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Evidence For Appropriate Pain Treatment Guidelines Ro g e r C h o u , M D Professor of Medicine Oregon Health & Science University D i r e c t o r, Pa c i f i c N o r t h w e s t E v i d e n c e - b a s e d P r a c t i c e C e n t e r Conflict of interest disclosure Dr. Chou has received researc h funding from the Agency for Healthcare Researc h and Quality Purpose • Understand opioid pharmacology • Understand opioid prescribing patterns • Understand risks and benefits of long term opioid therapy for c hronic pain • Understand implications for clinical practice Nothing is intrinsically good or evil, but its manner of usage may make it so. -St. Thomas Aquinas 5 Case • 53-year old female transferring care because her PCP is leaving practice • Shoulder and hip pain 2˚ avascular necrosis, s/p shoulder replacements, hip decompression, hip replacement • Fibromyalgia, non-radicular LBP, chronic headache • Depression, fatigue • Gastroparesis, irritable bowel syndrome • Morphine IR 30 mg 5 T (150 mg) q 8 hrs + oxycodone 5 mg 8 T (40 mg) q 6 hrs • • • • MED/day: 690 mg Modafinil 20 mg po qD Pain 6/10 on average, with day to day fluctuation Can carry out ADLs with pain, limited exercise, no aberrant behaviors Background • C h ro n i c • n o n c a n c e r p a i n h i g h l y p r e va l e n t , w i t h substantial burdens • Estimates vary, up to 1/3 of adults report some CNCP O p i o i d s h a ve b e c o m e c o m m o n l y p r e s c r i b e d fo r c h ro n i c noncancer pain • About 5% of adults report use of LOTa • The U.S. is ~5% of the world’s population, but accounts for 80% of the world’s supply of opioids (99% of hydrocodone) • Opioids a r e a s s o c i a t e d w i t h p o t e n t i a l h a r m s, b o t h t o patients and to society aBoudreau et al Pharmacoepidemiol Drug Saf 2009 US opioid sales quadrupled 2000-2010 Since 2008, 15,000 deaths per year. This exceeds MVA deaths in 30 states. Slide courtesy Mark Sullivan Trends in opioid prescribing and rates of abuse Dart RC 2015;372:241-8 10 Rate Of Death Association with Heroin and Prescription Opioids Dart RC et al. N Engl J Med 2015;372:241-248. 11 Opioid pharmacology • Opioid mu-receptors mediate analgesic effects and AE’s • • • Agonists, partial agonists, antagonists Natural, semisynthetic, synthetic Half-life 2-4 hours for most opioids; 15-30 hours for methadone • Ongoing exposure causes tolerance • • • Larger dose required to maintain original effects (analgesic and AE’s) Interindividual variability in development of tolerance “There appears to be no limit to the development of tolerance, and with appropriate dose adjustments, patients can continue to obtain pain relief.”—Inturrisi C. Clin J Pain 2002;18:S3-13 • No theoretical dose ceiling 12 Dose-response relationship for respiratory depression Dahan A. Br J Anaesth 2005;94:825-34 13 Prescribing trends • • 1980 vs. 2000: Opioid use for chronic pain increased from 8% to 16% • Use of more potent opioids increased from 2 to 9% 1997 vs. 2005: Across age groups and in men and women, increase in long-term opioid use ranged from 61% to 135% • Increased use of schedule II opioids; greatest increase in daily doses occurred in prescriptions of schedule II opioids • 2000 vs. 2005: Increases in opioid use in commercial and Medicaid populations • Greatest increase in schedule II opioids; yearly dose increase greatest for schedule II opioids Caudill-Slosberg MA. Pain 2004;109:514; Boudreau D. Pharmacoepidemiol Drug Safety 2009;18:1166; Sulivan MD 2008;138:440; Campbell CI Am J Pub Health 2010;100:2541 14 How did we get here? • Perceived undertreatment of chronic pain • Laws or regulations passed in >20 states to allow use of opioids for chronic pain • Low risk of abuse observed with use of opioids in palliative care settings • “…patients rarely demonstrate euphoric responses to opioid drugs, and neither analgesic tolerance nor physical dependence is a significant clinical problem.” –Portenoy RK. J Law Medicine Ethics 1996;24:296 • Case series describing benefits of long-term opioid therapy for chronic pain, with low rates of abuse, addiction, or other serious AE’s • Most prescribed low doses (<20 mg MED/day) • No ceiling dose used in palliative care settings • “Escalation of the opioid dose until either adequate analgesia occurs or intolerable and unmanageable side effects supervene is standard practice in cancer pain management.”