Appendix: Primary Clinical Questions, Detailed Methods, and Findings for the Systematic and Contextual Evidence Reviews

Primary Clinical Questions

Across reviews, the main outcomes were pain, function, and quality of life. Harms varied depending on the therapy evaluated but included serious adverse events when reported; for opioids, key harms included overdose and harms related to opioid use disorder. The reviews of therapies for chronic pain assessed outcomes at short- (1 to <6 months), intermediate- (6 to <12 months), and long-term follow-up (≥12 months). The reviews of therapies for acute pain assessed outcomes at <1 day, 1 day to <1 week, 1 week to <2 weeks, and 2–4 weeks; the review of treatments for acute nonmigraine pain also evaluated outcomes at ≥4 weeks. All reviews included key questions (KQs) or subquestions on how benefits and harms varied according to demographic (age, sex, race), clinical (severity and duration of pain, medical and psychiatric comorbidities, concomitant medications), and intervention (dose, duration, intensity) characteristics.

The systematic clinical evidence reviews addressed questions regarding the effectiveness and comparative effectiveness of noninvasive nonpharmacologic treatments; nonopioid pharmacologic treatments; and opioid treatments for chronic pain, acute pain, and episodic migraine pain (details including questions are available in the full AHRQ reports) (1–5).

Opioids for Chronic Pain

• The effectiveness and comparative effectiveness (benefits [KQ 1] and harms [KQ 2]) of long-term opioid therapy versus placebo, no opioid therapy, or nonopioid therapy.
• The comparative effectiveness of various opioid dosing strategies (KQ3):
  • Different methods for initiating and titrating opioids
  • Short-acting versus long-acting and extended-release opioids
  • Different long-acting opioids
  • Short- acting plus long-acting versus long-acting opioid alone
  • Scheduled, continuous versus as-needed dosing
  • Opioid dose escalation versus dose maintenance or use of dose thresholds
  • Opioid rotation versus maintenance
  • Different strategies for treating acute exacerbations of chronic pain
  • Decreasing opioid doses or tapering off opioids versus continuation of opioids
  • Different tapering protocols and strategies
  • Different opioid dosages and durations of therapy
• The accuracy of instruments for predicting risk for opioid overdose, addiction, abuse, or misuse; the effectiveness of risk prediction instruments; the effectiveness of various risk mitigation strategies; and comparative effectiveness of strategies for managing patients with opioid use disorder (KQ 4). The following are risk mitigation strategies:
  • Opioid management plans
  • Patient education
  • Urine drug screening
  • Use of prescription drug monitoring program (PDMP) data
  • Use of monitoring instruments in patients prescribed opioids
  • More frequent monitoring intervals
  • Pill counts
  • Use of abuse-deterrent formulations
  • Consultation with mental health specialists when mental health conditions are present or suspected
  • Avoidance of coprescribing of sedative hypnotics
  • Coprescribing of naloxone

Noninvasive Nonpharmacologic Treatments for Chronic Pain

• The effectiveness and comparative effectiveness (benefits and harms) of noninvasive nonpharmacologic treatments (exercise, mind-body practices, psychological interventions, multidisciplinary rehabilitation, mindfulness practices, musculoskeletal manipulation, physical modalities, and acupuncture) versus inactive treatments, usual care, no treatment, pharmacologic therapy, or selected active treatments (exercise [chronic pain conditions other than headache] or biofeedback [headache]), for the following conditions:
  • Chronic low back pain (KQ 1)
  • Chronic neck pain (KQ 2)
  • Osteoarthritis (knee, hip, hand) (KQ 3)
  • Fibromyalgia (KQ 4)
  • Chronic tension headache (KQ 5)

Nonopioid Pharmacologic Treatments for Chronic Pain

• Effectiveness and comparative effectiveness (benefits [KQ 1] and harms [KQ 2]) of nonopioid pharmacologic agents (nonsteroidal anti-inflammatory drugs [NSAIDs], antidepressants, anticonvulsants, acetaminophen, muscle relaxants, memantine, topical agents, and cannabis) versus placebo or other nonopioid pharmacologic agents.

Treatments for Acute Pain

• Effectiveness and comparative effectiveness (benefits and harms) of opioid therapy versus nonopioid pharmacologic therapy (acetaminophen, NSAIDs, skeletal muscle relaxants, benzodiazepines, antidepressants, anticonvulsants, and cannabis) or nonpharmacologic therapy (exercise, cognitive behavioral therapy, meditation, relaxation, music therapy, virtual reality, acupuncture, massage, manipulation or mobilization, and physical modalities); nonopioid pharmacologic therapy versus other nonopioid pharmacologic treatments or nonpharmacologic therapy; and nonpharmacologic therapy versus inactive treatments or usual care, for the following conditions:
  • Acute back pain (including back pain with radiculopathy) (KQ 1)
  • Acute neck pain (including neck pain with radiculopathy) (KQ 2)
  • Musculoskeletal pain not otherwise included in KQ 1 or KQ 2 (including fractures) (KQ 3)
  • Peripheral neuropathic pain (related to herpes zoster and trigeminal neuralgia) (KQ 4)
  • Postoperative pain (excluding inpatient management of pain following major surgical procedures (KQ 5)
  • Dental pain (KQ 6)
  • Kidney stones (including inpatient management) (KQ 7)
  • Sickle cell crisis (episodic pain) (KQ 8)

Treatments for Acute Episodic Migraine

• Effectiveness and comparative effectiveness (benefits and harms) of the following:
  • Opioid therapy versus nonopioid pharmacologic therapy (acetaminophen, NSAIDs, triptans, ergot alkaloids, combination analgesics, muscle relaxants, antinausea medications, cannabis, or others [e.g., gepants]) or nonpharmacologic therapy (exercise, cognitive behavioral therapy, acupuncture, or others) (KQ 1)
  • Nonopioid pharmacologic therapy versus a different nonopioid pharmacologic therapy or nonpharmacologic therapy (KQ 2)
  • Nonpharmacologic therapy versus inactive treatments, usual care, or no treatment (KQ 3)

Search Protocols

Complete methods and data, including detailed search protocols and inclusion and exclusion criteria, for the five AHRQ reports summarized here have been published (1–5). Study authors developed the search protocols using a standardized process with input from experts and the public. The review protocols were submitted for registration in the PROSPERO database before conducting the reviews. For each review, research librarians conducted searches on multiple electronic databases. For all reviews, searches were conducted on MEDLINE, Cochrane CENTRAL, and the Cochrane Database of Systematic Reviews; other databases that were used for one or more reviews (depending on the topic) were Embase PsycINFO, CINAHL, Scopus, and others. The searches were supplemented by a review of reference lists (including previous AHRQ and CDC reviews on these topics) (6–8) and gray literature sources. Searches were conducted in August or September 2019 for the chronic pain reviews and in July or August 2020 for the acute pain reviews.

