Opioid Stewardship 10/24/2017. Audience Survey. Raymond A Dionne, DDS, PhD October 26, 2017

Transcription

1 Challenges of Acute Dental Pain Management in the Opioid Overdose Era By being attentive for today s talk, attendees will be able to: Opioid Stewardship Raymond A Dionne, DDS, PhD October 26, 2017 Describe the magnitude and impact of the current opioid overdose epidemic in the US Explain the relationship between prescribed for therapeutic intent and their misuse, abuse and development of drug dependence Identify how to prevent acute dental pain to minimize opioid use raymond.dionne@icloud.com Audience Survey Disclaimer: The drugs, doses and therapeutic recommendations discussed in this talk are based on the speaker s interpretation of the scientific literature and 30 years of clinical research on the management of acute pain and perioperative anxiety. Clinical application of this information requires knowledge of the information contained in the FDA labeling of the specific drugs, careful review of the individual patient s medical history and current medications, appropriate monitoring of the response to the drug(s) and doses administered, and skill in the prevention and management of adverse reactions that occur with all drugs with variable but finite prevalence. Disclosures: The speaker is on the faculty of the ECU School of Dental Medicine and Brody School of Medicine, serves on the scientific advisory board of Charleston Laboratories and the Global Pain Faculty of GSK and has consulted for the pharmaceutical industry in the past. He is also on the editorial board of the Compendium, Applied Clinical Pharmacology and Toxicology, and Clinical Pharmacology and Translational Medicine. In 2016, how many Americans were estimated to have abused prescription pain relievers in the last year? a) 500 thousand b) 1 million c) 5 million d) >10 million Prescription and Illicit Opioid Epidemics Intertwined Used both, analgesics used first Heroin only Pain Management and the Opioid Epidemic National Academy of Science July

2 Unmet Need for Pain Management vs. Current Meds Chronic pain affects > 116 M adults in the US Estimated cost $560 to $635 B annually Chronic pain: debilitating, lower QoL, impairs functional status Relieving Pain In America, IOM 2012 Chronic use of analgesic drugs produce organ damage, overdose, tolerance leading to physical dependence, abuse > More deaths due to drugs, than MVA (35,332) or firearms (31,672) CDC March 2013 > 52,000 deaths due to opioid overdose CDC, 2016 ~15.3 deaths/100,000 NSAID/aspirin users ~1.4 CV risk due to high dose (rofecoxib ~ 1.4) Milestones Milestones in Understanding Pain and Improving Analgesics Major Drug Classes Placebo response Category scales 1950's narcotics aspirin adjuncts Clinical trials methodology 1960's opiates aspirin adjuncts Opiate receptor Aspirin MOA Dental model 1970's adjuncts Endogenous pain inhibitory system 1980's Gender, Genetics Imaging 1990's coxibs antidepressants anticonvulsants Pharmacogenomics Gene expression Proteomics Opioid OD epidemic 2000's gabapentin PRO's Phenotyping Personalized medicine beyond NEJM 1980 Letter: despite the widespread use of narcotic drugs in hospitals, the development of addiction is rare in medial patients with no history of addiction. Cited in 608 times as evidence of safety Washington Post June 2, 2017 Old Dogma from Pre-Evidence Based Era vs. Personalized Pain Medicine Basic Principle: Wide Variability in Pain and Analgesia Variability in self administered morphine dose for postsurgical pain: 1 48 mg mean dose = 13.3 mg Aubrun et al. Anesthesiology 2003; 98:1415 One Size Does Not Fit All for pain research? Trends in Pharmacol Sci 2005 Pharmacopeia of Pain Meds Precision Medicine Are Means Meaningless? for pain management. Witter et al Kim H et al., Pain 2004 Rare Conceptual Basis for Pain Variability at the Level of Individual Patients Atypical Common Variability Atypical Rare Basic Principles: Heritability of Drug Abuse x Expect wide variation in practice among patients, their symptoms and response to meds Sociocultural Influences, Expectations, Prior Experiences, Idiosyncrasy Neuroendocrine Functions, Autonomic Function, Stress Response Physiologic Augmentation & Descending Modulation: Inflammation, Plasticity Protein Expression & Modification Epigenetic Modification Pain Genes n > 400 Disease Process The addictions are moderately to highly heritable, which is paradoxical because these disorders require use; a choice that is itself modulated by both genes and environment. The addictions are interrelated and related to other psychiatric diseases by common neurobiological pathways, including those that modulate reward, behavioral control and the anxiety or stress response. Goldman D et al. Nature Reviews/Genetics 2005 The gateway hypothesis.the concept of common liability to addictions incorporates sequencing of drug use initiation as well as extends to related addictions and their severity, provides a parsimonious explanation of substance use and addiction co occurrence Vanyukov MM et al. Drug and Alcohol Dependence