— Portenoy RK. J Pain Symptom Management 1996;11:203 • Emphasis on round-the-clock dosing using sustained-release formulations Portenoy RK 1986;25:171; Haythornthwaite JA 1998;15:185 15 Randomized Trial Evidence for Commonly Used Medications from Recent Meta-Analyses Medication class Number of trials Number Personof patients years (est.) Number US adults using longterm Antihypertensivesa 147 ~464,000 ~1,857,000 48 million Statinsb 26 ~169,000 ~753,000 34 million NSAIDsc 31 ~116,000 ~117,000 6 million Opioidsd 62 ~12,000 ~1,500 7-9 million a. b. c. d. Law et al., BMJ 2009. CTT Collaboration, Lancet 2010. Trelle et al., BMJ 2011. Furlan et al. Pain Res Manage 2011. Courtesy Michael Von Korff • Short-term efficacy • Evidence on effectiveness of LOT for chronic non-cancer pain • • • 62 RCT’s in one recent meta-analysis, duration <16 weeks in 61a Opioids more effective than placebo for nociceptive and neuropathic pain (effect sizes 0.55-0.60) Maximum dose ≤180 mg MED/day in all trials except for 3 Long-term effectiveness • Cochrane review included 26 studies >6 monthsb • 25 studies were case series or uncontrolled long-term • trial continuations Many discontinuations due to adverse effects (23%) or insufficient pain relief (10%), but some evidence that patients who continue on opioids experience long-term pain relief aFurlan bNoble et al. Pain Res Manag 2011 et al. Cochrane Database Syst Rev 2010 • Other limitations of the evidence on effectiveness of LOT • • • • Effects on function generally smaller than effects on pain, with some trials showing no or minimal benefit High loss to follow-up Trials typically excluded patients at higher risk for abuse or misuse, psychological comorbidities, and serious medical comorbidities Limited evidence on commonly treated conditions • Low back pain, fibromyalgia, headache, others No trials compared LOT vs. CBT-based exercise therapy or interdisciplinary rehabilitation • Overdose 1 fair-quality study of chronic pain patients in a US healthcare system who had received opioids at some point • Recent opioid use associated with increased risk of any overdose event (adjusted HR 5.2, 95% CI 2.1 to 2.5) and serious overdose events (adjusted HR 8.4, 95% CI 2.5 to 2.8) Factors associated with increased risk of overdose, or observed in high proportions of overdoses • • • • • • • Aberrant behaviors Recent initiation of opioids Methadone Concomitant use of benzodiazepines Obtaining opioid prescriptions from multiple providers Substance abuse and other psychological comorbidities Higher dose • Tools for risk stratification are available, Patient selection and risk stratification but require further evaluation • Opioid Risk Tool • SOAPP version 1 and SOAPP-R • Accuracy for predicting future aberrant behaviors tend to be high in initial studies but poor in subsequent (limited) studies Administration Opioid Risk Tool (ORT) • On initial visit • Prior to opioid therapy Scoring • 0-3: low risk (6%) • 4-7: moderate risk (28%) • > 8: high risk (> 90%) Webster & Webster. Pain Med. 2005;6:432. 