Summarizing the Evidence

The reviews categorized magnitude of effects for pain and function using the same system as previous AHRQ reviews (6,9). A small effect was defined for pain as a mean between-group difference after treatment of 0.5–1.0 points on a 0- to 10-point numeric rating scale (NRS) or visual analog scale (VAS) and for function as a standardized mean difference (SMD) of 0.2–0.5 or a mean difference of 5–10 points on the 0- to 100-point Oswestry Disability Index (ODI) (10), 1–2 points on the 0- to 24-point Roland-Morris Disability Questionnaire (RDQ) (11), or equivalent. A moderate effect was defined for pain as a mean difference of 10–20 points on a 0- to 100-point VAS (1–2 points on a 0- to 10-point NRS) and for function as an SMD of 0.5–0.8, or a mean difference of 10–20 points on the ODI, 2–5 points on the RDQ, or equivalent (6,9). Large or substantial effects were defined as greater than moderate. Similar thresholds were applied to other outcomes measured. Small effects using this system might not meet proposed thresholds for clinically meaningful effects (12). However, estimated minimum clinically important differences vary across studies, and the clinical relevance of effects classified as small might vary for specific patients depending on preferences, baseline symptom severity, harms, cost, and other factors (13,14). The reviews also evaluated results on the basis of dichotomous outcomes (e.g., likelihood of experiencing clinically meaningful improvement in pain or function, often defined as >30% or >50% improvement from baseline).

Summary of Findings for Clinical Questions

Opioids for Chronic Pain

The AHRQ systematic clinical evidence review on opioids for chronic pain (1) updated the 2014 AHRQ report (7) and 2016 CDC update (8) and expanded on the previous reviews by adding evidence from randomized trials reporting short-term outcomes, including tramadol as an opioid intervention, addressing risks of coprescribing benzodiazepines or gabapentin, and addressing effects of co-use of cannabis.

Effectiveness (Benefits and Harms)

For short-term (1 to <6 month) outcomes, based on over 70 placebo-controlled trials (evidence type 1), opioids were associated with beneficial effects versus placebo but mean differences were small: for pain, <1 point on a 0–10 scale and for function, a SMD of 0.22 or <1 point on the 0- to 10-point Brief Pain Inventory (15) interference scale and <1 point on the 0- to 24-point RDQ. Opioids were associated with a number of patients needed to treat (NNT) of approximately 6.7 to achieve one additional case of short-term pain relief (e.g., ≥30% improvement in pain). Analyses based on a combination of head-to-head (within study) comparisons as well as a meta-regression of placebo-controlled trials indicated an association between higher opioid dosage and greater short-term effects on pain that appeared to plateau at approximately 50 mg morphine equivalent dose (MME)/day (evidence type 2). Evidence also indicated that effects of opioids dissipate with longer duration of therapy. Opioids were associated with a small mean improvement in short-term sleep quality (evidence type 2) versus placebo and a small mean short-term improvement in Short-Form 36-item (SF-36) (16) mental health status (evidence type 1). Effects of opioids on short-term outcomes were generally consistent across opioid types (opioid agonist, partial agonist, or mixed medication agent). Effects on pain were somewhat greater for neuropathic than musculoskeletal pain (effects on pain approximately 0.5 point greater for neuropathic versus musculoskeletal pain on a 0–10 scale). Use of a crossover or enriched enrollment randomized withdrawal (EERW) design (a type of trial in which potential participants receive the study drug for a period in a prerandomization phase and only those who benefit from the drug and can tolerate the side effects continue in the trial, randomly assigned to continue on the study drug or placebo) (17) was associated with greater effects on pain than parallel group or non-EERW studies.

Opioids were associated with increased risk versus placebo for discontinuation because of adverse events (number of patients treated to cause one adverse event [number needed to harm, NNH 10], and increased risk for gastrointestinal events [NNH 7.1 for nausea, 14.3 for vomiting, and 7.1 for constipation], somnolence [NNH 11.1], dizziness [NNH 12.5], and pruritus [NNH 14.3]) (evidence type 1). Few serious adverse events and no difference between opioids versus placebo in risk were reported in the short-term trials (evidence type 2); however, serious adverse events were not well defined by the trials, the trials excluded patients at higher risk (e.g., those with a history of substance use disorder), and the trials were not designed to assess serious but less common harms such as overdose, opioid use disorder death, cardiovascular events, and fractures. EERW studies tended to report lower risk with opioids of discontinuation because of adverse events and gastrointestinal adverse events than non-EERW studies. Uncontrolled studies (studies without a nonopioid control group) were not included in the AHRQ review, although a recent systematic review with such studies found that rates of misuse ranged from 21% to 29% (95% CI: 13%–38%) and rates of addiction ranged from 8% to 12% (95% CI: 3%–17%), based on higher-quality observational evidence (18).

As in the 2014 AHRQ report and 2016 CDC update, the clinical evidence review identified no long-term (>1 year) randomized controlled trials (RCTs) of opioid therapy versus placebo. One new cohort study found long-term opioid therapy was not associated with improved pain, function, or other outcomes versus no opioids (19). New observational studies included in the new AHRQ review were consistent with the 2014 AHRQ report in finding an association between use of prescription opioids and risk for addiction, overdose, fractures, falls, and cardiovascular events (evidence type 3); a new study also found an association between opioid use and risk of all-cause deaths (20) (evidence type 4). New observational studies also were consistent with the 2014 AHRQ report in finding associations between higher dosages of opioids and risks for overdose, addiction, and endocrinological adverse events; new studies also found an association between higher dosage and increased risk for incident or refractory depression (21,22). Observational studies also indicated an association between coprescription of gabapentinoids (23–25) or benzodiazepines (26–28) and increased risk for overdose, with most pronounced risk occurring soon after initiation of these medications (evidence type 3). All observational studies were susceptible to residual confounding.

