Opiods: An Overview fo Prehospital Providers

Slide 1: OPIOID ABUSE: A comprehensive review for EMS personnel Date: May 31st, 2006 By Robert S. Cole, Paramedic, CCEMT-P

Slide 2: OPIOID ABUSE: A COMPREHENSIVE REVIEW Opiates Abuse: An Comprehensive Overview for EMS personnel By Robert S. Cole, CCEMT-P "Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium." -Thomas Sydenham (1624-1689) Introduction: Since before history was recorded, mankind has been searching for ways to alter his perceptions, induce various states of hallucinations, euphoria, and enlightenment. One of the earliest substances used was opium. Wars have been fought over it, countries destroyed over it, and yet modern medicine remains dependant on it. In fact opium production remains one of the most effective means of financing crime syndicates, dictatorships, and terrorist organizations in the world today. Today Opium remains one of the most prolific illicit drugs in the world. While opium containing compounds are harvested and manufactured almost anywhere in the world today, most opium production occurs in either the “golden triangle” (Laos, Burma, and Thailand), the “golden crescent” (Pakistan, Afghanistan, and Iran), or Mexico. Incidentally, India is the world’s largest legal producer of opium, but Afghanistan produces more than 80% of the world’s illicit opium, mostly going to the production of heroin. According to government statistics, opioid abuse/misuse has surpassed levels seen in the 9060’s and 1970’s with heroin. Every day EMS providers encounter drug abuse and misuse. While opioid-based drugs are one of the most common, unfortunately many providers take the treatment of an opiate overdose as routine and simplistic. Opioid overdoses are fraught with unique and complex management pitfalls. This article will explore opioid use/abuse in detail for the EMS provider, review common opiate/opioid containing substances, discuss strategies for management, and review current approaches in opiate dependence treatment. Incidence and epidemiology: Page 2

Slide 3: OPIOID ABUSE: A COMPREHENSIVE REVIEW In 2004, over 2 million ED visits at Drug Abuse Warning Network (DAWN) participating hospitals were related directly to drug use, abuse, or misuse. Over 20% of those involve either Heroin (8%)or a prescribed opioid drug. Most opiate related deaths are polypharmacy affairs, or from IV opiate use. Most deaths are in aged 35-54, yet there is substantial increases in opiate use in high schools. Basic Path physiology What is opium? Opium is a derivative of the poppy plant, Papaver somniferum (variants include Papaver Giganthemum and Papaver Paeoniflorum), and is a distant relative of the common cabbage. Ideally, it is collected from the unripe poppy bud, for as the bud ripens and blossoms, the percentage of available opium is decreased. The process for collection is very delicate and typically done by hand. This produces raw opium. Opium is made up of about 25 different alkaloids. All alkaloids are poisonous in nature although, when taken in very small quantities, they have significant pharmacological use. The most important alkaloids are phenanthrenes (including morphine and codeine) and benzylisoquinolines (including papaverine, a drug that is used predominately as a vasodilator in coronary and neuro surgery.). Morphine is by far the most prevalent in opium, consisting of 10%-16% of the total (compared to 0.7-2.5% for codeine). One other alkaloid to be aware of is thebaine, which is a precursor to naloxone. The poppy plant is not the only plant to contain alkaloids. Other familiar alkaloids are nicotine, extracted from tobacco and atropine, extracted from belladonna. 5 Opioids or Opiates? The term opiate is often used to represent all classes of opioids, but it is properly used when describing naturally occurring opium derivatives (opium alkaloids) such as Laudanum, and “semi-synthetic” substances such as Heroin. The term opioid can be used to describe all sub- classes, however is used most commonly to refer to the synthetic opioids, such as Fentanyl Citrate and methadone. There is a third term, endogenous opioid peptides (also simply called opioids), that refers to the naturally occurring chemicals in the body that stimulate various opioid receptors as part of the bodies normal function. Commonly called endorphins, these actually are endorphins (also called β-endorphins), dynorphins, and enkephalins. It is important to note that there are many subclasses of these compounds with both agonist and antagonist effects across opioid receptors Page 3

Slide 4: OPIOID ABUSE: A COMPREHENSIVE REVIEW (described below). Regardless, these are all compounds acting on GABAnergic neurotransmission. What is GABA? One cannot really delve into pharmacology or neurology without running up against Gamma- aminobutyric acid (GABA). It is the primary inhibitory neurotransmitter in the body, and is found in 25-40% of all brain synapses. It is a key biochemical factor in drugs that suppress seizures, anxiety, the CNS, and psychiatric disorders. Benzodiazepines, alcohol, GHB, Haldol, Phenergan, and of course opioids all play a role in GABA function/dysfunction. GABA receptors contain five different protein sub receptors. GABA is the predominant amino acid transmitter used to mediate presynaptic inhibition in the spinal cord as well as an inhibitory transmitter in areas of the brain such as the cortex and basal ganglia. Opioid receptors The pharmacodynamic response to an opioid depends on which receptor it binds, its affinity for that receptor, and whether the opioid is an agonist (stimulates the receptor) or an antagonist (blocks the receptors). Some drugs are partial agonist/antagonist. They stimulate some opioid properties and block others. It is these subtle differences that enable a physician to choose an opioid that is best suited for the patient’s condition. Page 4

