Clinical and Contextual Evidence Reviews

Clinical and Contextual Evidence Reviews Roger Chou, MD Professor of Medicine Oregon Health & Science University Director, Pacific Northwest Evidence-based Practice Center

Purpose Summarize methods for updating AHRQ clinical evidence review and conducting new contextual evidence review Summarize results

Clinical Evidence Review Effectiveness of long-term opioid therapy

4 Original Review Funded by AHRQ for an NIH Pathways To Prevention Workshop Searches through August 2014 Focus on long-term opioid therapy (opioid use on most days for >3 months) for chronic pain (>3 months) that reported outcomes after at least 1 year For overdose, motor vehicle crashes, fracture, falls, included studies of any follow-up duration Included RCT s, cohort studies, case-control studies, cross-sectional studies, and studies on accuracy of risk prediction instrument Excluded: End of life, acute pain, addiction treatment, pregnant or breastfeeding, tramadol, parenteral opioids Presented at NIH September 2014, published Annals February 2015

5 Key Questions for Original Review KQ 1: Effectiveness and comparative effectiveness Opioids vs. no opioids or placebo; opioids vs. nonopioids Outcomes: Pain, function, quality of life Effects by pain condition, demographics, comorbidities KQ 2: Harms and adverse events Outcomes: Abuse, addiction; overdose; other harms (GI, falls, fractures, motor vehicle crashes, endocrinological, infections, CV, cognitive, psychological KQ 3: Dosing strategies Initiation and titration, short- vs. long-acting; comparative effectiveness of long-acting opioids; scheduled/continuous vs. PRN; dose escalation vs. maintenance; opioid rotation; treatment of acute exacerbations of pain; tapering vs. maintenance, tapering protocols KQ 4: Risk mitigation strategies Accuracy of risk assessment instruments Effectiveness of risk assessment instruments, opioid management plans, patient education, UDT, PDMP, monitoring instruments, more frequent monitoring, pill counts, use of abuse deterrent formulations Outcomes: Overdose, addiction, abuse, misuse Management of patients with addiction

6 Update Addressed same key questions as original review Added new key question In patients with acute pain, what are the effects of prescribing opioid therapy versus not prescribing opioid therapy on long-term opioid use? Update search performed in April 2015, using same search strategy 257 studies identified in update search 16 studies selected for full-text review 7 studies met inclusion criteria following full text review Opioid use and endocrinological harms: 1 study Mortality risk, methadone vs. SR morphine: 1 study Unintentional overdose with initiation of long-acting vs. short-acting opioids Predictive accuracy of risk prediction instruments Association between use of opioid therapy for acute pain and long-term use Some excluded studies included in a concurrently conducted review of contextual evidence

KQ 1: Effectiveness No study of opioid therapy vs. placebo, no opioid therapy, or non-opioid therapy for chronic pain evaluated long-term (>1 year) outcomes related to pain, function, or quality of life SOE (long-term effectiveness): No evidence Most placebo-controlled trials were six weeks or shorter in duration; cohort studies did not evaluate pain, function, or quality of life 62 RCT s in one recent meta-analysis, duration <16 weeks in 61(Furlan et al. Pain Res Manag 2011) 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 Short-term efficacy not re-reviewed

KQ 2: Abuse, addiction, misuse: Noncomparative studies No new studies Original report findings: 10 non-comparative studies Primary care settings: Opioid abuse 0.6% to 8%, dependence 3% to 26% Pain clinics: Misuse 8% to 16%, addiction 2% to 14%, aberrant behaviors 6% to 37% Definitions inconsistent across studies and poorly standardized methods to detect these outcomes SOE: very low

KQ 2: Overdose: Use vs. non-use 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) SOE: low

KQ 2: Overdose: Dose-dependent effects No new studies Cohort study (n=9940, 51 opioid overdoses, 6 fatal) 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) Nested case-control study (Ontario, 498 cases) Risk of opioid-related mortality (vs. 1 to <20 mg/day) >=200 mg/d: OR 2.9 (1.8-4.6) 100-199 mg/d: OR 2.0 (1.3-3.2) 50-99 mg/d: OR 1.9 (1.3-2.8) 20-49 mg/d: OR 1.3 (0.94-1.8) o Studies matched or adjusted for potential confounders available in administrative databases Potential for residual confounding by indication Other studies excluded b/c not clearly chronic pain or not limited to chronic pain; included in contextual review SOE: low Dunn et al. Ann Intern Med 2010;152:85-92; Gomes et al. Arch Intern Med 2011;171:686-91

