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Systematic scoping review of interactions between analgesic drug therapy and mindfulness-based interventions for chronic pain in adults: current evidence and future directions

Park, Rexa; Mohiuddin, Mohammeda; Poulin, Patricia A.b,c,d; Salomons, Time,f; Edwards, Robertg; Nathan, Howardd; Haley, Chrisa; Gilron, Iana,h,f,i,*

Author Information
doi: 10.1097/PR9.0000000000000868

1. Introduction

Chronic pain is a multidimensional health condition generally described as pain that persists for over 3 months.77 Chronic pain is estimated to affect 1.5 billion individuals worldwide and cost the United States up to $635 billion per year when direct healthcare and productivity costs are considered.9,13,17,33,53 Chronic pain is also one of the leading causes of human suffering and disability in the world and has major negative impacts on work-related outcomes.3,76

Pain is rarely managed effectively with pharmacological agents because of limited efficacy and dose-limiting adverse effects, leaving a significant unmet need for sufferers.36,54 However, despite the limited evidence supporting the effectiveness and safety of opioids for chronic pain, they have been the mainstay of treatment for chronic pain in the United States for the past 2 decades. The common practice of prescribing opioids for chronic pain has been associated with increases in opioid misuse and opioid-related mortality.1,36

Mindfulness-based interventions (MBIs) for the management of chronic pain have received considerable attention in the past 3 decades because of emerging evidence regarding their efficacy and safety.43,55,68,88 Mindfulness-based interventions for chronic health problems involve multiple components, which can include systematic meditation training, patient education, yoga exercises, and group dialogue.55 Mindfulness, the core component of MBIs, involves learning to purposefully and nonjudgmentally observe one's own thoughts, feelings, and sensations in the present moment without attempting to change them.47

A substantial body of evidence supports the possible benefits of MBIs for patients with chronic pain, such as its positive effects on distress, functioning, and quality of life.43,55,68 A recent systematic review with 38 randomized controlled trials (RCTs) demonstrated that mindfulness interventions resulted in significant improvements in chronic pain, depression, and quality of life, which are consistent to the findings of previous reviews in this area.43 However, the weakness in the body of evidence precluded any strong conclusions. Although mindfulness may reduce pain intensity directly, the primary goal of mindfulness is to improve functioning and quality of life and minimize distress.68 Mindfulness-based interventions for chronic pain are guided by the principle that the practice of mindfulness results in an attenuation of coupling between the sensory component of pain and the cognitive and emotional components of pain.47 Aligned with this principle, recent research demonstrates neural mechanisms that support mindfulness-based pain reduction, with mindfulness affecting areas of the brain related to attention, introspection, and emotional processing.40,87 The cognitive and emotional components can amplify pain, contribute to the development of depression and anxiety, and contribute to the avoidance of activity, thereby exacerbating disability.8 Diminishing the cognitive and emotional reactions to chronic pain through mindfulness is believed to reduce emotional distress and thus reduce suffering and disability.8

The experience of pain is influenced by biology, beliefs, culture, mood, anxiety, and the environment. As a result, a biopsychosocial approach that addresses the multiple dimensions of chronic pain is considered the “gold standard.” It is now common for chronic pain to be managed through the integration of various treatment modalities in an individualized patient-specific fashion.34,48,51,57 However, the body of evidence to support the rational use of specific treatment combinations is quite limited.36 The combined use of MBIs and analgesic drugs could provide added benefit, but there have been no reports of interaction effects of the combination of MBIs with any specific analgesic drugs. Thus, we performed a systematic scoping review to evaluate mindfulness-based trials for chronic pain to determine which concurrent drug therapies were used during each trial and look at the evidence for the efficacy and safety of combining MBIs with analgesic drugs compared with monotherapy.

2. Objectives

The objectives of this review are to examine clinical trials of MBIs for chronic pain with respect to concomitant drug therapy, evaluate the available evidence on the interactions between MBIs and various drug treatments, and assess harms of MBIs.

3. Methods

The review protocol has been previously published,63 registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=150576) and prepared in accordance with recommendations specified in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.58

3.1. Sources of evidence

We searched MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, and PsycINFO from their inception until July 2019. The search strategy included terms only related to the health condition (chronic pain) and intervention (mindfulness) to ensure a sensitive search strategy. The search excluded studies that were not published in English. The search strategies for MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, and PsycINFO are provided in Supplemental Appendix 1 (available at http://links.lww.com/PR9/A87).

We also reviewed the bibliographies of the RCTs included in our review, as well as searched clinical trial databases (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform, to identify additional published or unpublished data.

3.2. Types of studies

We included RCTs that evaluated the efficacy of MBIs in the treatment of chronic pain. Studies with less than 10 participants were excluded to minimize small study bias.

3.3. Types of participants

Studies of adults (older than 18 years) reporting any type of chronic pain for at least 3 months were included in the review. Chronic pain could include persistent (eg, fibromyalgia) and recurrent (eg, migraine) pain.