Slide 5: OPIOID ABUSE: A COMPREHENSIVE REVIEW Receptor Name Effect Mu-1 mediates supraspinal analgesia µ Mu-2 spinal level analgesia, respiratory depression, bowel func- Kappa-1 spinal analgesia, diuresis κ Kappa-2 unknown Kappa-3 supraspinal analgesia, feeding behavior Delta-1 spinal analgesia δ Delta-2 supraspinal analgesia Sigma Re- Cough Suppression, hallucinations, dysphoria, and spatial σ ceptors disassociation. µ Activation of the mu receptor by an agonist such as morphine causes analgesia, sedation, reduced blood pressure, itching, nausea, euphoria, decreased respiration, miosis (constricted pupils) and decreased bowel motility often leading to constipation. Some of these effects, such as sedation, euphoria and decreased respiration, tend to disappear with continued use as tolerance develops. Other effects, such as miosis and reduced bowel motility are not affected by tolerance. Tolerance develops to different effects at different rates largely because these effects are caused by activation of different mu receptor subtypes . Stimulation of mu-1 receptors blocks pain while stimulation of mu-2 receptor causes respiratory depression and constipation κ Kappa opioid receptors are also involved with analgesia, but activation also produces marked nausea and dysphoria. Kappa receptors are located in the periphery by pain neurons, in the spinal cord and in the brain. Some kappa receptor agonists, such as Salvinorin A have been found to be hallucinogenic although through a different mechanism than other hallucinogens (which typically effect 5ht2 –serotonin- to produce hallucinations) such as LSD. The endogenous opioids which target these receptors are the dynorphins. Page 5

Slide 6: OPIOID ABUSE: A COMPREHENSIVE REVIEW δ Delta opioid receptor activation also produces analgesia. Some research suggests that they may also be related to seizures. The endogenous ligands for the δ receptor are the enkephalins. σ Sigma receptors are not considered a true opioid receptor because neither morphine nor naloxone has any stimulation or inhibition on this receptor. However many morphine like drugs such as pentazocine and butorphanol do attach themselves to this receptor. In addition, other drugs such as PCP, Ketamine, and DXM may also act through this receptor as well. Stimulation of the sigma receptors cause cough suppression, hallucinations, dysphoria, and disassociation. There are two sigma receptors currently identified. There are other receptors being discovered and studied, but these are of scientific, not clinical value (yet). Chief these are the “orphan opioid receptors” (ORL). This receptor are being studied for the treatment of heart failure and depression. Abuse and Misuse For much of the history of opium, oral, sublingual, buccal, and inhalation of opium compounds have been the norm, and remains the preferred method of consumption in many second and third world countries. 2 Teas containing opium compounds are popular as well. In the western world, injection, inhalation, and insufflation of opioid compounds are popular, as is the illicit use of oral prescription opiates. Injection Definitely the most popularized method of consuming an opiate, intravenous administration of became popular in 1853, shortly after the invention of the hypodermic needle. In fact the wife of the inventor, Dr. Alexander Wood, is the first known intravenous (IV) Morphine addict (Morphine was isolated from the poppy plant in 1805). Opioids used in this matter must be diluted into a solute. Since most opioids distribute better in the solute when it is warm, a flame is often indirectly applied to heat up the solute. It is then sucked up into a syringe via a needle (a “spike”), and injected. Often a piece of cotton will be used (see cotton fever below) to act as a “filter”. When a clean cotton ball is not available, a cigarette filter may be used. Opioids used in this manner tend to have a rapid onset, particularly Morphine and Heroin. It is this spike in plasma levels that often causes “the nod”, a euphoric sleep-like state that most addicts strive for. It is this same rapid “front end” surge that often causes sudden respiratory arrest, the most common cause of Opioid related death. Page 6

