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Diabetic Peripheral Neuropathy

The Effects of Psychological Interventions on Diabetic Peripheral Neuropathy: A

Systematic Review and Meta-Analysis

Original research

Simona Racaru1,2 Jackie Sturt1 Celik Aycan1

1. Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King’s College London, UK

2. St. Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK

Corresponding author

Simona Racaru, RN, MSc

St. Mary’s Hospital, Zachary Cope Ward, 8th Floor,

Imperial College Healthcare NHS Trust

South Wharf Road,

London, W2 1BL, UK.

Telephone: 020 3312 6661;

Email: [email protected]

mailto:[email protected]


Abstract

Background: Psychological interventions are effective at ameliorating the experience of pain

in conditions such as rheumatoid arthritis and chronic back pain. However, their effect on

diabetic peripheral neuropathy (DPN) pain has yet to be established.

Aim: To assess the effectiveness of psychological interventions on pain and related outcomes

in adults with DPN.

Methods: Medline, Embase, PsychInfo, and CINAHL databases together with grey literature

and trial registers were searched. A meta-analysis and narrative synthesis of included studies

were undertaken.

Results: Nine studies were selected from 1610 citations. At short-term follow-up

psychological therapies showed a large effect on pain severity (SMD= -0.94, 95%CI[-1.50, -

0.37], p=.001) a small effect on pain interference (SMD= -0.39, 95%CI[-0.73, -0.05], p=.02),

and a moderate effect on depressive symptoms (SMD= -0.58, 95%CI[-0.95, -0.21], p=.002).

Quality of life significantly improved in experimental subjects, (MD= -2.35, 95%CI[-3.99, -

0.71], p=.005).

At medium-term follow-up there was a large effect on pain severity (SMD= -1.26, 95%CI[-

1.76, -0.77], p< .00001) and on pain interference (SMD= -0.91, 95%CI[-1.61, -0.21], p=.01)

and a moderate effect on depressive symptoms (SMD= -0.76, 95%CI[-1.48, -0.05], p=.04).

At long-term follow-up, improvements in pain interference, mood and self-care behaviors

were reported.

Conclusions. Psychological interventions can help to reduce pain levels and depressive

symptoms and improve QoL in adults with DPN. These findings demonstrate that


relationships between pain and perceived control among other groups who experience

chronic pain may also be replicated in the DPN population. This is an important outcome that

can guide further research and associated service developments.

Key words

Psychological interventions, diabetic peripheral neuropathy, diabetes, pain, quality of life,

systematic review

Key practice points

Mindfulness-based stress reduction can decrease pain and improve quality of life for

people who experience diabetic peripheral neuropathy.

Cognitive behavioral therapy can also decrease pain, improve mood and promote self-

care among this patient group.

It is not possible to confidently determine the effect size of these interventions based

on current evidence.

Further research is needed with larger samples and more robust methodologies to

confirm or refute these findings.

Diabetic peripheral neuropathy (DPN) is a common microvascular complication of

diabetes which is caused by nerve damage. On average, half of people with diabetes develop


peripheral neuropathies (Tesfaye et al., 2011). DPN commonly affects the nerves of the feet

and legs with symptoms varying between tingling and pain to numbness and complete loss of

sensation (Funnell, 2014). Chronic DPN can lead to complications, the most common of

which is diabetic foot disease which often leads to amputation (Hershey, 2017). Early

diagnosis and treatment of DPN to lessen its impact on quality of life (QoL) may impact

positively on self-care and therefore reduce the risk of diabetic foot ulceration and

amputation (Diabetes UK, 2017).

Chronic pain, experienced by 50% of individuals with DPN (Hershey, 2017), impairs

physical ability and diminishes freedom of movement and mental health, leading to

conditions such as depression, which affects social functioning (Breivik, Eisenberg, &

O’Brien, 2013). The level (or intensity) of pain felt by one person is defined as pain severity

while the degree to which DPN pain interferes or limits people’s daily functioning, such as

disturbing sleep, walking or general activity, is defined as pain interference (Zelman, Gore,

Dukes, Tai, & Brandenburg, 2005). Additionally, depression and diabetes specific distress are

common complications of diabetes (Fisher et al., 2010).

First line treatment for DPN is medication although sometimes pain is difficult to

manage with drugs (Tesfaye et al., 2011). Other therapies include alpha-lipoic-acid

supplements and spinal cord stimulation (Amato Nesbit et al., 2019), foot offloading (Mishra,

Chhatbar, Kashikar, & Mehndiratta, 2017), acupuncture (Zhang, Tang, & Gao, 2019) and

surgical decompression (Zhang, Li, & Zheng, 2013). In other conditions such as fibromyalgia

or chronic back pain, research has demonstrated that psychological interventions can be

effective for pain management (Sielski, Rief, & Glombiewski, 2017; Theadom, Cropley,

Smith, Feigin, & McPherson, 2015).

Psychological interventions are wide-ranging and aim to minimize emotional distress

resulting from chronic pain and comorbid depression, and to enhance individuals’


adaptability and attitudes to diminish the pain experience (Benzon et al., 2013). They can

therefore help people manage their condition in different ways to traditional medicine. For

example, by increasing their motivation to improve self-management and coping skills, and

by enhancing adherence to treatment (Tovote et al., 2017).

Since chronic pain is a life-long condition that can never be entirely cured, evidence

suggests that combining medication with psychological therapies might be a more sustainable

and efficient method of pain management in the long-term (Turk, Wilson, & Cahana, 2011).

Pain is an almost inextricable part of DPN which needs to be treated holistically (Turk,

Audette, Levy, Mackey, & Stanos, 2010), and psychological therapies can help improve a

person’s control of their bodies and their bodies’ response to both pain and treatment (Nijs et

al., 2017).