3.4. Types of interventions

We focused on MBIs administered for the treatment of chronic pain. To provide a discrete set of results and to summarize the current state of the mindfulness trials with respect to concomitant drug therapy, we focused on “mindfulness,” “mindfulness-based stress reduction,” “mindfulness-oriented recovery enhancement,” “mindfulness-based cognitive therapy,” “mindfulness meditation,” “mindfulness awareness in body-oriented therapy,” or any intervention that is a modification of these mindfulness-based therapies. We excluded studies in which mindfulness is only a component of the intervention (eg, physical-cognitive-mindfulness-training). Studies using any type of concomitant analgesic drug therapies (CADTs) for the treatment of chronic pain were eligible for inclusion in this review.

3.5. Comparators

We included studies that compared MBIs with usual care, wait-list control, or an active comparator.

3.6. Primary outcomes

Our primary outcomes were the following: (1) what CADTs the trial participants were receiving, (2) if and how trials controlled for what CADTs the participants were receiving, and (3) if trials analyzed the interaction between the MBI and the CADTs the trial participants were receiving. For the trials that analyzed the interaction between mindfulness and drug therapy, we planned to look at what the results were in terms of pain intensity and pain relief (eg, MBI plus concomitant drug therapy compared with only concomitant drug therapy in the control group in reducing pain intensity).

3.7. Secondary outcomes

Secondary outcomes included how MBIs plus concomitant drug treatment differed from only drug therapy in the control group in managing secondary features of chronic pain including depression, physical and mental health-related quality of life, and functional disability. Secondary outcomes also included participants reporting any or serious adverse events.

3.8. Data collection and analysis

Two authors (R.P. and M.M.) independently evaluated citation titles and abstracts for inclusion using Covidence software (www.covidence.org). Both authors were required to be in agreement for inclusion. We excluded studies that clearly did not satisfy our inclusion criteria, and full-text screening was performed on the remaining studies. Disagreements between the authors were resolved by discussion and consensus and, if necessary, resolution by a third author (I.G.). A Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart of this process is provided (Fig. 1).

Figure 1.
Figure 1.:
Study flow diagram. RCT, randomized controlled trial.

3.9. Data extraction and management

Two review authors (R.P. and M.M.) extracted data for primary and secondary outcomes independently. Disagreements between the reviewers were resolved by discussion and consensus. Other data, such as study characteristics, were extracted by one author (R.P.). Data extracted from each citation included information about the study design, trial duration, follow-up time, pain condition studied, participant inclusion and exclusion criteria, number of participants included, number of dropouts, details of the MBI, if and how adherence to the intervention was measured, primary and secondary outcome measures, and other study results.

3.10. Assessment of risk of bias in included studies

For each study included in the review, risk of bias was assessed using criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. We assessed the following for each study:

  1. (1) Random sequence generation for possible selection bias: The method used to generate the allocation sequence was scored at a high risk of bias if they used a nonrandom process (eg, odd or even date of birth), unclear risk of bias if the method used was not clearly stated, or low risk of bias if they used a truly random process (eg, computer random number generator).
  2. (2) Allocation concealment for possible selection bias: The method used to conceal allocation to interventions before assignments was scored at a high risk of bias if they did not conceal allocation (eg, open list), unclear risk of bias if the method was not clearly stated, and low risk of bias if they used methods where allocation could not have been foreseen (eg, consecutively numbered sealed opaque envelopes).
  3. Blinding of participants and personnel for possible performance bias: The method used to blind study personnel and participants was scored at a high risk of bias if the personnel and participants were not blinded or the study did not mention they were blinded, unclear if the study stated they were blinded but did not provide an adequate description of how it was achieved, and low risk of bias if the study described the method used to achieve blinding (eg, identical study drugs).
  4. Blinding of outcome assessment for possible detection bias: The method used to blind study outcome assessors from knowledge of which intervention a participant received was scored at a high risk of bias if the study was not blinded, unclear risk of bias if it was unclear how blinding was achieved, and low risk of bias if the study clearly stated the assessors were unaware of treatment allocation (and ideally described how this was performed).
  5. Incomplete outcome data for possible attrition bias: The method used for handling incomplete data was scored as a high risk of bias if they used a completer analysis or had a high dropout rate (>25%), unclear risk of bias if they used last-observation-carried-forward analysis or had a >10% dropout rate (but <25% dropout rate), and low risk of bias if they used baseline observation carried forward analysis, used multiple imputations, or had a <10% dropout rate.
  6. Selective reporting for possible reporting bias: We scored the risk of reporting bias as a high risk of bias if the prespecified outcomes of interest were not reported, unclear risk of bias if there was any anomaly in reporting (eg, some outcomes not participant-reported), and low risk of bias if it was clear that all prespecified and expected outcomes of interest were reported.
  7. The size of the study for possible biases confounded by the small sample size: The size of the study category was scored at a high risk of bias if the study had less than 50 participants per treatment arm, unclear risk of bias if the study had 50 to 200 participants per treatment arm, and low risk of bias if the study had greater than 200 participants per treatment arm.