3 Opioid Prescribing and Drug Abuse 1,2 Opioid Prescribing and Drug Abuse 1,2 12 billion dosage units dispensed annually make among the most frequently prescribed medications in US Opioids prescribed for therapeutic purposes may also result in: Diversion excess pills are given (diverted) to family members, friends, or sold on the streets. Dependence may be physical (body responds negatively when the drug is discontinued following chronic use) or psychological (loss of ability to make sound decisions about what is right or wrong related to their drug use) Addiction physical and psychological dependence characterized by neurochemical and molecular changes in the brain Death due to overdose 1. Oakley M, O Donnell J, Moore PA. The Rise in Prescription Drug Abuse: Raising Awareness in the Dental Community. Compendium. 2011;32(6): National Institute on Drug Abuse. Media Guide. The Basics: The Science of Drug Abuse and Addiction. Available at: Most commonly prescribed opioid amount is 20 doses and a 3 day supply. What Happens to These Drugs? Used in totality as prescribed Stored for a rainy day Sold on the street Given to friends/family 1.Oakley M, O Donnell J, Moore PA. The Rise in Prescription Drug Abuse: Raising Awareness in the Dental Community. Compendium. 2011;32(6): National Institute on Drug Abuse. Media Guide. The Basics: The Science of Drug Abuse and Addiction. Available at: < Half of prescribed for pain after oral surgery were used, only 5 patients used all of the prescribed pills (N=28) Drug and Alcohol Dependence 2016 Orally Effective Opioid Agonist Analgesics Codeine, Hydrocodone Moderate analgesics Usually combined with aspirin, or Codeine converted to morphine by P450 isozyme CYP2D6 - About 10% of codeine dose will be converted to morphine Hydrocodone converted by CYP2D6 to hydromorphone which has more activity than hydrocodone Clinical Consequences of CYP2D6 Deficiency Genetics of the CYP2D6 enzyme deficiency: Occurs in about 6 to 10 percent of Caucasians, 3 to 6 percent of Mexican Americans 2 to 5 percent of African Americans about 1 percent of Asians Americans Possible outcomes: Poor metabolizers - inadequate analgesia Intermediate metabolizers adequate analgesia Extensive metabolizers respiratory depression Audience Survey With the increasing awareness of the current extent of the opioid epidemic, what do you think are the most common reasons are still prescribed? Why Do We Prescribe Hydrocodone/APAP? Established prescribing behaviors Efficacy of APAP- established in 1970 s, before introduced Improved clinical analgesic research (Cooper & Beaver 1976) efficacy and safety >> opioid combinations Misperception of DEA Scheduling of Opioids Schedule 2 drugs have greater abuse potential, not efficacy Placebo response contribution to analgesic efficacy Placebo pills are effective 10-20% in clinical pain trials Placebo response is 30-40% for simple extractions Misperception that Rx analgesics are more potent than OTC analgesics Prescribing for Most Severe Outcome Often prescribe to manage the worse case scenario May benefit 20% with worse pain, but not needed for the other 80% Unfounded Expectations of APAP Efficacy Maximum dose reduced from 1000 mg to 650 mg Patient Expectations and Demands Not providing an opioid can be perceived as less than optimal treatment Moore, Dionne, Cooper, Hersh: JADA July