No differences were found across 16 trials between opioids versus nonopioids (most commonly NSAIDs, gabapentinoids, and nortriptyline) in short-term pain, function, health status or quality of life, sleep quality, or mental health outcomes (evidence type 1 for function; evidence type 2 for other outcomes), although opioids were associated with increased risk for short-term adverse effects (evidence type 1 or 2). Most trials were <6 months; one trial of patients with chronic low back pain or pain associated with osteoarthritis (mean pain intensity: 5.4 on a 0–10 scale at baseline) evaluated outcomes at 1 year (29). The trial found no differences between stepped therapy with opioids versus stepped therapy starting with nonopioids in function, sleep, or mental health outcomes; opioids were associated with slightly worse effects (by approximately 0.5 point on a 0–10 scale) on pain (evidence type 2). Although tramadol was an option in step 3 of the nonopioid stepped therapy arm, only 11% received tramadol; mean opioid doses for stepped opioid therapy and stepped therapy starting with nonopioids were 26 versus 1 MME/day, respectively, at 12 months.

Also, there were no differences between combination therapy versus a nonopioid alone in short-term effectiveness but increased risk for short-term adverse effects for combination therapy, on the basis of six trials (evidence type 3). Combination therapy was associated with a small (5–13 MME/day) opioid-sparing effect versus opioid therapy alone, with little effect on pain. All trials of combination therapy evaluated patients with neuropathic pain and primarily evaluated gabapentinoids or nortriptyline. Evidence on long-term effects of combination therapy versus an opioid or nonopioid alone was lacking.

Opioid Dosing Strategies

Evidence on the effectiveness of different opioid dosing strategies remains limited. One trial included in the 2014 AHRQ report found no differences between a more liberal dosage escalation strategy versus maintenance of current dosages in pain, function, or discontinuation because of opioid misuse; however, the difference in opioid dosages between arms was small (52 versus 40 mg MMD/day) (30) (evidence type 3). No clear differences were found between short- versus long-acting opioids (evidence type 3) or between different long-acting opioids (evidence type 2) in pain or function; however, in most trials, dosages were titrated to achieve adequate pain control. Evidence on comparative risks of methadone versus other opioids and risk for overdose remains limited and inconsistent. Evidence on the benefits and harms of different methods for initiating and titrating opioids, scheduled and continuous versus as-needed dosing of opioids, use of opioid rotation, and methods for titrating or discontinuing opioids remains insufficient. The 2014 AHRQ report found buccal or intranasal fentanyl more effective than placebo or oral opioids for treatment of exacerbations of chronic pain, based on immediate effects (up to 2 hours after administration). None of the trials of buccal or intranasal fentanyl was designed to assess longer-term benefits or harms, and no new trials were identified for the 2020 systematic review. In 2007, the Food and Drug Administration released a public health advisory due to case reports of deaths and other life-threatening adverse effects in patients prescribed buccal fentanyl (31).

Risk Mitigation Strategies

New evidence on the accuracy of risk prediction instruments was consistent with the 2014 AHRQ report, which found highly inconsistent estimates of diagnostic accuracy, methodological limitations, and few studies of risk assessment instruments other than the Opioid Risk Tool (32) and Screening and Opioid Assessment for Patients with Pain-Revised instrument (33) (evidence type 3). Evidence on the effectiveness of risk mitigation strategies also remains limited. One new observational study found that provision of naloxone to patients prescribed opioids in primary care clinics was associated with decreased likelihood of opioid-related emergency department visits; there were too few opioid poisoning deaths to assess effects on overdose mortality (evidence type 3) (34). Evidence on opioid tapering was largely limited to a trial that found a taper support intervention associated with better functional outcomes and a trend toward lower opioid doses versus usual opioid care (35) (evidence type 2). A cohort study found discontinuation of opioid therapy was associated with increased risk for overdose death versus continuation; however, there was no statistically significant difference in risk for all-cause deaths (36). Findings should be interpreted with caution because of potential confounding related to the reason for discontinuation.

No trial compared different rates of opioid tapering, although one observational study found an association between longer time to opioid discontinuation in patients on long-term, high-dosage opioid therapy and decreased risk of opioid-related emergency department visit or hospitalization (37) (evidence type 3). The review did not identify any study that evaluated the effectiveness of risk mitigation strategies, such as use of risk assessment instruments, opioid management plans, patient education, urine drug screening, PDMP data review, monitoring instruments in patients prescribed opioids, more frequent monitoring intervals, pill counts, abuse-deterrent formulations, or avoidance of coprescribing of benzodiazepines on risk for overdose, addiction, abuse or misuse.

Evidence on the effectiveness of interventions for opioid use disorder in patients with prescription opioid dependence or opioid use disorder was limited by such factors as small sample sizes, high attrition or crossover, and exclusion of patients with chronic pain.

Noninvasive Nonpharmacologic Treatment for Chronic Pain

The AHRQ systematic clinical evidence review (2) focused on commonly encountered pain conditions and frequently used interventions. Selection of conditions for review was informed by stakeholder input.

Benefits

Chronic Low Back Pain. The review found psychological therapies associated with small improvements versus usual care or an attention control for function and pain at short-, intermediate-, and long-term follow-up (evidence type 2). Exercise, low-level laser therapy, spinal manipulation, massage, yoga, acupuncture, and multidisciplinary rehabilitation were associated with improvements in function at short- and intermediate-term follow-up versus usual care, placebo, waiting list, or inactive therapies; effects on pain were small for all therapies except yoga, for which benefits were moderate (evidence type 2 at short term for exercise, massage, and yoga; evidence type 3 for others). Massage, mindfulness-based stress reduction, acupuncture, and multidisciplinary rehabilitation were associated with small short-term improvement in pain versus control (evidence type 2); exercise, low-level laser therapy, and yoga also were associated with small to moderate short-term improvement in pain, although evidence was not as strong (evidence type 3). At intermediate term, spinal manipulation, yoga, multidisciplinary rehabilitation (evidence type 2) and exercise and mindfulness-based stress reduction (evidence type 3) were associated with improved pain versus sham, usual care, or attention control; effects were small for all therapies except for yoga, for which effects were moderate. Compared with exercise, multidisciplinary rehabilitation was associated with small improvements in function and pain at short and intermediate terms (evidence type 2).

Chronic Neck Pain. The AHRQ systematic clinical evidence review found low-level laser therapy (evidence type 2) and massage (evidence type 3) associated with improved short-term function and pain for chronic neck pain. The magnitude of effect was moderate for low-level laser therapy and small for massage. Exercise was associated with small improvement in long-term function versus attention control (evidence type 3) and combination exercise was associated with improved short- and long-term function and short-term pain versus waiting list or attention control (evidence type 3). Acupuncture was associated with small improvements in short- and intermediate-term function versus sham, placebo, or usual care; however, there were no differences in pain versus sham acupuncture, an intervention meant to mimic acupuncture but without acupuncture effects (e.g., needles in nonacupuncture point, or nonpenetrating needles or pressure on acupuncture points) (evidence type 3). Pilates was associated with improved short-term function (small effect) and pain (large effect) versus acetaminophen (evidence type 3).