3.11. Analysis of outcomes

A descriptive approach was used to report the primary outcomes because the outcomes were expected to likely be varied across studies. We planned to use a descriptive approach to evaluate how combination treatments differ from monotherapy in managing secondary features of chronic pain such as depression, physical and mental health-related quality of life, and functional disability. We planned to evaluate the interactions between MBIs and drug therapy to the degree that each trial accounted for the drug effects. However, the interactions between MBIs and drug therapy were not analyzed in any of the included studies.

3.12. Dealing with missing data

No pooled analysis was planned for this review. Missing data regarding concomitant drug therapy were used to aid in describing the landscape of trials investigating MBIs for chronic pain patients with respect to drug therapy.

4. Results

4.1. Search results

The initial literature search identified 848 records with 1 additional citation identified through hand searching of other literature and clinical trial databases (Fig. 1). After excluding duplicates, there were 484 records. After initial screening of titles and abstracts, we identified 57 relevant records. After reading the full articles for these 57 studies, we excluded 17 studies (Supplemental Appendix 2, available at http://links.lww.com/PR9/A87). A total of 40 studies fulfilled the inclusion criteria and were included in our review.2,5,6,10–12,14,16,20,23,24,26,27,30,31,35,39,41,44,50,52,56,59–62,64,65,67,70–72,75,78,79,81,82,85,86,90

4.2. Included studies

The 40 included RCTs included a total of 2978 participants with chronic pain (Tables 1 and 2). The chronic pain conditions investigated varied and included unspecified or multiple chronic pain conditions,10,24,26,30,31,52,67,78,85,86 fibromyalgia,2,11,20,64,70,71,79,81 chronic low back pain,6,16,27,44,59–61,90 chronic headache,5,12,23,82 diabetic peripheral neuropathy,62,75 chronic musculoskeletal pain,65 postherpetic neuralgia,56 HIV-associated chronic pain,35 failed back surgery syndrome,27 provoked localized vulvodynia,39 spinal cord injury with chronic pain,41 sickle cell disease with chronic pain,72 bladder pain syndrome,50 and medically unexplained pain.14 Treatment periods ranged from a 10-minute body scan to, more commonly, 8 or more weeks of a structured mindfulness-based program. The most commonly used MBIs were mindfulness-based stress reduction (MBSR),2,5,6,11,14,16,27,35,50,62,65,70,71,81,82,85,86 a variation of MBSR,12,52,56,59–61,75 mindfulness-based cognitive therapy,23,24,26,64 mindfulness-oriented recovery enhancement (MORE),30,31 and others (mindfulness-based pain management program, mindfulness socioemotional regulation intervention, mindfulness-based group cognitive behaviour therapy, brief MBI, mindfulness awareness in body-oriented therapy, 6-week customized MBI, brief mindfulness-based body scan, second-generation MBI, and manualized meditation cognitive behavior therapy [CBT] intervention).10,20,39,41,44,67,72,78,79,90

