Section 6 Pharmacology

• Transmucosal form: Actiq® ("lozenge on a handle"). o Used in the management of breakthrough pain in patients. Abused as _________

"Perc-a-Pop."

Opiates and Opioid Drugs Pure opium has been used throughout history, but has limited use today. Many of today's baby-boomers were given_________ or camphorated tincture of opium as an infant and later in life for diarrhea and GI disorders. It is no longer available commercially in the U.S.

"paregoric"

• In November 2015, the FDA approved a nasal spray version of naloxone________to help stop or reverse the effects of opioid overdose. Previously, naloxone was only available in injectable forms, but many note that a nasal spray formulation is easier to deliver and there is no risk of a contaminated needle stick. Some individuals had been using unapproved naloxone kits that included an injectable formulation of naloxone with an atomizer that could deliver the drug nasally. The nasal spray naloxone received fast-track designation and priority review. Clinical trials showed that administering the nasal spray in one nostril delivered about the same levels or higher of naloxone as a single dose of FDA-approved naloxone IM injection, and it reached those levels in about the same time period. o Tennessee law now allows many police officers to carry and administer intranasal naloxone. EMS carries the injection. • Naloxone can precipitate withdrawal in an opioid-dependent patients, which is usually not life-threatening; however it can be extremely _____________ for the patient.

(Narcan®) uncomfortable

Example of Post-Op Adult Orders for Post-Anesthesia Care Unit (PACU) (Intended as a summary review of these discussions; not for testing purposes) Pain: • Morphine 3 mg IV every 5 minutes until pain is relieved. o Do not exceed 20 mg. If pain unrelieved, call anesthesiologist. o If allergic to morphine, use fentanyl. • Fentanyl 50 mcg IV every 5 minutes until pain is relieved o Do not exceed 250 mcg. If pain unrelieved, call anesthesiologist. Nausea: • Zofran® (ondansetron) 4 mg IV X 1 • Phenergan® (promethazine) 6.25 mg slow IVP every 15 minutes X 3 prn in running maintenance IV line • If N & V persists, call anesthesiologist Respiratory depression: • Narcan® (naloxone) 0.4 mg dilute to 10 ml with Normal Saline. Give 0.04 mg every 5 minutes until respirations are adequate. Max dose 2 mg. Notify anesthesiologist if used.

*not for testing purposes

o • Second-line choice is colchicine (Colcrys®, Mitigare®) Can also be used for chronic management combination with a urate-lowering drug such as probenecid (ColBenemid®). • Colchicine is usually discontinued after the serum urate concentration has been controlled and the client has not had an acute attack for ____________. • An interesting off-label use of colchicine is to improve the outcomes in the treatment of acute and/or recurrent __________.

1 to 3 months pericarditis

30 Day Limit on Opiates and Benzodiazepines in Tennessee • Effective in 2013, under a new Tennessee law, prescriptions for opioid pain medicines and benzodiazepine medicines may not be dispensed in Tennessee in quantities exceeding a _____________ o The new limits apply to all dispensers of these medications, including pharmacies, dispensaries and mail-order programs located either in or out of Tennessee.

30-day supply.

• The DEA has asked manufactures to voluntarily restrict the distribution of __________ to detoxification and maintenance treatment of opioid addiction. o It is not FDA approved for pain at the 40 mg dose. • According to a 2012 report from the CDC, methadone accounted for a mere 2% of prescriptions in 2009, but was responsible for 30% of prescription painkiller deaths in the last decade. o "Methadone is ________ than other opiates for treating non-cancer pain," said Dr. Thomas Frieden, director of the CDC, who added that there is limited scientific evidence it works for chronic non-cancer pain. "It should only be used for pain when other drugs haven't been effective."

40 mg methadone riskier

o Fentanyl (Schedule II) Available in 12, 25, 37.5, 50, 62.5, 75, 87.5 and 100 µg/hr strengths. "Start low and go slow in dosing." o In general, patients should be on at least ______________ or an equivalent for a week or longer before starting a fentanyl patch. o Due to the nature of the patch, the onset of analgesia may be delayed by 6 to 12 hours after placement of the patch. o Patient should also be given an immediate-onset opioid analgesic prn for breakthrough pain. o Upon removal of the patch, the fentanyl deposited in the subcutaneous tissue will continue to release active drug for about _____________, so the patches should be disposed of properly to prevent inadvertent access by children or household animals. o The patches can be diverted and abused (chewed, gel injected, etc.) o Drug absorption from a patch can be dangerously increased by ______: bathing, heating pads, exercise, even a fever.

60 mg/day of oral morphine another 8 to 12 hours heat

• Codeine is metabolized by the liver and excreted in the urine, mostly in inactive forms. However, some is demethylated to form morphine, an active moiety. o Patients who lack the enzyme________ may not be able to metabolize codeine to morphine and thus may not derive optimum analgesic benefits. Approximately 7% to 10% of white patients and 2% of Chinese patients lack CYP2D6. o On the other hand, a small proportion of people are "ultra-rapid metabolizers" who convert an appropriate dose of codeine into a potentially ________________ in the bloodstream. The percentage of ultrarapid metabolizers in the general population is 1% to 7%, but it goes as high as 29% among Ethiopians. Only a genetic test can determine whether a person is an ultra-rapid metabolizer, but there are FDA-approved tests for that. • The FDA and the Canadian Medical Association Journal recently warned that codeine's benefits as a pain treatment do not balance out its risks, which include respiratory depression and death, and that the drug should be phased out in favor of its principal metabolite, morphine.

CYP2D6 fatal level of morphine

The "Elephant Tranquilizer":__________ • In the fall of 2016, the DEA warned the public and police nationwide about the risks of carfentanil, an analogue of the synthetic opioid analgesic fentanyl, which is 100 times more potent than fentanyl. • Carfentanil is a Schedule II substance under the Controlled Substances Act and is used as a tranquilizing agent for elephants and other large mammals. It is ______ approved for use in humans.