Osteoarthritis Pain. The AHRQ systematic clinical evidence review found that for knee osteoarthritis, exercise was associated with small improvements in short- and long-term function and pain versus usual care, no treatment, or sham (evidence type 2 for short-term and type 3 for long-term) and moderate improvement in intermediate-term pain and function (evidence type 3). For hip osteoarthritis, exercise was associated with small improvement in short-term function and pain versus usual care (evidence type 3). Functional improvement persisted at intermediate-term follow-up but pain improvement did not (evidence type 3).

Fibromyalgia. The AHRQ systematic clinical evidence review found exercise, mind-body practices, multidisciplinary rehabilitation, and acupuncture associated with small improvement in short-term function versus usual care or inactive treatments for fibromyalgia (evidence type 2 for acupuncture; evidence type 3 for others). At intermediate term, exercise, acupuncture, cognitive behavioral therapy, mindfulness-based stress reduction, myofascial release, and multidisciplinary rehabilitation were associated with improvements in function versus inactive treatments, usual care, or waiting list (evidence type 2 for exercise and acupuncture; evidence type 3 for others). Effects on intermediate-term function were moderate for cognitive behavioral therapy and small for the other therapies. At long term, multidisciplinary rehabilitation was associated with persistent small improvement in function versus usual care but not for pain (evidence type 3). Tai chi was associated with small improvement in function versus exercise at short- to intermediate-term follow-up (evidence type 3). Therapies associated with improved pain versus usual care, waiting list, no treatment, or inactive treatments were exercise (small effect, short and intermediate term; evidence type 2), cognitive behavioral therapy (small, short term; evidence type 3), mindfulness practices (small, intermediate term; evidence type 3), and multidisciplinary rehabilitation (small, intermediate term; evidence type 3).

Chronic Tension Headache. The AHRQ systematic clinical evidence review found spinal manipulation was associated with moderate improvement in short-term pain and small improvement in function versus usual care for chronic tension headache (evidence type 3). For other interventions, evidence was sparse, and the majority of trials had serious methodological limitations.

Harms

Across conditions, data on harms of nonpharmacologic therapies were limited but no evidence suggested serious harms. Although reporting on harms was suboptimal, among studies that reported data, nonserious treatment-related adverse events (e.g., discomfort, soreness, bruising, increased pain, and worsening of symptoms) were infrequently reported, few withdrawals from nonpharmacologic therapies due to adverse events were reported, and no differences were found between comparison groups (either usual care or no nonpharmacologic therapy or another therapy) in the frequency of intervention-related adverse events or withdrawals (evidence type 2 or 3).

Nonopioid Pharmacologic Treatments for Chronic Pain

Benefits

For neuropathic pain, the AHRQ systematic clinical evidence review (3) found anticonvulsants (gabapentin, pregabalin, and oxcarbazepine) were associated with small short-term improvement in pain versus placebo (evidence type 2), with no difference between pregabalin versus gabapentin enacarbil (evidence type 3). The antidepressant duloxetine was associated with small improvements in short-term pain, function, and quality of life versus placebo in patients with diabetic peripheral neuropathy (evidence type 2 for pain and quality of life; evidence type 3 for function). Tetrahydrocannabinol (THC) and cannabidiol (CBD) oral spray had inconsistent effects on pain in patients with multiple sclerosis or with allodynia (evidence type 3). Topical capsaicin was not associated with statistically significant effects on pain versus placebo, or effects were below the threshold for a small effect (evidence type 2).

For fibromyalgia, serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants milnacipran and duloxetine were associated with small, short- and intermediate-term improvements in pain and quality of life versus placebo; a small beneficial effect on function was only observed at short-term (evidence type 2). Anticonvulsants pregabalin and gabapentin were associated with small short-term improvements in pain and function versus placebo; there were no effects on quality of life (evidence type 2). Memantine was associated with moderate intermediate-term improvements in pain, function, and quality of life versus placebo (evidence type 3).

For osteoarthritis, NSAIDs were associated with small short-term improvement in pain (evidence type 2) and function (evidence type 1). Topical diclofenac was associated with small improvement in short-term pain (evidence type 2) and function (evidence type 3) versus placebo. Duloxetine was associated with small improvement in pain severity, function, and quality of life and moderate improvement in likelihood of a pain response (evidence type 1). Acetaminophen was not associated with improvement in pain or function versus placebo (evidence type 3).

For inflammatory arthritis, NSAIDs were associated with small improvements in short-term pain and function versus placebo (evidence type 2); effects on pain and function were small at intermediate-term follow-up (evidence type 3). At long-term follow-up, effects on pain were large, with no effects on function (evidence type 3).

For low back pain, duloxetine was associated with a small short-term improvement in pain intensity and likelihood of a pain response versus placebo; however, improvements in function and quality of life did not meet the threshold for small improvement (evidence type 2).

Harms

Across all classes of nonopioid therapies, the AHRQ systematic clinical evidence review found that the incidence of serious adverse events was low; however, the trials were not designed to assess serious adverse events, and there were few serious adverse events (evidence type 3).

Antidepressants were associated with increased risk for withdrawal due to adverse events (WAE) versus placebo. SNRI antidepressants were associated with moderate to large increases in risk for nausea and excessive sweating (evidence type 2 or 3). Duloxetine was associated with a large, dose-dependent increase in sedation versus placebo (evidence type 2 or 3).

With regard to anticonvulsants, oxcarbazepine was associated with a large increase in risk for WAEs versus placebo (evidence type 2). Pregabalin and gabapentin were associated with moderate increased risk for WAEs (evidence type 2), with an association between higher dosages of pregabalin and increased risk. Pregabalin and gabapentin were associated with large increases in blurred vision, dizziness, weight gain, and cognitive effects (e.g., confusion) (evidence type 2). In addition, pregabalin was associated with large increases in risk for peripheral edema and sedation (evidence type 2).

NSAIDs were associated with increased risk for WAEs versus placebo; the magnitude was small for ibuprofen and diclofenac and moderate for naproxen (evidence type 2). There was no statistically significant increase in risk for any cardiovascular event for NSAIDs as a group; however, diclofenac was associated with a small increase in risk, particularly in the first 6 months, and with higher dosages (evidence type 2). Versus placebo, the risk for major coronary events was elevated with diclofenac and celecoxib (moderate effect) and with ibuprofen (large effect). For every 3,000 patients treated with diclofenac or celecoxib, there were an estimated three additional major coronary events. No difference was found in cardiovascular events between celecoxib versus nonselective NSAIDs in the intermediate or long term (evidence type 2). The risk for serious upper gastrointestinal events was increased with diclofenac (moderate effect) and ibuprofen or naproxen (large increase), particularly in the first 6 months of treatment (evidence type 1–2). In the intermediate term, diclofenac and naproxen were associated with large increase in risk for hepatic harms (evidence type 1–2).