The purpose of this review is to bring together for the first time, evidence relating to

the effectiveness of psychological interventions for DPN. It seeks to answer the following

research question: what is the effectiveness of psychological interventions compared to usual

care, active control or other interventions on DPN symptoms, management and quality of life

in adults with diabetes?

Methods

This systematic review followed PRISMA guidelines (Moher et al., 2009), the

Cochrane Handbook for Systematic Reviews of Interventions (Higgins & Green, 2011) and

was registered on the PROSPERO database for systematic reviews; number

CRD42019127274.


Eligibility criteria

Eligible studies were randomized controlled trials (RCTs) investigating the effect of

psychological interventions compared to usual care, active control or other intervention. To

be eligible the studies needed to capture outcome data relating to DPN symptoms, DPN

management and QoL in adults.

Psychological interventions in this review represent any treatment that is adapted for

each participant, focusing on mental healing, relaxation and behavior changes e.g. cognitive

behavioral therapy (CBT), mindfulness-based stress reduction (MBSR), motivational

interviewing (MI), acceptance therapy and counselling.

Studies that used mixed interventions (e.g. qigong, tai chi, yoga), or explored

neuropathy of nondiabetic causation were excluded. Selection of eligible studies was

performed by one reviewer (SR) under supervision of a second reviewer (JS).

Search strategy

To retrieve relevant papers a search strategy was constructed on three facets of a

Population, Intervention, Comparison, Outcome and Study design analysis: population,

intervention and study design (PIS) (Sackett, Richardson, Rosenberg, & Haynes, 1997). The

search strategy contained the key words: diabetes*, neuropath*, psycho* and the MeSH

terms: diabetes mellitus, peripheral neuropathy and cognitive behavioral therapy.

The search was conducted by one reviewer (SR) under supervision of a second

reviewer (JS) without limitations to language, year, place, type or status of publication on

four databases from inception to April 2019: Medline, Embase, PsychInfo, and CINAHL.

Additionally, grey literature databases OpenGrey and PsychExtra, and the following trial

registers were searched: World Health Organization International Clinical Trials Registry


Platform, ClinicalTrials.gov, European Union Clinical Trials Register. The reference lists of

selected studies were also hand searched.

Study selection

Database search results were combined in Endnote software and duplicates removed.

Titles and abstracts for the remaining papers were examined and irrelevant reports were

eliminated. Full texts were then retrieved and reviewed for eligibility criteria. Studies that did

not meet the eligibility criteria were excluded at this stage.

Papers retrieved for full text evaluation were read in full by two reviewers (SR, AC)

and any disagreements were resolved by discussion. In cases where agreement was not

reached, a third reviewer was consulted (JS).

Data extraction

Data were extracted by one reviewer (SR) using a data extraction template that

captured key study characteristics including sample, intervention, comparator, outcomes and

results. Data were presented to a second reviewer (JS) and any uncertainties were discussed.

Extractions were reviewed by a faculty staff member independently of the review

team and any uncertainties were discussed.

Risk of bias and GRADE assessment

The internal and external validity of the included studies were assessed independently

by two reviewers (SR, AC) using the GRADE system (Balshem et al., 2011) and the

Cochrane Collaboration “Risk of bias” tool (Higgins & Green, 2011). Any uncertainties were

resolved through discussion.


Data analysis

Meta-analysis was justified where at least two studies shared homogeneity in

participants, interventions, control groups and outcome (Higgins & Green 2011). Meta-

analysis was performed in Review Manager 5.3 (RevMan5.3), and the intervention effect

estimate was expressed as standardized mean difference (SMD), when continuous outcomes

were measured with various instruments. SMD effect estimate was calculated with a 95%

confidence interval (CI) using the inverse variance technique with random effect model

(Higgins & Green, 2011). SMD effect size was interpreted following Cohen (1988): 0.2 to

0.5= small effect, 0.5 to 0.8= moderate effect and over 0.8= large effect. When similar scales

were used for continuous outcome measurements, meta-analysis was calculated as a

difference in means between groups (MD) with a 95% CI using either a random or fixed

effect model. The level of significance (alpha) for the overall effect estimate was defined by

the p value of the test for overall effect (Z) (Higgins & Green, 2011). For a 95% CI, a p value

of less than .05 (p< .05) was considered significant. Statistical heterogeneity across studies

was quantified by computing I2 statistics. An I2 value between 30% to 60% was considered

moderate and an I2 value greater than 60%, was considered substantial heterogeneity (Higgins

& Green, 2011). A negative value for the effect size (e.g. SMD= -0.58) suggested that the

intervention was more probably to be favorable for a continuous outcome. In trials where

standard deviations (SD) were not provided these were calculated from the CI of the means in

each group (Higgins & Green, 2011). For studies which could not be meta-analyzed, a

narrative synthesis was undertaken. Follow-up times from pre-treatment were categorized in

intervals of short-term (between 2 and 12 weeks), medium-term (between 12 and 24 weeks)

and long-term (between 24 and 52 weeks).


Results

Selection of studies

The search strategy retrieved 1610 citations. After duplicates were removed, 1227

titles and abstracts were screened and 29 were retrieved for full text assessment (Figure 1).

