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Fentanyl Fentanyl Fentanyl is one of the most potent opioids used in medicine and is a being used as a street drug with sometimes fatal consequences. Pharmaceutical fentanyl is an analgesic (pain-killer) opiate 80-100 times more potent than morphine. Drug traffickers are using illicit fentanyl products as a cut in heroin and as the primary psychoactive ingredient in imitation Oxycodone pills, commonly sold as ‘Oxy 80’s’. 2 Fentanyl is an Opioid Fentanyl is a synthetic opioid (also known as an opiate). This means it is chemically manufactured. An opioid is any drug compound that binds to opiate receptors (protein molecules located on the membranes of some nerve cells) found in the brain, spinal cord and digestive tract. Opioids are drugs derived naturally, synthetically, or semi-synthetically from opium in the poppy plant. Opioids including Fentanyl are legally designated as narcotics. 3 How Do Opioids Work? Our bodies naturally make opioids called “endogenous opioids”. “Endogenous” simply means that it is produced within the body. An example of a specific kind of endogenous opioid would be endorphins, which are produced naturally in the body when we exercise. Morphine is also produced in small amounts naturally in the body. 4 How Do Opioids Work? “Opioid receptors” are specific receptors that attach only to opioids, which then cause pain relief. Opioid receptors are located in the brain, spinal cord, and digestive tract. When a person takes an opioid, such as Fentanyl or heroin, the opioids attach to the body’s opioid receptors in a lock and key manner. Once the opioids are attached to the opioid receptors, the effects of the opioid take place (pain relief, drowsiness, confusion, nausea, etc.). 5 6 Pleasure Effect of Fentanyl Opioids such as Fentanyl attach to receptors in the brain. When opiate drugs attach themselves to the body’s opioid receptors, they cause an increase in dopamine levels in the brain’s reward areas. Since dopamine is responsible for pleasure reward, attention, sleep, and mood, the body reacts by feeling euphoric, relaxed, and drowsy. Fentanyl produces a number of effects very similar to other opioid drugs (such as heroin, morphine). The main effect is euphoria (intense pleasure), and explains why it is popular as a street drug. 7 Fentanyl is an Analgesic Fentanyl belongs to a class of drugs known as analgesics. Analgesia means relief from pain. An analgesic or painkiller is a drug used to relieve pain. Analgesic drugs act in various ways on the peripheral and central nervous systems. Analgesics work in the brain to change how the body feels and responds to pain. Fentanyl is used to help relieve severe ongoing pain. 8 History of Pharmaceutical Fentanyl Fentanyl was first synthesized by Janssen Pharmaceutical (Belgium) in the late 1950s, as an alternative form of anesthesia. At the time, morphine-oxygen anesthesia was most commonly used for medical purposes, but it posed some issues: ◦ Incomplete amnesia ◦ Occasional histamine-related reaction ◦ Marked increases in respiratory depression Fentanyl was introduced into medical practice in the 1960s. Illicit use of Fentanyl first appeared in the 1970s within the medical community. 9 How is Fentanyl Used? Fentanyl is most commonly used intravenously, intramuscularly, via epidural injection, or transdermal patch (72-hour period). In powder form, Fentanyl can also be smoked, inhaled, and snorted. When pressed into pill form, Fentanyl can be swallowed and absorbed through the gastrointestinal tract. 10 Pharmaceutical Fentanyl Products Fentanyl is produced through chemical synthesis by the pharmaceutical industry. It is a synthetic (man-made) opioid sold under trade names including: ◦ Sublimaze® (injectable fentanyl citrate) ◦ Duragesic® (transdermal [skin] patch) ◦ Oralet® or Actiq® (buccal lozenge). Fentanyl lozenges (often called lollipops) sold as Oralet® deliver the drug transmucosally (through the membranes of the mouth). Note fentanyl lozenges are not available in Canada. 