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For peer review only

A guided and unguided internet- and mobile-based intervention for chronic pain: Health economic evaluation

alongside a randomized controlled trial

Journal: BMJ Open

Manuscript ID bmjopen-2018-023390

Article Type: Research

Date Submitted by the Author: 06-Apr-2018

Complete List of Authors: Paganini, Sarah; Albert-Ludwigs-Universitat Freiburg, Department of Rehabilitation Psychology and Psychotherapy, Institute of Psychology Lin, Jiaxi; University of Freiburg, Department of Sports and Sport Science

Kaehlke, Fanny; Friedrich-Alexander University of Erlangen-Nuremberg, Department of Clinical Psychology and Psychotherapy Buntrock, Claudia; Friedrich-Alexander-Universitat Erlangen-Nurnberg, Clinical Psychology and Psychotherapy Leiding, Delia; RWTH Aachen University, Department of Psychiatry, Psychotherapy and Psychosomatics Ebert, David; Friedrich-Alexander University Erlangen Nuremberg, Clinical Psychology and Psychotherapy Baumeister, Harald; Universitat Ulm, Institut of Psychology and Education, Department of Clinical Psychology and Psychotherapy;

Keywords: Chronic pain, Internet-and mobile-based intervention, Health economic evaluation, Cost-effectiveness, Cost-utility

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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A guided and unguided internet- and mobile-based intervention for chronic pain: Health

economic evaluation alongside a randomized controlled trial

S. Paganini 1a

, J. Lin2, F. Kählke

3, C. Buntrock

3, D. Leiding

4, D.D. Ebert

3, H. Baumeister

5

1Department of Rehabilitation Psychology and Psychotherapy, Institute of Psychology, University of

Freiburg, Germany, [email protected]

2Department of Sports and Sport Science, University of Freiburg, Germany, [email protected]

freiburg.de

3Department of Clinical Psychology and Psychotherapy, Friedrich-Alexander University of Erlangen-

Nuremberg, Germany, [email protected], [email protected], [email protected]

4Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Germany,

[email protected]

5Department of Clinical Psychology and Psychotherapy, Institute of Psychology and Education,

University of Ulm, Germany, [email protected]

a Corresponding author: Sarah Paganini, Department of Rehabilitation Psychology and

Psychotherapy, Institute of Psychology, University of Freiburg, Engelbergerstr. 41, D-79085 Freiburg,

Phone: ++49-761-203-3045, Fax: ++49-761-203-3040, Email: [email protected]

freiburg.de

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ABSTRACT

Objective: This study aims at evaluating the cost-effectiveness and cost-utility of a guided and

unguided internet-based intervention for chronic pain patients (ACTonPainguided/unguided) compared to a

waitlist control condition (WLC) and the comparative cost-effectiveness of ACTonPainguided/unguided.

Design: This is a health-economic evaluation alongside a three-armed randomized controlled trial.

Assessments were conducted at baseline, nine weeks after randomization and 6-month follow-up.

Setting: Participants were recruited through comprehensive online and offline strategies and in

collaboration with a German health insurance company.

Participants: All suitable participants (≥18 years, pain for at least six months, with at least Grade II in

the Chronic Pain Grade) filled out pre-treatment assessment. 302 individuals were randomly allocated

to one of the three groups (ACTonPainguided,ACTonPainunguided,WLC).

Interventions: ACTonPain consists of seven modules and is based on Acceptance and Commitment

Therapy. ACTonPainguided/unguided only differ in provision of human support.

Primary and secondary outcome measures: Main outcome of the cost-effectiveness analysis was

treatment response (in terms of pain interference). The outcome of the cost-utility analysis was

quality-adjusted life years (QALYs). Costs were measured from a societal perspective and were

related to treatment response and QALYs, respectively.

Results: If society is not willing to pay anything (€0) the probability of being cost-effective was 50%

for ACTonPainguided and 66% for ACTonPainunguided, respectively, for both treatment response and

QALY compared to WLC. The direct comparison revealed that from a willingness-to-pay of €2,188

(treatment response) and €27,221 (QALY), ACTonPainguided reaches higher probabilities of being cost-

effective than ACTonPainunguided.

Conclusions:

Findings indicate that ACTonPain might be a cost-effective alternative or adjunct to established pain

treatment. However, whether the intervention should be delivered guided or unguided depends on the

society´s willingness-to-pay and decision makers need to decide whether they focus on cost-

effectiveness or on patient health improvement at higher costs.

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Trial Registration: German Clinical Trial Registration: DRKS00006183,

URL:https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00006

183

Keywords: Chronic pain; internet- and mobile-based intervention; health economic evaluation; cost-

effectiveness; cost-utility

Strengths and limitations of this study

• This is the first study that evaluates the (comparative) cost-effectiveness of a guided and an

unguided internet-based intervention for chronic pain patients.

• In this study state-of-the-art statistical methods were applied, like seemingly unrelated

regression equations models or non-parametric bootstrapping techniques.

• Results should be interpreted cautiously, as the study was not powered to statistically test

health economic differences.

• As the costs and effects were evaluated over six months, no conclusions regarding the long-

term cost-effectiveness can be drawn.

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BACKGROUND

Chronic pain is highly prevalent [1–4] and associated with substantial decreases in quality of life [1, 5,

6] and high economic costs for society [3, 7–9]. Evidence supports psychological interventions as one

approach for effectively treating patients with chronic pain [10]. Treatment based on cognitive-

behavioral therapy (CBT) or third-wave therapies, like the Acceptance and Commitment Therapy

(ACT, a particular form of CBT) showed to be effective for chronic pain patients [11, 12] and could

show acceptable results concerning cost-effectiveness [13]. However, accessibility and availability of

treatment is often restricted and up to 40% of individuals with chronic pain do not receive adequate

pain management [1, 14]. Internet- and mobile- based interventions (IMIs) are an effective, acceptable

and feasible way for providing psychological interventions [15, 16]. IMIs for chronic pain have been

shown to effectively improve pain interference (standardized mean difference (SMD)=.4 [17],

SMD=−0.50 [18]).

IMIs can not only facilitate the access to psychological treatment, they also have the potential to

reduce treatment costs [19, 20], particularly by saving therapist resources. IMIs can be delivered as

guided or unguided self-help interventions, with both versions usually necessitating less therapist time

compared to traditional on-site therapies [21]. A relevant health care policy question is what amount of

professional human guidance is necessary in order to improve patients´ health, with guided IMIs being

seemingly more effective than unguided IMIs [21, 22]. However, as unguided IMIs can be delivered at

lower costs per participant, they might as well be an attractive option particularly given their high

scalability on a population level.

To the best of our knowledge, no randomized controlled trial (RCT) has investigated the

(comparative) cost-effectiveness of a guided and unguided IMI for chronic pain. However, Boer and

colleagues found that an IMI for chronic pain was cost-effective compared to a face-to-face group

intervention (concerning a one-point-improvement in a pain catastrophizing scale) [23]. Lin and

colleagues recently finalized a three arm RCT comparing a guided and unguided version of an

Acceptance and Commitment Therapy based IMI for chronic pain (ACTonPain) against a waitlist

control group [24, 25]. Compared to the waitlist control condition, ACTonPainguided showed

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significantly lower pain interference at post-treatment and 6-month post-baseline (d=0.58).

Differences between ACTonPainunguided and the control group and between both ACTonPain-groups

were not statistically significant [25].

The present paper provides the cost-effectiveness and cost-utility of ACTonPainguided/unguided compared

to the waitlist control condition as well as the comparative cost-effectiveness of

ACTonPainguided/unguided.

METHODS

Study design and sample

This health-economic evaluation was conducted with a 6-month time horizon from the societal

perspective alongside a three-armed RCT to investigate the cost-effectiveness and cost-utility of

ACTonPain. Full details of the trial design can be found in the study protocol and the main outcome

paper of this trial [24, 25]. The economic evaluation was conducted and reported in agreement with

the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement [26] and the

International Society For Pharmacoeconomics and Outcomes Research (ISPOR) guidelines [27].

