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Opioid Treatments for Chronic Pain. Comparative Effectiveness Review No. 229

Author/s: 
Chou, R, Hartung, D, Turner, J, Blazina, I, Chan, B, Levander, X, McDonagh, M, Selph, S, Fu, Pappas

Objectives. Chronic pain is common, and opioid therapy is frequently prescribed for this condition. This report updates and expands on a prior Comparative Effectiveness Review on long-term (≥1 year) effectiveness and harms of opioid therapy for chronic pain, including evidence on shorter term (1 to 12 months) outcomes.

Data sources. A prior systematic review (searches through January 2014), electronic databases (Ovid MEDLINE®, Embase®, PsycINFO®, Cochrane CENTRAL, and Cochrane Database of Systematic Reviews through August 2019), reference lists, and clinical trials registries.

Review methods. Predefined criteria were used to select studies of patients with chronic pain prescribed opioids that addressed effectiveness or harms versus placebo, no opioid use, or nonopioid pharmacological therapies; different opioid dosing methods; or risk mitigation strategies. Effects were analyzed at short-term (1 to <6 months), intermediate-term (≥6 to <12 months), and long-term (≥12 months) followup. Studies on the accuracy of risk prediction instruments for predicting opioid use disorder or misuse were also included. Random effects meta-analysis was conducted on short-term trials of opioids versus placebo, opioids versus nonopioids, and opioids plus nonopioids versus an opioid or nonopioid alone. Magnitude of effects was classified as small, moderate, or large using predefined criteria, and strength of evidence was assessed.

Results. We included 115 randomized controlled trials (RCTs), 40 observational studies, and 7 studies of predictive accuracy; 134 were new to this update. Opioids were associated with small benefits versus placebo in short-term pain, function, and sleep quality. There was a small dose-dependent effect on pain, and effects were attenuated at longer (3 to 6 month) versus shorter (1 to 3 month) followup. Opioids were associated with increased risk of discontinuation due to adverse events, gastrointestinal adverse events, somnolence, dizziness, and pruritus versus placebo. In observational studies, opioids were associated with increased risk of an opioid abuse or dependence diagnosis, overdose, all-cause mortality, fractures, falls, and myocardial infarction versus no opioid use; there was evidence of a dose-dependent risk for all outcomes except fracture and falls.

There were no differences between opioids and nonopioid medications in pain, function, or other short-term outcomes. Opioid plus nonopioid combination therapy was associated with little improvement in pain at short-term followup versus an opioid alone. Co-prescription of benzodiazepines or gabapentinoids was associated with increased risk of overdose versus an opioid alone. No RCT evaluated intermediate- or long-term benefits of opioids versus placebo. One trial found stepped therapy starting with opioids to be associated with higher pain intensity and no difference in function or other outcomes versus stepped therapy starting with nonopioid therapy.

Limited evidence indicated no differences between long- and short-acting opioids in effectiveness, but long-acting opioids were associated with increased risk of overdose. One RCT found a taper support intervention associated with greater improvement in function but no difference in pain versus usual care.

Estimates of diagnostic accuracy for various risk prediction instruments were highly inconsistent, and there was no evidence on the effectiveness of risk mitigation strategies for improving clinical outcomes, with the exception of one study that found provision of naloxone associated with decreased emergency department visits.

Trials of patients with prescription opioid dependence found buprenorphine maintenance associated with better outcomes than buprenorphine taper and similar effects of methadone versus buprenorphine. Evidence was insufficient to evaluate benefits and harms of opioid therapy in patients at higher risk for opioid use disorder.

Conclusions. At short-term followup, for patients with chronic pain, opioids are associated with small beneficial effects versus placebo but are associated with increased risk of short-term harms and do not appear to be superior to nonopioid therapy. Evidence on intermediate-term and long-term benefits remains very limited, and additional evidence confirms an association between opioids and increased risk of serious harms that appears to be dose-dependent. Research is needed to develop accurate risk prediction instruments, determine effective risk mitigation strategies, clarify risks associated with co-prescribed medications, and identify optimal opioid tapering strategies.