Table 1 - Main characteristics of included trials of mindfulness for chronic pain.
Mindfulness intervention First author, year Chronic pain condition No. of treatment arms Comparator(s) Treatment duration Trial size
MBSR Andres-Rodriguez,2 2019 Fibromyalgia 2 TAU Weekly sessions for 8 weeks MBSR, n = 35; TAU, n = 35
MBSR Bakhshani,5 2015 Migraine, headache 2 TAU Weekly sessions for 8 weeks Total of 40 participants randomized into MBSR or comparator group; no details provided
MBSR Banth,6 2015 Low back pain 2 TAU Weekly sessions for 8 weeks MBSR, n = 39; control, n = 48
MBSR Cash,11 2015 Fibromyalgia 2 TAU Weekly sessions for 8 weeks MBSR, n = 51; control, n = 40
MBSR Chavooshi,14 2016 Medically unexplained pain 3 ISTDP or TAU Weekly sessions for 8 weeks MBSR, n = 20; ISTDP, n = 23; TAU, n = 20
MBSR Cherkin,16 2016 Back pain 3 CBT or TAU Weekly sessions for 8 weeks MBSR, n = 116; CBT, n = 113; TAU, n = 113
MBSR Esmer,27 2010 Back pain, leg pain 2 TAU Weekly sessions for 8 weeks MBSR, n = 19; TAU, n = 21
MBSR George,35 2017 HIV-associated chronic pain 2 Health education control Weekly sessions for 8 weeks MBSR, n = 16; control, n = 16
MBSR Kanter,50 2016 Interstitial cystitis/bladder pain syndrome 2 TAU Weekly sessions for 8 weeks MBSR, n = 9; TAU, n = 11
MBSR Nathan,62 2017 Painful diabetic peripheral neuropathy 2 TAU Weekly sessions for 8 weeks MBSR, n = 33; control, n = 33
MBSR Plews-Ogan,65 2005 Musculoskeletal pain 3 Massage or TAU Weekly sessions for 8 weeks MBSR, n = 10; massage, n = 10; TAU, n = 10
MBSR Schmidt,70 2011 Fibromyalgia 3 Relaxation intervention or TAU Weekly sessions for 8 weeks MBSR, n = 59; relax intervention, n = 59; control, n = 59
MBSR Sephton,71 2007 Fibromyalgia 2 TAU Weekly sessions for 8 weeks MBSR, n = 51; control, n = 40
MBSR Weissbecker,81 2002 Fibromyalgia 2 TAU Weekly sessions for 8 weeks MBSR, n = 51; control, n = 40
MBSR Wells,82 2014 Migraines 2 TAU Weekly sessions for 8 weeks MBSR, n = 10; TAU, n = 9
MBSR Wong,85 2009 Unspecified 2 Multidisciplinary education program 8 weeks Not reported
MBSR Wong,86 2011 Unspecified 2 Multidisciplinary pain intervention Weekly sessions for 8 weeks MBSR, n = 51; control, n = 49
MBSR variation Cathcart,12 2014 Tension-type headache 2 TAU Twice weekly sessions for 3 weeks Treatment, n = 29; control, n = 29
MBSR variation La Cour,52 2015 Varied 2 TAU Weekly sessions for 8 weeks Treatment, n = 54; control, n = 55
MBSR variation Meize-Grochowski,56 2015 Postherpetic neuralgia 2 TAU Daily mindfulness meditation for 6 weeks Treatment, n = 16; TAU, n = 15
MBSR variation Morone,59 2016 Low back pain 2 Health education program Weekly sessions for 8 weeks Treatment, n = 140; control, n = 142
MBSR variation Morone,61 2009 Low back pain 2 Health education program Weekly sessions for 8 weeks Treatment, n = 20; control, n = 20
MBSR variation Morone,60 2008 Low back pain 2 TAU Weekly sessions for 8 weeks Treatment, n = 19; control, n = 18
MBSR variation Teixeira,75 2010 Diabetic peripheral neuropathy 2 Nutritional information and food diary Listen to guided compact disc 5 days per week for 4 weeks Treatment, n = 11; control, n = 11
MBCT Day,23 2014 Headache 2 TAU Weekly sessions for 8 weeks MBCT, n = 19; control, n = 17
MBCT De Jong,24 2018 Chronic pain with depression 2 TAU Weekly session for 8 weeks MBCT, n = 26; control, n = 14
MBCT Parra-Delagdo,64 2013 Fibromyalgia 2 TAU 8 group sessions over 3 months MBCT, n = 17; TAU, n = 16
MBCT computerize Dowd,26 2015 Chronic noncancer pain 2 Psychoeducation Two online sessions per week for 6 weeks MBCT, n = 62; control, n = 62
MORE Garland,31 2014 Chronic noncancer pain 2 Support group Weekly sessions for 8 weeks MORE, n = 57; control, n = 58
MORE Garland,30 2013 Chronic noncancer pain 2 Support group Weekly sessions for 8 weeks MORE, n = 50; control, n = 42
Manualized meditation-CBT intervention (“mindfulness for chronic pain”) Zgierska,90 2016 Low back pain 2 TAU and opioid therapy Weekly sessions for 8 weeks Treatment, n = 21; TAU and opioid therapy, n = 14
Mindfulness-based pain management program Brown,10 2013 Fibromyalgia, rheumatoid arthritis, osteoarthritis, and other musculoskeletal pain 2 TAU Weekly session for 8 weeks Treatment, n = 20; TAU, n = 20
Mindfulness-based pain management (online intervention) Hearn,41 2018 Spinal cord injury 2 Online psychoeducation 2 audio-guided meditations each day for 6 of 7 days a week, for 8 weeks Treatment, n = 36; control, n = 31
Second-generation mindfulness-based intervention Van Gordon,79 2017 Fibromyalgia 2 Cognitive behaviour theory for groups Weekly sessions for 8 weeks Treatment, n = 74; control, n = 74
Mindfulness-based group cognitive behaviour therapy Guillet,39 2019 Provoked localized vulvodynia 2 Education support group Weekly sessions for 8 weeks Treatment, n = 14; control, n = 17
Brief mindfulness-based body scan Ussher,78 2014 Unspecified 2 Reading about natural history Single 10-minute mindfulness body scan Treatment, n = 27; control, n = 28
Brief mindfulness-based intervention Howarth,44 2019 Back pain and other 2 Distraction audios Single 15-minute mindfulness body scan audio in the clinic, followed by independent use over 1 month Treatment, n = 37; control, n = 34
6-Week customized mindfulness-based intervention Simmons,72 2019 Sickle cell disease with chronic pain 2 TAU Weekly telephonic sessions for 6 weeks Treatment, n = 40; control, n = 20
Mindful socioemotional regulation intervention (Internet) Davis,20 2013 Fibromyalgia 2 Healthy lifestyle tips (Internet) Twelve modules to be completed over 6 weeks Treatment, n = 39; control, n = 40
Mindfulness awareness in body-oriented therapy Price,67 2007 Unspecified 2 TAU Weekly sessions for 8 weeks Treatment, n = 7; control, n = 7
CBT, cognitive behavioural therapy; ISTDP, intensive short-term dynamic psychotherapy; MBCT, mindfulness-based cognitive therapy; MBSR, mindfulness-based stress reduction; MORE, mindfulness-oriented recovery enhancement; TAU, treatment as usual.