Acetaminophen was not associated with increased risk for short- or intermediate-term WAEs versus placebo (evidence type 3). Capsaicin was associated with a large increase in risk for application site pain (evidence type 2) and a small increased risk for erythema (evidence type 3). Cannabis as oral dronabinol solution was associated with a large increase in risk for dizziness, and as THC or CBD was associated with a large increase in risk for WAEs, dizziness, and nausea (evidence type 3).

Treatments for Acute Pain

The AHRQ systematic clinical evidence review (4) found that most trials of treatments for acute pain focused on effects on pain at short-term (up to 1 week) follow-up. Evidence was somewhat stronger for pharmacologic than nonpharmacologic therapies.

For acute surgical dental pain (evidence type 3) and kidney stone pain (evidence type 2), the AHRQ systematic clinical evidence review found that opioids were associated with small to moderate increases in pain or need for rescue medication use versus NSAIDs. Findings for postoperative pain were somewhat inconsistent. Although opioids were associated with increased likelihood of repeat or rescue medication use at 1 day to 1 week (evidence type 3), evidence on pain intensity was insufficient due to inconsistency. Results for postoperative pain were based on a small number of trials and pain related to a limited set of surgical procedures (most commonly cesarean section, anterior cruciate ligament reconstruction, knee arthroplasty, and cholecystectomy), limiting generalizability to other surgical procedures. Opioids were associated with increased risk for adverse events such as nausea, dizziness, and sedation versus nonopioid pharmacologic therapies (evidence type 2 or 3). The trials were not designed to assess serious adverse events, and few such events were reported. Evidence on opioids versus acetaminophen was somewhat mixed: for dental pain, the systematic clinical evidence review found opioids were associated with small improvement in pain outcomes on certain measures (evidence type 2) but for kidney stone pain, opioids were associated with a small increase in pain (evidence type 2). Evidence on NSAIDs versus acetaminophen was also somewhat mixed: for dental pain, evidence indicated that NSAIDs were associated with moderate to large decrease in pain (evidence type 2) but for kidney stone pain, evidence was insufficient. Evidence on nonopioid pharmacologic therapies other than NSAIDs or acetaminophen was very limited.

Evidence on nonpharmacologic therapies for acute pain was limited. For low back pain, the AHRQ systematic clinical evidence review found that heat therapy was associated with a moderate decrease in pain versus usual care or placebo at 1 day to <1 week and at 2 to <4 weeks (evidence type 2–3). For nonradicular low back pain, there might be no difference between spinal manipulation versus inactive controls (evidence type 2–3), although one trial of patients with radiculopathy found manipulation was associated with increased likelihood of improvement in pain at 2 to <4 weeks and at ≥4 weeks (evidence type 3) (38). Acupuncture was associated with moderate improvement in pain and function versus an NSAID for low back pain; however, findings were based on one trial that evaluated one session of acupuncture and a single dose of an NSAID (evidence type 3) (39). For postoperative pain, there was type 3 evidence that massage might have some effectiveness, with likely no difference between cold therapy versus no cold therapy, with the possible exception of decreased pain medication use at <1 week. Evidence supporting effectiveness of acupressure for acute musculoskeletal pain was limited (evidence type 3). Reporting of harms for nonpharmacologic therapies was suboptimal. However, the noninvasive nonpharmacologic therapies evaluated in the AHRQ systematic clinical evidence review were generally not thought to be associated with serious harms, and harms were few when reported.

Trials of opioid therapy for acute pain were not designed to evaluate effects on long-term use of opioids or outcomes such as misuse or development of opioid use disorder. Limited evidence from observational studies found that being prescribed an opioid for acute low back pain or after minor or elective surgical procedures was associated with increased likelihood of opioid use at longer term (e.g., 6 months or 1 year) follow-up (evidence type 3). Evidence on factors associated with opioid prescribing in patients with acute pain conditions was very limited and suggested that legislation mandating use of PDMP data before prescribing was not associated with decreases in opioid prescribing for low back pain or postoperative pain. No studies were identified that evaluated the accuracy or effectiveness of risk assessment instruments to inform use of opioids for acute pain.

Treatments for Acute Episodic Migraine

The AHRQ review on treatments for acute episodic migraine (5) found limited evidence on the benefits and harms of opioids. The review found that opioids might be associated with decreased pain versus placebo but worse pain outcomes versus nonopioid pharmacologic therapy (evidence type 3). Most outcomes were assessed at short-term (2 hours or 1 day) follow-up. Opioids were associated with increased risk for adverse events, although evidence on serious adverse events was lacking. No studies were found on instruments for predicting opioid misuse, opioid use disorder, overdose, or risk mitigation strategies in patients prescribed opioids for migraine.

The AHRQ review found stronger (type 1 or 2) evidence supporting the effectiveness of multiple established nonopioid pharmacologic therapies for improving pain resolution in acute episodic migraine, including triptans, NSAIDs, dihydroergotamine, and ergotamine plus caffeine. Evidence also favored antiemetics versus placebo or no antiemetic but was more limited (evidence type 3). Newer treatments (calcitonin gene-related peptide [CGRP] antagonists [gepants], and lasmiditan [a 5-HT1F receptor agonist]) were associated with reduced pain and improved function versus placebo (evidence type 2 or 3). However, lasmiditan was associated with increased risk for serious adverse events (most commonly, dizziness; evidence type 3); evidence on serious adverse events of CGRP antagonists was insufficient.

Evidence on nonpharmacologic therapy for acute episodic migraine was sparse. Moderate evidence (evidence type 2) supported remote electrical neuromodulation. More limited evidence (evidence type 3) supported acupuncture, chamomile oil, external trigeminal nerve stimulation, and eye movement desensitization reprocessing. Evidence was insufficient to determine risk for serious adverse events with nonpharmacologic therapies for acute episodic migraine.