22 High-dose opioid therapy prescribing patterns • Small proportion of patients account for the majority of opioids prescribed • In one study, 5% of opioid users accounted for 48% to 70% of total use • Factors associated with high dose therapy include: • • • • • Presence of substance use disorders Presence of mental health disorders Use of sedative-hypnotics and multiple opioids Higher health service utilization Multiple pain problems and high levels of medical and psychiatric comorbidity • “Adverse selection” • Trends show increases in opioid prescribing in patients with substance use and mental health disorders Weisner CM. Pain 2009;145:287; Edlund MJ. J Pain Symptom Manage 2010;40:279; Morasco BJ 2010;151:625; Kobus AM. J Pain 2012;13:1131; Braden JB 2009;31:564 • Overdose: Doseresponse relationship • • • Observational studies consistently show an association between opioid dose and risk of overdose or death in patients with chronic pain Risk starts to increase at relatively low doses and continues to increase Studies matched or adjusted for potential confounders available in administrative databases • Potential for residual confounding by indication Difficult to determine whether patients had chronic pain and duration of therapy Cohort study (n=9940, 51 opioid overdoses, 6 fatal) Association between opioid dose and overdose risk Case-control study (VA, 750 cases) Risk of opioid overdose (vs. 1to <20 mg/day) >=100 mg/d: HR 8.9 (4.0-20) 50 -<100 mg/d: HR 3.7 (1.5-9.5) 20-<50 mg/d: HR 1.4 (0.57-3.6) Risk of opioid overdose-related death (vs. 1 to <20 mg/day) >=100 mg/d: HR 7.2 (4.8-11) 50-<100 mg/d: HR 4.6 (3.2-6.7) 20-<50 mg/d: HR 1.9 (1.3-2.7) Nested case-control study (Ontario, 498 cases) Risk of opioid-related mortality (vs. 1 to <20 mg/day) >=200 mg/d: 100-199 mg/d: 50-99 mg/d: 20-49 mg/d: OR 2.9 (1.8-4.6) OR 2.0 (1.3-3.2) OR 1.9 (1.3-2.8) OR 1.3 (0.94-1.8) Ref: Dunn et al. Ann Intern Med 2010;152:85-92; Bohnert et al. JAMA 2011;305:1315-21; Gomes et al. Arch Intern Med 2011;171:686-91 25 Dose-related risk of opioid overdose Risk of adverse event 10 9 8 7 6 Dunn 2010 Risk Ratio 5 Bohnert 2011 Gomes 2011 4 Zedler 2014 3 2 1 0 <20 mg/day 20-49 mg/day 50-99 mg/day Dose in mg MED >=100 mg/day Courtesy Gary Franklin • Estimates vary from 4% to 26%, or higher • One study (n=801) based on standardized interviewsa Abuse, addiction, misuse • • • • • • • • 26% purposeful oversedation 39% increased dose without prescription 8% obtained extra opioids from other doctors 18% used for purposes other than pain 12% hoarded pain medications Definitions inconsistent across studies and behaviors evaluated vary in seriousness Poorly standardized methods to detect these outcomes Data from efficacy trials underestimate risks aFleming et al. J Pain 2007 • Abuse, addiction, misuse: Dosedependent effects One fair-quality study of a large claims database found long-term prescribed opioid use (>90 days’ supply) associated with increased risk of an opioid abuse or dependence diagnosis vs. no opioid treatment • Low dose (1-36 mg MED/day): OR 15 (95% CI • • 10 to 21) Moderate dose (36-120 mg MED/day): OR 29 (95% CI 20 to 41) High dose (≥120 mg MED/day): 122 (95% CI 73 to 206) Edlund MJ. Clin J Pain 2014;30:557 • Opioid use associated with increased risk of fracture in 1 fair-quality cohort study (adjusted HR 1.28, 95% CI 0.99 to 1.64) • 1 to <20 mg MED/day: HR 1.2 (95% CI 0.92 to 1.56) • >=50 mg MED/day: HR 2.0 (95% CI 1.24 to 3.24) • Overall test for dose-response did not reach statistical Fracture significance • Similar increased risk of fracture in 1 goodquality case-control study (OR 1.27, 95% CI 1.21 to 1.33) • Risk highest with one prescription and no longer present with >20 cumulative prescriptions Saunders KW. J Gen Intern Med 2010;25:310 Li L. Am J Epidemiol 2013;178:559. • Cardiovascular events • Cohort study: adjusted IRR 2.66 (95% CI 2.30 to 3.08) for chronic opioid therapy user vs. general population • • • • • Versus cumulative dose of 0 to 1350 mg MED over 90 days 1350 to <2700 mg: IRR 1.21 (95% CI 1.02 to 1.45) 2700 to <8100 mg: IRR 1.42 (95% CI 1.21 to 1.67) 8100 to <18,000 mg: IRR 1.89 (95 5CI 1.54 to 2.33) >18,000 mg: IRR 1.73 (95% CI 1.32 to 2.26) Case-control study: adjusted OR 1.28 (95% CI 1.19 to 1.37) for MI with current opioid therapy versus nonuse • Highest risk with 11 to 50 cumulative prescriptions • OR 1.09 to 1.29 with 1-2, 3-10, or >50 cumulative prescriptions Carman WJ. Pharmacoepidemiol Drug Saf 2011;20:754; Li L. J Intern Med 2013;273:511 • Cross-sectional study • Men with back pain • Outcome: Use of medications for erectile Endocrinological events • • • dysfunction