Records identified through

database searching:

Medline = 456 Embase = 562 CINAHL = 204 Psychinfo = 54

(n = 1276)

Scre

enin

g In

clud

ed

Elig

ibili

ty

Iden

tifica

tion

Additional records identified

through other sources

(n = 334)

Records after duplicates removed

(n = 1227)

Records screened

(n = 1227)

Records excluded

(n = 1198)

Full-text articles assessed for eligibility

(n = 29)

Full-text articles excluded, with

reasons

(n = 20)

Not RCT=2

Not psychological intervention =9

Mixed therapies = 5

Not DPN=3

Not obtainable = 1

Studies included in analysis

(n = 9)

Figure 1. Prisma flow diagram (Moher et al., 2009)


Study characteristics

From 29 fully assessed papers, nine were included of which one was an unpublished

RCT retrieved from clinicaltrials.gov, registration number NCT00829387 (Ghavami, Radfar,

Soheily, Shamsi, & Khalkhali, 2018; Kerns, 2015; Keukenkamp, Merkx, Busch-Westbroek,

& Bus, 2018; Nathan et al., 2017; Otis et al., 2013; Pfammatter, 2012; Skafjeld et al., 2015;

Teixeira, 2010; Vedhara et al., 2012). The nine studies involved the randomization of 335

participants from which 298 datasets were analyzed. All studies were published in English

and used randomization at the individual level. Study characteristics are presented in Table 1.

Diabetic Peripheral Neuropathy 11

Table 1 Characteristics of included studies

Author, country, design

Sample size (I/C), follow-up period, intention-to-treat (Y/N), primary outcome

Mean age (years), % male, % T2DM, duration of condition (years)

Intervention, therapist, control treatment Outcomes: MD [95%CI], (p value)

Ghavami et al., (2018), Iran, RCT

Kerns, (2015), USA, RCT

Nathan et al., (2017), Canada, RCT

Otis et al., (2013), USA, RCT

I=40/C=40, 12 weeks, N, DPN severity assessed by mTCNS

I=23/C=24, 36 weeks, N, pain severity assessed by NRS

I=33/C=33, 12 weeks (20 weeks from baseline), N, pain interference assessed by BPI

I=11/C=8, 16 weeks, N/ NR, pain severity & interference assessed by

I=49/C=47, I=30%/C=19%, 100%, I=19/C=17

I=64/C=61, I=91%/C=96%, 100%, NR

60I=50%/C=62%, I=80%/C=75%, NR

63, 100%, 100%, NR

Lifestyle counselling, one-on-one sessions, therapist details not specified, 12 weeks duration but frequency of sessions not stated, usual care control group

Cognitive behavioural therapy, ten weekly sessions of 60 minutes, delivered one-on-one by a doctoral level psychologist, diabetes education control group

Mindfulness based stress reduction delivered in group over 8 weeks with 2.5-hour sessions, plus one 6-hour session delivered at mid-course, practitioners with more than 5 years-experience in MBSR, usual care control group.

Cognitive-behavioural pain management therapy delivered one-on-one, 60-minute weekly sessions over 11 weeks by PhD level psychologist or Master

mTCNS: ST= -3.60[-4.70, -2.50], (p<.00001)

NRS: ST= -0.38[-1.39, 0.63], (p=.46) MPI: ST= -0.34[-1.10, 0.42], (p=.38); LT= -0.93[-

1.70, -0.16], (p=.03). BDI: ST -2.35[-6.73, 2.03], (p=.29); LT= -4.15[-

9.37, 1.07], (p=.12).

BPI interference ST= -1.41[-2.96, 0.14], (p=.07); MT= -2.18[-3.73, -0.63], (p=.006):

BPI intensity ST= -1.60[-2.40, -0.80] (p<.0001), MT= -1.92[-2.71, -1.13] (p<.00001).

BDI depressive symptoms: ST= -3.53[-5.83, -1.23] (p=.003); MT= -4.81[-7.11, -2.51], (p<.0001).

NQoL ST= -2.44[-4.11, -0.77] (p=.004) pain catastrophising (p=.001) improved in the I

group.

MPI severity ST= -1.04[-2.00, -0.08], (p=.03); MT= -1.08[-1.73, -0.43], (p=.001)

MPI interference ST= -0.88[-2.39, 0.63], (p=.025), MT= -1.57[-2.56, -0.58], (p=.002)






Teixeira, (2010), USA, RCT

Pfammatter, (2012), USA, RCT

Keukenkamp et al, (2018), Netherlands, RCT

Skafjeld et al., (2015), Norway, RCT

MPI, depressive symptoms assessed by BDI

I=11/C=11, 4 weeks, N, quality of life assessed by NeuroQoL

I=16/C=16, 12 weeks, N, pain severity assessed by MPI

I=6/C=7, 12 weeks, N, footwear adherence assessed by @monitor

I=21/C=20, 1 year, Y, foot ulcer incidence assessed by Wagner classification system

75, 25%, 100%, 12.6.

I=61/C=57, I=50%/C=55%, NR

I=57/C=62, I=100%/C=80%, I=80%/C=80%, I=29/C=17

I=57/C=59, I=86%/C=75%, I=71% /C=70%, I=17/C=19.5

level therapist, usual treatment control group

Mindfulness meditation, one group session of 60 minutes plus individual listening to a CD 5 days per week for 4 weeks plus weekly telephone calls and maintenance of a food diary, delivered by principal investigator with experience in MM and diabetes education, attention placebo control group

Thermal Biofeedback Assisted Relaxation (TBAR), 15-minute weekly sessions delivered by the experimenter over 6-weeks, attention placebo control group

Motivational Interviewing (MI) delivered one-on-one by rehabilitation medicine specialist, standard education control.