Slide 7: OPIOID ABUSE: A COMPREHENSIVE REVIEW Heroin, for example, is more lipid soluble than many other opioids. This enables heroin to peak in serum much faster than morphine (for example) and have a higher bioavailability across the blood brain barrier. This is a leading reason why IV heroin is more addictive than IM or SQ heroin, and why more fatalities are associated with IV heroin. Other Opioids given, such as Methadone, do not have as steep a rise in peak plasma levels, and maintain a gradual plateau of efficacy (although they still can cause respiratory depression and/or arrest in sufficient levels or when combined with other substances). In addition to intravenous administration, subcutaneous/intradermal injection ( “skin popping” ) and intramuscular injection ( “muscle popping” ) are also common. These methods are usually used when no vascular access can be obtained by the addict, but occasionally is used to provide a longer, even experience to the opioid effect. As already mentioned, these routes have a lower associated fatality rate. Insufflation Snorting a drug provides ready access into the blood stream through the well perfused nasal mucosa, with a both bio-availability and onset of action comparable to IV use. It is an effective means of bypassing the GI tract (and first pass liver detoxification) with out resulting to a needle, and therefore had a certain appeal to those who were needle-shy. It is, however, somewhat uncomfortable, and frequently this is a reason users move on to intravenous methods. It has, however, gained recent popularity since the late 90’s with the rise of oxycontin and similar drugs as drugs of abuse. When prescription drugs are ingested in this manner, they are often crushed, and ground to a powder. This has two benefits for the user: First, the finer the powder, the quicker the absorption. Second, many prescription opioids have a time release outer coating. Crushing and grinding the pills removes this protective covering rendering most of the drug bio-available. It is this second feature that contributed to a number of oxycontin related deaths in the late 90’s. Chasing the Dragon Normally applying flame directly to an opium containing compound (like heroin) will destroy much of the product (although there are some reports of hashish oil and opium mixed with tobacco for recreational use in other countries). Many opium alkaloids will, however, convert much of the product into smoke when subjected to a high level of heat indirectly. Elaborate opium pipes have been used to facilitate this in the past, but today the most common method is called “chasing the dragon”. A user will place the opium product on a metal spoon, piece of foil, or the bottom of a soda can. He will then apply heat to the product through the bottom of the metal, converting the product into resin and smoke. A straw is placed next to the product and used to inhale the smoke as it appears. This method is effective, if somewhat wasteful, and tends to produce long, even experiences. Page 7

Slide 8: OPIOID ABUSE: A COMPREHENSIVE REVIEW Other Methods of use Elixirs, Tinctures, and teas have all contained opioid compounds. An elixir is the dilution of a compound into a liquid. This differs from a tincture, where the liquid is the result of the distillation process. In the case of an elixir, the solute is simply to dilute the primary compound (also usually alcohol), and in the case of opioids provide a better taste. A tincture is the distillation of a substance into a liquid (commonly using alcohol). The two most common tinctures were laudanum and perigoric. Laudanum was first (in the 1600’s) distilled into wine, but by the middle 1800’s was commonly distilled into a sweet brandy, making it very popular indeed (as popularized in the blockbuster movie Tombstone). Surprisingly, Laudanum is stll available by prescription int eh U.S. Paregoric, while also somewhat outdated, is still used in the United States today as an anti-diarrhea treatment. Laudanum USP contains approx 10 mg of morphine per milliliter, compared to 0.4mg/ml morphine found in paregoric. , In many parts of the world, and occasionally in the US, an opium tea is consumed. While the poppy buds are preferred in the tea, any part of the plant (including the poppy seeds) can be used. The tea is very bitter, and is often mixed with other teas, coffee or juices. Grapefruit juice is often preferred because it may inhibit histamine release, and prolong elimination. The tea can be evaporated into a concentrate which is much more potent. The concentrate can be further evaporated into a dry powder that can used orally or snorted. Finally, topical patches are used and abused. There have been reports of both new and used Duragesic (fentanyl) patches sold on the street and worn (sometimes several at a time) for their effect. There are some reports of users successfully extracting the fentanyl from the path and injecting it. Also, some users will freeze the patches, divide them, and chew them for buccal and sublinqual (as well as oral) absorption. Considering the potency of fentanyl, and the quantities involved, this is a very dangerous practice. Tolerance Understanding of opioid tolerance is an emerging science, and is still poorly understood. It is believed that tolerance tolerance to different opioid effects develop at different rates. This is called selective tolerance. While tolerance to nausea, vomiting, sedation, euphoria and respiratory depression occur rapidly, there is minimal development of tolerance to constipation Page 8