Contextual Evidence Review

Patient and Clinician Values and Preferences

Opioids for Chronic Pain. The contextual evidence review conducted for the 2016 CDC Opioid Prescribing Guideline (8) found data indicating that physicians frequently lacked confidence in their ability to safely prescribe opioids, predict or identify prescription medication misuse or opioid use disorder, or discuss these issues with their patients. Clinicians reported favorable beliefs and attitudes about effects of opioids on pain and quality of life; however, they also had concerns about risk for opioid use disorder and overdose yet did not consistently use risk mitigation strategies (e.g., use of PDMP data, urine toxicology testing, or opioid treatment agreements). Evidence on patient values and preferences was limited but indicated unfamiliarity with certain terms (“opioids”), more familiarity with the term “narcotics” but an association between “narcotics” and “addiction” or “abuse,” and concerns about addiction and abuse. Side effects such as nausea, constipation, and somnolence (rather than pain relief) accounted for most of the variation in patient preferences regarding use of opioids. Patients prescribed high-dose opioids reported reliance on opioids and ambivalence or uncertainty about benefits and side effects.

The AHRQ review identified new information on preferences and values. A survey of 961 clinicians found that 82% were reluctant to prescribe opioids and less than half (47%) expressed confidence in caring for patients with chronic noncancer pain (40). A total of 67% were aware of the 2016 CDC Opioid Prescribing Guideline and 55% were enrolled in the state PDMP; 2% always or frequently prescribed naloxone to patients on opioids, although results are difficult to interpret because the study did not specify whether patients met 2016 CDC Opioid Prescribing Guideline criteria for naloxone. Guideline awareness was associated with increased confidence in caring for patients with chronic pain. Other surveys found negative attitudes or concerns regarding prescription opioid use disorder but beliefs in potential effectiveness of opioids for treating pain and support for policies and guidelines aimed at mitigating risks, with increased confidence when following “best practices” (41–43).

Regarding patient preferences and values, a new systematic review found that among various opioid-related outcomes (effects), patients ranked pain relief, nausea, and vomiting as most important, followed by constipation (44). “Addiction” was only evaluated in two studies and rated as less important than pain relief. An online (non–peer reviewed) survey of approximately 3,000 patients 1 year after the release of the 2016 CDC Opioid Prescribing Guideline found that 84% reported more pain and worse quality of life and 42% said they had considered suicide; however, the survey did not attempt to sample patients with chronic pain using a rigorous methodological approach (45).

Noninvasive Nonpharmacologic Treatments for Chronic Pain. The contextual evidence review found that evidence on patient values and preferences related to noninvasive nonpharmacologic treatments for chronic pain was limited. A Gallup poll found that 78% of Americans preferred nonpharmacologic therapies (e.g., physical therapy and chiropractic care) to address pain over prescribed pain medication (46). Another survey indicated frequent use of complementary and integrative therapies for chronic pain (47).

Clinicians generally agreed with use of guideline-supported therapies and therapies supported by evidence, including nonpharmacologic therapies; clinicians also felt that treatments should be credible and individualized to the patient (48,49). Clinician concerns regarding nonpharmacologic treatments included costs and safety (49). Surveys indicated high support for use of exercise therapy, complementary medicine therapies, and psychological therapies (50–52); clinicians also supported chronic pain management informed by a biopsychosocial framework or using a multidimensional approach (53). Barriers to use of therapies included lack of knowledge or expertise and uncertainty regarding potential benefits (48,50,52–55).

Nonopioid Pharmacologic Treatments for Chronic Pain. The contextual evidence review found limited evidence on clinician and patient values and preferences related to nonopioid pharmacologic treatments. Evidence described variability in patient preferences regarding nonopioid pharmacologic treatments, interest in medical cannabis, cost as an important consideration, high priority on pain reduction as well as side effects and harms (including risk for opioid use disorder), and high value for having alternatives to opioids (56–58). A survey of pharmacists in Canada found that 38% agreed that nonprescription analgesics should be first line for chronic low back pain and 79% agreed that tricyclic antidepressants are effective for peripheral diabetic neuropathy (59).

Treatments for Acute Pain. The contextual evidence review found limited evidence suggesting variability in patient values and preferences regarding treatments for acute pain (60,61), with some evidence of high satisfaction when postoperative pain was managed using an opioid-sparing pathway (62). Also, there was variability in clinician values and preferences regarding acute pain treatments that were affected by clinical specialty, knowledge regarding effectiveness, and costs; negative attitudes toward acute pain conditions were associated with less likelihood of using or redosing opioids (63–67). A systematic review found inconsistent evidence that education increased clinician adherence with acute low back pain guideline recommendations in terms of referral rates to physiotherapy (67).

Treatments for Acute Episodic Migraine. The contextual evidence review found very limited evidence on clinician and patient values and preferences related to treatments for acute episodic migraine. One survey found that patients with headaches (primarily episodic or chronic migraine) prioritized efficacy of treatment over the safety or route of administration and preferred oral over parenteral medications (68). A survey of Canadian pharmacists found that 42% agreed that migraine patients should try nonprescription before prescription medications and 53% agreed that triptans should be reserved until failure of at least two other prescription medications (59).

Costs and Cost-Effectiveness

Opioid Therapy for Chronic Pain. The contextual evidence review conducted for the 2016 CDC Opioid Prescribing Guideline estimated (on the basis of studies published after 2010) yearly direct and indirect costs related to prescription opioids at $53.4 billion for nonmedical use of prescription opioids; $55.7 billion for abuse, dependence (i.e., opioid use disorder), and misuse of prescription opioids; and $20.4 billion for opioid-related overdoses (69–71). In 2012, total expenses for outpatient prescription opioids were estimated at $9 billion, an increase of 120% from 2002 (72). On the basis of a large national sample of 2008 claims data, direct costs of opioids in patients with osteoarthritis were estimated at $287.40 per patient; however, there was wide variability in estimates (SD: $1,652.10) (73). One study estimated costs of urine toxicology testing (including screening and confirmatory tests) at $211–$363 per test (74).

The AHRQ report included data that estimated the total economic burden of fatal overdose, abuse, and dependence of prescription opioids in 2013 at $78.5 billion, with $28.9 billion related to increased health care and substance use disorder treatment costs (75). More recent data indicate that spending on opioid prescriptions peaked at $1.6 billion in 2009, with a decrease to $1.2 billion in 2016 (76). However, costs of treatment for opioid use disorder and overdose increased ($646 million in 2009 and $2.6 billion in 2016). Data also indicate that Medicaid spending on opioids has declined since 2014, although spending on buprenorphine (a partial opioid agonist often used to treat opioid use disorder) has increased (77), likely because of greater numbers of persons accessing medication and treatment for opioid use disorder.

