • Developed in 1960 by Dr. Paul Janssen • Marketed and increasingly used in the 1960s by Janssen Pharmaceutica (trade name Sublimaze) • Properties of fentanyl and other analogues studied repeatedly with animal testing in 1970-80s • Analogues included carfentanil and 3-methylfentanyl • Fentanyl and some of the original analogues are still in legitimate use • sufentanil, alfentanil, remifentanil; carfentanil (not humans) Fentanyl abuse • Highly addictive narcotic; Injectable fentanyl can be abused by medical personnel with easy access (e.g. anesthetists, nurses) • Fentanyl 50 – 100 x more potent than morphine; 25x >heroin • Transdermal patch – for chronic pain (e.g. Duragesic) – Used to be widely abused: gel patch or matrix patch (oral suck/chew); when frozen and cut called ‘chicklets’ • Abuse also as illicit tablets and powder • Local or through the Internet in non-pharmaceutical form (e.g. powder; fake tablets) • Found in counterfeit ‘Oxycontin’ 80 mg tablets 9 *Fentanyl in Alberta 2011- 2023 • Pre-2011 used to see mostly patch-related fentanyl deaths – Abused, stolen, otherwise diverted • Now almost entirely illicit non-patch related – Fake green ‘oxycontin’ tablets were common – Mostly tablets crushed or ‘shaved’ and snorted; some injected; – Now lots of “fake heroin” containing fentanyl and/or carfentanil, with little or no heroin Rapid increase in cases due to fentanyl“abuse” 2011 (6); 2012 (29); 2013 (66); 2014 (127) 2015(279); 2016 (363); 2017 (565); 2018 (667); 2019 (513); 2020 (1055); 2021 (1541); 2022 (~1500+); 2023? Look for the cement mixers… 11 How is fentanyl abused? Snorting: powder or crushed tablet TD patch: inject, chew ‘Smoking’ Injecting Less-conventional modes of abuse Nasal Spray E-Cigarette *Apparent illicit opioid overdose deaths 2011-2021 400 363 Deaths per year 350 900 800 300 Fentanyl deaths 250 Cumulative total deaths 279 700 600 200 500 150 400 127 300 100 66 50 0 * 1000 200 29 100 6 2011 0 2012 2013 2014 2015 2016 Cumulative total deaths *2021: 1547 – a 258-fold increase from 2011 *Number of apparent unintentional non-prescribed opioid poisoning deaths 2018 – Sept 2023 (mostly fentanyl and carfentanil). Alberta substance use surveillance system Updated November 2023 Note: 2022 and 2023 data likely incomplete! Alberta deaths due to an apparent drug overdose related to non-prescribed opioids, by sex and age - 2020* *Alberta substance use surveillance system 2021 Fentanyl alone? – Rarely. • Most fentanyl fatalities include a stimulant • Usually methamphetamine or cocaine, some have both • Many fentanyl related deaths include ethanol and/or prescription or illicit benzodiazepines and/or other prescription drugs • About 35% 2015 cases included xylazine (veterinary sedative) • Now making a huge ‘comeback’ across Canda and the US • Also: • Carfentanil, fluorofentanyl, acetylfentanyl, butyrylfentanyl, 3-methylfentanyl, furanylfentanyl, cyclopropylfentanyl, methoxyacetylfentanyl, etc. • Now also “nitazines” and brorphine *Fentanyl poisoning deaths (unintentional) in Alberta, by most common additional substances causing death and year. Fentanyl Cocaine Alberta substance use surveillance system Updated November 2022 Carfentanil Methamphetamine Some perspective on fentanyl dose… • Estimated fatal dose of fentanyl (non-medical) • 0.5 – 1.0 mg (presuming low tolerance and IV administration) • will be lower with alcohol or depressant drugs • will be higher with tolerance, >2-3 mg • 1 mg is not a lot of powder! • ‘fake Oxys’ used to contain variable amounts of fentanyl (1-4 mg) • But not always fentanyl. May be carfentanil or another drug. Why fentanyl? • Highly addictive and popular • Easy to buy over the Internet • Dose for dose is about 1/1000th weight of cocaine • Dose for dose is about 1/20th weight of uncut heroin • Relatively easy to traffic in pure form • Canadian and U.S. fentanyl originally originated mainly from Asia (mostly China?). Now extensively from Mexico and some other countries. • Precursor chemicals shipped from China and fentanyl synthesized in Mexico 20 Carfentanil • Estimated 100x more potent that fentanyl (based on animal studies) • Very restricted veterinary use for large animals • Fatal doses could be as low as 10 – 20 MICROGRAMS!! Carfentanil Fentanyl 21 *When did carfentanil become an abused drug? • Reports of carfentanil abuse in eastern Europe 2012 & 2013 • May 2016: 4th International Conference Novel Psychoactive Substances discussed carfentanil abuse in Europe. • June 27 2016: 1 kilo of carfentanil seized by Canadian Border Services in Vancouver, destined for Calgary (10 – 20 ug can be fatal!) • July 2016: start(?) of media reports of deaths from carfentanil tainted heroin in