Slide 9: OPIOID ABUSE: A COMPREHENSIVE REVIEW and miosis. This suggests receptor-related differences in the speed of development of tolerance. In hospital studies (mainly from ICU enviroments)indicate that other compounds such as benzodiazepines, when given together with opioids, seem to speed up the rate of development of opioid tolerance. Such an effect very likely is due to a effect on GABAnergic activity. Cotton Fever? A common practice among IV drug users is to “filter” the drug as it passes through the needle. The idea is to remove or reduce any unwanted particles. Ironically, this filtering is completely ineffective and is often the result of particles (usually pieces of the filter) being aspirated into the syringe and then injected. The “filters” are often cotton balls, cigarette filters, and similar substances in varying stages of hygiene (sterility is not even a possibility). A number of well known complications scan result from this, including emboli, phlebitis, and local cellulites. Probably the least discussed (in emergency medicine) is what is called “cotton fever” (in Europe this is commonly called “the shakes”). Cotton fever is essentially a septicemia resultant from bacteria aspirated during the preparation stage f the injection. A specific organism, Enterobacter agglomerans, has an affinity for cotton fibers and has been reported as a cause in some cotton fever cases, any organism may be responsible. Therefore, while most IV drug users associate it with a dirty piece of filter being injected, simply lack of sterile technique can cause cotton fever. Symptoms onset soon after injection, typically within one hour. Symptoms that occur outside this window are typically from another cause, and may be more serious. Symptoms include: • Uncontrollable shaking, tremors, or shivering, • Fever*, • Shortness of Breath*, • Hot flashes, • Headaches • Nausea and/or Vomiting • Weakness, • Aching Joints • Flu like sensations * These symptoms are especially worrisome, especially fever that persist beyond 1-4 hours. Page 9

Slide 10: OPIOID ABUSE: A COMPREHENSIVE REVIEW Many times the symptoms are “self limiting” and resolve in 1-4 hours with out complications. Some literature classifies true “cotton fever” as a “benign febrile syndrome”, however studies show only 16-26% of cases were considered “trivial”. Since other potential causes, differentials, and complications associated with “cotton fever” include bacterial pneumonia, endocarditis, pulmonary emboli, localized infections (including necrotizing fascitis) and septic shock, all cases should be transported for physician evaluation. Risk factors for an overdose According to one study, approximately 68% of heroin users have experienced a non fatal overdose, with the average of 3 overdoses per patient , however only EMS is notified only approx 23% of the time. This naturally inhibits obtaining exact statistics of fatal or serious overdose, however some co-morbid factors have been identified. • IV opioid use: Due to the rapid bioavailability of opioids (discussed elsewhere) it is easier to suddenly and severely depress the respiratory drive, the gag reflex, and other vital functions. • Polypharmacy Overdose: This seems to be a leading cause of fatal overdoses, with alcohol and benzodiazepines the predominate substances. 13 This is especially true when such substances are consumed daily (such as alcohol addiction as well)., Presumably this is because, like opioids, these compounds also have GABAnergic and CNS depressant properties. • Returning to opioid use from abstinence: Even after a few weeks of opioid use, tolerance begins to develop. This requires the opioid consumer to consume increasing quantities, by more effective (and more risky) routes, to achieve the same effect. This tolerance also resolves over time Therefore a user who has been abstinent for a while (because of rehabilitation programs, therapy, self discipline, or incarceration) who tries to resume drug use at his old dose, may suddenly find him self in serious trouble. • The Weekend Warrior: This is the street term for someone who “dabbles” in opioid use and is not a daily consumer. These users tend to be less informed about their dosage, and tend to be more experimental in their drug use. • Using opioids alone: Often users will consume opioids using a type of buddy system, so that if one user overdoses, the other can render aid. This aid may be in the form of calling 911, placing the patient in recovery position, administering rescue breathing/CPR, placing the patient in a cold Page 10

Slide 11: OPIOID ABUSE: A COMPREHENSIVE REVIEW shower, or perhaps even administering naloxone. Obviously if the patient uses an opioid alone, then there is no one to render aid or even seek help. • New supply of Drug: Illicit production of drugs, as well as the cutting and dilution of street narcotics, leads to huge variability in street level opioids. Counterfeit opioids that substitute one opioid for another have even been reported. This variability means the patient may accidentally consume stronger than normal doses of an opioid, • Other social factors have been identified, with female bystanders more likely to call for help than males, and one or two people more likely to seek aid that larger groups. Finally, previous adverse contacts with police seem to be a strong deterrent to calling 911 Major contributing factors to an opioid overdose • IV opioid use • Polypharmacy Overdose • Returning to opioid use from abstinence • The “Weekend Warrior” • Using opioids alone • New supply of Drug While some of these factors are beyond the scope or ability of EMS to change, a good knowledge of the co-morbid factors can help in risk assessment. Treatment and care. Opioid Toxidrome The Opiate Toxidrome consists of: • Altered mental status • Miosis* • Unresponsiveness • Shallow respirations Page 11