or testosterone replacement Opioid use versus non-use: adjusted OR 1.5, 95% CI 1.1 to 1.9 >=120 mg MED/day vs. 0 to <20 mg day: OR 1.6, 95% CI 1.03 to 2.4 No increased risk at doses of 20 to <120 mg MED/day Deyo RA. Spine 2013;38:909 31 FDA Public Health Advisory, November 2006 “Methadone Use for Pain Control May Result in Death and Life-Threatening Changes in Breathing and Heart Beat” http://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm124346.htm • Increased methadone deaths nationwide Methadone • Half-life 15 to 60 hours, up to 120 hours • • Methadone accounted for 1.7% of opioid rx’s in 2009 and 9.0% of morphine equivalents in 2010a Involved in 31% of opioid-related deaths, and 40% of single-drug deathsa 60 hour half-life=12 days to steady-state Prolongation of QT intervals, sudden death Start at 2.5 mg q8 hrs, increase slowly Higher doses of methadone associated with greater QTc interval prolongation • High proportion of reported cases of torsades de pointes occurred in patients prescribed >200 mg/day Morphine to methadone conversion ratio increases at higher doses aMMWR 2012;61:493-7 Methadone • Little evidence on use of methadone for CNCP One small, poorly designed trial of methadone vs. placebo A VA cohort study found methadone associated with lower mortality risk compared to morphine (HR 0.38 to 0.66)a A cohort study based on Tennessee Medicaid data found methadone associated with higher mortlaity risk compared to methadone (HR 1.46, 95% CI 1.17 to 1.83)b No evidence on effects of ECG monitoring on risks associated with methadone, but some guidelines recommend routine ECG monitoring Krebs EE et al. Pain 2011;152:1789-1795; Ray WA et al. JAMA Int Med 2015;175:420-7 a 34 Time to reach steady state 35 Prolonged QTc and torsades de pointes 36 Morphine to methadone conversion Oral morphine to methadone 24 hour total oral morphine conversion ratio <30 mg 2:1 31-99 mg 4:1 100-299 mg 8:1 300-499 mg 12:1 500-999 mg 15:1 >1000 mg 20:1 Managing Cancer Pain in Skeel ed. Handbook of Cancer Chemotherapy. 6th ed., Phil, Lippincott, 2003, p 663 • Selection of opioids • No clear differences in benefits and harms of other long-acting opioids Limited evidence on benefits and safety of short- vs. long-acting opioids, round-the-clock versus PRN Practice of long-acting, round-the-clock dosing based on cancer guidelines and expert opinion, potential benefits not proven Potential harms of long-acting, round-the-clock opioids include development of hyperalgesia, tolerance, endocrinologic adverse effects VA cohort study found long-acting opioid associated with higher risk of overdose than short-acting opioids (HR 2.33, 95% CI 1.26 to 4.32) Risk highest in first 2 weeks after initiation (HR 5.25, 95% CI 1.88 to 14.72) Miller M. JAMA Intern Med 2015;175:608-15 One RCT (n=140) of more liberal dose Dose escalation versus dose maintenance escalation versus maintenance of current doses VA patients with musculoskeletal pain No differences in pain, function, or use of nonopioid medications or physical therapy after 12 months No difference in withdrawal due to opioid misuse (24% vs. 30%, RR 0.79, 95% CI 0.46 to 1.4) Limited separation between groups in opioid doses at end of trial (mean 52 vs. 40 mg MED/day) Naliboff BD. J Pain 2011;12:288 • 2007: Washington Agency Medical Dose threshold policies Directors’ Opioid Dosing Guidelines • 120 mg MED/day threshold dose • Re-evaluation and pain management consultation if needed • 2009: APS/AAPM guideline • 200 mg MED/day “watchful” dose • Based on doses evaluated in trials and observed in • observational studies Recommended re-evaluation for appropriateness of therapy, enhanced monitoring, consider consultation • Subsequent policies have generally recommended dosing thresholds of 80120 mg/day MED; as low as 50 mg/day MED (ACOEM) Effects of dose limitation strategies and policies on opioid-related deaths • In 2007, WA state implemented dosing policy of <120 mg/day morphine equivalents in workers’ compensationa • After 2007, proportion prescribed >120 • • • mg/day decreased by 35% 50% decrease from 2009 to 2010 in number of opioid-related deaths Data observational using pre-post analysis, subject to confounding and attribution bias No information about effects of policy on pain or function aFranklin et al, Am J Industrial Med 2011 41 * Monitoring, including urine drug testing Access prescription drug monitoring data Mitigating risks associated with higher doses of opioids Avoid sedative-hypnotics (particularly benzodiazepines) More frequent follow-up Addiction, pain, or psychiatric consultation More frequent refills with smaller quantities Abuse-deterrent formulations? Naloxone co-prescription? Available now in many states Prescription drug monitoring programs Studies show that use of PDMPs can identify cases of diversion and doctor shopping Recent study found decreased inappropriate drug prescribing with use of a centralized prescribing system in Canadaa Effects on clinical outcomes (e.g., overdose) not known Use variable and generally suboptimal PDMPs vary in who can access, information not available across states aDormuth et al. CMAJ 2012 Optimal frequency and usefulness of Urine drug tests individualized vs. routine testing uncertain Urine drug tests can be difficult to interpret Diagnostic accuracy for abuse/addiction difficult to study Need to understand metabolic pathways of different opioids Differential diagnosis for abnormal results includes poorly controlled pain, drug abuse, diversion Potential for false reassurance No evidence that urine drug testing improves patient outcomes; potential for harms Cost-effectiveness unclear Opioid-deterrant formulations Opioid-deterrant formulations have recently been approved by FDA or undergoing FDA approval process Designed to be tamper-resistant or co-formulated with medications that reverse opioid effects or produce noxious side effects when tampered with Effectiveness for reducing misuse/substance abuse and improving clinical outcomes yet to be established Likely to be primarily effective in patients who crush or inject opioids One study found patients placed on a new tamperresistant formulation of long-acting oxycodone frequently switched to an alternative opioid or heroina aCicero et al. NEJM 2012 Unintended effects? Larochelle MR. JAMA Intern Med 2015 48 Case • Patient initially transferred care in 2008 • Unclear if benefitting from very high doses of long-term opioid therapy, • ?worsening of GI symptoms; no signs of aberrant behaviors Slow taper initiated • Morphine 450 mg/day120 mg/day • Oxycodone 160 mg/day5 mg po bid prn • • 690 mg MED/day135 mg/day Added non-opioid medications • Duloxetine 20 mg qD • Buspirone 30 mg bid • Pain and function no worse than when on high doses, no serious withdrawal • Goal is to get down to <100-120 mg MED/day • Conclusions: What is the evidence? • • • • • • • Very limited data on long-term benefits of high dose opioid therapy Accumulating evidence on serious harms of long-term opioid therapy that appear to be dose-dependent Titrating to achieve pain relief is inconsistent with data on opioid benefits Unclear whether tolerance to analgesic effects of long-term opioid therapy occurs in clinical practice Special caution with methadone No clear advantage to long-acting, RTC prescribing Patients on high doses warrant re-evaluation, additional monitoring, and follow-up Decrease dose or discontinue in patients who are not improving Initiate at low doses and titrate slowly Evidenceinformed approach to opioids View initial treatment as a therapeutic trial Routine monitoring Titration should be based on responsiveness of patients to low doses Patients who do not respond to low doses probably will not respond to higher doses— “opioid non-responders” Taper in patients not responding or experiencing adverse effects Caution when reaching threshold doses Optimal dose threshold uncertain Much easier to titrate up doses than to titrate down Routinely integrate non-opioid therapies Opioid alone do not address the psychosocial contributors to chronic pain