4 Other Opioid Receptor Agonists Oxycodone Deaths linked to opioid abusers after pills crushed and dissolved for IV administration This agent is frequently combined with Oxycodone IR Uses tamper resistant technology to deter abuse Crushed tablets dissolved in water or alcohol turn to gel and snorting causes significant burning and irritation of the nasal passages. Abuse-Deterrent Formulations Incorporate an excipient that gels when mixed with water, alcohol, or other common solvents Incorporate a physical barrier that resists crushing, dissolving, melting, or chemical extraction (e.g., hard plastic polymer coatings) Formulation of tablets that are difficult to break Chemical engineering prodrugs that require in vivo activation to produce a pharmacological effect Incorporate aversive ingredients (e.g., a flushing agent [niacin], emetic [ipecac], diuretic, or irritant [capsaicin]) to create an unpleasant experience and thereby deter further experimentation Co-formulation with an antagonist or aversive agent that is released upon product tampering Opioid Receptors Two most important classes of opioid receptors Mu receptors Analgesia Respiratory depression Euphoria Sedation Physical dependence Constipation Miosis Kappa receptors Analgesia Some sedation No Euphoria Little respiratory depression Classification of Drugs That Act at Opioid Receptors Pure agonists Agonistantagonists Pure antagonists Comparison of Drug Effects Drugs Strong Opioid Agonists Morphine, meperidine, fentanyl, alfentanil, hydromorphone, levorphanol, methadone, oxymorphone, remifentanil, sufentanil Moderate to Strong Agonists Codeine, hydrocodone, oxycodone Agonist/ Antagonists Buprenorphine, butorphanol, nalbuphine, pentazocine Response Abuse Liability High Moderate Low Maximal Pain Relief High Low to Moderate Moderate to High 4

5 Mixed Agonist-Antagonist Opioids Pentazocine Butorphanol Nalbuphine Agonist at kappa receptors and mild antagonist at mu receptors Reduced respiratory depression and potential for abuse If given alone = analgesia If given to a patient already taking a pure opioid will antagonize or inhibit the analgesia Can increase work load of the heart Atypical Centrally Acting Analgesics Tramadol Moderate-strong analgesic Analog of codeine Agonist at mu receptors and blocks uptake of NE and 5-HT so spinal pain processing is less efficient Minimal potential for dependence or abuse Minimal potential for respiratory depression Effects partially blocked by naloxone Metabolized by CYPs (CYP2D6 and others) to 5 different metabolites Desmethyltramadol is 200 times more potent Depending on genetics analgesic effects can either increase or decrease FDA states that tramadol is contraindicated < 12 years of age for pain Can be prescribed over the phone or electronically per CVS Atypical Centrally Acting Analgesics Tapentadol Produces analgesia that ranges between that of tramadol and that of morphine Agonist at mu receptors and also blocks uptake of NE May have slightly more addictive properties than tramadol Also not to be used with MAOIs Does not depend on CYP2D6 for activation Antagonists for Opioid Reversal Naloxone Antagonist at mu and kappa receptors Naltrexone Oral and extended release parenteral agent Similar to naloxone Nalmefene Long-acting analog of naltrexone DEA schedule 2: requires written or electronic Rx per CVS Audience Survey Which of the following are alternatives for analgesia to assist in the minimization of opioid use? a) b) Local anesthetics c) Acetaminophen d) All of the above PAIN Management Paradigm P = Prevention A = Anti-inflammatory agents I = Individualize N = Narcotics () Opioid prescriptions should be written only to supplement the analgesic effects of or APAP Opioid prescriptions should be written with discretion In general, refills for acute pain medication, especially those containing an opioid, should be avoided. 5

6 Preventing the Transition from Tissue Injury to Hyperalgesia How Work: Decrease PGE 2 Levels at Surgical Site Blocked by Minimizes Resulting in Much Less Produces Little or No Slight Pain after LA offset, instead of 12 Relationship Between Pain and PGE 2 Levels at the Site of Injury Lower Exposure to Opioids Ceiling to analgesic effect with increased dose, but not to adverse events Max Analgesia Dose-sparing effect [NSAID + opioid] Dose Gordon SM et al Little additive analgesic effect in combination with an NSAID Toxicity Limits Increasing NSAID Dose * Pain Intensity Difference Ketoprofen 25 Placebo Ketoprofen Time Post-Drug (hrs.) Ibuprofen Dionne RA J Oral Maxillofac Surg 57: , 1999 Provides rationale for alternative strategies to decrease NSAID toxicity: coxibs, peripheral drug administration, preventive analgesia 6