Keywords 
opioid therapy chronic pain comparative review opioid-use disorder methadone Buprenorphine

Craniosacral therapy for chronic pain: a systematic review and meta-analysis of randomized controlled trials

Author/s: 
Haller, H, Lauche, R, Sundberg, T, Dobos, G, Cramer, H

OBJECTIVES:

To systematically assess the evidence of Craniosacral Therapy (CST) for the treatment of chronic pain.

METHODS:

PubMed, Central, Scopus, PsycInfo and Cinahl were searched up to August 2018. Randomized controlled trials (RCTs) assessing the effects of CST in chronic pain patients were eligible. Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated for pain intensity and functional disability (primary outcomes) using Hedges' correction for small samples. Secondary outcomes included physical/mental quality of life, global improvement, and safety. Risk of bias was assessed using the Cochrane tool.

RESULTS:

Ten RCTs of 681 patients with neck and back pain, migraine, headache, fibromyalgia, epicondylitis, and pelvic girdle pain were included. CST showed greater post intervention effects on: pain intensity (SMD = -0.32, 95%CI = [- 0.61,-0.02]) and disability (SMD = -0.58, 95%CI = [- 0.92,-0.24]) compared to treatment as usual; on pain intensity (SMD = -0.63, 95%CI = [- 0.90,-0.37]) and disability (SMD = -0.54, 95%CI = [- 0.81,-0.28]) compared to manual/non-manual sham; and on pain intensity (SMD = -0.53, 95%CI = [- 0.89,-0.16]) and disability (SMD = -0.58, 95%CI = [- 0.95,-0.21]) compared to active manual treatments. At six months, CST showed greater effects on pain intensity (SMD = -0.59, 95%CI = [- 0.99,-0.19]) and disability (SMD = -0.53, 95%CI = [- 0.87,-0.19]) versus sham. Secondary outcomes were all significantly more improved in CST patients than in other groups, except for six-month mental quality of life versus sham. Sensitivity analyses revealed robust effects of CST against most risk of bias domains. Five of the 10 RCTs reported safety data. No serious adverse events occurred. Minor adverse events were equally distributed between the groups.

DISCUSSION:

In patients with chronic pain, this meta-analysis suggests significant and robust effects of CST on pain and function lasting up to six months. More RCTs strictly following CONSORT are needed to further corroborate the effects and safety of CST on chronic pain.

Keywords 
chronic pain Complementary Therapies Craniosacral therapy meta-analysis systematic review

Exercise interventions and patient beliefs for people with hip, knee or hip and knee osteoarthritis: a mixed methods review

Author/s: 
Hurley, Michael, Dickson, Kelly, Hallett, Rachel, Grant, Robert, Hauari, Hanan, Walsh, Nicola, Stansfield, Claire, Oliver, Sandy

BACKGROUND:

Chronic peripheral joint pain due to osteoarthritis (OA) is extremely prevalent and a major cause of physical dysfunction and psychosocial distress. Exercise is recommended to reduce joint pain and improve physical function, but the effect of exercise on psychosocial function (health beliefs, depression, anxiety and quality of life) in this population is unknown.

OBJECTIVES:

To improve our understanding of the complex inter-relationship between pain, psychosocial effects, physical function and exercise.

SEARCH METHODS:

Review authors searched 23 clinical, public health, psychology and social care databases and 25 other relevant resources including trials registers up to March 2016. We checked reference lists of included studies for relevant studies. We contacted key experts about unpublished studies.

SELECTION CRITERIA:

To be included in the quantitative synthesis, studies had to be randomised controlled trials of land- or water-based exercise programmes compared with a control group consisting of no treatment or non-exercise intervention (such as medication, patient education) that measured either pain or function and at least one psychosocial outcome (self-efficacy, depression, anxiety, quality of life). Participants had to be aged 45 years or older, with a clinical diagnosis of OA (as defined by the study) or self-reported chronic hip or knee (or both) pain (defined as more than six months' duration).To be included in the qualitative synthesis, studies had to have reported people's opinions and experiences of exercise-based programmes (e.g. their views, understanding, experiences and beliefs about the utility of exercise in the management of chronic pain/OA).