Carfentanil not

Pneumonic for Side Effects of Opioids: SCHINIB S = Sleepy C = __________ H = High I = Itch N = Nausea I = Irritated (Angry) B = Buzz

Constipation

Fentanyl (Schedule II) • Available in several different dosage forms, e.g., injection, transdermal, sublingual, nasal spray, buccal tablet, and transmucosal. • Transdermal form: __________ o Transdermal fentanyl can be effectively used for the management of chronic pain when applied twice a week or every 72 hours. Some clients may need to change the patch every 48 hours to achieve adequate analgesia; this is off-label.

Duragesic® ("The Pain Patch")

•______ is caused by monosodium urate crystal deposition in tissues leading to arthritis, soft tissue masses (i.e., tophi) nephrolithiasis and urate nephropathy. The biologic precursor to gout is elevated serum uric acid levels. o At uric acid blood levels above _________________________ -- uric acid forms crystals that lodge in the joints and other body tissues. o These crystal deposits provoke an immune response that results in extremely painful swelling and in inflammatory arthritis that can permanently destroy the joints.

Gout 7 mg/dL -- and above 6 mg/dL in the extremities

• ____ is a serious, potentially fatal, autoimmune disease that attacks healthy tissues in many parts of the body and has traditionally been treated with anti-inflammatories. It disproportionately affects _____, and usually develops between ages 15 and 44. When common lupus symptoms appear (flare) they can present as "_______," swelling in the joints or joint pain, light sensitivity, fever, chest pain, hair loss, and fatigue.

Lupus women butterfly rash

Acute Treatment: "Agents that put out the fire" • First line therapy for acute gout is _______________ o Indomethacin (Indocin®) 50 mg tid until symptoms have resolved for 48 hours. Other NSAIDs may be safer in terms of ____________. o Corticosteroids are effective and are being used more often today. • Prednisone 20 to 60 mg/day for acute gout until symptoms resolve, usually about 5 to 7 days. • A steroid injection can be used if just one or two joints are affected.

NSAIDs or corticosteroids. GI toxicity

o Naproxen sodium (Aleve®) maximum daily dose is 660 mg (220 mg every 8 hours). • It is appropriate to provide an extended-release product like OxyContin® for chronic pain and an immediate-release product like __________ for breakthrough pain. • When switching between different opioid preparations, a narcotic analgesic conversion calculator or equi-analgesic table may be used as a guide. o A conversion calculator is available at Globalrph.com. • For example: Estimating oral equivalent analgesic doses: Morphine 30 mg PO is roughly equivalent to oral doses of: • Hydromorphone 7.5 mg • Oxycodone 20 mg • Hydrocodone 30 mg

Percocet® or Vicodin®

Implantable Buprenorphine for Treatment of Opioid Addiction • In 2016, the FDA approved _________, the first buprenorphine implant for the maintenance treatment of opioid dependence. • Probuphine® has four flexible matchstick-sized rods that are inserted subdermally on the inside of the _______ through a simple in-office procedure that delivers a continuous low-level dose of buprenorphine for up to six months in clinically stable patients who are on low-to-moderate doses of other forms of buprenorphine

Probuphine® upper arm

• The Medical Letter, April 18, 2011 concluded: o Transdermal buprenorphine (Butrans®) might be effective for treatment of chronic pain, but it has a slow onset of action, limited dosing flexibility and is poorly tolerated. The potential for __________ and difficulty in reversing the effects of the drug are additional concerns. Other analgesics are preferred.

QT prolongation

Morphine sulfate (MS) • Morphine is a __________ Controlled Substance and is the standard of comparison for injectable and oral opioid analgesics. o Trivial note: Morphine, first isolated in the mid-1800s, is named after the Greek God of Dreams, Morpheus. • Given orally, morphine is well absorbed but extensively metabolized on first pass through the liver, resulting in a low bioavailability of ~35%. • 10 mg is "normal" IM dose and is what others are compared against. o Oral doses are ~ 3-6 times the parenteral doses, e.g., 15-30 mg morphine orally = 5 mg parenteral. o This is due to significant __________ of morphine. o Patient Controlled Analgesia (PCA) morphine in opiate-naïve clients is usually given as 1 mg every 6 minutes or 2 mg every 10 minutes with a set maximum amount ("lockout").

Schedule II first-pass metabolism

• Febuxostat (Uloric®) (YOU-lor-ik) o It is a xanthine oxidase inhibitor similar to allopurinol, but unlike allopurinol, very little __________is excreted through the urine, making it safe for patients with kidney problems. o It seems to lower uric acid levels more than allopurinol, but may not decrease the number of gout flares. It is more expensive.

Uloric®

Switching/Dosing Opiates, NSAIDs and Acetaminophen • There is no true analgesic ceiling effect for pure opioid agonists such as morphine, hydromorphone, or fentanyl. o However, mixed agonist-antagonist opioids such as pentazocine, butorphanol, and nalbuphine and the partial agonist opioids such as buprenorphine do have ____________ and are poor choices for patients with severe pain. • When using combination opioid products containing acetaminophen or ibuprofen (such as Percocet® and Combunox®), the dose limiting toxicity is generally attributable to acetaminophen or ibuprofen. o Studies on patients with dental pain and/or postprocedural pain reveal that acetaminophen has an analgesic ceiling of 1000 mg. o Although ibuprofen is commonly used in dosages as high as 800 mg for acute pain, the analgesic ceiling is only 400 mg/dose with a maximum daily dose of 1200 mg/day. • However, 2400 mg daily can relieve __________without providing additional pain relief

a ceiling effect inflammation

• OxyContin® is dosed every 12 hours (sometimes every 8 hours in tolerant patients) and is intended for moderate to severe pain when a continuous, around-the-clock analgesic is needed for an extended period of time—NOT intended for use as ________ • Approved in 2015 for certain pediatric patients aged 11-16 years with pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. • A sustained-release product available in 10, 15, 20, 30, 40, 60, and 80 mg strengths. (The 80 mg strength is intended for use in opioid tolerant patients only.) • Tablets are to be swallowed whole and are not to be broken, chewed, or crushed. Taking broken, chewed, or crushed tablets leads to rapid release and absorption of a potentially ____________. (This is how and why it is abused.) • Becoming a highly abused "street" drug known as "Killers," "Hillbilly Heroin," "Oxy," or "High Cotton" with user crushing the tablet and snorting or injecting. On the street, the drug goes for ~ $1 per mg or more. • "Black Box" warning that calls OxyContin as potentially addictive as morphine and explains that chewing, snorting, or injecting it can lead to death.