The study has been registered in the German Clinical Trial Register (DRKS00006183) and was

approved by the ethics committee of the University of Freiburg (reference: 387/14). In total, 302

participants were recruited from 10/2014 until 08/2015 in German pain clinics, largescale

organizations for chronic pain (e.g. self-help groups), on websites and with assistance of a German

health insurance company. Inclusion criteria were 1) age 18 years or older, 2) chronic pain for at least

six months, with 3) considerable intensity (=at least Grade II in the Chronic Pain Grade [28]), 4) being

medically suitable for participation in a chronic pain IMI, 5) sufficient knowledge of the German

language, 6) sufficient computer and internet literacy, and 7) having internet access. Exclusion criteria

were 1) cancer-related pain, 2) ongoing or planned psychological pain intervention within the

forthcoming three months and 3) elevated risk of suicide.

Randomization

All eligible participants who provided informed consent were asked to fill out the baseline assessment

and were randomly allocated to one of the three conditions ACTonPainguided/unguided and waitlist.

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Permuted block randomization with variable block sizes (6, 9, 12) was performed by an independent

researcher not otherwise involved in the study using an automated, web-based randomization program.

Interventions

ACTonPain is a German adaption of an IMI by Buhrman and colleagues [29] for individuals suffering

from chronic pain. The intervention is based on ACT and consists of seven modules, which include

information, metaphors, assignments, and mindfulness exercises. Both treatment conditions differ only

in the provision of guidance. Participants were advised to work on one module every week (~60

minutes). In both intervention groups, participants had the option to receive daily automated text

messages that repeated content, reminded and motivated participants.

In ACTonPainguided trained and supervised eCoaches (psychologists) provided written feedback for

each module, which aimed at increasing participants' motivation and adherence. The total time of an

eCoach spent per participant was approximately 1.75 hours. Participants in the waitlist condition

received the offer to use ACTonPainunguided after the last follow-up assessment. Participants of all three

trial arms had unrestricted access to care-as-usual.

Outcome measures

Assessment took place at baseline (T0), post-treatment (T1; nine weeks after randomisation) and 6-

month follow-up (T2; six months after randomization). Outcomes were assessed by means of an

online self-report assessment using a secured internet-based platform (AES, 256-bit encrypted).

Treatment response

Main clinical outcome in the cost-effectiveness analysis was treatment response. According to the

Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT)

recommendations clinically important changes were identified with a combination of a distribution-

based approach (Pain Interference Scale of the Multidimensional Pain Inventory MPI [30, 31]) and an

anchor-based approach (Patient Global Impression of Change scale PGIC [32]) [33]. First, participants

with a change of 0.6 points (based on the scale’s standard deviation) on the Pain Interference Scale of

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the MPI (range of the scale:0-6) were identified as having minimal clinically important changes [33].

Second, participants were identified, that rated their global improvement in the PGIC [32] as

“minimally, much or very much improved”. Participants who fulfilled both criteria were classified as

having achieved a clinically important change [33], defined as “treatment response”.

Quality-adjusted life years

The clinical outcome in the cost-utility analysis was quality-adjusted life years (QALYs) based on the

AQoL-8D [34] and the EQ5D-3L [35]. Utility scores are a preference-based measure of quality of life

that is normed by the value 1 meaning complete health and 0 meaning death [36].

The AQoL-8D comprises 35 items, which load on three physical (independent living, pain, senses)

and five psycho-social (mental health, happiness, coping, relationships, self-worth) dimensions [34].

The utility scores are scaled by SPSS algorithm for AQoL-8D utility model [34]. The AQoL-8D has

been shown as a reliable and valid instrument, suitable when psychosocial elements of health are the

focus of research [34].

The EQ-5D-3L consists of five dimensions (mobility, self-care, usual activities, pain/discomfort, and

anxiety/depression), each of which is rated as causing ‘no’, ‘some’ or ‘extreme problems,’ and is a

well validated instrument [35, 37, 38]. Theoretically, the EQ-5D-3L generates 243 different health

states. Utility scores were calculated using the UK tariffs [39].

The AQoL-8D covers more dimensions that might be affected by chronic pain and shows a higher

sensitivity to mental health-related quality of life dimensions [40] compared to the EQ5D-3L.

Subsequently, and different to our protocol, this instrument was chosen for the main analyses[24].

QALY health gains for the 6-months period were estimated by calculating the area under the curve

(AUC) of linearly interpolated AQoL-8D and EQ-5D-3L utility scores [41].

Resource use and costing

The Trimbos and iMTA questionnaire for costs associated with psychiatric illness (TiC-P) [42, 43]

was adapted to the German health care system and used to assess the direct and indirect costs of the

past three month at T0 and T2. Costs were expressed in Euros (€) for the reference year 2015 (index

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factor 1.003 and 1.01 for outpatient medical service, respectively) referring to the German consumer

price index [44] (list of unit cost prices see Table 1).

Table 1: List of unit cost prices

Sector Unit Category 2015 (in Euro)

Outp

atie

nt

med

ical

ser

vic

e /

ou

tpat

ien

t se

ctor

Euro/contact

Physician

Gynecologist

Orthopedist Specialists for internal medicine

Ophthalmologist

Dermatologist

ETN specialist

Surgeon

Urologist Neurologist

Psychotherapist

Dentist

20.81

31.62

25.82 64.25

36.96

19.58

28.12

44.59

25.20 47.02

79.42

55.24

remedies Logopedics / speech therapy

Physiotherapy

Ergotherapy / occupational therapy

Podiatry / podology

Mean remedies

41.02

17.50

39.45

29.13

31.77

hospitals Euro/day

Completely stationary normal ward

Completely stationary intensive care

Completely stationary psychiatry Semi-stationary general hospital

Semi-stationary psychiatry

648.11

1,424.60

348.26 421.27

226.37

rehabilitation Euro/day Outpatient

Inpatient

49.43

138.19

opportunitiy costs Euro/hour

opportunity costs (free time)

opportunity costs (work) substitution costs for informal care

21.77

31.89 18.97

Note: Prices for outpatient medical service/outpatient sector were calculated fort the year 2013; all other prices

for the year

201444, 45

and adjusted by the German consumer price index for 201543

. ETN specialist, Ear, nose, and throat

specialist.

Direct medical costs

Healthcare costs (e.g. out-and inpatient care) were calculated according to the German guideline of

Bock and colleagues [45, 46]. The costs of therapeutic appliances (that were not listed in Bock and

colleagues [45, 46]) and medication were obtained from the Lauer-Taxe [47].

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Patient and family costs

Self-reported out-of-pocket expenses and direct non-medical costs (travel expenses, opportunity costs,

domestic help) were assessed. Participants reported the cost of travelling by bus or taxi. If not stated,

each kilometer was valued at €0.30. Opportunity costs (i.e.,time spent at the practitioners waiting

room) were estimated at €21.77 per hour. Costs of informal care were valued using a shadow price of

€18.97 per hour [45].

Indirect costs

Indirect costs included productivity losses caused by absenteeism and presenteeism. Absenteeism

costs were calculated according to the human capital approach [48]. Self-reported lost work days were

multiplied by the corresponding gross average of participants’ income per day. To calculate

presenteeism costs, participants reported the number of days of reduced efficiency at work. These days

were weighted by an inefficiency score. Productivity losses from unpaid work (i.e. domestic help from

family members) were valued using a shadow price of €18.97 per hour [45].

Intervention costs

Intervention costs of ACTonPainguided (€299) and ACTonPainunguided (€69) were based on actual

market prices for (un)guided interventions with a similar amount of modules that contain all costs for

developing and hosting the intervention (https://geton-institut.de/).

Statistical analysis

This study was not powered to statistically test differences in health economic outcomes. Therefore,

we took a probabilistic decision-making approach for health-economic inferences [49], that aims at

informing decision makers on probabilities rather than statistical significance. There was no need to

discount costs or outcomes as the time frame for the study was six months.

All analyses were conducted according to the intention-to-treat principle. All participants completed

T0. Missing clinical outcome data was imputed using the expectation maximization algorithm in

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Statistical Package for the Social Sciences (SPSS, version 20). Analyses of clinical outcomes were

conducted and reported elsewhere [25] in accordance with the CONSORT 2010 Statement[50].

Missing cost data was imputed using the regression imputation procedure in Stata version 13 [51].

Predictors of cost data and dropout were identified by logistic regression analysis and were used to

obtain the most likely values of the missing cost data. At baseline, AQoL-utilities were similar

between groups (ACTonPainguided:M=0.496, SD=0.16; ACTonPainunguided: M=0.485, SD=0.17; waitlist:

M=0.463, SD=0.15). Therefore, no baseline adjustments were made when calculating QALYs.

We tested group differences in treatment response using the chi-squared test and the Kruskall-Wallis

test for QALYs both followed by post-hoc comparisons (Bonferroni and Dunn´s test, respectively).