Theory based counselling for foot temperature monitoring, recording of daily steps and footwear adherence. Training on using digital infrared thermometer, study nurse, standard care control

Cognitive behaviour therapy delivered in group by

BDI depressive symptoms ST= -7.40[-18.68, 3.88], (p=.20), MT= (p=.58)

NQoL: insignificant improvement in QoL NRS: pain severity did not improve; insignificant

improvement in pain interference. PSQI: Sleep did not improve following intervention

MPI: pain severity did not decrease following intervention

SOPA: pain perception and perceived control did not improve following intervention

@monitor: footwear adherence improved at ST: I= 90% (30%–98%)* but not at MT: I=56% (28%–90%)*

Wagner foot classification system: foot ulcer incidence at LT was better in the intervention group: I=33% /C=50%,

SOS social support ST= 3.60 [-0.26, 7.46], p=.07;






Vedhara et al., (2012), UK, RCT

I=10/C=5, 36 months, N/NR, SOS, BIPQ, POMS, SDSCA

65, 77%, 77%, NR diabetes specialist nurse and diabetes specialist podiatrist, usual care control group

LT= 4.30[-1.46, 10.06], p=.14. BIPQ illness cognition ST= (p=.97); LT= (p=.26); POMS mood ST= -13.00[-24.27, -1.73], p=.02; LT=

-10.20[-18.70, -1.70], p=.02 SDSCA self-care behaviour ST= 12.80 [1.09,

24.51], (p=.03); LT= 14.80 [1.92, 27.68], (p=.02)

Key: RCT=randomised controlled trial, I/C=intervention/control, T2DM= type 2 diabetes, mTCNS=modified Toronto Clinical Neuropathy Score, BPI=brief pain inventory, MPI=Multidimensional Pain Inventory, BDI=Beck Depression Inventory, QoL=quality of life, NQoL=Neuropathy Quality of Life, POMS=profile of mood state, SOS=Significant Others Scale, BIPQ=Brief Illness Perceptions Questionnaire, SDSCA=Summary of Diabetes Self-Care Activities, NRS= Numeric Rating Scale, SOPA=Survey of pain attitudes, DPN=diabetic peripheral neuropathy, NR= not reported, p≤.05=significant, MD= difference in means between groups, [95%CI] = 95% Confidence Interval, negative scores (-) = psychological intervention is favourable (e.g. reduction in pain symptoms), ST=short term, MT=medium term, LT=long term, [*]=data provided as Median (range).


Intervention type

Two studies used CBT strategies that focused on relaxation techniques, challenging

negative thoughts, anger management, sleep hygiene and behavioral goals (Otis et al., 2013;

Vedhara et al., 2012). One study did not specify type of CBT intervention (Kerns, 2015).

Three studies used variants of CBT: a mindfulness-based stress reduction (MBSR)

intervention to allow the objective assessment of pain rather than catastrophizing it (Nathan

et al., 2017); a mindfulness meditation intervention to increase awareness and relaxation

(Teixeira, 2010); and thermal biofeedback assisted relaxation (TBAR), which used breathing

techniques and imagery to aid relaxation (Pfammatter, 2012). Two studies investigated

counselling techniques on lifestyle changes, goal setting and foot temperature monitoring

(Ghavami et al., 2018; Skafjeld et al., 2015) and one study assessed a motivational

interviewing intervention (Keukenkamp et al., 2018).

Mode of delivery

Two interventions were delivered in groups (Vedhara et al., 2012; Nathan et al.,

2017), four were one-on-one interventions (Otis et al., 2013; Kerns, 2015; Ghavami et al.,

2018; Keukenkamp et al., 2018), one was mixed (group and one-on-one) (Teixeira, 2010) and

two did not specify the delivery method (Pfammatter, 2012; Skafjeld et al., 2015).

Intervention duration varied from two weeks to one year.

Delivery staff

The interventions were delivered by psychologists (Otis et al., 2013; Kerns, 2015), a

diabetes specialist nurse and podiatrist (Vedhara et al., 2012), experienced practitioners

trained in MBSR with more than 5 years of experience as workshop leaders (Nathan et al.,

2017), a principal investigator (Teixeira, 2010; Pfammatter, 2012), care provider (details not


specified) (Ghavami et al., 2018), study nurse (Skafjeld et al., 2015) and a rehabilitation

medicine specialist (Keukenkamp et al., 2018).

The included studies assessed clinical and psychosocial outcomes which are

summarized in Table 2 together with the instruments used for their assessment.


Table 2 Patient Reported Outcome Measurements (PROMs)

Outcome Outcome measure Study IDDiabetes and DPN specific

Pain Severity

Pain Interference

QoL

Modified Toronto Clinical Neuropathy Score (mTCNS)Neuropathic Pain Scale (NPS)

Neuropathic Pain Scale

Neuropathic Quality of Life scale (NQoL): NQoL/Pain, NQoL/Feeling, NQoL/Motor, NQoL/Restriction, NQoL/Disruption subscales, NQoL/Emotion, Overall Quality of Life, NQoL/Symptom

Ghavami et al., (2018)Teixeira, (2010)

Teixeira, (2010)

Nathan et al., (2017); Teixeira, (2010)

GenericPain Severity

Pain interference

QoL

Psychosocial functioning

Brief Pain Inventory (BPI)West Haven Yale Multidimensional Pain Inventory (WHYMPI)/MPINumeric Rating Scale (NRS)

Brief Pain Inventory (BPI)West Haven Yale Multidimensional Pain Inventory (WHYMPI)/MPIMultidimensional Pain Inventory (MPI)

The 12 item- Short Form Health Survey version 2 (SF-12v2): (Mental Composite Score (MCS), Role Emotion subscale (RE), Social Function subscale (SF), Vitality subscale (VT), Mental Health subscale (MH); Physical Composite Scale (PCS), General Health subscale (GH), Role Physical subscale (RP), Physical Function subscale (PF), Bodily Pain subscale (BP)