a prn analgesic. fatal dose of oxycodone

Noteworthy Effects of Narcotic and Some "Non-opiate" Analgesics 1) Analgesia 2) Sedation and euphoria—Can adversely affect ___________, etc. For example, in Australia, if you are taking morphine, you are not allowed to drive a car. 3) Antitussive 4) ________ rashes (not generally considered an allergic reaction). Treat with antihistamines since pruritus is due to histamine release. Can also treat pruritus from epidurals with Nubain®. 5) Allergic reactions (anaphylaxis—rare) 6) Smooth muscle relaxation (causes constipation). Prophylax with a stool softener combined with a stimulant laxative. One does not develop tolerance to constipation. 7) Seizures (primarily with meperidine due to its metabolite normeperidine) 8)____________ due to dopamine stimulation of CTZ. Occurs in ~25% of clients. Often given with hydroxyzine (Vistaril®) or promethazine (Phenergan®) to decrease N & V and to potentiate analgesia 9) Increased intracranial pressure 10) Hypogonadism, leading to fatigue, depression, weakness, and sexual dysfunction. Chronic opioids can lead to lower testosterone and estrogen. 11) Rarely can be associated with Serotonin Syndrome when combined with other serotonergic drugs. 12) Respiratory depression 13) Physical dependence 14) Tolerance—Generally clients reporting "tolerance" are likely suffering disease progression or are drug-seekers.

ability to drive Pruritic Nausea and vomiting

Neonatal Abstinence Syndrome or NAS • Babies born _______ (called Neonatal Abstinence Syndrome or NAS) crowd hospital maternity wards, creating new challenges for doctors in an unexplored field — and new dilemmas for parents still hooked on the same drugs. • According to the Knoxville News Sentinel, May 13, 2013, in 2008 East Tennessee Children's Hospital in Knoxville treated 33 infants for drug dependence, aka, NAS. o In 2012, they treated 283, and for 2013, they predict 320 infants will be treated for NAS. • The News Sentinel reported on Baby Liam receiving morphine and showed the following photograph at ETCH in Knoxville. The baby is one of many infants born dependent on drugs being treated at the facility.

addicted to painkillers

Effects of Opioids for Low Back Pain JAMA Internal Medicine, May 23, 2016 • Australian researchers examined 13 trials involving more than 3,400 participants using opioid analgesics for chronic low back pain. • One-half of those trials saw at least 50% of the participants withdraw due to ____________ • While the researchers report there was "moderate-quality evidence that opioid analgesics reduce pain in the short term," they add that "clinically important pain relief was not observed within the dose range evaluated." • Furthermore, the review found _________ on opioid analgesics for acute low back pain or to help manage extended use of the drugs for individuals with chronic low back pain.

adverse events or a lack of efficacy. no evidence

• Now available only in an "abuse-resistant" formulation that contains polyethylene oxide which makes the oxycodone insoluble in ________and made harder to crush, intended to prevent it from being cut, broken, chewed, crushed or dissolved to release more medication. The original OxyContin® was "OC," while the newer abuse-resistant formulation is "OP."

alcohol

Naltrexone (ReVia®, Vivitrol®) • Originally used orally to prevent narcotic abuse as ReVia®, but found to also be useful in the treatment of ________ based on the theory that alcohol induces the release of endorphins and other "morphine-like" substances. • Approved as Vivitrol® as a monthly injection for alcoholism and opiate addiction. It is increasingly being tried by courts, prisons and jails across the U.S. to combat opiate abuse. o Patients must be __________ when they start taking Vivitrol® or could experience severe withdrawal symptoms. They should be aware that resuming drug use after stopping Vivitrol® treatment could make them more susceptible to overdose.

alcoholism opioid-free

o Effective July 1, 2015, under the Tennessee "Addiction Treatment Act of 2015," any person who in good faith seeks medical assistance for a person experiencing or believed to be experiencing a drug overdose shall not be ___________________ if the evidence for the arrest, charge, or prosecution of the drug violation resulted from seeking such medical assistance. o Tennessee Public Chapter 596, passed by the 2016 Tennessee Legislature, sets up a statewide pharmacy practice agreement that authorizes the Tennessee Department of Health's chief medical officer to enter the collaborative agreement with any willing licensed, practicing Tennessee pharmacist with proper training in opioid antagonist therapy. This agreement allows an authorized pharmacist to dispense an opioid antagonist such as naloxone to help prevent an opiate-related overdose. The pharmacist must provide proof of completing an _________________ within the past two years before he or she can enter into the agreement to dispense naloxone.

arrested, charged, or prosecuted for a drug violation opioid antagonist training program

Methadone (Dolophine®, Methadose®) (Schedule II) • Used for pain and in narcotic addiction treatment programs. • FDA has issued a Public Health Advisory warning that death due to respiratory depression and ____________ may occur in patients taking methadone. o Analgesia from a dose of methadone lasts about 4 to 8 hours. However methadone stays in the body much longer—from 8 to 59 hours after it is taken. This can lead to serious toxicity.....and death. As a result, patients may feel the need for more pain relief before methadone is eliminated resulting in accumulation.

arrhythmias (QT prolongation)

2016 FDA Initiative on Opioid Medications FDA.gov, February 5, 2016 In response to the ongoing opioid abuse epidemic, FDA in February 2016 announced plans to reassess the agency's approach to opioid medications. The plan includes: • Re-examine the risk-benefit paradigm for opioids and ensure that the agency considers their wider public-health effects; • Convene an expert advisory committee ___________ for an opioid that does not have abuse-deterrent properties; • Assemble and consult with the Pediatric Advisory Committee regarding a framework for pediatric opioid labeling before any new labeling is approved; • Develop changes to immediate-release opioid labeling, including additional warnings and safety information that incorporate elements similar to those of the extended-release/long-acting (ER/LA) opioid analgesics labeling that is currently required; • Update Risk Evaluation and Mitigation Strategy requirements (REMS) opioids after considering advisory committee recommendations and review of existing requirements; • Expand access to, and encourage the development of, ___________of opioid products; • Improve access to naloxone and medication-assisted treatment options for patients with opioid-use disorders; and • Support better pain-management options, including alternative treatments.