DATA COLLECTION AND ANALYSIS:

We used standard methodology recommended by Cochrane for the quantitative analysis. For the qualitative analysis, we extracted verbatim quotes from study participants and synthesised studies of patients' views using framework synthesis. We then conducted an integrative review, synthesising the quantitative and qualitative data together.

MAIN RESULTS:

Twenty-one trials (2372 participants) met the inclusion criteria for quantitative synthesis. There were large variations in the exercise programme's content, mode of delivery, frequency and duration, participant's symptoms, duration of symptoms, outcomes measured, methodological quality and reporting. Comparator groups were varied and included normal care; education; and attention controls such as home visits, sham gel and wait list controls. Risk of bias was high in one and unclear risk in five studies regarding the randomisation process, high for 11 studies regarding allocation concealment, high for all 21 studies regarding blinding, and high for three studies and unclear for five studies regarding attrition. Studies did not provide information on adverse effects.There was moderate quality evidence that exercise reduced pain by an absolute percent reduction of 6% (95% confidence interval (CI) -9% to -4%, (9 studies, 1058 participants), equivalent to reducing (improving) pain by 1.25 points from 6.5 to 5.3 on a 0 to 20 scale and moderate quality evidence that exercise improved physical function by an absolute percent of 5.6% (95% CI -7.6% to 2.0%; standardised mean difference (SMD) -0.27, 95% CI -0.37 to -0.17, equivalent to reducing (improving) WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) function on a 0 to 100 scale from 49.9 to 44.3) (13 studies, 1599 participants)). Self-efficacy was increased by an absolute percent of 1.66% (95% CI 1.08% to 2.20%), although evidence was low quality (SMD 0.46, 95% CI 0.34 to 0.58, equivalent to improving the ExBeliefs score on a 17 to 85 scale from 64.3 to 65.4), with small benefits for depression from moderate quality evidence indicating an absolute percent reduction of 2.4% (95% CI -0.47% to 0.5%) (SMD -0.16, 95% CI -0.29 to -0.02, equivalent to improving depression measured using HADS (Hospital Anxiety and Depression Scale) on a 0 to 21 scale from 3.5 to 3.0) but no clinically or statistically significant effect on anxiety (SMD -0.11, 95% CI -0.26 to 0.05, 2% absolute improvement, 95% CI -5% to 1% equivalent to improving HADS anxiety on a 0 to 21 scale from 5.8 to 5.4; moderate quality evidence). Five studies measured the effect of exercise on health-related quality of life using the 36-item Short Form (SF-36) with statistically significant benefits for social function, increasing it by an absolute percent of 7.9% (95% CI 4.1% to 11.6%), equivalent to increasing SF-36 social function on a 0 to 100 scale from 73.6 to 81.5, although the evidence was low quality. Evidence was downgraded due to heterogeneity of measures, limitations with blinding and lack of detail regarding interventions. For 20/21 studies, there was a high risk of bias with blinding as participants self-reported and were not blinded to their participation in an exercise intervention.Twelve studies (with 6 to 29 participants) met inclusion criteria for qualitative synthesis. Their methodological rigour and quality was generally good. From the patients' perspectives, ways to improve the delivery of exercise interventions included: provide better information and advice about the safety and value of exercise; provide exercise tailored to individual's preferences, abilities and needs; challenge inappropriate health beliefs and provide better support.An integrative review, which compared the findings from quantitative trials with low risk of bias and the implications derived from the high-quality studies in the qualitative synthesis, confirmed the importance of these implications.

AUTHORS' CONCLUSIONS:

Chronic hip and knee pain affects all domains of people's lives. People's beliefs about chronic pain shape their attitudes and behaviours about how to manage their pain. People are confused about the cause of their pain, and bewildered by its variability and randomness. Without adequate information and advice from healthcare professionals, people do not know what they should and should not do, and, as a consequence, avoid activity for fear of causing harm. Participation in exercise programmes may slightly improve physical function, depression and pain. It may slightly improve self-efficacy and social function, although there is probably little or no difference in anxiety. Providing reassurance and clear advice about the value of exercise in controlling symptoms, and opportunities to participate in exercise programmes that people regard as enjoyable and relevant, may encourage greater exercise participation, which brings a range of health benefits to a large population of people.