In the cost-effectiveness analyses, the outcome estimate is the incremental cost-effectiveness ratio

(ICER), where incremental costs over the 6-month period are divided by incremental effects

(treatment response or QALYs): ICER=(CostsIG–CostsCG)/(EffectsIG–EffectsCG) subscripted with IG

for the two intervention groups and CG for the comparison groups. Different to the protocol [24],

ICERs are reported for a 6-month horizon (baseline data; T0 and 6-month follow-up; T2) and not

based on pre-post (T0 and post-treatment; T1). As participants are asked for their health care

utilization during the last three months, the TiC-P can only be evaluated appropriately at T0 and T2 (as

T1 assessments are conducted nine weeks after randomization).

Non-parametric bootstrapping by resampling patient-level data with 5,000 replications was used to

take into account the sampling uncertainty of the ICER estimates. Seemingly unrelated regression

equations models were bootstrapped to allow for correlated residuals of the cost and effect equations.

Bootstrapping was used to obtain 95% confidence intervals for the ICERs based on the percentile

method, since parametric techniques are inappropriate for use on skewed variables and ratios [49].

The bootstrapped ICERs were plotted on a cost-effectiveness plane. In addition, a cost-effectiveness

acceptability curve was graphed to assess the probability that the intervention is cost-effective relative

to the comparator condition given varying willingness-to-pay (WTP) ceilings. In order to increase

readability of the direct comparison ACTonPainguided vs. ACTonPainunguided the inverse cost-

effectiveness acceptability curve (ACTonPainunguided vs. ACTonPainguided) was additionally plotted. All

analyses were performed using Stata version 13 [51].

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Sensitivity analysis

We tested the robustness of the outcomes of the main analysis in a sensitivity analysis. Therefore we

used the EQ-5D-3L as a widely used instrument for calculating QALYs.

Patient and public involvement

No patients or public were involved in developing the research question or the outcome measures, nor

were they involved in developing plans for design or implementation of the study. The burden of the

interventions on participants was not assessed, but the satisfaction with the intervention. The results of

the research will be disseminated to those study participants who wished to be notified.

RESULTS

Sample characteristics

The overall sample size was 302. Due to missing assessments the dropout rate was 25.8% at 6-month

follow-up (ACTonPainguided:33/100; ACTonPainunguided:35/101; waitlist:10/101). At 6-month follow

up, dropout rates differed significantly between groups (χ2(2)=20.17, p<.001). Pairwise comparison

revealed significant differences for ACTonPainguided vs. waitlist (t(1)=-3.85, p<.001) and

ACTonPainunguided vs. waitlist (t(1)=-4.14, p<.001). Study dropout was not associated with baseline

pain interference or socio-demographic factors.

The average participant was female, 52 years of age, with an above average level of education,

employed and was already treated for chronic pain. Detailed participants’ characteristics and the

CONSORT flowchart have already been reported elsewhere [25].

Outcomes

Table 2 shows treatment response and QALY outcomes as well as group differences. At 6-month

follow-up, treatment response differed significantly between groups (ACTonPainguided: 44/100;

ACTonPainunguided: 28/101; waitlist: 16/101). Pairwise comparison revealed significant differences for

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ACTonPainguided vs. waitlist and ACTonPainguided vs. ACTonPainunguided but not for ACTonPainunguided

vs. waitlist. Between-group differences in AQoL-8D QALY gains were statistically significant.

Pairwise comparison revealed significant differences only for ACTonPainguided vs. waitlist. Incremental

EQ5D-3L QALY gains did not differ significantly between study groups.

Table 2. Treatment response and quality-adjusted life-year (QALY) outcomes and group differences at

6-month follow up.

ACTonPain guided

(n = 100)

ACTonPain unguided

(n = 101)

WLC group

(n = 101)

Test statistic

Mean (SD) Mean (SD) Mean (SD) χ2 (df=2) Post-hoc test

c:

p

Treatment response

(pain interference)

0.44 (0.5)

0.28 (0.45)

0.16 (0.37)

19.44 a

<001

ACTonPain guided vs. WLC group t(1)=4.52 <.001

ACTonPain unguided vs. WLC group t(1)=1.91 .17

ACTonPain guided vs. unguided t(1)=2.61 .03

QALY

AQoL-8D

0.28 (0.08)

0.27 (0.09)

0.24 (0.08)

9.45 b

.009

ACTonPain guided vs. WLC group Z=-3.07 .003

ACTonPain unguided vs. WLC group Z=-1.61 .16

ACTonPain guided vs. unguided Z=-1.47 .21

EQ5D-3L 0.27 (0.12) 0.25 (0.12) 0.25 (0.13) 2.17 b .34

WLC group, waitlist control group; SD, standard deviation; df, degrees of freedom; QALY, quality-adjusted life-

year a Chi-squared test

b Kruskall-Wallis H test

c Post-hoc test for treatment response: Bonferroni pairwise comparison; Post-hoc test for QALY: Dunn´s test

Costs

At baseline, mean total costs were €3,233 in ACTonPainguided, €3,724 in ACTonPainunguided and €3,570

in the waitlist group. The 6-month accumulated per-participants costs by study condition are presented

in Table 3. ACTonPainguided showed the highest mean total costs (€6,945), followed by the waitlist

group (€6,908) and ACTonPainunguided (€6,560). Mean direct costs were the highest in the guided

group, followed by the unguided group and waitlist. The opposite order was found for the indirect

costs. Medication, domestic help and opportunity costs were major cost drivers. Productivity losses

produced the highest cost differences between the intervention groups and waitlist of -€871

(ACTonPainguided vs. waitlist) and -€721 (ACTonPainunguided vs. waitlist).

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Table 3. 6-month accumulated per-participants costs (in €) by condition (based on intention-to-treat

sample, N = 302).

ACTonPain guided

(n = 100)

ACTonPain unguided

(n = 101)

WLC group

(n = 101)

Incremental costs

Difference, €

Mean, €

(SD)

Mean, €

(SD)

Mean

, €

(SD)

ACTon

Pain guided

vs.

WLC

ACTon

Pain unguided

vs.

WLC

ACTon

Pain guided

vs. unguided

Intervention 299 (-) 69 (-) 0 (-) 299 69 230


Health care costs

Medical specialist 576 (478) 511 (381) 511 (382) 65 0 65

Mental health care 212 (431) 181 (397) 258 (455) -46 -77 31

Other medical

specialist a

369 (515) 357 (435) 406 (576) -37 -49 12

In-patient care

(hospital)

198 (479) 173 (369) 141 (420) 57 32 25

Day care 147 (687) 122 (381) 306 (1,584) -159 -184 25

Rehabilitation 190 (794) 134 (507) 191 (773) -1 -57 56

Medication 1,092 (2,748) 784 (1,438) 660 (1,638) 432 124 308

Therapeutic appliances 65 (139) 86 (222) 46 (96) 19 40 -21

Direct non-medical costs


Travel 131 (229) 105 (150) 101 (100) 30 4 26

Domestic help 1,297 (4,064) 1,147 (1,936) 840 (1,490) 457 307 150

Opportunity costs b 1,553 (1,965) 1,925 (3,251) 1,759 (3,116) -206 166 -372

Indirect costs

Productivity losses

Absenteeism 517 (1,647) 647 (1,979) 1,133 (3,333) -616 -486 -130

Presenteeism 300 (740) 320 (774) 555 (1,360) -255 -235 -20

Total direct costs 5,829 (7,129) 5,525 (4,959) 5,220 (5,133) 611 306 305

Total indirect costs 817 (1,978) 966 (2,283) 1,688 (3,735) -871 -721 -150

Total societal costs 6,945 (7,327) 6,560 (5,549) 6,908 (6,279) 39 -346 385

WLC group, waitlist control group a i.e. physiotherapist, occupational therapist

b i.e. for waiting time before treatment

Health-economic evaluation

Table 4 shows the incremental costs, effects and cost-effectiveness ratios for the main analysis and the

sensitivity analysis.

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Table 4. Results of the main and sensitivity analyses (based on 5,000 bootstrap simulations).

Analysis

ACTonPain guided vs.