before approving any new drug application abuse-deterrent formulations

Limit Prescribing Opioids, Benzos Together, FDA Warns With Black Box FDA.gov, August 31, 2016 • To reduce the risk for overdose deaths, clinicians should not prescribe opioid pain medicines together with _________ to patients unless there are no adequate alternative treatments available, the FDA announced in August 2016. • Both classes of drugs are central nervous system (CNS) depressants, which can trigger respiratory depression, coma, and death. • The FDA is spelling out this and other precautions in class-wide boxed warnings on the labels of opioids and benzodiazepines.

benzodiazepines

• Morphine sulfate (MS) There is no "maximum" dose in opiate-tolerant patients, i.e., doses must be individualized and may reach high amounts if the patient is tolerant to opiates. • Morphine releases histamine which can cause ______________ which causes itching which is sometimes mistaken for as an "allergic" reaction. o It also has the potential to precipitate or exacerbate asthmatic attacks. o Other µ receptor agonists that do not release histamine, such as the fentanyl derivatives, may be better choices for such persons. • Oral extended-release formulations: MS Contin®, Kadian®, Oramorph-SR®, Avinza®. • Also available in implantable pump, PCA subdermal formulations and epidural or intrathecal administration as Infumorph® and Duramorph®

bronchoconstriction and vasodilation

• Buccal "melt-in-your-mouth" tablet: Fentora®. o Approved for the management of breakthrough pain in patients with________who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. o Fentora® tablets should be placed above a ________ between the upper cheek and gum, and allowed to dissolve for up to 30 minutes. A single Fentora® tab can be fatal to a child, and is dangerous for anyone not tolerant to opioids.

cancer rear molar

Phenylpiperidines • Meperidine • Fentanyl Diphenylheptanes • Methadone • Propoxyphene (No longer on the market due to QT prolongation) Allergic reactions may _________ within the same chemical structural class, but are less likely between classes. Thus, in patients with true allergic reactions, treatment can be switched to a product in one of the other chemical groups.

cross-react

Oxymorphone (Opana®) • Oral Opana® 10 mg is comparable to oxycodone 20 mg or morphine 30 mg orally. Oral Opana® is formulated in a _____________. • Also available as an injection.

crush-resistant formulation

Buprenorphine for Opiate Addiction • When buprenorphine is used for opiate addiction, naloxone (Narcan®) is added to buprenorphine (Suboxone®) to decrease the likelihood of diversion and misuse. When these products are taken as sublingual tablets, buprenorphine's opioid effects dominate and naloxone blocks opioid withdrawals. If the sublingual tablets are ____________, however, the naloxone effect dominates and can bring on opioid withdrawals.

crushed and injected

Methadone Availability Available only in a limited number of federally regulated clinics. Patients must visit clinic ______ for their doses. Suboxone Availability Can be prescribed by any doctor who gets federal certification. Patients get their prescriptions filed in a local pharmacy and take their sublingual tablets at home. Methadone Dosage The higher the dose, the greater the effects, making it especially useful for treating long-standing addiction but also increasing the potential for abuse or a fatal overdose. It is given in a liquid form. Suboxone Dosage Doses above a certain threshold don't increase the drug's effectiveness. This ceiling also lowers the ________and makes an overdose death from the drug alone unlikely.

daily abuse potential

Tolerance and Pseudo-tolerance • Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a _________________. It is a common physiologic finding that results from neuroadaptation by the body during chronic use. • It may be seen after several days of therapy and can be first recognized by a decrease in the ___________ of analgesia. Tolerance develops to most of the adverse effects of opioids, including respiratory and CNS depression, at least as rapidly as tolerance to the analgesic effect. • Patients who develop tolerance will require an increase in the opiate dose to achieve the same level of analgesia. These patients should be informed that the need for increasing doses is expected and does not indicate addiction. • Pseudo-tolerance is the need for an increased dosage, _____________, but because of other factor, e.g., disease progression or increased activity.

diminution of one or more of the drug's effects over time duration not because of tolerance

Joint Commission Alert for Opiates The Hospitalist. 2013;17(2):34-36. • Opioid overuse can spell the onset of onerous consequences. The analgesics can slow breathing to dangerous levels and lead to ____________ o Citing these concerns, The Joint Commission recently issued a Sentinel Event Alert that urged hospitals to take specific measures to help avoid serious complications and even deaths from the use of such opioids as morphine, oxycodone, and methadone. • "The Joint Commission recognizes that there is an opportunity to improve the care of patients on opioids in acute-care settings," spokeswoman Elizabeth Eaken Zhani says. "Healthcare workers need to be aware of the risks to patients in prescribing opioids." • Adverse events involving opioids include dosing errors and improper monitoring of patients and drug interactions. Patients who have sleep apnea, are obese, or very ill—with such conditions as pulmonary disease, congestive heart failure, or impaired renal function—might be at higher risk for harm from opioids. • "The alert was issued in response to concerns that opioid analgesics are among the top three drugs in which medication-related adverse events are reported to The Joint Commission," Zhani says. "They also rank among the drugs __________ associated with adverse drug events."

dizziness, nausea, and falls. most frequently

• Transdermal, iontophoretic battery-operated PCA system of fentanyl (Ionsys®) o Approved for short-term treatment of acute post-op pain. Each transdermal system administers up to 6 doses/hour and operates for up to 24 hours or 80 doses. It may be more convenient to use than IV patient-controlled analgesia, but lacks ____________. Some patients will require supplemental analgesia during the first 3 hours after application of the device. o Ionsys® may only be used in hospitals enrolled in ____________and must be stopped prior to hospital discharge.