Keywords 
exercise therapy chronic pain osteoarthritis

Effect of Opioid vs Nonopioid Medications on Pain-Related Function in Patients With Chronic Back Pain or Hip or Knee Osteoarthritis Pain The SPACE Randomized Clinical Trial

Author/s: 
Krebs, Erin E., Gravely, Amy, Nugent, Sean, Jensen, Agnes C., DeRonne, Beth, Goldsmith, Elizabeth S., Kroenke, Kurt, Bair, Matthew J, Noorbaloochi, Siamak

Importance  Limited evidence is available regarding long-term outcomes of opioids compared with nonopioid medications for chronic pain.

Objective  To compare opioid vs nonopioid medications over 12 months on pain-related function, pain intensity, and adverse effects.

Design, Setting, and Participants  Pragmatic, 12-month, randomized trial with masked outcome assessment. Patients were recruited from Veterans Affairs primary care clinics from June 2013 through December 2015; follow-up was completed December 2016. Eligible patients had moderate to severe chronic back pain or hip or knee osteoarthritis pain despite analgesic use. Of 265 patients enrolled, 25 withdrew prior to randomization and 240 were randomized.

Interventions  Both interventions (opioid and nonopioid medication therapy) followed a treat-to-target strategy aiming for improved pain and function. Each intervention had its own prescribing strategy that included multiple medication options in 3 steps. In the opioid group, the first step was immediate-release morphine, oxycodone, or hydrocodone/acetaminophen. For the nonopioid group, the first step was acetaminophen (paracetamol) or a nonsteroidal anti-inflammatory drug. Medications were changed, added, or adjusted within the assigned treatment group according to individual patient response.

Main Outcomes and Measures  The primary outcome was pain-related function (Brief Pain Inventory [BPI] interference scale) over 12 months and the main secondary outcome was pain intensity (BPI severity scale). For both BPI scales (range, 0-10; higher scores = worse function or pain intensity), a 1-point improvement was clinically important. The primary adverse outcome was medication-related symptoms (patient-reported checklist; range, 0-19).

Results  Among 240 randomized patients (mean age, 58.3 years; women, 32 [13.0%]), 234 (97.5%) completed the trial. Groups did not significantly differ on pain-related function over 12 months (overall P = .58); mean 12-month BPI interference was 3.4 for the opioid group and 3.3 for the nonopioid group (difference, 0.1 [95% CI, −0.5 to 0.7]). Pain intensity was significantly better in the nonopioid group over 12 months (overall P = .03); mean 12-month BPI severity was 4.0 for the opioid group and 3.5 for the nonopioid group (difference, 0.5 [95% CI, 0.0 to 1.0]). Adverse medication-related symptoms were significantly more common in the opioid group over 12 months (overall P = .03); mean medication-related symptoms at 12 months were 1.8 in the opioid group and 0.9 in the nonopioid group (difference, 0.9 [95% CI, 0.3 to 1.5]).

Conclusions and Relevance  Treatment with opioids was not superior to treatment with nonopioid medications for improving pain-related function over 12 months. Results do not support initiation of opioid therapy for moderate to severe chronic back pain or hip or knee osteoarthritis pain.

Trial Registration  clinicaltrials.gov Identifier: NCT01583985

Keywords 
chronic pain back pain osteoarthritis opioids elderly Elderly care elderly patients older adults RISEOK

Six Building Blocks: A Team-Based Approach to Improving Opioid Management in Primary Care

Most patients taking opioids for chronic pain are managed by primary care providers and their staff. Many practices are looking for help in managing their patients using chronic opioid therapy. To meet this need, AHRQ funded the Six Building Blocks project  through grant number R18HS0237850. Additional funding was provided by Washington State Department of Health subcontract (HED23124) of Cooperative U17CE002734, funded by the Centers for Disease Control and Prevention.

Keywords 
opioids chronic pain primary health care patient care

Noninvasive Nonpharmacological Treatment for Chronic Pain: Evidence Summary

Author/s: 
Skelly, Andrea C., Chou, Roger, Dettori, Joseph R., Turner, Judith A., Friedly, Janna L., Rundell, Sean D., Fu, Rongwei, Brodt, Erika D., Wasson, Ngoc, Winter, Cassandra, Ferguson, Aaron J. R.