Slide 12: OPIOID ABUSE: A COMPREHENSIVE REVIEW • Slow respiratory rate • Decreased bowel sounds • Hypothermia • Hypotension* * these symptoms are very subjective, and may not be present in polypharmacy overdoses. KEY POINT: Miosis and Hypotension are not definitive for ruling in or ruling out a opioid overdose. Basic Treatment Most acute opioid emergencies are the result of CNS depression, respiratory failure, anoxia, and inability to maintain an airway. Therefore most treatment is predominantly supportive of these vital functions. As discussed above, often it is a rapid “front end” surge of opiate bioavailability and effect that often causes sudden respiratory and airway compromise. Simply providing stimulation, oxygen and/or positive pressure ventilation alone will often suffice to bring the patient to a satisfactory level of oxygenation and ventilation, with out the complications of more advanced methods. Stimulation, oxygenation, and positive pressure ventilation (if indicated) should be provided for several minutes prior to administration of naloxone in all but the most serious patients. Cricoid pressure, low airway pressures, slow gentle ventilation, good face mask technique, and proper airway positioning are essential to prevent gastric distention and resulting aspiration. It is important to mention that other causes for altered mental status should be ruled out. Use of a glucometer, complete assessment, scene assessment, and detailed interview of any bystanders should be performed before being lead “down a primrose path”. A common mnemonic to remember differential diagnosis is A E I O U, T I P S: • A - alcohol, alcohol withdrawal, and anoxia • E – epilepsy and other neurological disorders • I - insulin (Hyper or Hypo-glycemia) • O- overdose (Poly-pharmacy?) • U - uremia, underdose of current medications. • T- trauma • I - infection Page 12

Slide 13: OPIOID ABUSE: A COMPREHENSIVE REVIEW • P - psychiatric • S – stroke, shock states Opioid Antagonist Narcan Opioid Antagonists drugs have long been considered the standard of care for opioid overdoses. The two most common are naloxone (Narcan) and nalmefene (Revex). Both are pure opioid antagonist with no agonist properties. Nalmefene has a significantly longer half-life than naloxone, but is also more expensive. Therefore the overwhelming number of EMS systems and ER’s use naloxone in the emergent setting. While namefene was originally designed for opiate toxicity, it has been used with significant success in the chronic treatment of alcoholism and other addictions., Because of its almost exclusive use in EMS, this article will primarily focus on naloxone. Naloxone is a pure opioid antagonist with no appreciable agonist properties. It, like morphine, has its strongest affinity for mu receptors, although it inhibits kappa and delta receptors as well. It has no effect on sigma receptors. It competitively binds to these receptors, meaning it will “kick off” opioids with a weaker bond. It is commonly believed that some of the synthetic opiates (such as fentanyl, methadone, oxycodone, and dilauded) have a stronger bond with their respective receptor sites and may take higher than normal amounts of naloxone to have an appreciable effect. Naloxone will typically last 30-45 minutes, after which the patient may re- sedate. Naloxone can be administered intravenously (bolus or infusion), subcutaneously, intramuscularly, sublingual and buccally, intranasally, and via an endotracheal tube (although this no longer encouraged). Dosing regimens are: Adults: • Repeat as needed. Failure to obtain reversal after 10 mg usually indicates another disease process or overdose on non-opioid drugs. • IV, SL: 0.1-2 mg PRN to a max of 10 mg.* • IN/IM/ETT, IV in cardiac arrest: 2 mg. Pediatrics: • 0.01-0.05 mg/kg IV, IO, IM, SubQ, ET. Repeat PRN. • MAX 2 mg/dose It should be noted that a response to (or failure to respond) naloxone is not considered a reliable Page 13

Slide 14: OPIOID ABUSE: A COMPREHENSIVE REVIEW diagnostic tool in determining if a patient has consumed opoiods. A naloxone infusion may be useful over prolonged patient contact times to reduce the incidence of adverse effects, re-sedation, and maintain naloxone’s effects though a more even administration than a simple re-bolus. Infusions have also proved useful with the more potent opioids. There are several naloxone infusions recommended, however many of these are not individualized to the patient. There is a recommended infusion (presented below) that is relatively simple, and individualized to the patient. This infusion is not common in EMS systems, but is relatively easy to prepare. Infusion**: • Give the loading dose of naloxone according to protocol. Repeat as protocol allows until desired effect. • Mix 2/3 of the total effective dose of naloxone in 100 cc. Infuse over 1 hour (approx 90 gtt/min or 1.5 drops/sec) • Rebolus naloxone 15-20 minutes at half the effective dose. • Monitor closely for over sedation and titrate infusion for effect. Failure to respond to a total dose of 10 mg of naloxone usually indicates: • that poisoning is not due to opioids (or opioids alone); • that poisoning is due to a partial agonist/antagonist; • or that hypoxic brain damage has occurred. It should be noted that dextropropoxyphene ( Darvon, Darvocet) has been reported to produce cardiac toxicity that is not reversible by naloxone administration. Also naloxone is often ineffective against buprenorphine. Page 14