Beck Depression Inventory (BDI) Patient Health Questionnaire-9 (PHQ-9)Pain Catastrophising Scale (PCS)Profile of mood state (POMS-2A)Perceived Stress Scale (PSS)State Measure of Affect, Pain, and ControlSurvey of Pain Attitudes (SOPA)

Nathan et al., (2017)Otis et al., (2013); Pfammatter, (2012)Kerns, (2015)

Nathan et al., (2017)Otis et al., (2013)Kerns, (2015)

Nathan et al., (2017)

Otis et al., (2013); Kerns, (2015)Nathan et al., (2017)Nathan et al., (2017)Nathan et al., (2017); Vedhara et al., (2012)Nathan et al., (2017)Pfammatter, (2012)Pfammatter, (2012)


Outcome Outcome measure Study IDPsychosocial functioning

Footwear adherence

Significant Other Scale (SOS)Brief Illness Perception Questionnaire (BIPQ)Summary of Diabetes Self-Care Activities (SDSCA)

Self-reported questionnaire

Vedhara et al., (2012)Vedhara et al., (2012)Vedhara et al., (2012)

Skafjeld et al., (2015)

Other measurements Non-PROMsFootwear adherence

Incidence of foot ulcer

Skin temperature monitoring

‘@monitor

Wagner classification

Thermometer

Keukenkamp et al., (2018)




Risk of bias and GRADE assessment

Internal reliability assessments are presented in Figure 2 with full judgements for each

study provided as online supplementary information (Appendix A). Among the nine studies

five were pilot studies with sample sizes insufficient to detect the effectiveness of

interventions. Four studies scored high risk of bias for not blinding participants, personnel or

outcome assessors, two studies scored high risk of bias for high subject attrition rates, and

five studies had inadequate quality reporting. Only one study had no risk of bias, however,

the investigators stopped recruiting participants before attaining the sample size calculated to

detect effectiveness (Nathan et al., 2017). GRADE rankings were performed for each

outcome, all of which were graded as low quality due to serious imprecisions and serious

limitations but no serious inconsistencies or serious indirectness. All outcomes in this study

had very wide confidence intervals denoting imprecision in results. Publication bias could not

be assessed due to the small number of studies. Judgements for rating and ranking evidence

followed GRADE assessment criteria (Balshem et al., 2011).


Figure 2 Risk of bias summary and graph

Effect of interventions

Meta-analyses were performed on short-term follow-up pain severity and pain

interference scores in four studies, QoL in two studies and depressive symptoms in three

studies. Additionally, two studies provided data for medium-term follow-up for pain severity,

pain interference and depressive symptoms (Figure 3). A narrative synthesis is provided for

seven studies. In cases where interventions did not reach statistical significance this does not

mean that the intervention had 'a negligible' or 'no effect'. Indeed, positive but non-significant

results were described by authors as 'clinically meaningful' and may, with more robust

research designs on larger samples, reach statistical significance.


Figure 3 Meta-analyses - Outcomes: Pain severity (1.1.1 & 1.1.2), pain interference (1.1.3 &


1.1.4), depressive symptoms (1.1.5 &1.1.6), quality of life (1.2.1); Sensitivity analysis

(1.3.1).

Pain severity

Overall scores at short-term (Ghavami et al., 2018; Kerns, 2015; Nathan et al., 2017;

Otis et al., 2013) and medium-term follow-up (Nathan et al., 2017; Otis et al., 2013)

generated large effect sizes favoring psychological interventions (SMD= -0.94, 95%CI[-1.50,

-0.37], Z=3.25, p=.001, I2=68% [analysis 1.1.1] and, SMD= -1.26, 95%CI[-1.76, -0.77],

Z=5.03, p<.00001, I2=0% [analysis 1.1.2]) respectively. Pain severity significantly decreased

with counselling (Ghavami et al., 2018) and MBSR (Nathan et al., 2017) at short-term while

patients receiving MBSR (Nathan et al., 2017) or CBT (Otis et al., 2013) reported

significantly less pain severity at medium-term follow-up compared to usual care.

Additionally, two studies reported no reductions in pain severity following mindfulness

meditation (Teixeira, 2010) or Thermal Biofeedback Assisted Relaxation (Pfammatter, 2012)

at short-term compared with an attention placebo group. A further study of an unspecified

CBT intervention reported no difference in pain severity levels between experimental and

control group at long-term follow-up (Kerns, 2015).

Pain interference

Overall results generated a small effect size at short-term follow-up (Kerns, 2015;

Nathan et al., 2017; Otis et al., 2013; Teixeira, 2010) (SMD= -0.39, 95%CI[-0.73, -0.05],

Z=2.27, p=.02, I2=0% [analysis 1.1.3]) and a large effect size at medium-term follow-up

(Nathan et al., 2017; Otis et al., 2013) (SMD= -0.91, 95%CI[-1.61, -0.21], Z=2.54, p=.01, I2

=35% [analysis 1.1.4]) favoring psychological interventions. MBSR (Nathan et al., 2017) and

CBT (Otis et al., 2013) significantly decreased pain interference at medium-term follow-up

and the unspecified CBT intervention resulted in less pain interference among experimental


subjects compared to controls at long-term follow-up (MD= -0.93, 95%CI[-1.70, -0.16],

Z=2.38, p=.02) (Kerns, 2015).