WLC group

Incremental

costs, €

(95% CI)

Incremental

effects

(95% CI)

Mean

ICER

(95% CI)

Distribution over the

ICER plane

NE NW SE SW

Cost-effectiveness,

treatment response

(MPID and PGIC)

6

(-916-953)

0.14

(0.08-0.2)

171

(-6,671-8,260)

50% - 50% -

Cost-utility, AQoL QALYs

6

(-916-953)

0.018

(-0.007-

0.029)

7,514

(-49,275-

88,521)

50%

-

50%

-


EQ5D QALYs 6

(-916-953)

0.01

(-0.006-

0.027)

-8,116 a

42% 8% 47% 3%

Analysis

ACTonPain unguided vs.

WLC group

Incremental

costs, €

(95% CI)

Incremental

effects

(95% CI)

Mean

ICER

(95% CI)


ICER plane

NE NW SE SW

Cost-effectiveness,

treatment response

(MPID and PGIC)

-352

(-1,968-

1,272)

0.12

(0.006-

0.232)

-3,320

(-82,925-

29,821)

32% 1% 66% 1%


-352

(-1,968-

1,272)

0.023

(-0.0002-

0.046)

-11,689 a

31%

2%

66%

1%


EQ5D QALYs -352

(-1,968-

1,272)

0.001

(-0.032-

0.035)

46,304 a

11% 22% 41% 25%

Analysis


ACTonPain unguided

Incremental

costs, €

(95% CI)

Incremental

effects

(95% CI)

Mean

ICER

(95% CI)


ICER plane

NE NW SE SW

Cost-effectiveness,

treatment response

(MPID and PGIC)

388

(-1,416-

2,185)

0.164

(0.034-0.29)

2,949

(-11,097-

25,276)

65% - 35% -


388

(-1,416-

2,185)

0.013

(-0.011-

0.037)

22,290 a

54%

11%

32%

3%


EQ5D QALYs 388

(-1,416-

2,158)

0.02

(-0.014-

0.053)

1,734 a

54% 11% 33% 2%

WLC group, waitlist control group; 95% CI, 95% confidence interval; EQ-5D QALYs, Quality-adjusted life

years based on EuroQol; ICER, incremental cost-effectiveness ratio; NE, northeast quadrant; NW, northwest

quadrant; SE, southeast quadrant; SW, southwest quadrant. a A dependably accurate 95% confidence interval for this distribution cannot be defined because there is no line

through the origin that excludes α/2 of the distribution[52].

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Cost-effectiveness

The cost-effectiveness planes and acceptability curves, representing the 5,000 bootstrap replications,

are shown in Figure 1(a,b,c) and 2(a,b). ACTonPainguided showed the same and ACTonPainunguided a

higher potential of being cost-effective compared to waitlist at a WTP of €0 (ACTonPainguided 50%,

ACTonPainunguided 66%). The probability of ACTonPainguided being more cost-effective compared to

waitlist increased up to 70% at a WTP of €1,738 and to 95% at a WTP of €6,490 for an additional

treatment response, and for ACTonPainunguided to 70% at a WTP of €660 and to 95% at a WTP of

€13,460.

The probability that ACTonPainguided is more cost-effective than ACTonPainunguided was 35% at a WTP

of €0 for an additional treatment response. When society’s WTP increases up to €5,535 or €17,170

this probability rises to 70% or 95%, respectively. The break even point (where ACTonPainguided and

ACTonPainunguided have the same possibility of being cost-effective at same costs) is at €2,188 (see

Figure 2b).

- Figure 1-

- Figure 2-

Cost-utility

Cost-effectiveness planes and acceptability curves that refer to cost-utility are shown in figure 1(d,e,f)

and 2(c,d). ACTonPainguided showed the same and ACTonPainunguided a higher potential of being cost-

effective compared to waitlist at a WTP of €0 (50% and 66%, respectively). The interventions’

probability of being more cost-effective compared to waitlist increased up to 70% and to 95% at a

WTP of €14,680 and €62,580, respectively, in ACTonPainguided and €3,920 (70%) and €117,000 (95%)

in ACTonPainunguided for one additional QALY. The probability that ACTonPainguided is more cost-

effective than ACTonPainunguided was 32% at a WTP of €0 for one additional QALY. When society’s

WTP increases up to €92,400 this probability rises to 70% and stagnates on this level. The break-even

point is at €27,221 (see Figure 2d).

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Compared to the AQoL-8D, using the EQ-5D-3L resulted in smaller incremental QALY gains for

ACTonPainguided and ACTonPainunguided vs. waitlist, but still in favor of the intervention group,

respectively. QALY gains were higher and in favor of ACTonPainguided vs. ACTonPainunguided

compared to the AQoL-8D QALY gains.

DISCUSSION

Whether an intervention can be considered as cost-effective or not strongly depends on the society's

willingness-to-pay (WTP). At first glance, ACTonPainunguided seems to be more cost-effective and

shows the lower incremental societal cost than ACTonPainguided when compared to waitlist. The

probability of being cost-effective at a WTP of €0 compared to waitlist is higher in ACTonPainunguided,

for both, treatment response and QALYs gained (66%) than in ACTonPainguided (50%).

However, when increasing the WTP threshold for a treatment response, the probability of being cost-

effective rises more for ACTonPainguided than for ACTonPainunguided. The direct comparison of

ACTonPainguided/unguided shows the same pattern with ACTonPainguided exceeding ACTonPainunguided

given a WTP threshold higher than €2,188 and €27,221 for treatment response and QALY,

respectively.

The results of ACTonPain being cost-effective are in line with a recent study and a review on IMIs

for depression [23, 53]. The guided IMI for chronic pain of Boer and colleagues revealed an ICER of

40 (defined as cost savings of €40) for an one-point improvement in a pain catastrophizing scale

compared to a face-to-face group intervention [23]. QALYs where not reported. ACTonPainguided

reached higher ICERs for the clinical outcome pain interference (171 compared to waitlist group and

2,949 compared to ACTonPainunguided). However, generic measures, like QALYs should be used to

compare between studies [48]. In the systematic review, IMIs that were classified as cost-effective

were all guided and showed probabilities of being cost-effective between 28% and 49% at a WTP of

€0 for a QALY gained (50-66% in ACTonPain). Thus, integrating psychological e-health approaches

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in pain management programs might even be more promising from an economical point of view when

compared to the well-established area of depression e-health care. The higher direct costs over a 6-

month period in both intervention groups compared to waitlist might be explained by higher or stable

health care utilization similar to findings in a previous study on the costs of established depression

treatments [54]. However, research indicates that indirect rather than direct costs represent the

majority of overall costs [55, 56], where ACTonPain seemingly has its core advantage. Mean indirect

costs over the 6-month period were almost half as high in the intervention groups compared to waitlist,

regarding both absenteeism and presenteeism.

Next to the question of whether ACTonPain is cost-effective with a “highly probable” and whether it

should rather be provided guided or unguided with an “it depends on the WTP” as answers, it would

be of interest how ACTonPain performs compared to established medical, psychological,

physiotherapeutical, and surgical treatments that result in enormous direct costs [57–60]. However,

surprisingly little is known about the cost-effectiveness of these established pain treatments. In two

reviews it was highlighted, that interdisciplinary pain rehabilitation programs are more cost-effective

or produce lower costs than interventions such as surgery and conservative care [61, 62].For

individuals with low back pain it was concluded that interdisciplinary rehabilitation, exercise,

acupuncture, spinal manipulation and CBT are potentially cost-effective [63]. A further systematic

review focused on economic evaluations of third-wave CBT therapies (including ACT), were available

ICERs ranged from -€19,300 (National Health Service perspective, converted into Euro [64]) to

€56,637 (societal perspective) per QALY gained [13]. The three ICERs based on the AQoL-8D in this

study were €7,514, -€11,689 and €22,290 per QALY gained. Thus, it seems safe to argue that

ACTonPain, as an example of an innovative IMI for the treatment of chronic pain, is effective [25] and

can be an cost-effective intervention. A comparison across treatment approaches for chronic pain,

however, cannot be provided as the evidence base for the cost-effectiveness of established pain

treatments is rather weak and the comparability of results across studies is limited due to very

heterogeneous methods across trials [65].

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Limitations

First, when interpreting the results, it has to be considered that the study was not powered to

statistically test health economic differences. Second, the costs and effects were evaluated over six

months. Therefore, no conclusions regarding the long-term cost-effectiveness can be drawn. Finally,

costs were assessed via self-report. However, as the questionnaire used in this study is a valid

instrument to recall periods up to 3 months [66], the impact of this bias on results is limited.