Slide 15: OPIOID ABUSE: A COMPREHENSIVE REVIEW Narcan in a Nutshell Adults: • Repeat as needed. Failure to obtain reversal after 10 mg usually indicates another disease process or overdose on non-opioid drugs. • IV, SL: 0.1-2 mg PRN to a max of 10 mg.** • IN/IM/ETT, IV in cardiac arrest: 2 mg. Pediatrics: • 0.01-0.05 mg/kg IV, IO, IM, SubQ, ET. Repeat PRN. • MAX 2 mg/dose Infusion**: • Give the loading dose of naloxone according to protocol. Repeat as protocol allows until desired ef- fect. • Mix 2/3 of the total effective dose of naloxone in 100 cc. Infuse over 1 hour (approx 90 gtt/min or 1.5 drops/sec) • Rebolus naloxone 15-20 minutes at half the effective dose. • Monitor closely for over sedation and titrate infusion for effect. Dose for patients who are dependant on opioids for pain management • 0.4-0.5 mg of naloxone in 10 cc, • Slowly IV: 0.5 cc boluses (0.025 mg)** every 2 minutes until desired effects are seen: ** This dosing is not covered in ACEMS SWO’s. Narcan for those under analgesia? Occasionally EMS will encounter patients who are over theraputic on a legitimately administered opioid.. These patients may be cancer/hospice patients, post operative, or otherwise have severe chronic pain disorders. Normal doses of naloxone in these patients would be cruel and inhumane, as well as clinically counterproductive. It must be noted that some cancer patients who present with an altered mental status may not be suffering from an opioid overdose, may instead be suffering from end stage encephalopathy. Care should be taken to rule out other causes, and to thoroughly revaluate the need for naloxone in this population. KEY POINT “…If a cancer patient treated with opioids is experiencing clinically significant respiratory depression,tThe immediate administration of naloxone is an appropriate therapeutic and diagnostic modality. However, the more common clinical presentation is that of a sedated and altered patient without sign of respiratory depression, who is taking opioids, but has other potential causes for the abnormal mental status. The rush to make a rapid diagnosis of opioid overdose should be tempered by the concern for causing severe withdrawal symptoms and pain... It is generally unwise to treat these patients with am opioid antagonist unless life threatening Page 15

Slide 16: OPIOID ABUSE: A COMPREHENSIVE REVIEW respiratory depression is a reasonable concern…” "Inappropriate use of naloxone in cancer patients with pain.." J Pain Symptom Manage. 11(2)(1996): 131-134. EMS should consider diluting 0.4-0.5 mg of naloxone in 10 cc, and slowly administering 0.5 cc boluses (0.025 mg)* every 2 minutes until desired effects are seen. 28 ∗ Side Effects Of Naloxone Administration Naloxone has long been considered a benign drug, with the most common side effect being agitation when the patient “lost his high”. The increase in polypharmacy overdoses involving stimulants (cocaine and methamphetamine being most common) has lead to a change in this thought process. A number of clinically significant adverse effects have been reported to occur in between 0.4 and 3% of patients., Most adverse effects presented themselves with in 10 minutes of IV bolus administration of naloxone. The most common effects were: • Nausea and vomiting • Seizures, • Agitation, combativeness, and related issues, • Pulmonary edema • Cardiac Arrest (Ventricular Tachycardia and Asystole have been reported). The exact mechanism of these adverse effects is not clearly known, but two theories are commonly presented: • The first is that acidosis from prolonged hypoxia contributes to the adverse effect, and when the opiate is reversed the cardiovascular system cannot handle the resultant sympathetic dump in such a state. • The second theory is that in the case of polypharmacy overdoses involving stimulants, the opiate is actually mediating some of the adverse effects of the stimulant. When the opiate is removed, a significant stimulant enhanced sympathetic dump causes many of the adverse s/s (especially the cardiovascular symptoms). In addition, patients who are habitual users of opiod seem to be at increased risk for lethal complications. Regardless of the exact cause, there seems to be a direct correlation with adverse effects and the speed and dose of the naloxone given, as well as the amount of ventilation administered before naaloxone was given. Simply put, rapid or large boluses of naloxone increase the incidence of adverse effects dramatically. Therefore small, slowly pushed, minimal Page 16