7 Cyclooxygenase-1 and -2 Black Box Warning for Non-selective Cardiovascular Risk may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. These are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. Gastrointestinal Risk cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal.these events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events. These products are also available in nonprescription forms. Downloaded from: StudentConsult (on 3 December :27 PM) COX2 Cardiovascular Risk Might Only be Due to Rofecoxib Cardiovascular Risk Might be a Risk of all? Contribution of COX-1 and COX-2 to Acute Inflammation COX-1+ COX-2 Inhibition SC-560 Rofecoxib Vehicle 21 Highly COX-2 Selective Toxicity of are Based on Their Selectivity For COX1 or COX2 Relatively COX-1 Selective 37 7

8 Adverse effects GI/Cardiovascular Toxicity Acetaminophen Mechanism of Action Inhibits Prostaglandin Hydroperoxidase Blocks Cox 2 Metabolites of act on TRPA1 receptors in the spinal cord to suppress the signal transduction from the superficial layers of the dorsal horn, to alleviate pain. One metabolite (AM 404) inhibits Na channels and the reuptake of endogenous cannabinoids 1 Is Acetaminophen a COX 2 Inhibitor? Strategies for Intervention PGE2 (pg/ml) placebo * * rofecoxib Reduce peripheral nociceptive barrage Local anesthetics Alter CNS processing of nociceptive input Opioid with less potential for abuse and overdose Time Post-Surgery (min) ketorolac * Additive Preemptive Analgesia for NSAID and LLA Preventive Effects of Postop Pain Control Pain Intensity (VAS) Standard Treatment Time Post-Surgery 4 Effect of NSAID Pretreatment 6 8 Effect of Long-Acting Local Anesthetic Combined Effect NSAID & Long-Acting Local Anesthetic Dionne et al Immediate Postop. Pain Pain at 48 Hours Gordon SM et al

9 Table 2. Prescribing Options for Acute Pain to Minimize Opioid Misuse or Abuse Mild Pain OTC ibuprofen, naproxen or ketoprofen as needed Mild to Moderate Pain Ibuprofen mg every 4-6 hours by the clock for first hours, not to exceed maximum recommended daily dose. As needed until pain subsides Moderately Severe Pain Prescription dose of NSAID administered prior to the procedure or immediately afterwards Administration of long-acting local anesthetic 0.5% bupivacaine with epinephrine for procedural anesthesia and postoperative analgesia Severe Pain Provide a prescription of an opioid drug in combination with to be filled and administered only if needed for pain not relieved by regimen for Moderately Severe pain. Example: 2 tablets of 325 mg plus 37.5 mg tramadol every 4-6 hours for pain, not to exceed 8 tablets every 24 hours NB: Separate dosing of 600/650 mg needs to be discontinued Postoperative administration of prescription dose of NSAID administered by the clock for hours combined with administration of 600/650 mg by the clock; the two medications can be given concurrently or alternated to maintain blood levels of both medications Dionne, Gordon, Moore: Compendium 2016; 37: Dionne, Gordon, Moore: Compendium 2016; 37: Comparison of Conventional Approach to Targeted Strategies Opioid Combinations Preventive/Additive/Adaptive Analgesia Adverse Effects Abuse Potential (without opioid) + (with tramadol) ++ (with oxycodone or hydrocodone) Overdose Risk ++ 0 (without opioid) + (with tramadol) ++ (with oxycodone or hydrocodone) Relative effects based on well-established pharmacology of drug classes and specific agents in Table 1 ranked on a 0 to ++++ ranking Dionne, Gordon, Moore: Compendium 2016; 37: Opioid Prescribing Recommendations Revisited Assess medical and drug histories. Communicate with patients. Limit the quantity of opioid analgesics prescribed. Inform patients not to share medications. Alert adolescent patients/parents to abuse potential. Educate parents about secure medication storage. Dispose of unused prescription medications. Consider alternative strategies for pain control. Dionne RA, Gordon SM, Moore PA. Prescribing opioid analgesics for acute dental pain: Time to change clinical practices in response to evidence and misperceptions. Compendium 2016; 37: Dionne RA, Gordon SM. Changing paradigms for acute dental pain: Prevention is better than PRN. California Dental Journal 2015; 43: Determinants of Safe, Effective, and Patient-Centered Therapeutics Therapeutic Efficacy Patient Safety & Needs Clinical Judgment Monitoring Training & Experience Adverse Drug Reactions * Patient Risk Factors * Drug-Drug Interactions * Inter-Individual Variability Dose, Route & Rate of Administration * Pharmacologic Properties of Drugs * 9