KQ 2: Dosedependent risks of other harms Higher doses of opioids associated with increased risk of: Opioid abuse or dependence diagnosis (1 study, SOE: low) 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) Fractures (2 studies, SOE: low) Cardiovascular events (2 studies, SOE: low) Endocrinological AE s (testosterone deficiency, use of testosterone replacement or meds for ED) (2 studies, SOE: low) Motor vehicle crashes (1 study, SOE: low) No evidence on dose-dependent effects on pain or function Edlund MJ. Clin J Pain 2014;30:557; Saunders KW. J Gen Intern Med 2010;25:310; Li L. Am J Epidemiol 2013;178:559, Carman WJ. Pharmacoepidemiol Drug Saf 2011;20:754; Li L. J Intern Med 2013;273:511; Deyo RA. Spine 2013;38:909; Rubinstein A. Am J Med 2014;127:1195; Gomes T. JAMA Intern Med 2013;173:196-201

KQ 3: Initiation and titration Original report: 3 fair-quality, open-label trials of sustained-release vs. immediaterelease opioids Inconsistent results and differences in dosing protocols and opioid doses New evidence: VA cohort study (n=840,606) Initiation with long-acting opioid associated with increased risk of overdose injury vs. initiation with shortacting opioid: adjusted HR 2.33, 95% CI 1.26 to 4.32 Risk greatest in first 2 weeks: adjusted HR 5.25, 95% CI 1.88 to 14.72) SOE: very low Miller M. JAMA Intern Med 2015;175:608-15

KQ 3: Comparative effectiveness and harms of long-acting opioids Original report No differences between long-acting opioids (3 RCTs) Fair-quality VA cohort study (n=38,756): Methadone associated with lower mortality risk compared to morphine (HR 0.38 to 0.66) Fair-quality cohort study of Oregon Medicaid (n=5,684): SR oxycodone associated with lower risk of ED visit or hospitalization for opioid-related AE vs. SR morphine (adjusted HR 0.45, 95% CI 0.26 to 0.77) and death (adjusted HR 0.71, 95% CI 0.54 to 0.94); no differences between methadone vs. SR morphine and AE s were nonspecific for opioids New evidence: Fair-quality cohort study based on Tennessee Medicaid data Methadone associated with higher mortality risk compared to morphine (HR 1.46, 95% CI 1.17 to 1.83) SOE: low for pain/function, very low for mortality Krebs EE et al. Pain 2011;152:1789-1795; Hartung DM et al. Ann Pharmacother 2007;41:921-8; Ray WA et al. JAMA Int Med 2015;175:420-7

KQ 3: Dose escalation versus dose maintenance One fair-quality RCT (n=140) of more liberal dose 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) SOE: low Naliboff BD. J Pain 2011;12:288

KQ 3: Long-vs. short-acting opioids No study in original report New evidence: 1 fair-quality crosssectional study found long-acting opioids associated with increased risk of androgen deficiency (a.m. testosterone <250 ng/dl) vs. short-acting opioids: adjusted OR 3.39, 95% CI 2.39 to 4.77 SOE: very low

KQ 4: Accuracy of risk prediction instruments Original report: 4 studies with inconsistent estimates and serious methodological shortcomings ORT: Sensitivity 0.20 to 0.99 (3 studies) and specificity 0.16 and 0.88 (2 studies) SOAPP-1: Sensitivity 0.68 and 0.73 (2 studies) and specificity 0.38 (1 study) New evidence: 1 fair-quality (n=124) and 1 poor-quality (n=196) study ORT: Sensitivity 0.58 and 0.76 and specificity 0.54 and 0.86 SOAPP-R: Sensitivity 0.53 and 0.25 and specificity 0.62 and 0.73 Brief Risk Interview: Sensitivity 0.73 and 0.83 and specificity 0.43 and 0.88 SOE: very low for ORT, low for SOAPP-1, SOAPP-R, Brief Risk Interview Jones T. J Opioid Manage 2014;10: 353; Jones T. J Opioid Manage 2013;9:19-27

KQ 4: Effectiveness of risk mitigation strategies No evidence on effects on clinical outcomes