Implications and future research

For patients with chronic pain, IMIs might become an important alternative to established

interventions. IMIs can expand treatment options for people, whose physical impairment or location

makes access to relevant care difficult [19]. Findings from this health economic evaluation study show

that both the guided and unguided version of ACTonPain have the potential of being cost-effective.

Thus, the decision whether to choose the guided or unguided version is a public health issue and

strongly depends on whether to mainly focus on patients´ health or societies´ resources. If the focus is

set on health improvement, the guided version should be preferred. Under economic aspects

ACTonPainunguided might be the preferred intervention. Future research should examine long-term

follow-up studies and further evaluate the (comparative) cost-effectiveness of different guidance

formats of IMIs, particularly of ACTonPain, and established pain treatments. Moreover, future studies

should examine ACTonPain as integrated part of multi-component pain programs and aim to

dismantle the ingredients that are effective and cost-effective in those complex approaches.

DECLARATIONS

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-

profit sectors. The article processing charge was funded by the German Research Foundation (DFG)

and the Albert Ludwigs University Freiburg in the funding programme Open Access Publishing.

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Competing interests

Two of the authors of the manuscript were involved in the development of ACTonPain (JL and HB).

HB and DDE are consultants for several stakeholders (insurance companies, ministries, psychotherapy

chambers, companies). DDE is part of the GET.ON Institut GmbH, which aims at implementing

evidence-based internet- and mobile based interventions into routine care. SP, CB, FK and DL declare

that they have no competing interests.

Data sharing statement

The datasets used and/or analyzed during the current study are available from the corresponding

author on reasonable request.

Authors’ contributions

JL and HB initiated the randomized control trial for this health economic evaluation. SP, FK, CB, DL

and DDE contributed to the design of this health economic evaluation. SP, DL, FK and CB

contributed to the data analysis. SP had full access to all the data in the study and had responsibility

for the decision to submit for publication. SP wrote the draft of the manuscript. All authors contributed

to the further writing and approved the final version of the manuscript.

Acknowledgements

We would like to thank Yannik Terhorst and Nelli Hirschauer for their assistance in data processing.

Figure Legends

Figure 1. Cost-effectiveness planes of all group comparisons based on 5,000 replicates of the

incremental cost-effectiveness ratio using mean differences in costs from a societal perspective and

mean incremental effects (treatment response: a, b, c; QALYs: d, e, f)

Figure 2. Cost-effectiveness acceptability curves of all group comparisons based on 5,000 replicates

of the incremental cost-effectiveness ratio using mean differences in costs from a societal

perspective and mean incremental effects (treatment response: a, b; QALYs: c, d). For the

comparison of ACTonPain guided vs. ACTonPain unguided the inverse function (ACTonPain

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unguided vs. ACTonPain guided) was included.

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53. Paganini S, Teigelkötter W, Buntrock C, Baumeister H. Economic evaluations of internet-based

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56. Dagenais S, Caro J, Haldeman S. A systematic review of low back pain cost of illness studies in the

United States and internationally. The spine journal. 2008;8:8–20.

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58. Katz JN. Lumbar disc disorders and low-back pain: socioeconomic factors and consequences.

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61. Turk DC. Clinical Effectiveness and Cost-Effectiveness of Treatments for Patients With Chronic

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62. Phillips CJ. Economic burden of chronic pain. Expert Rev Pharmacoecon Outcomes Res.

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63. Lin C-WC, Haas M, Maher CG, Machado LAC, van Tulder MW. Cost-effectiveness of guideline-

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03.01.2017. Accessed 24 Jan 2018.

65. Furlan AD, Yazdi F, Tsertsvadze A, Gross A, van Tulder M, Santaguida L, et al. A systematic review

and meta-analysis of efficacy, cost-effectiveness, and safety of selected complementary and

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Figure 1. Cost-effectiveness planes of all group comparisons based on 5,000 replicates of the incremental cost-effectiveness ratio using mean differences in costs from a societal perspective and mean incremental

effects (treatment response: a, b, c; QALYs: d, e, f)

363x190mm (150 x 150 DPI)

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Figure 2. Cost-effectiveness acceptability curves of all group comparisons based on 5,000 replicates of the incremental cost-effectiveness ratio using mean differences in costs from a societal perspective and mean incremental effects (treatment response: a, b; QALYs: c, d). For the comparison of ACTonPain guided vs.

ACTonPain unguided the inverse function (ACTonPain unguided vs. ACTonPain guided) was included.

296x195mm (150 x 150 DPI)

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Additional file 1 – CHEERS checklist

Section/item Item

No

Recommendation Reported on page

No

Title and abstract

Title 1 Identify the study as an economic evaluation or

use more specific terms such as “cost-

effectiveness analysis”, and describe the

interventions compared.

Page 1

Abstract 2 Provide a structured summary of objectives,

perspective, setting, methods (including study

design and inputs), results (including base case

and uncertainty analyses), and conclusions.

Page 2 and 3 (the

sensitivity analysis

is not mentioned

in the abstract

due to limited

words)

Introduction

Background and

objectives

3 Provide an explicit statement of the broader

context for the study.

Present the study question and its relevance for

health policy or practice decisions.

Page 4 and 5

Methods

Target population

and subgroups

4 Describe characteristics of the base case

population and subgroups analysed, including

why they were chosen.

Page 5

Setting and location 5 State relevant aspects of the system(s) in which

the decision(s) need(s) to be made.

Page 5

Study perspective 6 Describe the perspective of the study and relate

this to the costs being evaluated.

Page 5, 8 and 9

Comparators 7 Describe the interventions or strategies being

compared and state why they were chosen.

Page 6

Time horizon 8 State the time horizon(s) over which costs and

consequences are being evaluated and say why

appropriate.

Page 6 and 7

Discount rate 9 Report the choice of discount rate(s) used for

costs and outcomes and say why appropriate.

Page 9

Choice of health

outcomes

10 Describe what outcomes were used as the

measure(s) of benefit in the evaluation and their

relevance for the type of analysis performed.

Page 6 and 7

Measurement of

effectiveness

11a Single study-based estimates: Describe fully the

design features of the single effectiveness study

and why the single study was a sufficient source

of clinical effectiveness data.

Page 4 and 5

11b Synthesis-based estimates: Describe fully the

methods used for identification of included

studies and synthesis of clinical effectiveness

data.

N/A

Measurement and

valuation of

preference based

outcomes

12 If applicable, describe the population and

methods used to elicit preferences for outcomes.

Page 7

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Section/item Item

No


No

Estimating costs and

resources

13a Single study-based economic evaluation:

Describe approaches used to estimate resource

use associated with the alternative

interventions. Describe primary or secondary

research methods for valuing each resource item

in terms of its unit cost. Describe any

adjustments made to approximate to

opportunity costs.

Page 7 and 8,

Table 1

13b Model-based economic evaluation: Describe

approaches and data sources used to estimate

resource use associated with model health

states. Describe primary or secondary research

methods for valuing each resource item in terms

of its unit cost. Describe any adjustments made

to approximate to opportunity costs.

N/A

Currency, price date

and conversion

14 Report the dates of the estimated resource

quantities and unit costs. Describe methods for

adjusting estimated unit costs to the year of

reported costs if necessary. Describe methods for

converting costs into a common currency base

and the exchange rate.

Page 7 and 8

Choice of model 15 Describe and give reasons for the specific type of

decision-analytical model used. Providing a figure

to show model structure is strongly

recommended.

N/A

Assumptions 16 Describe all structural or other assumptions

underpinning the decision-analytical model.

N/A

Analytical methods 17 Describe all analytical methods supporting the

evaluation. This could include methods for

dealing with skewed, missing, or censored data;

extrapolation methods; methods for pooling

data; approaches to validate or make

adjustments (such as half cycle corrections) to a

model; and methods for handling population

heterogeneity and uncertainty.

Page 9, 10 and 11

Results

Study parameters 18 Report the values, ranges, references, and, if

used, probability distributions for all parameters.

Report reasons or sources for distributions used

to represent uncertainty where appropriate.

Providing a table to show the input values is

strongly recommended.

Page 11-16, Table

2 and 4

Incremental costs

and outcomes

19 For each intervention, report mean values for the

main categories of estimated costs and outcomes

of interest, as well as mean differences between

the comparator groups. If applicable, report

incremental cost-effectiveness ratios.

Page 12 and 13;

Table 3

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Section/item Item

No


No

Characterising

uncertainty


Describe the effects of sampling uncertainty for

the estimated incremental cost and

incremental effectiveness parameters, together

with the impact of methodological assumptions

(such as discount rate, study

perspective).