dosing flexibility the IONSYS REMS program

Drug Overdoses Kill More People Than Automobile Accidents • A report released by the US Centers for Disease Control and Prevention suggests that more Americans now die from drug overdoses than in car accidents. • There has been a 90% increase in poisoning deaths since 1999, while deaths from car accidents have __________ in the same period.

dropped 15%

Lidocaine (Xylocaine®)—available in several dosage forms and concentrations. • Lidocaine injection and lidocaine with epinephrine injection o It has long been contraindicated to use lidocaine with __________ for digital anesthesia due to fear that vasoconstriction from the epinephrine would cause necrosis and possible amputation of the digit. However, recent literature debunks this theory since there are numerous reports of Epi-Pen® being held upside down and inadvertently being injected into the thumb instead of the thigh without necrosis. Auto-injectors administer 0.3 mg (adult) or 0.15 mg (pediatric) of epinephrine per dose. For comparison, one ml of commercially prepared 1% lidocaine with epinephrine contains only 0.01 mg of epinephrine. • Lidoderm®, a 5% lidocaine patch for shingles pain. • Lidocaine and prilocaine mixture (EMLA®) [Eutectic Mixture of Local Anesthetics] • ELA-Max® liposomal delivery system (used like EMLA®) o A 4% lidocaine in a liposomal delivery system which increases the rate and extent of dermal absorption and length of action. o Requires administration _________ prior to procedure and needs no occlusive dressing. EMLA® requires one hour application period. It is less expensive than EMLA® and is sold OTC. • Lidocaine viscous 2% is used for oral pain. In 2014, the FDA required a Boxed Warning about the dangers of the use of oral viscous lidocaine 2% for ___________ infants or young children.

epinephrine 30 minutes teething

Opioid Use and Abuse • The current recommendations regarding the place of opioids in the management of chronic, non-cancer pain is limited. • When using opiates to treat severe pain for more than a few days, several phenomena can occur. o The terms used to describe these phenomena are tolerance, physical dependence, addiction and pseudo-addiction. • We must understand the differences and the context in which these phenomena occur in order to differentiate between ____________

expected developments and drug abuse

o• Pegloticase (Krystexxa®) Approved 2010 to treat gout in adults who do not respond to or who cannot tolerate conventional therapy. Indicated only for refractory gout since it is very expensive, ~$5000/dose, or ~$35,000 for 12 weeks therapy. o Pegloticase is an enzyme that lowers uric acid levels by metabolizing it into a _____________ o It is administered every two weeks as an intravenous infusion. o Several patients in the clinical trials experienced a severe allergic reaction when receiving an infusion of Krystexxa®, so health care providers should dispense _______________ to their patients beforehand to minimize the risk of such a reaction. o It is approved with a Risk Evaluation and Mitigation Strategy (REMS) that includes a medication guide for patients and materials for healthcare providers to communicate the risk of severe infusion and allergic reactions.

harmless chemical that is excreted in the urine. a corticosteroid and an antihistamine

Topical and Local Analgesics 1) Topical salicylates (e.g., Aspercreme®, BenGay®) • Do not apply a ____________ over the application of these rubefacient agents. o Note that many of these brand names have multiple ingredients under slightly different names, e.g., Aspercreme with lidocaine®, Bengay® products may contain camphor, menthol methyl salicylate, etc.

heating pad

• Fentanyl buccal film: Onsolis® o It is packaged as a dime-size film that is placed against the inside of the moistened cheek, ________________ • Sublingual tablet: Abstral® and Subsys® for fast acting fentanyl transmucosal delivery for breakthrough pain. • Nasal spray of fentanyl (Lazanda®).

held for 5 seconds and then left in place.

Managing Side Effects and Allergic Reactions to Opioids/Opiates Prescriber's Letter, June 2010 • When patients say they are allergic to an opioid, are all opioid analgesics off limits? The key is getting a detailed description of the reaction. • Some types of "reactions" may be due to a pseudoallergy—the result of the release of _____________ that causes a local wheal, burning, itching, and erythema at the site of injection. o Coadministration of diphenhydramine (Benadryl®) or hydroxyzine (Vistaril®) prevents histamine-induced itching and also provides antianxiety effects that may add to the opiates analgesic benefit. • However, some patients taking opioid analgesics often develop severe ______________of the face, lips, mouth and pharynx, severe pruritic rashes and other true allergic-type reactions. • Chemically, there are three distinct structural categories of opioids:

histamine from mast cells hypotension, swelling

Capsaicin (Zostrix HP®, Captrix®, Capzasin-P®, Qutenza®) • Derivative of the ___________ that depletes substance P. It will usually increase pain initially. • It is applied topically for relief of pain from _______________________ • Qutenza® is a Rx strength (8%) of capsaicin. It is applied by a health care professional and was shown to provide 12 weeks of pain reduction from a single one hour treatment for post-shingles pain. Prior to applying, lidocaine is applied to the area to prevent the "burning" pain it can initially cause.

hot pepper plant peripheral diabetic neuropathy, post-herpetic neuralgia and arthritis.

• It is used "off-label" to reverse _____________, to improve neurologic recovery after ischemic stroke, and to treat hypercapnic COPD, although response in these conditions is not as dramatic or predictable as when reversing the effects of opiates. • Also used "off-label" orally to lessen _____________in clients using chronic opioids. It is not systemically absorbed to any significant extent, so does not affect the analgesia. • In 2014, the FDA approved a prescription naloxone _______ that can be used by family members or caregivers to treat a person known or suspected to have had an opioid overdose. Evzio® delivers a single dose via a hand-held auto-injector that can be carried in a pocket or stored in a medicine cabinet. Price for one kit with two auto-injectors is ~$600. It is available in Tennessee under the "Good Samaritan Law." o There is some support to make it available OTC, but this is controversial.

hypotension associated with spinal injury "gut paralysis" (constipation) (Evzio®)