KQ 5: Effects of opioid therapy for acute pain on long-term use (new question) Two fair-quality retrospective cohort studies Among patients (n=391,139) who underwent low risk surgery (cataract, lap-chole, TURP, varicose vein stripping), use of opioids within 7 days associated with increased likelihood of use at 1 year: adjusted OR 1.44, 95% CI 1.39 to 1.50 Among patients with worker s compensation claim for acute LBP (n=8,443), early opioid use (within 15 days following onset) associated with increased likelihood of receiving 5 or more opioid prescriptions from 30 to 730 days following onset Versus no opioid use: 1 to 140 mg morphine equivalents: adjusted OR 2.08 (95% CI 1.55 to 2.78) >=450 mg morphine equivalents: adjusted OR 6.14 (95% CI 4.92 to 7.66) SOE: low Alam A. Arch Intern Med 2012;172:425; Webster BS. Spine 2007;32:2127

Conclusions Main findings consistent with original report Insufficient evidence to determine long-term benefits Increased risk of serious harms that appears to be dose-dependent SOE very low (insufficient) to low for all KQs For dose response and risk of overdose, findings consistent from studies not clearly restricted to patients with chronic pain or that enrolled mixed population New study on methadone consistent with epidemiological data suggesting disproportionate involvement in opioid overdoses New study found initiation with LA opioid associated with greater risk of overdose than SA opioid Limited evidence that use of opioids for acute pain associated with increased risk of longterm use

Contextual Evidence Review Benefits and harms Values and preferences Costs ---------------- Effectiveness of nonpharmacologic and nonopioid pharmacologic therapies

Search Methods Rapid Evidence Review Systematic searches for both original studies and systematic reviews Original studies limited to controlled designs Majority of original studies include observational methods, short follow-up periods, and select samples Multiple search strings employed for each topic area Double coding of abstracts for inclusion/exclusion Evidence NOT graded No limitations on length of follow-up

Effectiveness Nonpharmacologic therapies CBT Helps patients understand and modify factors and processes that exacerbate pain Has been shown to have small, positive effects on disability and catastrophizing, and an improvement in symptoms Exercise Helps to restore the normal range of motion and muscle conditioning Demonstrated effectiveness in improving pain and function in CLBP and reduced pain in other conditions such as OA and fibromyalgia

Effectiveness Non-opioid pharmacologic therapies Acetaminophen and NSAIDs (e.g., first-line pharmacotherapy for OA and low back pain) Potential harms: GI, renal, and cardiovascular risks Anticonvulsants and antidepressants (e.g., neuropathic pain) Pregabalin, gabapentin TCAs, SNRIs Useful in patients with concurrent pain and depression

Comparative Effectiveness Non-opioid pharmacologic therapies Limited comparative effectiveness data Welsch et al systematic review of RCTs: opioids did not differ from non-opioids in pain reduction for neuropathic pain, OA, or low back pain; non-opioids superior to opioids for improvement in physical function and tolerability

Benefits and Harms Overdose Risk Opioid-related overdose risk is dosedependent Five additional studies on the association of opioid dosage and overdose risk excluded from clinical review Compared to doses < 20 MME, odds of overdose increased: 1.3 1.9 at dosages of 20 to <50 MME 1.9 4.6 at dosages of 50 to <100 MME 2.0 8.9 at dosages of <= 100 MME Overdose risk significantly elevated >1830 MME total over 6 months 58-62% of fatal overdoses > 50 MME 19% of controls (no overdose) prescribed daily doses > 60 MME vs. 48% fatal OD

Benefits and Harms Factors that increase risk for harm Pregnancy Older age Mental health disorder Substance use disorder Sleep-disordered breathing Note: Sensitivity and specificity of risk stratification instruments are poor

Values and Preferences Provider perspective Lack confidence in their ability to prescribe opioids safely,, to predict or detect prescription drug abuse, and to discuss abuse with their patients. Feel pressured to treat with opioids Have difficulties interpreting patients' reports of pain Worry about secondary gain/diversion, and "abusive" or "difficult" patients Feel frustrated, ungratified, and guilty when providing chronic pain care

Values and Preferences Patient perspective Many patients do not have an opinion about opioids, or know what this term means One in three associate narcotics with addiction or abuse Half fear addiction from long-term narcotic use Patients with chronic conditions: Ambivalent about risks and benefits Continue taking opioids even while recognizing them to be ineffective in controlling pain

Resource Allocation Costs and costeffectiveness Comparison of direct medical costs of opioid treatment to pharmacologic and non-pharmacologic treatments for OA and CLBP (2012) Acetaminophen, NSAIDs, TCAs, and massage therapy were associated with lower mean and median annual costs relative to opioid therapy COX-2 inhibitors, SNRIs, anticonvulsants, topical analgesics, PT, and CBT also associated with lower median costs Cost-benefit estimates for opioid therapy are difficult to estimate due to a lack of available evidence on benefits