Ohio, later Michigan, Florida • August 2016: first Alberta death due to carfentanil • 402 carfentanil related deaths Q3 2016 – Q1 2020 *Fatal dose of carfentanil?? More recent opioids – “nitazenes” • Isotonitazene was first detected in an Alberta death in 2019 • • • • • Estimated to be approx. the same potency as fentanyl Some nitazenes estimated to be up to 20x more potent than fentanyl Classed as benzimidazole opioid analgesics Benzimidazoles investigated as analgesics in the 1950s by CIBA / Novartis Several nitazenes now identified across Canada / U.S. since 2019 • Isotonitazene, butonitazene, etodesnitazene, metonitazene, flunitazene, protonitazene, • desethyl isotonitazene, N-pyrrolidino etonitazene, and brorphine (chemically related) Isotonitazene Benzodiazepines as fentanyl adulterants • Pharmaceutical benzodiazepines: • Alprazolam, bromazepam, clonazepam, diazepam, nitrazepam • Illicit benzodiazepines (illicitly synthesized or not licenced in Canada): • Adinazolam, bromazolam, clonazolam, desmethylgidazepam, desalkylflurazepam, deschloroetizolam, diclazepam, estazolam, etizolam, flualprazepam, flualprazolam, flubromazolam, flubromazepam, fluclotizoam, meclonazepam, pyrazolam, …etc. Case Report: Very sudden death of an opioid addict • Middle-aged male, long-standing opioid/fentanyl addict • Lapses into opioid withdrawal (shakes, sweating, nausea) • Girlfriend contact their drug dealer and arranges a supply • Girlfriend fetches the supply, ‘cooks’ the powder in a spoon and the male then injects himself • Male almost immediately loses consciousness and shortly after stops breathing; girlfriend calls 911 after a few minutes • Paramedics able to partially resuscitate the addict (ROSC), but male declared dead after about 2 hours • Toxicology on postmortem blood: • Fentanyl 25 ng/mL, etizolam 5 ng/mL, flualprazolam 15 ng/mL, xylazine 30 ng/mL, methamphetamine 45 ng/mL, plus metabolites and naloxone • Cause of death: fentanyl toxicity contributed to by benzodiazepines and xylazine How to increase the success of finding the more potent fentanyl and other opioid analogues: • Seizing and analyzing drug paraphernalia • Higher concentrations make for easier detection • Provides authentic drug source for new drugs • Optimizing and/or developing new analytical methods • Applying to purchase more sensitive equipment • Investigating screening urine samples (likely more concentrated) • Information gathering • • • • • Keeping in touch with colleagues (Canada, USA and elsewhere) Contact with police agencies, Health Canada Reading current scientific literature, news articles Following popular drug related ‘blogs’ Looking at ‘research chemicals’ that are being offered • Now many more sources of information that at the start of the opioid “epidemic” Other ‘Novel’ Psychoactive Substances Stimulants, Psychedelics & Hallucinogens • Cocaine • Amphetamines • Phenethylamines • 2C-X series and N-BOMe drugs • Cathinones (aka “Bath Salts”) • Tryptamines • Others (LSD, PCP, mescaline, psilocin) 29 Cocaine • Powerful stimulant, local anesthetic, highly addictive • Used routinely in lower doses in (some cultures in South America) • Still very widely abused • Widely adulterated: – [Diltiazem – cardiac drug] – [Hydroxyzine – antihistamine / sedative] – Levamisole - anticancer / veterinary de-worming agent • Life-threatening blood discrasias (agranulocytosis / neutropenia) – Phenacetin – Obsolete OTC analgesic (“Superbuff”) • Kidney damage (and carcinogenic?) 30 Amphetamines • Methamphetamine / amphetamine – Methamphetamine may be “crystal meth” – Amphetamine a metabolite and used for ADHD, narcolepsy, weight-loss • “Ecstasy” group – MDMA (methylenedioxymethamphetamine) – MDA (methylenedioxyamphetamine) – MDEA (methylenedioxyethamphetamine) – PMMA (paramethoxymethamphetamine) – PMA (paramethoxyamphetamine) – Many others (e.g. DOB, DOM, TMA) • Methamphetamine has become a MAJOR contributing factor in the opioid crisis 31 Psychopharmacology of cocaine and methamphetamine • Cocaine and methamphetamine both stimulate release and block reuptake, to varying degrees of dopamine, serotonin and norepinephrine, causing increased stimulation of the CNS, cardiovascular and other systems. • Abuse leads to tolerance and eventually massively increasing doses, sleep disturbances, psychosis, potentially violent and aggressive behavior (esp. meth!). • The biggest difference between the drugs is half-life: cocaine 0.5 – 1.5 h; methamphetamine 10 – 15 h. • A methamphetamine “binge” can last 2 – 3 days and involve doses of up to 1000 mg or more a day (may be in 100 – 250 mg doses; ‘therapeutic’ 5 – 20 mg). • Users will “crash” after 1 – 3 days depending on “supply” and onset of