Depressive symptoms

Experimental subjects reported an overall significant improvement in depressive

symptoms at short-term (Kerns, 2015; Nathan et al., 2017: Otis et al., 2013) and medium-

term follow-up (Nathan et al., 2017: Otis et al., 2013), with moderate effect sizes (SMD= -

0.58, 95%CI[-0.95, -0.21], Z=3.09, p=.002, I2 =0% [analysis 1.1.5], and SMD= -0.76,

95%CI[-1.48, -0.05], Z=2.10, p=.04, I2=44% [analysis 1.1.6]) respectively. In these two

analyses, participants receiving MBSR (Nathan et al., 2017) reported a significant decrease in

depressive symptoms at short-term and medium-term follow-up compared to control group.

Additionally, the unspecified CBT intervention reported improvements in the experimental

group compared to controls at long-term follow-up, but results did not reach statistical

significance (MD= -4.15, 95%CI[-9.37, 1.07], Z=1.56, p=.12) (Kerns, 2015).

Quality of life

Short-term follow-up QoL scores (Nathan et al., 2017; Teixeira, 2010) showed an

overall significant improvement following psychological interventions compared to controls

(MD= -2.35, 95%CI[-3.99, -0.71], Z=2.82, p=.005, I2 =0% [analysis 1.2.1]). In this meta-

analysis only experimental subjects receiving MBSR (Nathan et al., 2017) attained

statistically significant improvements in QoL compared with control group. At medium-term

follow-up only Nathan et al. (2017) reported QoL outcomes which also indicated statistically

significant improvements for subjects receiving MBSR compared with controls (MD= -3.10,

95%CI[-4.77, -1.43], Z=3.64, p=.0003).


Mood

Participants receiving CBT reported significant improvements in mood at short-term

(MD= -13.00, 95%CI[-24.27, -1.73], Z=2.26, p=.02) and long-term follow-up (MD= -10.20,

95%CI[-18.70, -1.70], Z=2.35, p=.02) (Vedhara et al., 2012). Participants receiving MBSR

reported promising improvements in mood at short-term (MD= -12.38, 95%CI[-30.90, 6.14],

Z=1.31, p=.19) and at medium-term follow-up (MD= -15.28, 95%CI[-33.80, 3.24], Z=1.62,

p=.11) compared with usual care, but these scores didn’t reach statistical significance (Nathan

et al., 2017).

Psychosocial functioning

Self-care behaviors at short-term follow-up were significantly improved following

CBT (MD= 12.80, 95%CI[1.09, 24.51], Z=2.14, p=.03), whilst social support improvements

approached significance (p=.07) and no difference between groups was reported for illness

cognition (p=.97) (Vedhara et al., 2012). Additionally, at long-term follow-up, CBT

significantly improved self-care behaviors (MD= 14.80, 95%CI [1.92, 27.68], Z=2.25,

p=.02), while social support and illness cognition showed promising improvements but scores

did not reach significance (p=.14 and p=.26 respectively) (Vedhara et al., 2012). Perceived

control did not significantly improve with Thermal Biofeedback Assisted Relaxation at short-

term follow-up (Pfammatter, 2012).

Pain catastrophizing

Pain catastrophizing significantly decreased following MBSR at short-term (MD= -

7.88, 95%CI[-12.56, -3.20], Z=3.30, p=.001) and at medium-term follow-up (MD= -12.36,

95%CI[-17.04, -7.68], Z=5.18, p< .00001) (Nathan et al., 2017).


Perceived stress

Perceived stress decreased in the MBSR group at short-term follow-up approaching

significance (MD= -3.33, 95%CI[-6.94, 0.28], Z=1.81, p=.07), and significantly decreased at

medium-term follow-up compared with usual care (MD= -6.39, 95%CI[-10.00, -2.78],

Z=3.47, p=.0005) (Nathan et al., 2017).

Footwear adherence

Motivational interviewing improved footwear adherence at short-term but this was not

maintained at medium-term follow-up compared with an education group (Keukenkamp et

al., 2018). Compared with usual care, footwear adherence did not improve with counselling

at long-term follow-up (Skafjeld et al., 2015).

Incidence of foot ulcers

Foot ulcer incidence did not significantly decrease at long-term follow-up (Skafjeld et

al., 2015).

Sleep

Sleep did not improve in a mindfulness meditation group compared with an attention

placebo group at short-term follow-up (Teixeira, 2010).

Sensitivity analysis

A sensitivity analysis for pain severity outcomes was performed to determine if

temporary exclusion from the meta-analysis of certain studies influenced the treatment effect

(Polit & Beck, 2012). Pain severity scores were not reported separately by Ghavami et al.

(2018) but were included in the overall DPN severity score. This study was included in the


meta-analysis as it followed the same direction of effect. The study by Teixeira (2010)

showed unfavorable results for experimental subjects and followed the opposite effect

direction to other studies turning favorable results negative. This study was removed and only

four studies were pooled for analysis (Figure 3 analysis 1.3.1).

Discussion

Findings from this review suggest that psychological interventions can have a

significant beneficial effect on pain severity, pain interference, depressive symptoms and

QoL in adults with DPN. Pain severity and pain interference levels were significantly lower

in the MBSR and CBT groups compared with usual care. MBSR also improved QoL and

reduced depressive symptoms at short-term and medium-term follow-up. Additionally,

MBSR was associated with decreased pain catastrophizing and perceived stress at both time

points.

CBT was associated with improvements in mood at short-term and long-term follow-

up, while MBSR showed promising improvements in mood at short-term and medium-term

follow-up. CBT also significantly improved self-care behaviors and showed promising results

for social support and illness cognition at short-term and long-term follow-up.

Although non-significant relationships were reported between some interventions and

outcome measures, such as sleep patterns and mindfulness meditation at short-term follow-

up, they may still be considered clinically meaningful. For example, the short-term benefits

of MI on adherence to the use of custom-made footwear in the home environment.