No study was identified that formally evaluated the cost-effectiveness of opioid therapy versus no opioid therapy or nonopioid pharmacologic therapy for noncancer pain. A modeling study that estimated 80% of opioid overdose deaths to be attributable to illicit opioids projected that interventions targeting prescription opioid misuse (e.g., prescription monitoring programs) would decrease the number of opioid overdose deaths by 3.0%–5.3% (78). Also, there were no cost-effectiveness analyses of risk mitigation strategies in persons prescribed opioids for chronic pain. A systematic review that included 43 economic evaluation studies of treatments for opioid use disorder found evidence supporting the cost-effectiveness of methadone therapy, with less evidence for other opioid use disorder therapies (79). Additional analyses from the United Kingdom and California also found treatment for opioid use disorder to be cost-effective or cost-saving (80,81).

Noninvasive Nonpharmacologic Treatments for Chronic Pain. The contextual evidence review found that for nonpharmacologic treatments covered by commercial insurers, out-of-pocket costs ranged from $25 to $60 per visit ($150–$720 for a 6- to 12-visit course of therapy) (55). Studies found that a number of nonpharmacologic therapies were cost-effective for various chronic pain conditions. For osteoarthritis, cost-effective interventions (relative to a comparison such as no therapy or usual care) included exercise, acupuncture, and transcutaneous electrical nerve stimulation (82–90). For low back pain, cost-effective interventions included interdisciplinary rehabilitation, exercise, yoga, acupuncture, spinal manipulation, cognitive behavioral therapy, mindfulness-based stress reduction, biofeedback, and multidisciplinary rehabilitation (91–99). For neck pain, cost-effective interventions included manual therapy, physiotherapy, acupuncture, exercise, and spinal manipulative therapy (94,100–104). For fibromyalgia, cost-effectiveness analyses of nonpharmacologic therapies were very limited (105); however, certain evidence suggested that cognitive behavioral therapy dominated (associated with cost savings and greater benefits) pharmacologic therapy or usual care (106).

Nonopioid Pharmacologic Treatments for Chronic Pain. The contextual evidence review found certain evidence indicating that nonopioid pharmacologic therapies are cost-effective for chronic pain. For osteoarthritis and low back pain, there was evidence that nonopioid pharmacologic therapies (NSAIDs and duloxetine) are cost-effective versus opioids (107–109); studies also found NSAIDs, duloxetine, and pregabalin to be cost-effective versus usual care or no treatment (108,110–112). For neuropathic pain, cost-effective treatments included tricyclic antidepressants, duloxetine, pregabalin, and topical capsaicin or lidocaine (113–126). For fibromyalgia, cost-effective treatments included duloxetine, pregabalin, and amitriptyline, although analyses of relative cost-effectiveness among these therapies were inconsistent (127–134).

Treatments for Acute Pain. The contextual evidence review found limited evidence that exercise was cost-effective for acute low back pain and interdisciplinary rehabilitation cost-effective for low back pain that was identified as high risk for becoming chronic (102,135,136). Evidence that acetaminophen and spinal manipulation were not cost-effective for acute low back pain was limited (the acetaminophen analysis was based on a randomized trial that found acetaminophen to be ineffective for acute low back pain, and the spinal manipulation analysis was based on a cohort study that found manipulation for acute low back pain did not reduce follow-up visits or days of sick leave for low back pain) (137,138). One cohort study of patients with postsurgical pain found use of long-acting opioids within 30 days to be associated with greater costs of services ($11,900 versus $8,400; p<0.0001) (139).

Treatments for Acute Episodic Migraine. The contextual evidence review found that studies on costs and cost-effectiveness of treatments for acute episodic migraine focused almost exclusively on triptans. Triptans were consistently found to be associated with low costs per pain-free episode and other outcomes (e.g., migraine-disability days averted) (140–148). Triptans were dominant (more effective and less costly) over a fixed-dose combination of ergotamine tartrate plus caffeine (149).

Summary of Surveillance Reports

Opioid Treatments for Chronic Pain

To identify new evidence on opioid treatments for chronic pain that might have an impact on the conclusions or findings of the original (2020) systematic review, a series of three updates was conducted; searches for the final (third) update were conducted on March 16, 2022 (150). New evidence did not change the main findings of the original systematic review. For opioids versus placebo, updated meta-analyses that included three additional trials (151–153) reported a small reduction in pain intensity (mean difference: −0.78: 95% CI: −0.91 to −0.65), increased likelihood of experiencing >30% improvement in pain (RR: 1.33; 95% CI: 1.22–1.46), and small improvement in function (standardized mean difference: −0.21; 95% CI: −0.27 to −0.15), with estimates very similar to the original review. Findings for increased risk of opioids versus placebo of short-term harms (discontinuation because of adverse events, constipation, nausea, vomiting, dizziness, somnolence, and pruritus) also were unchanged. One new randomized trial (154) found transcutaneous electrical nerve stimulation to be associated with a small improvement in short-term function versus opioids and with decreased risk for any adverse event, nausea, constipation, and dizziness (strength of evidence: low); no study evaluated this comparison in the original review. No new randomized trials of opioids versus other nonpharmacological therapies or nonopioid medications were found. Two new cohort studies (155,156) found opioid dosage reduction or discontinuation to be associated with increased risk for mental health crisis events or fatal or nonfatal suicide attempts; however, evidence on the association between tapering or discontinuation and risk for overdose was inconsistent. The studies were not designed to evaluate the indication or circumstances for dosage reduction or methods used to support dosage reductions or discontinuation and had methodologic limitations, including potential for confounding. New evidence on long-term benefits and harms, risk mitigation strategies, dose-dependent risks of opioids, and management of opioid use disorder was limited; for all of these areas, findings with the addition of studies identified in the updates were consistent with the original report.

Nonopioid Pharmacologic Treatments for Chronic Pain

To identify new evidence on nonopioid pharmacologic treatments for chronic pain that might have an impact on the conclusions or findings of the original (2020) systematic review, a series of three updates was conducted; searches for the final (third) update were conducted on April 1, 2022 (157). The addition of evidence identified during the updates did not change the main conclusions of the original review, which found nonopioid drugs (mainly SNRI antidepressants, pregabalin and gabapentin, and NSAIDs) to be associated with small to moderate improvements in short-term pain and function outcomes in patients with specific types of noncancer chronic pain. Evidence on intermediate- and long-term outcomes of nonopioid pharmacologic treatments for chronic pain remained limited. Findings after the addition of new studies were also consistent with the original review in finding nonopioid drugs to be associated with increased risk for class-specific harms (e.g., gastrointestinal events with NSAIDS), with certain patients withdrawing because of adverse events. For neuropathic pain, new evidence resulted in certain changes to strength of evidence of magnitude of effects assessments, including a change to low strength of evidence for small increased likelihood of experiencing a pain response with cannabis (RR: 1.30; 95% CI: 0.88–1.94; magnitude of reduction previously assessed as moderate) and large risk for sedation with cannabis (RR: 5.84; 95% CI: 1.90–17.92; previously insufficient evidence), due to the addition of one new randomized trial (158); strength of evidence was changed to low for no difference between gabapentin or pregabalin and duloxetine in pain intensity (previously insufficient evidence), due to the addition of two new randomized trials (159,160). An updated meta-analysis found capsaicin to be associated with a large increased risk for discontinuation because of adverse events (strength of evidence moderate) compared with placebo (previously no increase in risk), due to the addition of one new randomized trial (161), although the absolute number of participants who withdrew because of adverse events was small (<1%).