11 Fentanyl Patch Fentanyl is easily absorbed through the skin (transdermal absorption). Fentanyl patches work by releasing fentanyl into body fats, which then slowly release the drug into the blood stream over 72 hours, allowing for long lasting relief from pain. ◦ Takes 12 hours for onset of analgesia (pain relief) ◦ Need adequate subcutaneous tissue for absorption ◦ Takes 24 hours to reach maximum effect. ◦ Suitable for stable pain only ◦ Has a half-life of about 17 hours after removal 12 Onset of Effects of Fentanyl When injected intravenously, the effects of Fentanyl occur almost immediately. ◦ Analgesic effects last 30 to 60 minutes (100mcg) When injected intramuscularly, the effects of Fentanyl occur after approximately 8 minutes ◦ Analgesic effects last up to 2 hours (100mcg) When used as a transdermal patch, Fentanyl is slowly delivered for up to 72 hours (pain management) 13 Medical Use of Fentanyl Fentanyl provides short-duration pain relief during anesthesia as a presurgical medication, inducing anesthesia and managing pain for those patients requiring continuous opioid analgesia for chronic persistent pain relief (such as for cancer patients). It can be also used for sedation in procedures such as colonoscopies. It is often used in the operating room and intensive care unit. Fentanyl has a rapid onset and very short half-life – it needs to be delivered intravenously or in transdermal patch for constant analgesia (pain relief). Fentanyl causes similar effects as other opioids, but is less likely to cause vomiting Fentanyl is odourless and tasteless. 14 What Does Fentanyl Look Like? Fentanyl citrate comes in the form of a white crystalline powder, which is soluble in water and slightly soluble in alcohol. The transdermal (absorbed through the skin) delivery system (Fentanyl patch) is composed of four layers: 1. 2. 3. 4. Backing layer Gel layer (containing Fentanyl) Membrane layer (controlling drug release) Adhesive layer 15 Potency of Fentanyl Fentanyl is extremely potent with as little as two milligrams of fentanyl enough to cause overdose and death. Fentanyl is approximately 80 - 100 times more potent than morphine. A 100 mcg dose of fentanyl has the potency equivalent to approximately 10 mg of morphine. 1 mcg = 0.001mg. This means a tiny amount of fentanyl is very potent. That amount is as small as 2 grains of salt. 16 Potency Comparison Comparison of potency of fentanyl and other prescription opioid drugs to morphine Fentanyl 100:1 Oxycodone (Percocet®, OxyContin®) 2:1 Hydromorphone (Dilaudid®) 5:1 Codeine 1:10 Methadone 10:1 17 Short-term Effects of Fentanyl Use (low dose) The following are some of the possible short-term effects of Fentanyl (low doses): ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ Euphoria Muscle rigidity Respiratory depression Pain relief Anxiety Depression Drowsiness Confusion ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ Dizziness Weakness Pupillary constriction Suppression of cough reflex Reduction in blood pressure Fainting Nausea and vomiting Constipation Slowing of breathing Constriction of bronchi and impairment of ventilation 18 Short-term Effects of Fentanyl Use (high dose) The following are some of the possible short-term effects of Fentanyl (high doses): ◦ ◦ ◦ ◦ ◦ Loss of consciousness Cessation of breathing Respiratory depression Chest muscle paralysis Increase in blood pressure 19 Effects of Long-Term Use With long-term use of Fentanyl, users are at risk of developing a tolerance to the drug, as well as a cross-tolerance to other opioids. When discontinuing use of Fentanyl, doses should be gradually reduced in order to avoid serious withdrawal symptoms. Long-term use of Fentanyl may result in the slowing of respiration, although this may occur at any time during use. 20 Adverse Effects on Respiration The most concerning adverse effect of Fentanyl is its effect on respiration. Adverse effects include: ◦ Respiratory depression - (slowed breathing). Even low doses can cause respiratory depression. The respiratory depressant effect lasts longer than the pain killing effects. ◦ Respiratory cessation (in other words the user stops breathing). The risk for respiratory cessation is higher than for other opioid drugs (like morphine and heroin). 