Purpose of Review

To assess which noninvasive nonpharmacological treatments for common chronic pain conditions improve function and pain for at least 1 month after treatment.

Key Messages

• Interventions that improved function and/ or pain for at least 1 month when used for—

– Chronic low back pain: Exercise, psychological therapies (primarily cognitive behavioral therapy [CBT]), spinal manipulation, low-level laser therapy, massage, mindfulness-based stress reduction, yoga, acupuncture, multidisciplinary rehabilitation (MDR).

– Chronic neck pain: Exercise, lowlevel laser, Alexander Technique, acupuncture.

– Knee osteoarthritis: Exercise, ultrasound.

– Hip osteoarthritis: Exercise, manual therapies.

– Fibromyalgia: Exercise, CBT, myofascial release massage, tai chi, qigong, acupuncture, MDR.

– Chronic tension headache: Spinal manipulation.

• Most effects were small. Long-term evidence was sparse.

• There was no evidence suggesting serious harms from any of the interventions studied; data on harms were limited.

Keywords 
chronic pain

Confronting Pain Management and the Opioid Epidemic: Balancing Societal and Individual Benefits and Risks of Prescription Opioid Use

Author/s: 
Ford, Morgan A., Phillips, Jonathan K., Bonnie, Richard J.

The ongoing opioid crisis lies at the intersection of two substantial public health challenges—reducing the burden of suffering from pain and containing the rising toll of the harms that can result from the use of opioid medications. In March 2016, the U.S. Food and Drug Administration (FDA) asked the National Academies of Sciences, Engineering, and Medicine (the National Academies) to convene an ad hoc committee to

• update the state of the science on pain research, care, and education since publication of the 2011 Institute of Medicine (IOM) report Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research, including the evolving role of opioids in pain management;

• characterize the epidemiology of the opioid epidemic and the evidence on strategies for addressing it;

• identify actions the FDA and other organizations can take to respond to the epidemic, with a particular focus on the FDA’s development of a formal method for incorporating individual and societal considerations into its risk-benefit framework for opioid approval and monitoring; and

• identify research questions that need to be addressed to assist the FDA in implementing this framework.

Keywords 
opioids pain management chronic pain public health

Noninvasive Nonpharmacological Treatment for Chronic Pain: A Systematic Review

Author/s: 
Skelly, Andrea C., Chou, Roger, Dettori, Joseph R., Turner, Judith A., Friedly, Janna L., Rundell, Sean D., Fu, Rongwei, Brodt, Erika D., Wasson, Ngoc, Winter, Cassandra, Ferguson, Aaron J. R.

Objectives. Many interventions are available to manage chronic pain; understanding the durability of treatment effects may assist with treatment selection. We sought to assess which noninvasive nonpharmacological treatments for selected chronic pain conditions are associated with persistent improvement in function and pain outcomes at least 1 month after the completion of treatment.

Data sources. Electronic databases (Ovid MEDLINE®, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews) through November 2017, reference lists, and ClinicalTrials.gov.

Review methods. Using predefined criteria, we selected randomized controlled trials of noninvasive nonpharmacological treatments for five common chronic pain conditions (chronic low back pain; chronic neck pain; osteoarthritis of the knee, hip, or hand; fibromyalgia; and tension headache) that addressed efficacy or harms compared with usual care, no treatment, waitlist, placebo, or sham intervention; compared with pharmacological therapy; or compared with exercise. Study quality was assessed, data extracted, and results summarized for function and pain. Only trials reporting results for at least 1 month post-intervention were included. We focused on the persistence of effects at short term (1 to <6 months following treatment completion), intermediate term (≥6 to <12 months), and long term (≥12 months).

Results. Two hundred eighteen publications (202 trials) were included. Many included trials were small. Evidence on outcomes beyond 1 year after treatment completion was sparse. Most trials enrolled patients with moderate baseline pain intensity (e.g., >5 on a 0 to 10 point numeric rating scale) and duration of symptoms ranging from 3 months to >15 years. The most common comparison was against usual care.