Table 2 - Main results of this review's outcome measures.
Mindfulness intervention First author, year Chronic pain condition Were concomitant pain treatments prohibited? (yes/no) If concomitant pain treatments were described, what were they? Did the trials control for concomitant pain treatments? (yes/no) Did the trials analyze the interaction between the mindfulness-based intervention and the concomitant drug therapies? (yes/no) Adverse events
MBSR Andres-Rodriguez,2 2019 Fibromyalgia No Treatment group: 50.0% analgesics, 32.3% NSAIDs, 17.6% anticonvulsants, 44.1% antidepressants, 26.5% opioids, 2.9% muscle relaxants, and 32.4% anxiolytics.

Control group: 37.5% analgesics, 37.5% NSAIDs, 6.3% anticonvulsants, 28.2% antidepressants, 9.4% opioids, 0.0% muscle relaxants, and 43.8% anxiolytics
No No Not reported
MBSR Bakhshani,5 2015 Chronic headache No Not described No No Not reported
MBSR Banth,6 2015 Low back pain No Not described No No Not reported
MBSR Cash,11 2015 Fibromyalgia No Not described No No Not reported
MBSR Chavooshi,14 2016 Medically unexplained pain No Not described No No Not reported
MBSR Cherkin,16 2016 Back pain No 11.1% reported using opioids for their pain in the past week; 73.9% reported using any medication for their pain in the past week No No 29% participants attending at least 1 MBSR session reported an adverse experience (mostly a temporary increase in pain with yoga)
MBSR Esmer,27 2010 Back pain, leg pain No Not described No No Not reported
MBSR George,35 2017 HIV-associated chronic pain No Not described No No Not reported
MBSR Kanter,50 2016 Interstitial cystitis/bladder pain syndrome No Not described No No Not reported
MBSR Nathan,62 2017 Painful diabetic peripheral neuropathy No Not described No No Not reported
MBSR Plews-Ogan,65 2005 Musculoskeletal pain No All participants continued their use of prescribed pain medications. 60% were taking at least 1 narcotic medication, and 40% were taking only non-narcotic medications. No No Not reported
MBSR Schmidt,70 2011 Fibromyalgia No Not described No No Not reported
MBSR Sephton,71 2007 Fibromyalgia No Incompletely described

Medications reported among the sample included antidepressants (63.7%), anxiolytics (23.1%), and hypnotics (9.9%)
No No Not reported
MBSR Weissbecker,81 2002 Fibromyalgia No Not described No No Not reported
MBSR Wells,82 2014 Migraines No Incompletely described

80% of the treatment group and 89% of the control group were taking daily prophylactic medications. All participants were taking abortive headache medications.
No No No adverse events occurred among participants
MBSR Wong,85 2009 Unspecified No Not described No No Not reported
MBSR Wong,86 2011 Unspecified No Treatment group: 64.7% acetaminophen, 29.4% rheumatic pain killer, 2.0% opioids, and 17.6% no analgesic use.

Control group: 64.5% acetaminophen, 31.3% rheumatic pain killer, 0% opioids, and 12.5% no analgesic use.
No No Not reported
MBSR variation Cathcart,12 2014 Tension-type headache Yes N/a N/a N/a Not reported
MBSR variation La Cour,52 2015 Varied No Incompletely described

Opioid use in years, mean (SD): 4.13 (4.32) in the treatment group and 5.69 (5.88) in the control group
No No At least 2 participants experienced transient strong feelings of anger toward their pain condition and at least 2 participants experienced greater anxiety
MBSR variation Meize-Grochowski,56 2015 Postherpetic neuralgia No Not described No No Not reported
MBSR variation Morone,59 2016 Low back pain No Not described No No No adverse events occurred among participants
MBSR variation Morone,61 2009 Low back pain No Not described No No No adverse events occurred among participants
MBSR variation Morone,60 2008 Low back pain No Treatment group: 21.1% opioids, 68.4% other analgesics, and 10.5% none

Control group: 16.7% opioids, 66.7% other analgesics, and 16.7% none
No No No adverse events occurred among participants
MBSR variation Teixeira,75 2010 Diabetic peripheral neuropathy No Incompletely described

Extrastrength acetaminophen was reported as the most frequently used over-the-counter pain reliever. Most reported pain medications included narcotics, antidepressants, pregabalin, and gabapentin (numbers not provided).