21 Withdrawal Symptoms Withdrawal effects from Fentanyl can be very strong and unpleasant. Symptoms may include: ◦ ◦ ◦ ◦ ◦ Extreme restlessness Yawning Sweating Muscle and bone pain Anxiety ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ Irritability Weakness Stomach cramps Insomnia Nausea and vomiting High blood pressure Watery eyes and runny nose Chills 22 Lethality The risk for death is greater than for morphine and heroin. Fentanyl overdose deaths are usually as a result of inadequate oxygen supply associated with the combined respiratory depressant effects of the drug and paralysis of the chest muscles. ◦ ◦ ◦ ◦ Death can be immediate (while the needle is still in the user’s arm). Even one small dose of fentanyl can be fatal. Symptoms of overdose include extreme drowsiness and sedation. Large doses of the drug naloxone are needed to reverse overdose effects of fentanyl. 23 Overdosing Overdose from Fentanyl requires higher doses of opioid receptor antagonists than other opioids, however, overdose from Fentanyl shares the same characteristics as other opioid overdoses, making it very difficult to identify whether a person is overdosing from Fentanyl, or whether they are overdosing from a milder opioid. 24 Potential for Abuse Dependence liability: ◦ As great as that of heroin ◦ Rapid onset of action after intravenous use increases Fentanyl’s dependence liability Inherent harmfulness: ◦ As great as heroin and morphine, but higher risk of breathing cessation 25 Signs of Abuse The signs and symptoms of Fentanyl abuse will vary depending on the person, the amount they are using, and whether or not they are mixing Fentanyl with any other drugs. The signs and symptoms of Fentanyl abuse may be similar to the signs and symptoms of heroin abuse. 26 Signs of Abuse Some possible signs and symptoms of Fentanyl abuse may include: ◦ ◦ ◦ ◦ ◦ ◦ ◦ Sudden change in behavior Mood swings Withdrawal from family members Careless about personal grooming Loss of interest in hobbies, sports and other favorite activities Changed sleeping pattern; up at night and sleeping during the day Red or glassy eyes 27 Signs of Abuse ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ Sniffling or runny nose Tiny pupils Slow breathing Flushed skin Tendency to nod off Scratching Slurred speech Complaints of constipation Complaints of nausea Change in appetite (not eating) Covering arms with long sleeves (hiding needle marks) 28 Illicit Fentanyl 29 Illicit Fentanyl Products There has been a lot of focus in the international, national and local news lately on illegal Fentanyl products sold on the street and causing fatal overdoses. Illicit fentanyl products include powdered fentanyl marketed as such or combined with illicit drugs (e.g. heroin); and illicit synthetic drug tablets manufactured in domestic clandestine labs, notably those produced to resemble OxyContin (fake Oxy-80’) and more recently fake Percocets. 30 Illicit Fentanyl Market Fentanyl is finding its way to the Canadian illicit drug market via three means: 1. 2. 3. Diversion of pharmaceutical fentanyl products (primarily transdermal patches) medicines from legitimate sources (e.g. buying/stealing from people legitimately prescribed Fentanyl, stealing from hospitals, pharmacies etc.). Importation or smuggling of pharmaceutical-grade fentanyl into Canada from abroad, notably China. Illicit production, most commonly in a clandestine laboratory. A clandestine laboratory, also referred to commonly as a ‘lab’, is a place where illegal drugs are made, often by organized crime groups. 31 Potency of Illicit Fentanyl Only a small amount of Fentanyl is required for the desired effect, for example .1 mg - .2 mg can be used to turn one (1) ounce of heroin into two (2) ounces of ‘fentanyl heroin’ with sometimes-fatal consequences. Also, one (1) gram of Fentanyl can be mixed with filler and other substances, such as caffeine, to make 1000 of imitation ‘Oxy 80’s’. 32 Powder Fentanyl Use in Street Drugs Powdered fentanyl is often sold as ‘synthetic heroin’, or mixed with heroin to increase the heroin's potency or to compensate for poor quality heroin. The powder is dissolved and injected. It can also be smoked or inhaled. 