Narcotic Agonists Related to Codeine 1) Codeine • Codeine alone is Schedule II alone, but in combination products like Tylenol #3® and Fiorinal with Codeine #3, it is Schedule III. o Tylenol #3® contains 300 mg of acetaminophen and 30 mg of codeine as the active ingredients. o Tylenol #4® contains the same amount of acetaminophen (300 mg) as Tylenol #3®, but a greater amount of codeine (60 mg). • Young infants are more susceptible to codeine intoxication due to their _______________. Therefore, it is not recommended in young children and nursing mothers. o In 2016, the American Academy of Pediatrics (AAP) recommended that parents and health care providers cease giving codeine to children because of life-threatening or fatal respiratory depression. o Alternative drugs to treat pain in children are available, including tramadol (Ultram®) and tapentadol (Nucynta®), which are not prodrugs like codeine.

immature hepatic glucuronidation system

• Oxaydo® is a brand of immediate-release oxycodone "designed to discourage _________ o It is formulated with sodium lauryl sulfate, an inactive ingredient that may cause __________when snorted. • July 2014, the FDA approved Targiniq ER® (oxycodone hydrochloride and naloxone hydrochloride extended-release tablets), an abuse deterrent extended-release/long-acting (ER/LA) opioid analgesic.

intranasal abuse." nasal burning and throat irritation

Nalmefene (Revex®) • Used I.V., and___________ than naloxone, making it as long-acting as most opiates, thus reducing or eliminating repeat dosing as is often necessary with naloxone (Narcan®).

longer acting

Buprenorphine for Pain • Buprenorphine mono is also approved for treating pain. • Buprenorphine has some advantages over methadone and other opioids. It has a slightly _______ abuse potential and is less dangerous in an overdose and causes fewer withdrawal symptoms when it's stopped. However, it is still abused. • Rxs for buprenorphine for pain do not need the 2nd special DEA number. o Prescribers should write for "chronic pain" on the Rx when appropriate. Buprenorphine is usually given 3 to 4 times daily for pain instead of once a day for addiction. It's only for patients who are already opioid tolerant. • It is available for pain (not for addiction) as a buccal film called ________®. Also available as a once-weekly buprenorphine transdermal system (Butrans®) {BYOO-trans} for the management of moderate to severe chronic pain in patients requiring a continuous, around-the-clock opioid analgesic for an extended period.

lower Belbuca

Benzocaine (Americaine®, Solarcaine®, Oragel®) • Commonly used for many years and considered very safe. However, in 2011, the FDA announced that topical benzocaine sprays, gels, and liquids used as anesthesia during medical procedures and for analgesia from tooth and gum pain may cause _____________.

methemoglobinemia

Hydrocodone • High abuse potential, it was switched from Schedule III to Schedule II in 2014. • It is the _______ prescribed drug in the U.S. • More potent and more abused than codeine. • Causes less __________ effect than morphine or codeine, this is one reason it's legitimate use is so high. • Metabolized in part to hydromorphone (Dilaudid®).

most emetogenic

• Opiates are derived from opium and work by presynaptic reduction of the release of inflammatory transmitters (e.g., tachykinin, excitatory amino acids, and peptides) from the terminals of afferent C-fiber neurons after activation of opioid receptors. o Opiate receptors include __________, which have been reclassified by an International Union of Pharmacology subcommittee as OP1 (delta), OP2 (kappa), and OP3 (mµ). • Dopamine levels are also increased. • Opioids also inhibit neuronal activity via ________________ in the substantia gelatinosa.

mµ, kappa, and delta GABA and enkephalin neurons

• In 2014, the FDA approved an extended-release combination of oxycodone and acetaminophen (Xartemis XR®) for the management of acute pain. o The drug has both immediate- and extended-release components to allow pain relief within an hour, with twice-daily dosing. • In 2016, the FDA approved an oral, abuse-deterrent, extended-release (ER) formulation of oxycodone hydrochloride and ____________ for severe pain. • In 2016, the FDA approved a twice-daily abuse-deterrent oxycodone medication Xtampza ER®.

naltrexone (Troxyca ER®)

Hydromorphone (Dilaudid®, extended-release Exalgo®) • Schedule II. • Hydromorphone is being used more because it might cause less __________ than morphine, but it's much more potent. o ORAL hydromorphone 2 mg is equal to morphine 8 mg (4 times more potent) o IV hydromorphone 1 mg is equal to morphine 7 mg (7 times more potent) • Exalgo® is an osmotic delivery system to minimize peaks and troughs, which will hopefully lessen abuse potential.

nausea and itching

Uricosurics • Probenecid (Benemid®) o Increases urinary excretion of uric acid (thus it is called a "uricosuric"). Must have adequate renal function to be effective, so it is contraindicated in clients with renal impairment (i.e., creatinine clearance less than 20 to 30 ml/min). o High risk of ___________—encourage hydration. o Used today as second-line therapy.

nephrolithiasis

• Second-line choice is colchicine (Colcrys®, Mitigare®) o It is administered as two initial tablets, followed by one tablet one hour later. More than 3 tablets total is not more effective. • It used to be given as two 0.6 mg tablets, followed by one tablet every hour until relief or intolerable side effects (vomiting, cramps). Also, the old formulation was available generically and was much less expensive than Colcrys®. In 2015, the FDA approved a less expensive branded generic called Mitigare®. Also in 2015, a generic capsule of colchicine was approved. o The I.V. form of colchicine and older oral forms of generic colchicine are ____________

no longer available.

Tapentadol (Nucynta®) (C-II) • Tapentadol immediate-release tablets approved for the relief of moderate to severe acute pain in 50 mg, 75 mg and 100 mg doses in a long-acting crush-resistant version. • Tapentadol is a centrally acting oral analgesic that works via two mechanisms, like tramadol: o a mu-opioid receptor agonist o ________ reuptake inhibitor • It is "stronger" than tramadol, and is a Schedule II Controlled Substance. • 100 mg of tapentadol is said to be equal to 15 mg of oxycodone, with less __________

norepinephrine constipation, nausea and vomiting

Alvimopan (Entereg®) • Approved for treatment of postoperative ileus. This is a µ-opioid receptor antagonist indicated to accelerate the time to upper and lower GI recovery following partial large or small bowel resection surgery with primary anastomosis. It can be given ____________.