Slide 17: OPIOID ABUSE: A COMPREHENSIVE REVIEW doses after a couple of minutes of good ventilation are preferred. Given the potential adverse outcomes, the clinical goal of naloxone administration is NOT to wake the patient up, but merely to support respirations and the airway. KEY POINT Given the potential adverse outcomes, the clinical goal of naloxone administration is NOT to wake the patient up, but merely to support respirations and the airway. Take Home Narcan The concept of giving addicts and other patients who are high risk of an opioid overdose naloxone to self administer is not new. There are several mid sized studies (in Chicago and San Francisco in the US) , pilot projects, and articles written on the benefit. There have been numerous points of opposition to this practice. The majority of criticism is a philosophical debate between drug prevention and harm reduction, and the topic is surrounded by some sensationalism. Perhaps one of the most shocking, however, is the report that opiate antagonist may be used as weapons against other drug users ( Anecdotal reports of this practice after naltrexone – an oral opioid antagonist- was introduced in a prison environment). Another risky practice is “flatlining” in which one drug user stands guard with naloxone while another uses opiates in a dose that far exceeds tolerance. Both reports are anectdotal at best. Regardless, this is an emerging topic that is important to both EMS and drug addiction specialist. Naloxone Treat and Release? The practice of obtaining a refusal on an opioid overdose after resuscitation is well documented. This practice has been in place for many years in several major metropolitan areas, and appears to be well received in the medical communities. Advocates say that it reduces resource utilization in emergency departments for a patient population that has a high AMA rate, low reimbursement rate, and seldom require significant intervention during their stay in the ER. Critics argue that it deprives the opioid user a rout into the healthcare system for potential detoxification. They also argue that resedation is possible under some protocols, and studies on this subject matter have been flawed and underpowered. Finally, critics argue that with the frequency of polypharmacy overdoses, potential complications and other social factors prevent adequate screening of patients who can be safely discharged in the field. While treat and release of this patient is still controversial, and goes against other practices of not fully resuscitating an opioid patient, a research review has failed to turn up any documented Page 17

Slide 18: OPIOID ABUSE: A COMPREHENSIVE REVIEW adverse outcomes. The literature does provide some helpful guidance however: • Most serious adverse effects occur within 10 minutes of naloxone administration. 29 • Most opioid overdoses are safe to release after an hour of observation.,,, This doesn’t help much in normal responses, but at event standbys and similar roles this may be helpful. Christenson, et al, described screening criteria for the safe release of patients: o The patient can mobilize as usual; o The patient has an oxygen saturation on room air of >92%; 3) have a respiratory rate >10 breaths/min and <20 breaths/min; o The patient has a temperature of >35.0°C and <37.5°C; o The patient has a heart rate >50 beats/min and <100 beats/min; and o The patient has a Glasgow Coma Scale score of 15. • The use of IM naloxone up to 2 mg in addition to IV (or IN) naloxone may be helpful in preventing resedation. In one study subcutaneous naloxone was shown even more effective n this role than IM naloxone, presumably due to longer absorption times. Page 18

Slide 19: OPIOID ABUSE: A COMPREHENSIVE REVIEW “First Aid?” A number of common myths and practices exist in the drug culture for when an emergency occurs. Among the more common (and notorious) are: • Injected with salt water or Milk • Injected with cocaine or speed, or vice versa. This “myth” was actually common practice at the turn of the century. . • Narcan Used prior to arrival of EMS- as discussed above. • Ice immersion or impaction: There have been a number of reports of a patient being found with ice on the genitals , or even more disturbing, inserted into rectal or cranial vaults. In addition to the obvious shock value of such an act, this practice may induce a severe vagal response that results in bradycardia or asystole. • Placed in a cold shower: This practice is so common that it is considered a reliable sign of illicit drug activity by some coroners. Opioid Withdrawal Syndromes and Treatment Despite its dramatic appearance, the opioid withdrawal syndrome is rarely life-threatening or permanently disabling to an adult. If the patient is reasonably healthy, it is entirely possible to detox with out medical assistance (its just not very pleasant). This may be “cold turkey’ or using a gradually decreasing dose of opiates. The prevalence of opiates such as methadone on the street makes this very possible. Induction of acute opioid withdrawal through the use of an opioid antagonist is, however, extremely unpleasant at best, and has been associated with the adverse effects noted above. Mild withdrawal signs and symptoms include: • Generalized anxiety • Opioid craving • Restlessness • Slight aching of muscles, joints, and bones • Lower back pain • Flu like symptoms • Tension • Poor sleep (mild insomnia) Page 19

Slide 20: OPIOID ABUSE: A COMPREHENSIVE REVIEW • Mydriasis (pupils dilated) • Lethargy • Diaphoresis Moderate withdrawal signs and symptoms include: • Chills alternating with flushing and diaphoresis (sweating) • Nausea and/or stomach cramps • Rhinorrhea (runny nose) • Lower back pain • Anorexia • Nausea and/or stomach cramps • Yawning Lacrimation (tearing) • Goose flesh (earlier if client is in a cold, drafty room) • Elevated pulse and blood pressure Moderate to severe withdrawal signs and symptoms include: • Diarrhea, Severe stomach cramps • Vomiting • Tremors • Sustained resting tachycardia • Mild Tachypnia with mild SOB • Mildly elevated temperature (usually low grade, less than 101° F) Note: This does not include the severe and potentially life threatening effects of acute abstinence syndrome caused by over-aggressive use f an opioid antagonist. Note: Withdrawal signs and symptoms differ in their order of appearance from one individual to another. Some individuals may not exhibit certain Page 20