Page 15 and

Figure 1

20b Model-based economic evaluation: Describe the

effects on the results of uncertainty for all input

parameters, and uncertainty related to the

structure of the model and assumptions.

N/A

Characterising

heterogeneity

21 If applicable, report differences in costs,

outcomes, or cost-effectiveness that can be

explained by variations between subgroups of

patients with different baseline characteristics or

other observed variability in effects that are not

reducible by more information.

N/A

Discussion

Study findings,

limitations,

generalisability, and

current knowledge

22 Summarise key study findings and describe how

they support the conclusions reached. Discuss

limitations and the generalisability of the findings

and how the findings fit with current knowledge.

Page 16-18

Other

Source of funding 23 Describe how the study was funded and the role

of the funder in the identification, design,

conduct, and reporting of the analysis. Describe

other non-monetary sources of support.

Page 18

Conflicts of interest 24 Describe any potential for conflict of interest of

study

contributors in accordance with journal policy. In

the absence of a journal policy, we recommend

authors comply with International Committee of

Medical Journal Editors recommendations.

Page 19

N/A, Not applicable

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For peer review onlyA guided and unguided internet- and mobile-based

intervention for chronic pain: Health economic evaluation alongside a randomized controlled trial

Journal: BMJ Open

Manuscript ID bmjopen-2018-023390.R1


Date Submitted by the Author: 17-Jul-2018

Complete List of Authors: Paganini, Sarah; Albert-Ludwigs-Universitat Freiburg, Department of Rehabilitation Psychology and Psychotherapy, Institute of PsychologyLin, Jiaxi; University of Freiburg, Department of Sports and Sport ScienceKählke, Fanny; Friedrich-Alexander University of Erlangen-Nuremberg, Department of Clinical Psychology and PsychotherapyBuntrock, Claudia; Friedrich-Alexander-Universitat Erlangen-Nurnberg, Clinical Psychology and PsychotherapyLeiding, Delia; RWTH Aachen University, Department of Psychiatry, Psychotherapy and PsychosomaticsEbert, David; Friedrich-Alexander University Erlangen Nuremberg, Clinical Psychology and PsychotherapyBaumeister, Harald; Universitat Ulm, Institut of Psychology and Education, Department of Clinical Psychology and Psychotherapy;

<b>Primary Subject Heading</b>: Mental health

Secondary Subject Heading: Health economics, Mental health



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1

A guided and unguided internet- and mobile-based intervention for chronic pain: Health

economic evaluation alongside a randomized controlled trial

S. Paganini 1a

, J. Lin2, F. Kählke

3, C. Buntrock

3, D. Leiding

4, D.D. Ebert

3, H. Baumeister

5

1Department of Rehabilitation Psychology and Psychotherapy, Institute of Psychology, University of

Freiburg, Germany, [email protected]

2Department of Sports and Sport Science, University of Freiburg, Germany, [email protected]

freiburg.de

3Department of Clinical Psychology and Psychotherapy, Friedrich-Alexander University of Erlangen-

Nuremberg, Germany, [email protected], [email protected], [email protected]

4Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Germany,

[email protected]

5Department of Clinical Psychology and Psychotherapy, Institute of Psychology and Education,

University of Ulm, Germany, [email protected]

a Corresponding author: Sarah Paganini, Department of Rehabilitation Psychology and

Psychotherapy, Institute of Psychology, University of Freiburg, Engelbergerstr. 41, D-79085 Freiburg,

Phone: ++49-761-203-3045, Fax: ++49-761-203-3040, Email: [email protected]

freiburg.de

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ABSTRACT

Objective: This study aims at evaluating the cost-effectiveness and cost-utility of a guided and

unguided internet-based intervention for chronic pain patients (ACTonPainguided/ACTonPainunguided)

compared to a waitlist control (WLC) condition as well as the comparative cost-effectiveness of the

two interventions.

Design: This is a health-economic evaluation alongside a three-armed randomized controlled trial

from a societal perspective. Assessments were conducted at baseline, nine weeks and six months after

randomization.

Setting: Participants were recruited through comprehensive online and offline strategies and in

collaboration with a German health insurance company.

Participants: 302 adults (≥18 years, pain for at least six months, with at least Grade II in the Chronic

Pain Grade) were randomly allocated to one of the three groups (ACTonPainguided, ACTonPainunguided,

WLC).


Therapy. ACTonPainguided/ACTonPainunguided only differ in provision of human support.

Primary and secondary outcome measures: Main outcomes of the cost-effectiveness and the cost-

utility analyses were treatment response (meaningful change in pain interference) and quality-adjusted

life years (QALYs), respectively.

Results: At 6-month follow-up treatment response and QALYs were highest in ACTonPainguided (44%

and 0.280; mean costs=€6,945), followed by ACTonPainunguided (28% and 0.266; mean costs=€6,560)

and WLC (16% and 0.244; mean costs=€6,908). At a willingness-to-pay of €0 the probability of being

cost-effective was 50% for ACTonPainguided and 66% for ACTonPainunguided, respectively, for both

treatment response and QALY compared to WLC and in the comparative analysis 35% per treatment

response and 31% per QALY gained.

Conclusions:

Findings indicate that ACTonPain has the potential of being a cost-effective alternative or adjunct to

established pain treatment, with ACTonPainunguided (vs. WLC) even leading to lower costs at better

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health outcomes. The direct comparison of the two interventions indicates a preference for

ACTonPainunguided under health economic aspects.

Trial Registration: German Clinical Trial Registration: DRKS00006183,


183




• This is the first study that evaluates the (comparative) cost-effectiveness of a guided and an

unguided internet-based intervention for individuals with chronic pain.

• In this study state-of-the-art statistical methods such as seemingly unrelated regression

equations models or non-parametric bootstrapping techniques were applied.

• Results should be interpreted cautiously, as the study was not powered to statistically test


• As the costs and effects were evaluated over six months, no conclusions regarding the long-


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BACKGROUND





(ACT, a particular form of CBT) have shown to be effective for chronic pain patients [11, 12] and

could show acceptable results concerning cost-effectiveness [13]. However, accessibility and

availability of treatment is often restricted and up to 40% of individuals with chronic pain do not

receive adequate pain management [1, 14]. Internet- and mobile- based interventions (IMIs) are an

effective, acceptable and feasible way for providing psychological interventions [15, 16]. IMIs for

chronic pain have been shown to effectively improve pain interference compared to different control

groups, such as standard (medical) care, text-based material and mostly waitlist control condition

(standardized mean difference (SMD)=.4 [17], SMD=−0.50 [18]).









To the best of our knowledge no randomized controlled trial (RCT) has investigated the (comparative)

cost-effectiveness of a guided and unguided IMI for chronic pain. However, Boer and colleagues

found that an IMI for chronic pain was cost-effective compared to a face-to-face group intervention

(concerning a one-point-improvement in a pain catastrophizing scale) [23]. Lin and colleagues

recently finalized a three arm RCT comparing a guided and unguided version of an Acceptance and

Commitment Therapy based IMI for chronic pain (ACTonPain) against a waitlist control group [24,

25]. Compared to the waitlist control condition, ACTonPainguided showed significantly lower pain

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5

interference at nine weeks and six months after randomization (d=0.58). Differences between

ACTonPainunguided and the control group and between both ACTonPain groups were not statistically

significant [25].




METHODS


















Randomization


and were randomly allocated to one of the three conditions ACTonPainguided, ACTonPainunguided and

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waitlist. Permuted block randomization with variable block sizes (6, 9, 12) was performed by an

independent researcher not otherwise involved in the study using an automated, web-based

randomization program.

Interventions












Outcome measures

Assessment took place at baseline (T0), post-treatment (T1; nine weeks after randomization) and 6-



Treatment response

Main clinical outcome in the cost-effectiveness analysis was treatment response. This outcome was

not defined in the protocol paper. However, it was chosen to calculate a reliable and meaningful

change in pain interference according to the recommendations of the Initiative on Methods,

Measurement, and Pain Assessment in Clinical Trials (IMMPACT) [33] instead of a one-point change

on the MPI, that would be difficult to interpret.

