Table 1Inclusion and exclusion criteria



All KQs

General Inclusion Criteria
  • Adults with the following chronic pain (defined as pain lasting 12 weeks or longer or pain persisting past the time for normal tissue healing) conditions: low back pain, neck pain, osteoarthritis pain, fibromyalgia, or tension headache.
  • Pregnant or breastfeeding women who have a history of chronic pain prior to pregnancy
General Exclusion Criteria
  • Acute pain
  • Children (<18 years), pregnant or breastfeeding women with pregnancy-related back or pelvic pain or who do not have chronic pain prior to pregnancy;
  • Patients with chronic pain related to “active” cancer, infection, inflammatory arthropathy,
  • <90% of study sample has the defined condition of interest or <90% received the treatment(s) of interest
  • Treatment for addiction
  • Pain at the end of life
  • Neuropathic pain



KQ1: Low back pain
  • Adults with chronic, nonradicular low back pain
KQ1: Low back pain
  • Patients with radiculopathy
  • Low back pain associated with severe or progressive neurological deficits
  • Failed back surgery syndrome



KQ2: Neck pain
  • Adults with chronic neck pain
KQ2: Neck pain
  • Patients with radiculopathy or myelopathy
  • Traumatic spinal cord injury
  • Neck pain associated with progressive neurological deficit, loss of strength



KQ3: Osteoarthritis
  • Adults with osteoarthritis-related pain (primary or secondary osteoarthritis) of the hip, knee or hand
KQ3: Osteoarthritis
  • Other types of arthritis (e.g., rheumatoid)
  • Patients with joint replacement



KQ4: Fibromyalgia
  • Adults with fibromyalgia
KQ4: Fibromyalgia
  • Conditions with generalized pain not consistent with fibromyalgia
  • Systemic exertion intolerance disease, (myalgic encephalomyelitis/chronic fatigue syndrome)
  • Somatization disorder (Briquet’s syndrome)



KQ5: Headache
  • Adults with primary chronic tension headache (International Classification of Headache Disorders, 3rd edition definition).
    • Primary headaches are attributed to the headache condition itself, not headache caused by another disease or medical condition. Tension headaches are the most common.
Chronic headache is defined as 15 or more days each month for at least 12 weeks or history of headache more than 180 days a year.
KQ5: Headache
  • Migraine headache
  • Mixed headache (also known as coexistent tension and migraine headache, chronic daily headache, transformed migraine)
  • Trigeminal neuralgia
  • Cluster headache
  • Secondary headache types as defined in The International Classification of Headache Disorders, 3rd edition (i.e., headaches due to an underlying pathology such as cancer, prior medical procedures, temporomandibular joint disorders, neck pathology, cervicogenic headache, and medication over-use headache)
  • Traumatic brain injury
InterventionsAll KQs:
  • Exercise (exercise as part of physical therapy, supervised exercise, home exercise, group exercise, formal exercise program)
  • Psychological therapies (cognitive and/or behavioral therapy, biofeedback, relaxation training)
  • Physical modalities (traction, ultrasound, transcutaneous electrical nerve stimulation, low-level laser therapy, interferential therapy, electro-muscular stimulation diathermy, superficial heat or cold, bracing for knee, back, neck, hand and magnets)
  • Manual therapies (musculoskeletal manipulation, massage)
  • Mindfulness practices (meditation, mindfulness-based stress reduction practices)
  • Mind-body practices (yoga, tai chi, qigong)
  • Acupuncture
  • Multidisciplinary/interdisciplinary rehabilitation
All KQs:
  • Invasive nonsurgical treatments (e.g., injections, nerve block, spinal cord stimulators, parenterally-administered medications)
  • Surgical interventions (including minimally invasive surgical interventions)
  • Diet interventions or dietary supplementation
  • Studies evaluating incremental value of adding a noninvasive nonpharmacological intervention to another noninvasive nonpharmacological intervention
  • Self-management interventions or programs, self-management education programs
  • Others not listed for inclusion
ComparatorsAll KQs, subquestion a
  • Sham treatment
  • Waitlist
  • Usual care
  • No treatment
  • Attention control intended to control for nonspecific effects (e.g., time, attention, expectations);
All KQs subquestion b
  • Commonly used nonopioid pharmacological therapy used to treat chronic pain [NSAIDS, acetaminophen, anti-seizure medications, antidepressants (SNRIs, TCAs), muscle relaxants (including benzodiazepines)]
  • Topical agents (lidocaine, diclofenac, capsaicin)
  • Medical cannabis (inhaled, oral, topical); phytocannabinoids (plant derived, THC and CBD); FDA approved synthetic cannabinoids [Dronabionol (THC), Nabilone (similar to THC)]
  • Opioid analgesics
KQs 1-4, 6 subquestion c
  • Exercise
KQ 5, 6 subquestion c
  • Biofeedback
All KQs:
  • Supplements (e.g., glucosamine, chondroitin, d-ribose, herbal or homeopathic treatments)Invasive nonsurgical treatments (e.g., injections, nerve block, spinal cord stimulators, parenterally-administered medications)
  • Antidepressants not typically used for chronic pain including SSRIs and MAOIs
  • Anti-seizure medications not typically used to treat chronic pain including topiramate, lamotrigine, levetiracetam, phenytoin, valproic acid, zonisamide, tiagabine
  • Surgical interventions (including minimally invasive surgical interventions)
  • Studies evaluating incremental value of adding a noninvasive nonpharmacological intervention to another noninvasive nonpharmacological intervention
  • Comparisons within nonpharmacological intervention types (e.g., comparisons of different types of exercise with each other, different types of massage with each other)
  • Corticosteroids, biologic drugs
  • Salicylates (oral and topical)
  • Topical menthol preparations
  • Others not listed for inclusion