33 Fentanyl Patches in Street Drug Use Users may heat the contents of a new or used patch (in a container such as a pipe or on foil) and inhale the fentanyl. Some users cut up patches into pieces and suck on them or swallow them. 34 ‘Oxy-80’s’ Fentanyl is the drug in counterfeit OxyContin® (oxycodone) pills sold as ‘Oxy-80’s’. They are made in clandestine drug labs most often by organized crime groups. Fake Oxy 80s contain no OxyContin®. OxyContin® is no longer manufactured. 35 ’Oxy-80’s’ Street Names Street names for ‘Oxy 80s’ include: ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ Green beans Beans Green apples Apples Eighties Fake Oxy Shady eighties Hulks 36 Manufacturing ‘Oxy-80s’ Fentanyl is mixed with other ingredients – most commonly caffeine and glucose in clandestine [illegal] drug labs and pressed into pills. The pills are often dyed green and stamped to look the legitimate pills (e.g. as fake Oxy 80s they will have '80' pressed on one side and 'CDN' pressed on the other). The pills may also be stamped with other logos or made in other colours. Photo source: Pill press http://www.cbc.ca/news/canada/calgary/calgarykelowna-fentanyl-operation-1.3493932 37 Concentration Due to uneven mixing in blenders and Magic Bullets in illicit labs, the percentage of fentanyl in each tablet cannot be controlled. Consequently some tablets may contain very little fentanyl and others can contain deadly amounts. 38 Cross-Contamination Cross-contamination from equipment such as scales can cause fentanyl to be transferred to other drugs such as marijuana, meth amphetamine and cocaine. In other words, drug dealers are not necessarily deliberately ‘lacing’ other drugs with fentanyl – rather, fentanyl is easily absorbed into other drugs in the same location. 39 Legal implications Fentanyl is considered a Schedule 1 Controlled Substance. Without a legitimate prescription, possession of Fentanyl is illegal and could result in financial penalties, and/or jail or prison sentence. Buying and selling of Fentanyl on the street is illegal and could also result in either financial penalties, or jail/prison sentence. 40 Fentanyl Use Is Not Always Known In a recent study conducted by the B.C. Centre for Disease Control, clients at 17 participating harm reduction sites were asked to complete an anonymous questionnaire describing what drugs they used within the last three days and provide a urine sample to test for fentanyl. Nearly 30% of participants tested positive for fentanyl even though 73% did not report using it. This study indicates users are not always aware they have taken Fentanyl. 41 Fentanyl Related Deaths: Canada The following is a summary of Fentanyl related deaths in Canada (CCSA): ◦ Between 2009 and 2014: 655 deaths ◦ Between 2009 and 2014: 1019 drug poisoning deaths with presence of Fentanyl in toxicology screening (more than 50% of these were between 2013 and 2014) These numbers are likely underestimated due to unreported instances, or unknown Fentanyl related deaths. 42 Alberta Statistics Overdose Deaths 43 Alberta Fentanyl Deaths: 2011-2014 Between 2011 and 2014 there were a total of 162 fentanyldetected and 61 fentanylimplicated deaths in Alberta. The number of fentanyl-detected deaths for 2014 was 120. Source: Office of the Chief Medical Examiner of Alberta 44 Alberta Fentanyl Deaths: 2015 From January to December, 2015, there were 272 Albertan deaths associated with fentanyl: ◦ ◦ ◦ ◦ ◦ 90 in the Calgary Zone 75 in the Edmonton Zone 57 in the North Zone 35 in the Central Zone 15 in the South Zone 45 2015 Emergency/Urgent Visits From January 1, 2015 to September 30, 2015 there were: • 1,173 Emergency Department and Urgent Care visits in Alberta, due to “poisoning by other opioid” • 250 visits due to “poisoning by heroin” • 350 visits due to “poisoning by synthetic narcotic” These data categories include, but are not limited to, fentanyl. 