20% of participants reported using complementary therapies to treat their painful symptoms (eg, chiropractics).
No No Reported side effects experienced included dizziness, unsteadiness, and inability to think clearly
MBCT Day,23 2014 Headache No Not described No No Not reported
MBCT De Jong,24 2018 Chronic pain with depression No Not described No No One participant experienced spiritual issues, possibly related to the intervention
MBCT Parra-Delgado,64 2013 Fibromyalgia No Incompletely described

Treatment group: 33.3% antidepressants

Control group: 43.7% antidepressants
No No Not reported
MBCT computerize Dowd,26 2015 Chronic noncancer pain No Incompletely described

Previous treatments in the treatment group: 51.6% medication only, 38.7% medications + other treatments, 1.6% yoga, 1.6% meditation, and 3.2% psychological

Previous treatments in the control group: 58.1% medication only, 38.7% medications + other treatments, and 1.6% psychological
No No Not reported
MORE Garland,31 2014 Chronic noncancer pain No Incompletely described

Inclusion criteria required participants to have been prescribed and taken opioids for analgesia daily or nearly every day for at least the past 90 days
Yes

Both groups required patients to be prescribed and have taken opioids for their pain
No Not reported
MORE Garland,30 2013 Chronic noncancer pain No Incompletely described

Inclusion criteria required participants to have been prescribed and taken opioids for analgesia daily or nearly every day for at least the past 90 days
Yes

Both groups required patients to be prescribed and have taken opioids for their pain
No Not reported
Manualized meditation-CBT intervention, usual care, and opioid therapy Zgierska,90 2016 Low back pain No Incompletely described

Participants were treated with opioid therapy for 7.9 ± 5.7 years.
Yes

To be eligible, participants had to have been treated by a clinician with daily opioid therapy (at least 30 mg/d of morphine-related dose) for at least 3 months.
No Only anticipated, mild, and self-limited mild side effects were reported by the participants
Mindfulness-based pain management program Brown,10 2013 Fibromyalgia, rheumatoid arthritis, osteoarthritis, and other musculoskeletal pain No Not described No No Not reported
Mindfulness-based pain management (online intervention) Hearn,41 2018 Spinal cord injury No Not described No No Not reported
Second-generation mindfulness-based intervention Van Gordon,79 2017 Fibromyalgia No Not described No No Not reported
Mindfulness-based group cognitive behaviour therapy Guillet,39 2019 Provoked localized vulvodynia No Not described No No Not reported
Brief mindfulness-based body scan Ussher,78 2014 Unspecified No Treatment group: 55.6% opioids, 63.0% nonopioid analgesia, and 48.1% neuropathic analgesia

Control group: 39.3% opioids, 71.4% nonopioid analgesia, and 28.6% neuropathic analgesia
No No Not reported
Brief mindfulness-based intervention Howarth,44 2019 Back pain and others No Not described No No Not reported
6-Week customized mindfulness-based intervention Simmons,72 2019 Sickle cell disease with chronic pain No Not described No No Not reported
Mindful socioemotional regulation intervention (Internet) Davis,20 2013 Fibromyalgia No Not described No No Not reported
Mindfulness awareness in body-oriented therapy Price,67 2007 Unspecified No Not described Yes

Participants must have been taking analgesics for their chronic pain to be enrolled.
No Not reported
CBT, cognitive behavioural therapy; MBCT, mindfulness-based cognitive therapy; MBSR, mindfulness-based stress reduction; MORE, mindfulness-oriented recovery enhancement; NSAIDs, nonsteroidal anti-inflammatory drugs.

4.3. Excluded studies

We excluded 17 studies after the full articles were reviewed.4,15,21,22,28,29,32,37,38,42,45,46,74,83,84,89,91 Additional details regarding the reason(s) for exclusion can be found in Supplemental Appendix 2 (available at http://links.lww.com/PR9/A87).

4.4. Risk of bias

The results of each individual risk of bias domain are presented with a risk of bias graph shown in Figure 2 and a risk of bias summary shown in Figure 3.

  • (1) Random sequence generation: All included studies were randomized, but only 26 of 40 adequately described the method that was used to generate the random sequence.
  • (2) Allocation concealment: 16 of 40 studies described how the sequence was concealed.
  • (3) Blinding of participants and personnel: Given the nature of MBIs, as with other psychological interventions, blinding of participants and personnel is difficult and thus contributed to a high risk of bias in all studies.
  • (4) Blinding of outcome assessment: None of the studies adequately described how outcome assessment was blinded.
  • (5) Incomplete outcome data: Only 6 of 40 studies were judged at a low risk of bias for incomplete outcome assessment, which meant the remaining studies had greater than a 10% dropout rate and used last outcome carried forward imputation method or completer analysis.
  • (6) Selective reporting: 12 of 40 studies were judged to be at a low risk of bias for selective reporting, 26 of 40 studies at an unclear risk of bias, and only 2 of 40 studies at a high risk of bias.
  • (7) Other potential sources of bias: 0 of 40 studies contained over 200 participants per treatment arm and only 10 of 40 studies contained 50 to 199 participants per treatment arm. The remaining studies contained less than 50 participants per treatment arm.