Slide 21: OPIOID ABUSE: A COMPREHENSIVE REVIEW withdrawal signs and symptoms. Signs may also include uterine irritability, increased fetal activity, or rarely, hypotension. Treatment of opioid withdrawal. Most opioid withdrawal treatment is supportive care only. In extreme cases low dose benzodiazepines may be helpful, or even (on medical control order) low dose opiates. The more severe form of opioid withdrawal, acute opioid abstinence syndrome induced by rapid administration of an opioid antagonist, is best avoided altogether by using the strategies discussed above. In the event of severe reactions, supportive care, rhythm appropriate therapy, and benzodiazepines are the order of the day. Opioid withdrawal in pregnant patients. There is good evidence that the fetus may be more susceptible to withdrawal symptoms than the mother. In the mother, the initial signs of opioid withdrawal progress to increasingly painful physical symptoms (including uterine contractions, as noted above). There is some evidence that the use of opioid antagonist in an opioid dependant pregnant patient may result in intera-uterine death of the fetus due to acute withdrawal. Therefore the use of naloxone should be approached with caution in the pregnant patient, and only used after a thorough risk-benefit assessment. It should only be used on those with severe respiratory depression. When used, the smallest effective dose possible should be administered. KEY POINT The use of naloxone should be used with caution in the opioid dependant pregnant patient. Remember that pregnant patient who is a regular abuser of illicit substances also has a higher risk of complication with the pregnancy, delivery, and fetal development. Treatment of Opioid Addiction Most treatment is focused on weaning the patient off of the opioid without withdrawal symptoms (as these are a major cause of relapse), while addressing the behaviors though therapy and addiction programs. The most common drug therapies involve using either an opioid agonist or a mixed opioid agonist/antagonist. In the United States, the most common opioid agonist used for addiction treatment is Methadone. Methadone is in and of itself a potent opioid analgesic, very similar to morphine. Unlike morphine, its affinity for opioid receptor sites actually increases over time. This makes it a good drug for switching addicts off of illicit opiates (including IV heroin) but has also made Page 21

Slide 22: OPIOID ABUSE: A COMPREHENSIVE REVIEW weaning the patient off of methadone a prolonged affair. In fact, many addicts say that getting off of methadone is far more difficult than heroin. Some addicts, may remain on a maintenance dose of methadone for the rest of their lives. Another approach is to use a partial agonist/antagonist, such as burprenorphine. It will stimulate some opiod receptors, attenuating cravings and withdrawal symptoms, with out inducing the levels euphoria or CNS depression (it is still possible, although extremely difficult and rare, to overdose on burprenorphine) seen other opiates. Larger amounts can be taken (even overdoses) with no increased effect and no reduction or loss of consciousness. (In this respect it is distinctly safer than methadone.) Notably, while buprenorphine is being used, no other opiate will have any effect -- oxycontin, morphine, even heroin cannot replace it from nerve receptors, thus minimizing, to some degree, the risk of sudden or impulsive return to opiate use. Asa result, buprenorphine will have minimal or no response to naloxone. Another approach is to mix an oral opiate agonist with an opioid antagonist, commonly naloxone (although other antagonist have been used). Normally naloxone is rendered almost completely inactive by first pass hepatic function, therefore when the substance maintenance opioid is taken as prescribed, the naloxone is ineffective. If the oral opioid is crushed to be snorted, or injected (both practices bypass first pass detoxification) the naloxone remains active, rendering the opioid inactive. Showing new promise is suboxone a combination of both buprenorphine and naloxone. The END? In this article we dove into the pharmodynamics of opioids in the body, as well as their role in illicit drug use. We have discussed the prudent use of treatments in opioid overdoses. We have discussed some of the controversial topics in opioid abuse, and discussed withdrawal strategies. In short we have seen how this “routine” emergency is anything but. References "Afghanistan." The World Factbook. 16 May 2006. United States Central Intelligence Agency. 30 May 2006 <http://www.cia.gov/cia/publications/factbook/geos/af.html>. "Opium." Wikipedia. 29 May 2006. Wikimedia Foundation, Inc. 30 May 2006 <http:// en.wikipedia.org/wiki/Opium>. Substance Abuse and Mental Health Services Administration, Office of Applied Studies. Drug Abuse Warning Network, 2004: National Estimates of Drug-Related Emergency Department Visits. DAWN Series D-28, DHHS Publication No. (SMA) 06-4143, Rockville, MD, 2006. Drug Abuse Warning Network, "Opiate-Related Drug Misuse Deaths-2003." The Dawn Report Page 22

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