Furthermore, the psychological interventions were safe with no studies reporting worsening

of symptoms or other detrimental effects on the progression of DPN. Low attrition rates were

also reported among experimental group samples suggesting that the interventions were well

received and that they were feasible treatment options.


Findings compared with the wider literature

The findings of this review are consistent with the wider psychological literature on

chronic pain management. Meta-analyses have demonstrated the efficacy of CBT and MBSR

to lessen painful symptoms across a range of chronic pain populations (Hoffman, Papas,

Chatkoff, & Kerns, 2007; Grossman, Niemann, Schmidt, & Walach, 2004). More recent

reviews appear to shore up these findings. For example, mindfulness (Veehof, Trompetter,

Bohlmeijer, & Schreurs, 2016) and CBT interventions (Richmond et al., 2015) for chronic

pain and lower back pain respectively resulted in significant beneficial effects on pain levels

that echo the findings of this review.

Collectively, these findings support a biopsychosocial model of pain, which posits

that the experience of pain is moderated by affective and cognitive processes in the central

nervous system and not just levels of nociceptor activation (Gatchel, Peng, Peters, Fuchs, &

Turk, 2007). On that basis the positive findings from this review provide evidence for the

mediating effects of MBSR and CBT on the experience of pain and on the physical and

emotional consequences of living with chronic pain.

Limitations

The nine studies contained in this review had small sample sizes; the risk of a Type II

error is therefore high and was acknowledged by a number of authors. Measurements were

performed at various points in time and assessment instruments were highly variable.

Additionally, the studies reported wide confidence intervals denoting imprecise results.

Although difficult to generalize the effect of the psychological interventions, significant

relationships commensurate with the wider psychological literature were reported. This

provides some confidence in the results which are also supported by the biopsychosocial

model of pain.


Although publication bias was minimized by searching for unpublished studies no

search strategy can retrieve 100% of relevant articles. This review may therefore be affected

by a publication bias that could not be assessed on a funnel plot due to the limited number of

included studies. Consequently, it is difficult to estimate whether the results of possible

undetected studies might influence the review findings.

The aforementioned methodological quality of papers is a limitation with more than

30% of domains scoring unclear risk of bias. When interpreting the review findings, it should

be taken into consideration that more than 50% of studies did not blind participants,

personnel or outcome assessors. Authors did not report the costs of the psychological

interventions although some judged them to be low cost. However, without such data it is not

possible to judge the benefit of these interventions in relation to each other and when

compared with other treatments including the pharmacological management of pain.

Implications for nursing practice and research

First line treatment for neuropathic pain is typically pharmacological interventions

that carry the risk of adverse effects and the development of tolerance and dependence over

time. The results of this review suggest that nursing staff might expect patients with DPN to

benefit from psychological interventions either to augment medication or to be trialed as an

initial alternative. Significant challenges will be the availability and integration of

psychological approaches to pain management within traditional care. However, it should be

noted that the MBSR and CBT programs used in the studies by Nathan et al. (2017) and Otis

et al. (2013) respectively were established community programs, and in the latter case, study

participants followed a protocol for chronic pain management that was not tailored

specifically for patients with DPN. Nursing staff are beholden therefore to research local

community resources, educate their patients on the potential benefits of psychological


interventions for pain management, signpost patients to available resources when appropriate,

and advocate for the integration of these treatment options within existing care pathways.

DPN is painful, highly prevalent and challenging to manage pharmacologically.

Further investigation of psychological interventions is therefore warranted. This review

represents an important step in the systematic appraisal of available evidence and points to

the value of further work. However, given the low quality of current evidence, larger trials

with sufficient statistical power are needed to confirm or refute the effectiveness of these

interventions on the experience of pain and their impact on the quality of life of people with

DPN. In particular, CBT and MBSR have demonstrated the potential to improve DPN

management and, if researched with more robust methodologies, might provide increased

confidence for the interventions’ effectiveness.

Conclusions

Diabetic peripheral neuropathy (DPN) impacts on individuals’ physical and

psychosocial wellbeing, and is the cause of all diabetic foot disease in people with diabetes.

Managing DPN at an earlier stage in its development to lessen its impact on quality of life

may impact on positive self-care and therefore prevent the development of diabetic foot

disease.

This review suggests that by augmenting pharmacological treatment with

psychological interventions, adults with diabetes can benefit from better DPN management.

However, there was insufficient evidence to confidently interpret the effect size of the

psychological interventions. Nevertheless, this systematic review demonstrates that the

known relationships between pain and perceived control among other groups who experience

chronic pain may also be replicated in the DPN population. This is an important finding that

can guide further research and associated service developments.


Acknowledgements

The authors acknowledge the contribution to Iain Ryrie for his reading and advice on

the manuscript.

Declarations of interest

None


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Appendix A

Risk of bias assessment for each studyGhavami 2018

Criteria Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low Quote: "Eligible participants were systematically randomized by computer into the control or lifestyle intervention group"

Allocation concealment (selection bias)

Unclear Not reported

Blinding of participants and personnel (performance bias)


Blinding of outcome assessment (detection bias)


Incomplete outcome data (attrition bias)

Low Attrition clearly described 3 (7.5%) participants from each arm discontinued participation. Complete outcome data

Selective reporting (reporting bias)

Unclear Protocol number not provided. Insufficient information to permit a judgement

Other bias Unclear Baseline characteristics for both groups were similar. Possible risk of bias: Participants enrolled from one hospital only & relatively short intervention time. Source of funding not stated.


Kerns 2015

Bias Authors' judgement



Unclear Quote: "Participants will be randomized in equal numbers to the two conditions."




Low Single masked-participants. Personnel not blinded.