Figure 2.
Figure 2.:
Risk of bias graph: Review the authors' judgement about each risk of bias item presented as percentages across all included studies.
Figure 3.
Figure 3.:
Risk of bias summary: Review the authors' judgements about each risk of bias item for each included study.

4.5. Primary and secondary outcomes

The summary of findings is presented in Tables 1 and 2.

Only 1 of the 40 (2.5%) included trials prohibited participants to take CADTs during the trial. The one trial that explicitly did not allow CADTs investigated a MBSR variation for tension-type headaches.12 This trial required participants to not be currently receiving, or have received in the past 12 months, intervention for their headache.

Only 6 of the 39 (15.4%) trials allowing CADTs provided adequate details on what CADTs participants were receiving,2,16,60,65,78,86 such as what percentage of participants were receiving opioid and nonopioid treatments for their chronic pain. A trial by Andrés-Rodríguez et al.2 that investigated MBSR for fibromyalgia reported that of 66 participants, 34.8% were taking NSAIDs, 12.1% were taking anticonvulsants, 36.4% were taking antidepressants, and 18.2% were taking opioids. A trial by Cherkin et al.16 that investigated MBSR for low back pain reported that of 341 participants, 11.1% of participants were taking opioids and 73.9% were taking any medication for their low back pain. A trial by Plews-Ogan et al.65 that investigated MBSR for musculoskeletal pain reported that of 30 participants, 60% were taking at least 1 narcotic medication and 40% were taking only non-narcotic medications. A trial by Wong et al.86 that investigated MBSR for chronic pain that was unspecified reported that of 100 participants, 64% were taking acetaminophen, 30% were taking a rheumatic pain killer, 1% were taking opioids, and 15% were taking no analgesics. A trial by Morone et al.60 that investigated a MBSR variation for low back pain reported that of 37 participants, 18.9% were taking opioids, 70.3% were taking other analgesics, and 13.5% were taking no medications for their low back pain. Finally, a trial by Ussher et al.78 that investigated a brief mindfulness-based body scan for chronic pain that was unspecified reported that of 55 participants, 47.3% were taking opioids, 67.3% were taking nonopioid medications, and 38.2% were taking neuropathic analgesics. Otherwise, 9 of 39 (23.1%) trials provided incomplete details on what CADTs trial participants were receiving, and the remaining trials provided no details. Additional details can be found on Table 2.

Of the 39 trials that allowed CADTs, only 4 (10.3%) trials had specific medication requirements for entry.30,31,67,90 Two of these trials by Garland et al.,30,31 which investigated MORE for chronic noncancer pain, required all participants to have had used prescription opioids for analgesia every day or nearly every day for at least 90 days. A trial by Zgierska et al.90 that investigated mindfulness meditation with CBT for low back pain required participants to have had been treated by a clinician with daily opioid therapy (at least 30 mg/d of morphine-equivalent dose) for at least 3 months. Finally, a trial by Price et al.67 that investigated mindfulness awareness in body-oriented therapy for chronic pain that was unspecified required participants to be using prescription analgesics.

Of great relevance to this review, none of the 39 trials that allowed for CADTs analyzed the interaction between MBIs and the CADTs to determine whether they have additive analgesic benefit. Because the interaction was not analyzed, the review's secondary outcome of how MBIs plus CADTs differed from only drug therapy in managing secondary features of chronic pain (ie, depression, physical and mental health-related quality of life, and functional disability) could not be reported.

4.6. Adverse events

The adverse events experienced by participants between those who received MBI compared with those who received another control treatment were inconsistently reported, and no meaningful statistical analyses could be performed. Only 9 of 40 (22.5%) trials reported any information on adverse events. Four reported no adverse events occurred59–61,82; one stated only mild and self-limited mild side effects were reported90; one stated that at least 2 participants experienced transient strong feelings of anger toward their pain condition and at least 2 participants experienced greater anxiety52; one reported no serious adverse events but reported that 30 of 103 (29%) participants attending at least 1 MBSR session reported an adverse event (mostly a temporary increase in pain with yoga)16; one reported no significant adverse events except one participant in the mindfulness-based cognitive therapy group who had spiritual issues possibly related to the treatment24; and one reported side effects of dizziness, unsteadiness, and inability to think clearly.75

5. Discussion

This systematic scoping review evaluated the current state of mindfulness-based clinical trials for chronic pain with respect to CADTs, attempted to evaluate available evidence on interaction effects between MBIs and various drug treatments, and assessed harms of MBIs. We found that only one of 40 (2.5%) included trials forbid participants from taking CADTs during the trial, meaning that participants in the remaining 39 (97.5%) trials were permitted to take, and were likely taking, CADTs.7 However, our review found that only 15.4% of trials provided sufficient details on what CADTs participants were taking and only 10.3% of trials had specific medication requirements for entry. Of great relevance to this review, none of the included trials analyzed the interactions between MBIs and the CADTs the participants were taking to determine whether they had an antagonistic, additive, or even multiplicative effect.