only in a hospital

2) Methylnaltrexone (Relistor®) • Approved for ____________. Helps restore bowel function in patients with advanced illness who are receiving chronic opioids. Relistor® blocks opioid effects on the gut, without blocking their analgesic effects in the CNS.

opiate-induced constipation (OIC)

• Asymptomatic hyperuricemia is common and usually does not progress to clinical gout. • Acute gout most often presents as attacks of ___________________ of one or a few joints in the lower extremities, especially the big toe.

pain, erythema, and swelling

• The FDA has approved sublingual buprenorphine/naloxone (Suboxone®, Zubsolv®) and Bunavail® buccal film for the office management/treatment of opiate addiction. o At this time, only __________(not APNs or PAs) that meet certain criteria may prescribe buprenorphine for addiction and only treat a limited number of patients at a time. However HHS announced in November 2016 that nurse practitioners (NPs) and physician assistants (PAs) can immediately begin taking the required training to prescribe buprenorphine for addiction. NPs and PAs who complete the required 24 hours of training and seek to prescribe buprenorphine for up to 30 patients will be able to apply to do so starting early 2017. HHS also announced its intent to initiate rulemaking to allow NPs and PAs who have prescribed at the 30-patient limit for 1 year to apply for a waiver to prescribe buprenorphine for up to 100 patients. • APNs and PAs can prescribe for pain o Physicians must be certified and there are two DEA numbers required: the regular one and a special one ("X") just for buprenorphine. o Suboxone® contains __________ to ensure that addicts don't use buprenorphine intravenously or insufflation. o Buprenorphine/naloxone (Suboxone®) improves access to treatment. Methadone is available only at state-managed clinics.

physicians naloxone

Bupivacaine (Marcaine®, Exparel® liposome injection)—can be used as a local anesthetic, or in the liposome formulation to decrease_____________ and delay the use of opioids for up to 72 hours.

post-surgical pain

Oxycodone (Schedule II) • ~1.5 times more _______ than hydrocodone; ~10 times more potent than codeine. • Metabolized in part to oxymorphone (Opana®). • Several formulations available: o oxycodone plus aspirin: Percodan® o oxycodone plus ibuprofen: Combunox® o oxycodone plus acetaminophen: Percocet®, Roxicet® or 'Roxies' • Percocet comes in 4 strengths of oxycodone: 2.5, 5, 7.5 & 10 mg o oxycodone sustained-release: OxyContin®

potent

Partial Agonists and Mixed Agonist/Antagonists Note on the use of mixed agonist/antagonists: The following drugs have both narcotic agonist and antagonist properties and should not be used in patients physically dependent on opioids since they may _________ 1) Butorphanol (Stadol®) (Schedule IV) • Available as an injection (generic) and a nasal spray (Stadol NS®) 2) Pentazocine (Talwin®, with acetaminophen, Talacen®)—Schedule______ • Pentazocine parenteral: Talwin • Pentazocine oral: Talwin NX® (contains naloxone to prevent I.V. misuse) • 50 mg oral equivalent to codeine 60 mg orally

precipitate withdrawal IV

Addiction • Addiction is characterized by impaired control over drug use, compulsive use, continued use despite harm, and craving. • Addiction implies psychological dependence and is characterized by a dysfunctional pattern of use for ___________. • It may involve loss of control of their use and preoccupation with obtaining opioids despite the presence of adequate analgesia. • It is important to realize that the presence of tolerance and physical dependency does not necessarily imply addiction. • Addiction may involve any or all of the following: o Continued use despite harm o Loss of control over the use of opioids o Preoccupation with obtaining opioids, despite the presence of adequate analgesia

purposes other than alleviation of pain

• Lesinurad (Zurampic®) o In December 2015, the FDA approved lesinurad (Zurampic®) hyperuricemia associated with gout. It is used in combination with a xanthine oxidase inhibitor. It is similar to probenecid in that the drug works by helping the kidney excrete uric acid by inhibiting the function of transporter proteins involved in uric acid reabsorption in the kidney. But probenecid can be used alone. Zurampic® must be used with allopurinol or Uloric® (febuxostat) because using Zurampic® alone may increase the risk of ______________.

renal failure or kidney stones

• Since hydrocodone is now a Schedule II drug, what can the practitioner, e.g., dentist order via telephone for acute pain? o Tylenol #3® (30 mg of codeine) is equivalent to 5 mg of hydrocodone; Tylenol #4® (60 mg of codeine) is equivalent to 10 mg of codeine. o Tramadol (Ultram®) 50 mg is equivalent to 10 mg of hydrocodone. • Caution with tramadol in a patient with ___________ o The Medical Letter, October 13, 2014 states: "In single full doses, some NSAIDs have shown equal or greater analgesic effect than usual doses of an oral opioid combined with acetaminophen." • Several dosage forms of hydrocodone are available: o hydrocodone "cough syrups" o hydrocodone with acetaminophen: Lortab®, Lorcet®, Vicodin® o hydrocodone with ibuprofen: Vicoprofen®, Reprexain® o Single-entity hydrocodone extended-release: Zohydro ER® and Hysingla ER®

seizure disorders.

Narcotic Antagonists 1) Naloxone (Narcan®) • Naloxone antagonizes opiate receptors. This antagonism is competitive and ________. Thus, repeat doses of naloxone may be required when long-acting opiates are involved. • Naloxone can be given ___________. The usual dose is 0.4 to 2 mg IV. In patients with suspected opioid dependence, incremental doses of 0.2 mg IV should be administered, titrated to reversal of respiratory depression and coma, to avoid precipitating acute opioid withdrawal. Doses may be repeated every 2 to 3 minutes up to 20 mg. Due to the increased abuse of fentanyl, in October 2016, an FDA Advisory Committee recommended increasing the minimum dose from the current dose of 0.4 mg.

short-lived intravascularly, intramuscularly, subcutaneously, intranasally or endotracheally