46 Fentanyl Analogues 47 Fentanyl Analogues New fentanyl drug analogues are appearing on the illicit drug market, some of which are far more dangerous than Fentanyl. A drug analogue is one whose physical structure is related to that of another drug. Although they have similar physical properties, analogues can have very different chemical and biological properties. Fentanyl analogues are synthetic opioid drugs that are like fentanyl ‘cousins’. 48 W-Series Compounds The “W-series” compounds are a class of opioids discovered at the University of Alberta in 1982. There are 32 compounds, denoted W-1 to W-32. They have never been used clinically. The most toxic are W-18 (100 times the potency of fentanyl/10,000 times the potency of morphine), W-19 (10x fentanyl) and W-11(1.5 x fentanyl) while some are many times less toxic than fentanyl. These compounds are not currently regulated under the Controlled Drug and Substances Act and as such can be manufactured and transacted freely. 49 W-18 Full name: W-18 - 1-(4-Nitrophenylethyl) piperidylidene-2-(4chlorophenyl) sulfonamide W-18 is very potent opioid that is roughly 10,000 times the potency of morphine and 100 times more toxic than fentanyl. It is usually used as an anesthesia for large animals. The Canadian Community Epidemiology Network on Drug Use (CCENDU) issued an Advisory on the new drug (W-18) that is similar to, but much more toxic than fentanyl. Health Canada laboratories identified this new drug in tablets that looked like fentanyl seized by Calgary law enforcement in 2016. 50 MT-45 Another synthetic drug on the illicit drug market horizon is MT-45. It has properties similar to morphine and is attributed to overdose deaths in the United States and Sweden in the last 2 years. It is reported to be 400 – 6000 times more powerful than fentanyl. 51 Other W-series compounds 3-Methylfentanyl (3-MF): Estimated to be between 400-6000 times stronger than morphine. Street names: 3-MF, China White Acetyl-Fentanyl: 40 times more potent than heroin, 80 times more potent than morphine, and 15 times less potent than fentanyl. Street names: a-f, China White, Apache, Goodfella, Jackpot, TNT, Murder 8 and Tango and Cash W-15: A potent opioid that is 5.4x more potent than Morphine. MT-45: Roughly 80% potency of morphine AH-7921: Approximately 80% the potency of morphine U-47700: 7.5 more potent than morphine Butyr-fentanyl: ¼ the potency of fentanyl. Street name: b-f Parafluorobutyrfentanyl: Similar effects to fentanyl which include itching nausea and potentially serious respiratory depression which can be life-threatening 52 Naloxone & W-Series Compounds The mixed agonist-antagonist effect and varying toxicity makes the administration of naloxone challenging as it is unlikely that the identity of the specific compound will be known. When tested with mice, Naloxone successfully reversed the analgesic (painkilling) effects of W-3. Reversal of respiratory depression, the means by which opioid overdose causes death, was not assessed. While reversal has never been tested in humans, naloxone should theoretically be effective, with two stipulations: 1. 2. Given the high toxicity of some of the W-compounds, high doses of naloxone may be required. Second, the agonist-antagonist effects of W-20 to W-32 mean that effects of naloxone would be difficult to predict. Thus, it is important that the naloxone dose be titrated to reverse of respiratory depression during overdose – in other words, more than one dose may be given based on the response to each dose. 53 References Brands, B., Sproule, B., & Marshman, J. (eds) (1998). Drugs & drug abuse (3rd ed.). Canada: Centre for Addiction and Mental Health BC Centre for Disease Control www.towardtheheart.com Canadian Centre on Substance Abuse. (2015) CCENDU Bulletin: Deaths Involving Fentanyl in Canada, 2009-2014. Center for Substance Abuse Research. (Dec. 7 2015). NDEWS Special Report: Fentanyl and Fentanyl Analogs. http://www.ndews.org/sites/ndews.umd.edu/files/NDEWSSpecialReportFentanyl120 72015.pdf Narcanon. http://www.narconon.org/drug-abuse/signs-symptoms-heroin-use.html O’Neille, N. (2013). Pharmacy Intro Opioids and other drugs we use on palliative care. http://slideplayer.com/slide/735151/ The National Alliance of Advocates for Buprenorphine Treatment https://www.naabt.org 54