It is recognized that it was not the intention or aim of the authors undertaking the included RCTs to analyze the interaction between MBIs and CADTs. To better quantify the individual effects of MBIs, future studies should collect and report what CADTs participants were taking. Precise details of these interventions and how and when they were actually administered should be reported. It would also be beneficial if attempts are made to ensure that CADTs are equivalent between groups (eg, stratified randomization). Trials could also have specific medication requirements for entry (eg, patients required to be taking a specific opioid) or exclude participants taking specific medications. Precise details of the eligibility criteria should be reported. Although this does not guarantee that the groups are equivalent, the results can be interpreted with greater confidence.

The emerging evidence supporting the safe use of MBIs for chronic pain, well-established efficacy and safety of many analgesic drugs, and assumption that MBIs and analgesic drugs manage pain by different mechanisms suggests that MBIs may be complementary to pharmacotherapy. Ideally, combination therapies should have different pain-reducing mechanisms or site of actions. Mechanistically, pharmacotherapy can target a variety of peripheral, spinal, and supraspinal sites (depending on the drug) to reduce pain, whereas MBIs likely act through different mechanisms. Although our understanding of the physiological impacts of MBIs on the brain is in its early stages, recent functional magnetic resonance imaging studies demonstrate neural mechanisms supporting mindfulness-based pain reduction. As an example, pain reduction after prolonged mindfulness-based practice (greater than 1000 hours) was associated with deactivation of prefrontal and greater activation of somatosensory cortical regions, showing its ability to attenuate reactions of arising sensory events.40,87 Mindfulness-based interventions have also been shown to moderate the relationship between pain intensity and pain catastrophizing.66 In addition, treatments should have nonoverlapping side effects, which is also the case for MBIs and most pharmacotherapies. This is especially important in light of the opioid crisis and given the dose-limiting adverse effects of many drug treatments. Thus, their rational combination for chronic pain should be studied, especially because less than a third of patients report at least moderate pain relief with a single agent.36

The rational combination of psychotherapy and pharmacotherapy has been studied in many other medical contexts. A meta-analysis by Cuijpers et al.19 found that combining psychotherapy with antidepressant medications was more effective than treatment with antidepressants alone for major depression, panic disorder, and obsessive-compulsive disorder. Another meta-analysis by Kamenov et al.49 also found that the combination of psychotherapy and pharmacotherapy performed better than either alone in improving functioning and quality of life in patients with depression. The combination of pharmacotherapy and psychosocial interventions has also been found to be more beneficial than monotherapy in treating smoking cessation (eg, combination of bupropion with psychological support) and alcohol dependence (eg, naltrexone or acamprosate combined with CBT).25,69,73,80 Studies have also suggested that psychotherapy combined with pharmacotherapy was more acceptable to patients than pharmacotherapy alone.18 These findings are likely, at least in part, attributable to the principle that targeting 2 different mechanisms is more effective than one. In theory, the same rationale can be applied to combination therapy for chronic pain. Thus, comparable attention is now needed for the combination of analgesic drugs with MBIs and other similar interventions in chronic pain.

A major limitation of this review must be acknowledged. The purpose of our review was to summarize the landscape of mindfulness-based trials with respect to drug therapy. Thus, to provide a discrete set of results, we only focused on a subset of mindfulness interventions. However, despite us selectively excluding potentially relevant trials, our findings still emphasize the need for further research in this area.

6. Conclusion

In conclusion, this systematic scoping review suggests that, currently, mindfulness-based trials for chronic pain rarely describe what CADTs the participants were receiving and rarely control for these CADTs. Notably, we found that none of the included trials analyzed interaction effects between MBIs and CADTs for chronic pain. No judgments could be made about safety because adverse events were inconsistently reported. To better understand how MBIs can and should be integrated into patients' multidisciplinary pain management, large clinical trials that analyze the interaction between MBIs and CADTs are needed. Better harms assessment and reporting are also needed in mindfulness-based chronic pain trials.

Disclosures

The authors have no conflicts of interest to declare.

Appendix A. Supplemental digital content

Supplemental digital content associated with this article can be found online at http://links.lww.com/PR9/A87.

Acknowledgements

The authors thank Sandra Halliday for her assistance in building the search strategy.

This work was supported, in part, by the Queen's University Department of Anesthesiology & Perioperative Medicine and the Chronic Pain Network of the Canadian Institutes of Health Research Strategy on Patient-Oriented Research.

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Keywords:

Chronic pain; Mindfulness; Analgesic therapy; Clinical trials; Systematic review; Meditation

Supplemental Digital Content

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.