Nalbuphine (Nubain®) • Binds to mu, kappa and delta receptors, but not to _________ • Analgesic effects equivalent to morphine on a mg per mg basis • Parenteral only • Less psychotomimetic effects than pentazocine • Also used for __________ • Not a controlled substance, and doesn't usually show up on opiate drug screens

sigma receptors itching from epidurals

Synthetic Opioid Agonists 1) Meperidine (Demerol®, in Mepergan Fortis®) (Schedule II) • Compared with equianalgesic doses of morphine, meperidine may cause less ____________. It also has a shorter duration of action than morphine, i.e., ~3 hours. • The American Pain Society (2008) and ISMP (2007) do not recommend meperidine's use as an analgesic since it has a higher risk of dependency and is more likely to cause ________________, etc. Its major indication is in those patients allergic to morphine-like agents. • Interacts with several drugs such as SSRIs, triptans, and MAOIs. • Off-label use for __________.

smooth muscle spasm, constipation, and depression of the cough reflex seizures (due to its metabolite normeperidine), tremors and mood changes than morphine shivering

Local Anesthetics • These agents can be applied topically or given parenterally as nerve block or infiltration and reversibly block nerve conduction by decreasing nerve membrane permeability to __________. They have a rapid onset of action (~2-3 minutes), with a duration of action of ~30-45 minutes). • Parenteral local anesthetics are often co-administered with ___________ or other local vasoconstrictors to delay systemic absorption, prolong duration of action, and promote local hemostasis.

sodium epinephrine

• In 2011, the FDA approved the use of belimumab (Benlysta®) in combination with _________ to treat active autoantibody-positive systematic lupus erythematosus.

standard therapies

Phenanthrenes ("Morphine Group") • Morphine • Codeine • Hydrocodone • Hydromorphone • Oxycodone • Nalbuphine • Butorphanol • Dihydrocodeine • Pentazocine • Tramadol (Contraindicated in PI labeling, but there is not good evidence for cross-sensitivity of tramadol with opioids.) • Tapentadol (Not contraindicated in U.S. PI labeling, but it is structurally similar to ___________.)

tramadol

Pseudo-addiction • Pseudo-addiction has been used to describe patient behaviors that may occur when pain is ____________or the patient has developed "Opioid Induced Hyperalgesia" where there is a dramatic increase in sensitivity to panful stimuli (without worsening pathophysiology) that worsens with increased opioid dosage. It is a type of behavior that clinicians must understand and recognize because it can easily be misinterpreted as addiction. • Pseudo-addictive behaviors may be seen in patients with severe, unrelieved pain. These behaviors may mimic those seen with ___________. These patients may become preoccupied with obtaining opioids; however, their underlying focus is on finding relief for their pain. They may become focused on obtaining medications, may "clock watch," and may otherwise seem inappropriately "drug seeking." The fear of not having an adequate amount of medication available to control their pain may result in medication hoarding. When patients with pseudo-addiction are provided adequate analgesia, the behaviors that mimic addiction resolve, the medications are used as prescribed, and the patient's daily functioning increases.

under-treated addiction

Buprenorphine (Buprenex® I.V., Subutex® oral)—Schedule III • Buprenorphine is an opioid partial agonist. This means that, like opioids, it produces effects such as euphoria or respiratory depression. With buprenorphine, however, these effects are _______ than those of full opiate agonists such as heroin, hydrocodone, oxycodone and methadone. It is longer acting and more potent than morphine. • It is approved for treating __________ when combined with naloxone. It can also be used as monotherapy for pain, but there are restrictions on its use since it is highly abused due to its opioid effects.

weaker opiate addiction

• Not effective orally unless extremely large doses are administered. Oral naloxone is 1/50 as potent as parenteral naloxone due to a significant first-pass effect in the liver. • Naloxone itself produces no physical or psychological dependence and__________ worsen respiratory depression if administered for non-opiate overdose. • Naloxone antagonizes both the toxic and clinical effects of opiates. Thus, not only are _______________ o Clinicians should use discretion when considering administering naloxone to patients who are sedated from opiates but do not exhibit respiratory depression. Reversal of analgesia is undesirable in patients known to be in severe pain. • Will not effectively reverse the seizure effects of meperidine (Demerol®) since most of the toxicity is due to its active metabolite ___________ • Will also reverse pentazocine and even clonidine—so see an increase in blood pressure if given to a client is on clonidine.

will not respiratory depression, hypotension, and sedation reversed, but so is analgesia normeperidine.

Physical Dependency • Physical dependence is a state of adaptation that is manifested by a ___________ that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. • Signs and symptoms are seen only when opiates are _________ or the dose is markedly decreased and include: body aches, diarrhea, anorexia, goose bumps, shivering, sweating, insomnia, irritability, tachycardia and fever. • Physical dependency does not indicate addiction, and the difference should be made clear to patients by their caregivers.

withdrawal syndrome stopped abruptly

o This is the first lupus drug to be approved since 1955, when the FDA approved hydroxychloroquine (Plaquenil®) and corticosteroids. In 1948, aspirin was approved to treat lupus. • Belimumab is a _____________ protein inhibitor that is thought to decrease the amount of abnormal β cells, which is hypothesized to be a mechanism of action in lupus. • It is suggested that patients be treated with an antihistamine prior to a belimumab infusion. • A greater number of deaths and serious infections were reported in patients treated with belimumab than in those treated with placebo. o________ vaccines should not be administered during treatment

β-lymphocyte stimulator Live

Urate-lowering Agents for Chronic Treatment: "Remove the matches from the body" Xanthine Oxidase Inhibitors (XOI) __________________ o Decreases synthesis or production of uric acid from purines by inhibiting the enzyme xanthine oxidase. o Can cause a hypersensitivity reaction in many clients, especially in those of Han Chinese, Korean or Thai descent. Use with caution in patients reporting an "allergy" to "penicillin" and discontinue at first sign of an "allergic" reaction. • _____________ and other hypersensitivities may occur with allopurinol second only to sulfonamides. Although rare, allopurinol hypersensitivity syndrome is fatal 20% to 30% of the time. o It is not dependent on renal function to be effective as is probenecid, but it is still excreted through the kidney thus requiring lower doses in clients with decreased renal function. • An interesting off-label use of allopurinol has emerged in the last few years in the treatment of _________.

• Allopurinol (Zyloprim®) Stevens-Johnson Syndrome heart disease and hypertension