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According to the IMMPACT recommendations clinically important changes were identified with a

combination of a distribution-based approach (Pain Interference Scale of the Multidimensional Pain

Inventory MPI [30, 31]) and an anchor-based approach (Patient Global Impression of Change scale

PGIC [32]) [33]. First, participants with a change of 0.6 points (based on the scale’s standard

deviation) on the Pain Interference Scale of the MPI (range of the scale: 0-6) were identified as having

minimal clinically important changes [33]. Second, participants were identified, that rated their global

improvement in the PGIC [32] as “minimally, much or very much improved”. Participants who

fulfilled both criteria were classified as having achieved a clinically important change [33], defined as

“treatment response”.



AQoL-8D [34] in the main analysis and the EQ5D-3L [35] in the sensitivity analysis. Utility scores

are a preference-based measure of quality of life that is normed by the value 1 meaning complete

health and 0 meaning death [36].





focus of research [34], whereas utility weights are derived from the Australian adult population [37].








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was adapted to the German health care system and to the healthcare use of individuals with chronic

pain. It was used to assess the direct and indirect costs of the past three month at T0 and T2. Costs

were expressed in Euros (€) for the reference year 2015 (index factor 1.003 and 1.01 for outpatient

medical service, respectively) referring to the German consumer price index [45] (list of unit cost

prices see Table 1). To calculate the 6-month accumulated per-participants costs, the area under curve

(AUC) method was used by linearly interpolating 3-month costs (measured at T0 und T2) to cover the

full period of six months [42].

�� = ��03 + ��232 � ∗ 3 + ��2

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9



Ou

tpat

ien

t m

edic

al s

erv

ice

/

outp

atie

nt

sect

or

Euro/contact

Physician Gynecologist

Orthopedist

Specialists for internal medicine Ophthalmologist

Dermatologist

ETN specialist Surgeon

Urologist

Neurologist

Psychotherapist

Dentist

20.81 31.62

25.82

64.25 36.96

19.58

28.12 44.59

25.20

47.02

79.42

55.24

remedies Logopedics / speech therapy Physiotherapy

Ergotherapy / occupational therapy

Podiatry / podology Mean remedies

41.02 17.50

39.45

29.13 31.77

hospitals Euro/day

Completely stationary normal ward

Completely stationary intensive care Completely stationary psychiatry

Semi-stationary general hospital

Semi-stationary psychiatry

648.11

1,424.60 348.26

421.27

226.37

rehabilitation Euro/day Outpatient

Inpatient

49.43

138.19

opportunitiy costs Euro/hour

opportunity costs (free time)

opportunity costs (work)

substitution costs for informal care

21.77

31.89

18.97

Note: Prices for outpatient medical service/outpatient sector were calculated fort the year 2013; all other prices

for the year 2014 [46, 47] and adjusted by the German consumer price index for 2015 [45]. ETN specialist, Ear,

nose, and throat specialist.


Healthcare costs (e.g. out- and inpatient care) were calculated according to the German guideline of






each kilometer was valued at €0.30. Opportunity costs (i.e., time spent at the practitioners waiting

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€18.97 per hour [47].

Indirect costs







Intervention costs












conducted and reported elsewhere [25] in accordance with the CONSORT 2010 Statement[51].



obtain the most likely values of the missing cost data. At baseline, AQoL-utilities differed between

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groups (ACTonPainguided: M=0.496, SD=0.16; ACTonPainunguided: M=0.485, SD=0.17; waitlist:

M=0.463, SD=0.14). Therefore, baseline adjustments were made in further calculations.























We tested the robustness of the outcomes of the main analysis in a sensitivity analysis. Therefore, we

used the EQ-5D-3L as a widely used instrument for calculating QALYs. As baseline EQ5D-utilities

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12

differed between groups (ACTonPainguided: M=0.469, SD=0.32; ACTonPainunguided: M=0.436,

SD=0.31; waitlist: M=0.494, SD=0.3), baseline adjustment was made in the sensitivity analyses.



were they involved in developing plans for design or implementation of the study. Possible negative

effects were assessed as well as the satisfaction with the intervention (for results, see [25]). The results

of the research will be disseminated to those study participants who wished to be notified.

RESULTS



follow-up (ACTonPainguided: 33/100; ACTonPainunguided: 35/101; waitlist: 10/101). At 6-month follow








Outcomes






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Table 2. Treatment response and quality-adjusted life-year (QALY) outcomes and group differences at

6-month follow up.

ACTonPain guided

(n = 100)

ACTonPain unguided

(n = 101)

WLC group

(n = 101)

Test statistic

Mean (SD) Mean (SD) Mean (SD) χ2 (df=2) Post-hoc test

c: p

Treatment response

(pain interference)

0.44 (0.05)

0.277 (0.04)

0.158 (0.04)

19.44 a

<001

ACTonPain guided vs. WLC group t(1)=4.52 <.001

ACTonPain unguided vs. WLC group t(1)=1.91 .17

ACTonPain guided vs. unguided t(1)=2.61 .03

QALY

AQoL-8D

0.280 (0.08)

0.266 (0.09)

0.244 (0.08)

9.45 b

.009

ACTonPain guided vs. WLC group Z=-3.07 .003

ACTonPain unguided vs. WLC group Z=-1.61 .16

ACTonPain guided vs. unguided Z=-1.47 .21

EQ5D-3L 0.274 (0.12) 0.255 (0.12) 0.253 (0.13) 2.17 b .34

WLC group, waitlist control group; SD, standard deviation; df, degrees of freedom; QALY, quality-adjusted life-

year a Chi-squared test b Kruskall-Wallis H test

c Post-hoc test for treatment response: Bonferroni pairwise comparison; Post-hoc test for QALY: Dunn´s test

Costs









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Table 3. 6-month accumulated per-participants costs (in €) by condition (based on intention-to-treat

sample, N = 302).

ACTonPain guided

(n = 100)

ACTonPain unguided

(n = 101)

WLC group

(n = 101)

Incremental costs

Difference, €

Mean, €

(SD)

Mean, €

(SD)

Mean

, €

(SD)

ACTon

Pain guided

vs.

WLC

ACTon

Pain unguided

vs.

WLC

ACTon

Pain guided

vs. unguided

Intervention 299 (-) 69 (-) 0 (-) 299 69 230


Health care costs

Medical specialist 576 (478) 511 (381) 511 (382) 65 0 65

Mental health care 212 (431) 181 (397) 258 (455) -46 -77 31

Other medical

specialist a

369 (515) 357 (435) 406 (576) -37 -49 12

In-patient care

(hospital)

198 (479) 173 (369) 141 (420) 57 32 25

Day care 147 (687) 122 (381) 306 (1,584) -159 -184 25

Rehabilitation 190 (794) 134 (507) 191 (773) -1 -57 56

Medication 1,092 (2,748) 784 (1,438) 660 (1,638) 432 124 308

Therapeutic appliances 65 (139) 86 (222) 46 (96) 19 40 -21

Direct non-medical costs


Travel 131 (229) 105 (150) 101 (100) 30 4 26

Domestic help 1,297 (4,064) 1,147 (1,936) 840 (1,490) 457 307 150

Opportunity costs b 1,553 (1,965) 1,925 (3,251) 1,759 (3,116) -206 166 -372

Indirect costs

Productivity losses

Absenteeism 517 (1,647) 647 (1,979) 1,133 (3,333) -616 -486 -130

Presenteeism 300 (740) 320 (774) 555 (1,360) -255 -235 -20

Total direct costs 5,829 (7,129) 5,525 (4,959) 5,220 (5,133) 611 306 305

Total indirect costs 817 (1,978) 966 (2,283) 1,688 (3,735) -871 -721 -150

Total societal costs 6,945 (7,327) 6,560 (5,549) 6,908 (6,279) 39 -346 385

WLC group, waitlist control group a i.e. physiotherapist, occupational therapist

b i.e. for waiting time before treatment




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Analysis


WLC group

Incremental

costs, €

(95% CI)

Incremental

effects

(95% CI)

Mean

ICER

(95% CI)

Distribution over the ICER

plane

NE NW SE SW

Cost-effectiveness,

treatment response

(MPI and PGIC)

6

(-916-953)

0.14

(0.08-0.2)

171

(-6,671-8,260)

50% - 50% -

Cost-utility

AQoL QALYs

6

(-916-953)

0.01

(0.005- 0.015)

3,033

(-92,924-

114,325)

50%

-

50%

-


EQ5D QALYs 6

(-916-953)

0.014

(0.004- 0.024)

4726 (-69,407-

122,314)

50% - 50% -

Analysis

ACTonPain unguided vs.