Noninvasive Nonpharmacologic Treatments for Chronic Pain

To identify new evidence on noninvasive nonpharmacologic treatment for chronic pain that that might have an impact on the conclusions or findings of the original (2020) systematic review, a series of three updates was conducted; searches for the final (third) update were conducted in March 2022 (162). The addition of evidence identified during the updates did not change the main conclusions of the original review, which found exercise, multidisciplinary rehabilitation, acupuncture, cognitive behavioral therapy, mindfulness practices, massage, and mind-body practices to be associated with improved function, pain, or both, beyond the course of therapy for specific chronic pain conditions. Updated meta-analyses with the addition of new studies were conducted for low back pain (exercise, psychological therapies, manual therapy, mind-body practices, and acupuncture), neck pain (exercise), knee osteoarthritis (exercise, physical modalities [low-level laser therapy], ultrasound, and mind-body therapies), and fibromyalgia (exercise, mindfulness practices, acupuncture, and multidisciplinary rehabilitation). On the basis of the updated meta-analyses, the strength of evidence for mind-body therapies for knee osteoarthritis was upgraded to low for moderate improvement in pain and small improvement in function (previously insufficient evidence), due to the addition of one new trial (163); the strength of evidence for low level laser therapy for knee osteoarthritis was also upgraded to low for no difference in pain improvement and small improvement in function (previously insufficient evidence), due to the addition of one new trial (164). Otherwise, findings were unchanged from the original review. As in the original review, harms were poorly reported across interventions, although serious intervention-related adverse events were not identified.

Treatments for Acute Pain

To identify new evidence on noninvasive nonpharmacologic treatment for chronic pain that might have an impact on the conclusions or findings of the original (2020) systematic review, a series of three updates was conducted; searches for the final (third) update were conducted on May 6, 2022 (165). The addition of evidence identified during the updates did not change the main conclusions of the original review. Specifically, opioid therapy was associated with decreased or similar effectiveness for pain versus an NSAID for surgical dental pain, kidney stone pain, and low back pain. New evidence was identified for low back pain (acupuncture), musculoskeletal pain (opioid versus acetaminophen, and topical ibuprofen versus capsaicin), postoperative pain (opioid versus NSAID and opioid versus acetaminophen; cold therapy; music therapy; abdominal binder; and transcutaneous electrical nerve stimulation), and dental pain (opioid versus NSAID, opioid versus acetaminophen, and NSAID versus acetaminophen). As in the original review, opioids and NSAIDs were more effective than acetaminophen for surgical dental pain and acute musculoskeletal pain, but opioids were less effective than acetaminophen for kidney stone pain. Opioids were associated with increased risk for short-term adverse events versus NSAIDs or acetaminophen, including any adverse event, nausea, dizziness, and somnolence. Serious adverse events were uncommon for all interventions; however, studies were not designed to assess risk for overdose, opioid use disorder, or long-term harms. Being prescribed an opioid for acute low back pain or postoperative pain was associated with increased likelihood of use of opioids at long-term follow up versus not being prescribed, on the basis of observational studies, although potential confounding could have had an impact on findings. Evidence on nonpharmacologic therapies for acute pain remained limited; however, heat therapy, spinal manipulation, massage, acupuncture, acupressure, a cervical collar, music therapy, transcutaneous electrical nerve stimulation, and exercise were effective for specific acute pain conditions. Evidence remained limited on the comparative effectiveness of therapies for sickle cell pain, acute neuropathic pain, neck pain, and management of postoperative pain after discharge; effects of therapies for acute pain on nonpain outcomes; effects of therapies on long-term outcomes, including long-term opioid use; and variations of benefits and harms of therapies among subgroups. A new finding from the updates was an association of preoperative education with decreased opioid use with similar or reduced pain intensity versus no preoperative education; this finding was based on three new trials (166–168) (no previous trials).

Treatments for Acute Episodic Migraine

To identify new evidence on treatments for acute episodic migraine that might have an impact on the conclusions or findings of the original (2020) systematic review, a series of three surveillance reports was conducted; searches for the final (third) update were conducted on March 21, 2022 (169). The addition of new evidence identified in the updates did not change the main conclusions of the original review regarding the effectiveness for improving short-term (<1 day) pain and function of established pharmacological treatments (e.g., triptans, NSAIDs, antiemetics, and ergot alkaloids) and newer treatments (e.g., gepants and ditans); pharmacological treatments were associated with mild adverse events. Evidence on opioids for acute treatment of episodic migraine remain remained low or insufficient, and evidence on nonpharmacological treatments remained low, except for remote electrical neuromodulation (strength of evidence moderate). New evidence identified for the updates supported effectiveness of the calcitonin gene-related peptide eptinezumab (one new RCT) (170) and propofol (one new RCT) (171), occipital and supraorbital nerve blocks (two new RCTs) (172,173), transcranial stimulation (one new RCT) (174), and inhaled oxygen (one new RCT) (175) in acute treatment of episodic migraine (moderate strength of evidence for eptinezumab; otherwise low strength of evidence).

A Note on Historically Used Terms

Historically, terms such as “abuse,” “drug abuse,” and “opioid abuse” have been used in research and diagnostic terminology. For example, opioid use disorder, defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) as a problematic pattern of opioid use leading to clinically significant impairment or distress (176), was previously referred to as opioid abuse or opioid dependence in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (177,178). However, more recent research indicates that use of terms such as “abuse” negatively affects perceptions and judgments about persons with drug use and substance use disorders (179–181). In the CDC Clinical Practice Guideline for Prescribing Opioids for Pain — United States, 2022, “abuse” is sometimes used to accurately reflect underlying sources or to report findings from research conducted using this terminology; however, terms such as “drug use” or “opioid use” typically are used to describe behaviors, and terms such as “substance use disorder” or “opioid use disorder” are used when discussing relevant diagnoses (176).

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