All KQs:

Primary efficacy outcomes; we will focus on outcomes from validated measures for

  • Function/disability/pain interference
  • Pain
Harms and Adverse effects

Secondary outcomes

  • Psychological distress (including measures of depression and anxiety)
  • Quality of life
  • Opioid use
  • Sleep quality, sleep disturbance
  • Healthcare utilization

All KQs:
  • Intermediate outcomes (e.g., biomarkers for inflammation)
  • Other nonclinical outcomes

Duration of followup: short term (1 to <6 months), intermediate term (≥6 to <12 months) and long term (≥12 months); focus on longer term (>12 month) effects.

Trials lasting ≥6 months that include a supervised intervention followed by continued home treatment as part of the intervention will be included even though the only followup occurs directly after the intervention.

  • Studies with <1 month followup after treatment
StudiesRandomized controlled trials or high quality systematic reviews of randomized controlled trials published in English; cross-over trials with random assignment of initial treatment will be considered.All KQs:
  • Studies reporting on intermediate outcomes only
  • Nonrandomized studies
  • Abstracts, editorials, letters, conference proceedings
  • Duplicate publications of the same study that do not report on different outcomes
  • Single site reports from multicenter trials
  • White papers
  • Narrative reviews
  • Articles identified as preliminary reports when results are published in later versions
  • Indirect comparisons
  • Studies with fewer than 15 patients per treatment arm
  • Systematic reviews on treatment of chronic neck pain, fibromyalgia, chronic headache, or osteoarthritis that are of low methodological quality. Those that do not report outcomes or time frames of interest may be excluded. Systematic reviews may be excluded based on currency or relevance (e.g., if there is a substantial new body of evidence reflected in a later review).
SettingsAny nonhospital setting or in self-directed care
  • Hospital care, hospice care, emergency department care

CBD = cannabidiol; FDA = Food and Drug Administration; KQ = Key Question; MAOI = monoamine oxidase inhibitor; = nonsteroidal anti-inflammatory drug; = populations, interventions, comparators, outcomes, timing, settings, study designs; SNRI = serotonin and norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; THC = tetrahydrocannabinol.


Multidisciplinary rehabilitation (MDR) (also known as interdisciplinary rehabilitation), is defined as a coordinated program with biopsychosocial treatment components (e.g., exercise therapy and cognitive-behavioral therapy) provided by professionals from at least two different specialties. Functional restoration training is included as part of MDR.


Different forms of exercise will not be compared to each other. Exercise will be compared with nonexercise interventions for low back pain, neck pain, fibromyalgia and osteoarthritis


Different forms of biofeedback will not be compared to each other. Biofeedback will be compared with the noninvasive interventions for chronic headache


The magnitude of effects for pain and function will be classified using the same system as in the AHRQ-funded noninvasive treatment for low back pain review recognizing that small effects using this system may not meet standard thresholds for clinically meaningful effects. A small effect was defined for pain as a mean between-group difference following treatment of 5 to 10 points on a 0- to 100-point visual analog scale (), 0.5 to 1.0 points on a 0- to 10-point numeric rating scale, or equivalent; for function as a mean difference of 5- to 10-point difference on the 0- to 100-point Oswestry Disability Index () or 1 to 2 points on the 0- to 24-point Roland-Morris Disability Questionnaire (), or equivalent; and for any outcome as a standardized mean difference () of 0.2 to 0.5. A moderate effect was defined for pain as a mean difference of 10 to 20 points on a 0- to 100-point VAS, for function as a mean difference of 10 to 20 points on the ODI or 2 to 5 points on the RDQ, and for any outcome as an SMD of 0.5 to 0.8. Large/substantial effects were defined as greater than moderate. We will apply similar methodology to outcomes measures for the other condition. The clinical relevance of effects classified as small might vary for individual patients depending on preferences, baseline symptom severity, harms, cost, and other factors

From: Methods

Cover of Noninvasive Nonpharmacological Treatment for Chronic Pain: A Systematic Review Update
Noninvasive Nonpharmacological Treatment for Chronic Pain: A Systematic Review Update [Internet].
Comparative Effectiveness Review, No. 227.
Skelly AC, Chou R, Dettori JR, et al.

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