increasing fatigue due to lack of sleep, even though blood methamphetamine may be high. • Neurotransmitter levels in the brain may be depleted and sensitivity of neurons to methamphetamine decreased. Cocaine, methamphetamine and other stimulants can cause psychosis • Psychosis • A severe mental disorder in which thought and emotions are so impaired that contact is lost with external reality. • Can be a form of medical illness unrelated to drugs, or can be caused by alcohol or drug use. Can include: • Delusional behavior • Where a person has strong beliefs that are not shared by others • A common delusion is someone believing there's a conspiracy to harm them (aka paranoia). • Hallucinations • Where a person hears, sees and, in some cases, feels, smells or tastes things that do not exist outside their mind but can feel very real to the person affected by them; a common hallucination is hearing voices. • Delirium • A temporary mental state characterized by confusion, anxiety, incoherent speech, and hallucinations. *Case #1: Police shoot man who threatened them with a firearm • Police saw a man sleeping in his vehicle by the side of the road. He seemed harmless, so they continued on patrol. • Sometime later the same patrol found the vehicle was still in the same position and the man still appeared to be sleeping. • The police knocked on the car window to make sure than man was OK. • The man woke up, glared at the police shouted “f**k you police” and started to pull a rifle from between his legs in a threatening manner. • Police fired multiple shots at the man, killing him. *Case #1: Autopsy and toxicology • Autopsy: confirmed multiple gunshot wounds including to the heart and other organs. • Toxicology (femoral blood): • • • • • • • Ethanol – 40 mg/100 mL Methamphetamine – 1880 ng/mL* Amphetamine – 180 ng/mL Cocaine – detected (less than 20 ng/mL) Cocaethylene – trace amount Benzoylecgonine – 130 ng/mL Delta-9-THC and carboxy-THC detected in cavity blood (*Peak blood level ~20 ng/mL after 12.5 mg methamphetamine) • But how can a person with such a high blood methamphetamine sleep – possibly for “hours”? *Case #2: MV Accident causing death of passenger • A family was traveling by car very early in the morning when it left the road and crashed into a tree, with children in the back seat (one of the children died). • Collision analysts said the vehicle appeared to leave the road well prior to a bend with no evidence of braking. • The driver was unresponsive while fire department personnel were extracting him from the car, but woke and became incoherent and very agitated when EMS personnel tried to assess him. They subsequently sedated him with midazolam. He suffered non-life threatening injuries. • Police found methamphetamine in the vehicle. • Toxicology testing on the driver’s blood drawn about 3 hours after the accident found methamphetamine (160 ng/mL) and amphetamine (21 ng/mL). Midazolam and ketamine were also detected, resulting from medical treatment. • It appears the driver fell asleep and left the road despite having a significant concentration of methamphetamine in his blood. *Case #3: Cocaine excited delirium death • Police were called to a downtown location because a man was reported to be causing a disturbance and acting in an excitable and very erratic manner. • Notably, he was trying to attack a public transit bus with a baseball bat. • Police were finally able to apprehend him and paramedics were able to sedate him and transfer him to a gurney. • However, he was still violently struggling so they restrained his arms and legs. • He died suddenly while he was being transported to the emergency department and could not be resuscitated. Excited delirium – What is it? • A potentially fatal state, involving extreme agitation and delirium, and potentially violent behavior (aka: “agitated delirium”). • Often related to the acute abuse of cocaine, methamphetamine or other powerful stimulants, but not always • May involve “super-human strength”. • Deaths are not necessarily related to blood concentrations of drugs (if involved). • Deaths may be related to restraint by police or medical personnel. • Not necessarily restraint that causes asphyxia. • Recognized by NAME and the American College of Emergency Physicians. • Not recognised by the American Medical Association “as a medical diagnosis unless clear diagnostic criteria are validated”. • AMA opines that apparent “excited delirium deaths” frequently involve heavy police restraint (sometimes dangerously so, such as “hog tying”), and disproportionately persons of color. Methamphetamine vs. MDMA vs. PMMA • ALL can kill at higher doses • Initial effects: stimulant, wakefulness, hyperactivity, risk-taking, mydriasis • Toxicity: jerky movements, muscle rigidity, hyperthermia, reduced consciousness, rhabdomyolysis, coma, death • MDMA so-called ‘love drug’ (serotonin effects) • PMMA has similar effects, but: • Slower to act; less potent initially • Users may take additional doses • Increased lethality compared to MDMA 39 *Ecstasy / Molly= MDMA? • Not necessarily • Can be • Methamphetamine • Dextromethorphan • Benzylpiperazine &/or TFMPP • Cocaine • Ketamine • Nicotinamide • Caffeine • Anything else, or Nothing • Dose may vary enormously • In 2012…PMMA caused 20 deaths in Alberta and 7 in BC. 40 Other Toxic Phenethylamines • Phenethylamine – Structurally related to amphetamine – Has been used as a ‘weight’ loss ingredient – Putrefactive amine seen in decomposing samples • Substituted phenethylamines have stimulant and psychedelic properties – Most common are 2C-X series: 2C-B, 2C-C, 2C-I etc. • Detection: not as easy as methamphetamine, but a good lab should be able to detect if they know what to look for (need a current mass spectral database) • What distinguishes these drugs? • Degree of psychedelic properties and overt toxicity 41 Phenylethylamine Cathinone 42 *2C- structures vs. phenethylamine • Substitute different elements or groups in the 3 and 4 positions • 2 and 5 positions are 2, 5methoxy • Numerous different combinations 43 ‘N-Bombs (NBOMe) • Very potent derivatives of the 2C-X family of phenethylamines with effects similar to LSD • Strongly hallucinogenic, toxic, lowdose drugs • (sub-milligram doses 0.05 – 0.8 mg) • 25I-NBOMe is the most common, but also • 25B-NBOMe, 25C-NBMe, 25HNBOMe, 25N-NBOMe • Very difficult for laboratories to detect in body fluids!! 44 *NBOMe Cases – from the literature • Case 1: 21 y.o. took ‘acid’ and developed a sudden rage, flailing about violently and eventually unconsciousness. Had multiple external injuries due to the flailing, but none fatal. • Blood 25I-NBOMe 4.7 ng/mL • Case 2: 15 y.o. took ‘acid’ at a rave, developed bizarre behavior, multiple external contusions, hyperthermia, deteriorated and died. • Blood 25I-NBOMe 16 ng/mL • Case 3: 19 y.o. took ‘acid’, developed bizarre, paranoid behavior and fell (flew?) from 7th floor of a building; died from injuries. • Blood 25I-NBOMe 0.4 ng/mL 45 “Bath Salts” – the Cathinones • Cathinone – found in Khat • Used by some African cultures, much as some South Americans chew coca leaf and ‘Europeans’ use caffeine • The ‘Bath Salts’ designer drugs are substituted and modified cathinone • At least 30 are/were relatively common • Stimulants with some psychedelic activity • Examples: • methylenedioxypyrovalerone (MDPV), mephedrone, pyrovalerone • ethcathinone, butylone, fluoromethcathinone, methedrone 46 Canada vs. USA – The Legislative Differences • Canada: • Federal drug laws (Controlled Drugs and Substances Act – CDSA) • Controls specific named substances, but also chemically related drugs that may have a similar pharmacological effect • USA: • DEA (Drug Enforcement Administration) has “federal” rules, but slow to add new substances • Did have Federal Analogue Act 1986 but sometimes difficult to get a prosecution • e.g., what is an analogue (how similar to a scheduled drug) • Also state control of illicit substances, but huge variation from state to state, plus states are also slow to add substances and on a very ad hoc basis 47 Summary of the Non-opioid ‘Designer Drugs’ Cocaine: still a major abused stimulant Amphetamines: (mainly stimulant, some with “feel good” properties) Methamphetamine (MAJOR resurgence) 3,4-Methylenedioxymethamphetamine (MDMA) 3,4-Methylenedioxyamphetamine (MDA) Paramethoxymethamphetamine (PMMA – much more toxic than MDMA) Phenethylamines: (stimulant plus psychedelic) Phenethylamine (illicit diet medication) 2C-X series (at least 50 known, some extremely toxic) N-BOMe series (also substituted phenethylamines, but highly potent and toxic hallucinogens with LSD-like effects) Cathinones: (Khat: mild to moderate stimulant related to ephedrine) Designer cathinones (aka ‘Bath Salts’) are more potent and have more psychedelic activity [Tryptamines: (chemical analogues of the neurotransmitter tryptamine) Stimulants with some hallucinogenic activity; at least 55 described in the literature e.g. 5-Methoxy-diisopropyltryptamine (“Foxy”), psilocybin/psilocin, LSD, ibogaine LSD analogues are illicitly available] – not covered in these lectures PCP, ketamine: (anaesthetics with hallucinogenic and dissociative side-effects) Synthetic analogues illicitly available Cannabinomimetics: (synthetic cannabinoids; 100s known) May or may not have cannabis-like effects Most are untested in humans and potentially very toxic 48