High Not reported. Probably not done. (single masked – participants)


High Comment: Attrition clearly described. High rate of drop out at F/U 36 weeks assessment: 6 (26%) IG and 10(42%) CG. Intention to treat analysis not stated.


Low Comment: Study Protocol available (NCT01269502) and all outcomes are reported.

Other bias Unclear Quote: "There were no significant differences in demographics characteristics between the intervention and control groups at baseline." Conflicts of interest not stated.

Keukenkamp 2018




Low Quote:" Patients were randomly assigned to either standard education (control group) or standard education plus two sessions of motivational interviewing (intervention group). Block randomization with variable block sizes was used."


Low Quote: "A sealed envelope randomization sequence was created and managed by an independent investigator."

Blinding of participants and

Low Quote: "Participants were not blinded to treatment allocation, but we blinded them at


personnel (performance bias)

baseline to the goal of monitoring treatment adherence. The participants’ rehabilitation medicine specialist was blinded to treatment allocation. Patients were asked not to disclose their study allocation to their rehabilitation medicine specialist"


Unclear Not reported/ maybe yes? “The participants’ rehabilitation medicine specialist was blinded to treatment allocation”


Low Quote: “One participant in the intervention group withdrew. Two patients in the standard education group dropped out because of a fractured foot (n = 1) and death (n = 1). These events were not related to the study intervention”. Comment: high dropout rate but attrition clearly described: 1 (17%) IG and 2 (29%) CG lost to follow up.


Unclear Comment: Protocol number not provided. Insufficient information provided to permit a judgement

Other bias Low Comment: No significant differences between groups at baseline. The study appears to be free of other sources of bias.

Nathan 2017




Low Quote: "Patients were randomly allocated to a waiting list or MBSR using computer-generated random numbers in a permuted block design with randomly varying block lengths. Allocations were stratified by type 1 or type 2 diabetes and by pain severity as indicated by an average of the four pain-severity numeric rating scales of the Brief Pain Inventory (BPI)".


Low Comment: Concealed by opaque envelope.

Blinding of participants and

Low Quote: "Allocations were generated by an independent statistician and concealed from


personnel (performance bias)

investigators and treating physicians. Treatment allocation occurred as close as possible to the start of the MBSR course when the next consecutively numbered opaque envelope for the appropriate strata was opened".


Low Quote: “Allocations were generated by an independent statistician and concealed from investigators and treating physicians.”


Low Comment: Attrition clearly described: 3 (9%) participants withdrew from IG and 1 (3%) participant withdrew from CG.


Low Comment: Protocol available (NCT02127762) and all outcomes reported.

Other bias Low Comment: No significant differences between groups at baseline. The study appears to be free of other sources of bias.

Otis 2013




Low Quote: "participants were randomized via flip of a coin to 1 of the treatment conditions: CBT versus TAU."




High Comment: participants and investigators not blinded


High Not reported. Probably not done.


Low High attrition rate in IG 3 (27%) discontinued participation but this was clearly described and attrition was not related to the intervention.


Unclear Comment: Protocol not provided (the study followed the CONSORT of reporting trials). Insufficient information provided to permit a


judgement

Other bias Low Comment: Study participants similar at baseline characteristics. Incentives to participants reported.

Pfammatter 2012




Unclear Quote: "Participants were randomly assigned to one of the groups"




Low Single - participants


High Not reported. Probably not done.


High Quote: “The current study suffered from low recruitment as well as many participants withdrawing from the study.”Comment: Very high attrition rate and although this was described no reasons were given. 32 randomized/ 21 analysed, 6 (37.5%) dropped out from IG, and 5 (31%) dropped out from CG.


Low Comment: study protocol available NCT00858351 and all outcomes are reported.

Other bias Unclear Quote: there were no significant baseline differences between groups on Haemoglobin A1C, age, measures of pain, measures of control, or temperature in any limb.” Conflicts of interest not stated.

Skafjeld 2015



Random sequence generation (selection

Low Quote: "Block randomization was used to assign each four subjects to blocks with two


bias) in each group. Randomization was stratified for patients with a history of Charcot foot, who have an extra high risk of recurrence."




High Comment: clearly stated - single blinded- assessors (hence participants and personnel not blinded)


Low Comment: single blinded- assessors


Low Comment: Attrition reported: 3(7.3%) CG, dropped out. Analysis performed for all participants randomized.


Low Comment: Study Protocol provided (NCT01269502) and all outcomes are reported.

Other bias Low Quote: "There were no significant differences in demographics characteristics between the intervention and control groups at baseline."

Teixeira 2010




Low Quote: "A convenience sample of 22 adults with diabetes who described symptoms of PDPN participated in this pilotstudy. Participants were assigned by random number assignment to either the intervention group (Group A) or attention-placebo group (Group B)".





Blinding of outcome Unclear Not reported


assessment (detection bias)


Low Comment: Attrition clearly described. One participant in each group dropped out.


Unclear Protocol not provided. Insufficient information provided to permit a judgement. Baseline data, not provided, for the outcomes.

Other bias Unclear Baseline data did not differ between groups. Incentives to participants reported. Source of funding and conflicts of interest not stated.

Vedhara 2012




Unclear Quote: "eligible individuals were randomized 2:1 to the intervention or control groups" Comment: Randomization method not described.






Low Comment: Interviews transcripts anonymised and coded; assessor did not participate in intervention.


Low Comment: high attrition in the intervention group (20%) but this was clearly described: 2 participants randomized to IG withdrew before the intervention commencement.


high Comment: study protocol available ISRCTN17915181 available at https://doi.org/10.1186/ISRCTN17915181. Not all outcomes reported: (SF-12, HADS), intervention duration = 10 weeks instead of 13 weeks.

Other bias Low Nothing detected

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