Chronic low back pain: At short term, massage, yoga, and psychological therapies (primarily CBT) (strength of evidence [SOE]: moderate) and exercise, acupuncture, spinal manipulation, and multidisciplinary rehabilitation (SOE: low) were associated with slight improvements in function compared with usual care or inactive controls. Except for spinal manipulation, these interventions also improved pain.

Effects on intermediate-term function were sustained for yoga, spinal manipulation, multidisciplinary rehabilitation (SOE: low), and psychological therapies (SOE: moderate). Improvements in pain continued into intermediate term for exercise, massage, and yoga (moderate effect, SOE: low); mindfulness-based stress reduction (small effect, SOE: low); spinal manipulation, psychological therapies, and multidisciplinary rehabilitation (small effects, SOE: moderate). For acupuncture, there was no difference in pain at intermediate term, but a slight improvement at long term (SOE: low). Psychological therapies were associated with slightly greater improvement than usual care or an attention control on both function and pain at short-term, intermediate-term, and long-term followup (SOE: moderate). At short and intermediate term, multidisciplinary rehabilitation slightly improved pain compared with exercise (SOE: moderate). High-intensity multidisciplinary rehabilitation (≥20 hours/week or >80 hours total) was not clearly better than non–high-intensity programs.

Chronic neck pain: At short and intermediate terms, acupuncture and Alexander Technique were associated with slightly improved function compared with usual care (both interventions), sham acupuncture, or sham laser (SOE: low), but no improvement in pain was seen at any time (SOE: llow). Short-term low-level laser therapy was associated with moderate improvement in function and pain (SOE: moderate). Combination exercise (any 3 of the following: muscle performance, mobility, muscle re-education, aerobic) demonstrated a slight improvement in pain and function short and long term (SOE: low).

Osteoarthritis: For knee osteoarthritis, exercise and ultrasound demonstrated small short-term improvements in function compared with usual care, an attention control, or sham procedure (SOE: moderate for exercise, low for ultrasound), which persisted into the intermediate term only for exercise (SOE: low). Exercise was also associated with moderate improvement in pain (SOE: low). Long term, the small improvement in function seen with exercise persisted, but there was no clear effect on pain (SOE: low). Evidence was sparse on interventions for hip and hand osteoarthritis. Exercise for hip osteoarthritis was associated with slightly greater function and pain improvement than usual care short term (SOE: low). The effect on function was sustained intermediate term (SOE: low).

Fibromyalgia: In the short term, acupuncture (SOE: moderate), CBT, tai chi, qigong, and exercise (SOE: low) were associated with slight improvements in function compared with an attention control, sham, no treatment, or usual care. Exercise (SOE: moderate) and CBT improved pain slightly, and tai chi and qigong (SOE: low) improved pain moderately in the short term. At intermediate term for exercise (SOE: moderate), acupuncture, and CBT (SOE: low), slight functional improvements persisted; they were also seen for myofascial release massage and multidisciplinary rehabilitation (SOE: low); pain was improved slightly with multidisciplinary rehabilitation in the intermediate term (SOE: low). In the long term, small improvements in function continued for multidisciplinary rehabilitation but not for exercise or massage (SOE: low for all); massage (SOE: low) improved long-term pain slightly, but no clear impact on pain for exercise (SOE: moderate) or multidisciplinary rehabilitation (SOE: low) was seen. Short-term CBT was associated with a slight improvement in function but not pain compared with pregabalin.

Chronic tension headache: Evidence was sparse and the majority of trials were of poor quality. Spinal manipulation slightly improved function and moderately improved pain short term versus usual care, and laser acupuncture was associated with slight pain improvement short term compared with sham (SOE: low).

There was no evidence suggesting increased risk for serious treatment-related harms for any of the interventions, although data on harms were limited.

Conclusions. Exercise, multidisciplinary rehabilitation, acupuncture, CBT, and mind-body practices were most consistently associated with durable slight to moderate improvements in function and pain for specific chronic pain conditions. Our findings provided some support for clinical strategies that focused on use of nonpharmacological therapies for specific chronic pain conditions. Additional comparative research on sustainability of effects beyond the immediate post-treatment period is needed, particularly for conditions other than low back pain.

Keywords 
chronic pain nonpharmacological treatment noninvasive treatment
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