WLC group

Incremental

costs, €

(95% CI)

Incremental

effects

(95% CI)

Mean

ICER

(95% CI)


plane

NE NW SE SW

Cost-effectiveness,

treatment response

(MPI and PGIC)

-352

(-1,968-

1,272)

0.12

(0.006-0.232)

ACTonPain unguided

dominates

WLC

32% 1% 66% 1%

Cost-utility

AQoL QALYs

-352

(-1,968-

1,272)

0.013

(0.002-0.024)

ACTonPain unguided

dominates

WLC

32%

1%

66%

1%


EQ5D QALYs -352

(-1,968-

1,272)

0.017

(-0.005- 0.04)

ACTonPain unguided

dominates

WLC

30% 4% 64% 3%

Analysis


ACTonPain unguided

Incremental

costs, €

(95% CI)

Incremental

effects

(95% CI)

Mean

ICER

(95% CI)


plane

NE NW SE SW

Cost-effectiveness,

treatment response

(MPI and PGIC)

388

(-1,416-

2,185)

0.164

(0.034-0.29)

2,949

(-11,097-

25,276)

65% - 35% -

Cost-utility

AQoL QALYs

388

(-1,416-

2,185)

0.008

(-0.003-0.019)

198,377 a

60%

5%

33%

2%


EQ5D QALYs 388

(-1,416-

2,158)

0.01

(-0.01- 0.031)

114,858 a

53% 12% 31% 4%

WLC group, waitlist control group; MPI, Pain Interference Scale of the Multidimensional Pain Inventory;

PGIC, Patient Global Impression of Change scale; 95% CI, 95% confidence interval; EQ-5D QALYs,

Quality-adjusted life years based on EuroQol; ICER, incremental cost-effectiveness ratio; NE, northeast

quadrant; NW, northwest quadrant; SE, southeast quadrant; SW, southwest quadrant. aA dependably accurate 95% confidence interval for this distribution cannot be defined because there is no line

through the origin that excludes α/2 of the distribution[53].

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Cost-effectiveness


are shown in Figure 1(a,b,c) and 2(a,b). ACTonPainguided showed the same and ACTonPainunguided a





€13,460.





Figure 2b).

- Figure 1-

- Figure 2-

Cost-utility

Cost-effectiveness planes and acceptability curves that refer to cost-utility are shown in figure 1(d,e,f)

and 2(c,d). ACTonPainguided showed the same and ACTonPainunguided a higher potential of being cost-

effective compared to waitlist at a WTP of €0 (50% and 66%, respectively). The interventions’





WTP increases up to €113,550 this probability rises to 70% and stagnates on this level. The break-

even point is at €41,350 (see Figure 2d).


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After non-parametric bootstrapping, using the EQ-5D-3L resulted in smaller incremental QALY gains

in all comparisons compared to the results using the AQoL-8D (see table 4).

At a WTP of €0 the probability of ACTonPainguided of being cost-effective compared to waitlist was

50%. The probability of ACTonPainunguided of being cost-effective compared to waitlist was 64% at a

WTP of €0. ACTonPainguided vs. ACTonPainunguided resulted in a probability of being cost-effective of

31% at a WTP of €0.

DISCUSSION

Comparing both ACTonPain interventions to waitlist and by taking uncertainty into account,

ACTonPainunguided can be judged as a potentially cost-effective intervention as it dominates WLC by

leading to higher QALY gains and more individuals with a treatment response at lower costs.

ACTonPainguided also causes better results in the main outcome parameters, but at (slightly) higher

costs with ICERs of 171 (treatment response) and 3,033 (AQoL QALY gains). The probability of

being cost-effective at a WTP of €0 compared to waitlist is higher in ACTonPainunguided, for both,

treatment response and QALYs gained (66%) than in ACTonPainguided (50%).

However, when comparing the costs that would have to be invested by using ACTonPainguided

(compared to waitlist) for a QALY gained (€3,033) to the only official WTP threshold stated by the

National Institute for Health and Clinical Excellence (NICE) of £20,000 to £30,000 [54] (~ €22,647 -

€33,971; conversion according to the European Central bank [55]), this intervention would also be

categorized as a potentially cost-effective treatment, whereas again uncertainty has to be considered.

The direct comparison of ACTonPainguided and ACTonPainunguided shows more treatment responders

and higher QALY gains for the guided version, but at higher costs. According to the NICE guidelines

costs are far above the WTP threshold for a QALY gain and would thus be judged as probably not

cost-effective. In terms of QALYs gained, the guided version only reaches a probability of 31% of

being cost-effective at a WTP of €0 and even with rising WTP threshold, the probability does not

increase much (e.g. at a WTP of €50,000 to about 53%).

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The results of the sensitivity analyses revealed slightly higher incremental QALY gains by using the

EQ5D-3L compared to the AQoL-8D but overall conclusions are the same as in the main analyses.

Estimated EQ-5D utility scores for one year ranged from 0.50 to 0.54, what appears rather low

compared to national EQ-5D estimates for (back) pain from other countries (e.g. 0.74-0.79 [56, 57]).

Lower estimates in the current study could have occurred due to the sociodemographic properties of

this study sample, as participants were predominately women (84%), reported comorbid medical or

mental conditions (57% and 39%, respectively) and the back was the most often reported pain location

(34%) [25]. Several studies showed that the mentioned characteristics (female sex, musculoskeletal

and mental disorders) are associated with lower quality of life scores [56–58]. Furthermore, Burström

et al. (2001) reported in their study that participants with low back pain showed quality of life weights

of 0.55 [58], what is comparable to the sample in the current study.

The conclusion of ACTonPain being cost-effective are in line with a recent study and a review about

the cost-effectiveness of IMIs for depression [23, 59]. The guided IMI for chronic pain of Boer and

colleagues revealed an ICER of 40 (defined as cost savings of €40) for an one-point improvement in a

pain catastrophizing scale compared to a face-to-face group intervention, while QALYs were not

reported [23]. ACTonPainguided reached higher ICERs for the clinical outcome pain interference (171

compared to waitlist group and 2,949 compared to the unguided group). However, these values were

calculated for treatment response in terms of pain interference and therefore, a meaningful change and

not for a one-point improvement on the scale. In a systematic review, IMIs that were classified as cost-

effective were all guided and showed probabilities of being cost-effective between 28% and 49% at a

WTP of €0 for a QALY gained, whereas ACTonPainguided and the unguided version even reached

higher probabilities at this WTP level (50% and 66%, respectively). Thus, integrating psychological e-

health approaches in pain management programs might even be more promising from an economical

point of view when compared to the well-established area of depression e-health care.

The higher direct costs over a 6-month period in both intervention groups compared to waitlist might

be explained by higher or stable health care utilization similar to findings in a previous study on the

costs of established depression treatments [60]. However, research indicates that indirect rather than

direct costs represent the majority of overall costs [61, 62], where ACTonPain seemingly has its core

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advantage. Mean indirect costs over the 6-month period were almost half as high in the intervention

groups compared to waitlist, regarding both absenteeism and presenteeism.

Next to the questions of whether ACTonPain is cost-effective compared to waitlist and whether it

should rather be provided guided or unguided with possible answers such as “both interventions are

potentially cost-effective, but uncertainties have to be taken into account” and “in terms of cost-

effectiveness, the unguided version should be preferred”, it would be of interest how ACTonPain

performs compared to established medical, psychological, physiotherapeutical, and surgical treatments

that result in high direct costs [63–66]. However, surprisingly little is known about the cost-

effectiveness of these established pain treatments. In two reviews it was highlighted, that

interdisciplinary pain rehabilitation programs are more cost-effective or produce lower costs than

interventions such as surgery and conservative care [67, 68]. For individuals with low back pain it was

concluded that interdisciplinary rehabilitation, exercise, acupuncture, spinal manipulation and CBT are

potentially cost-effective [69]. A further systematic review focused on economic evaluations of third-

wave CBT therapies (including ACT), were available ICERs ranged from -€19,300 (National Health

Service perspective, converted into Euro [55]) to €56,637 (societal perspective) per QALY gained

[13]. When compared to waitlist the ICERs based on the AQoL-8D in this study were €3,033 and a

negative ICER (indicating dominance of the unguided intervention over WLC) per QALY gained.

Thus, it seems safe to argue that ACTonPain, as an example of an innovative IMI for the treatment of

chronic pain, is effective [25] and can be an cost-effective intervention. A comparison across treatment

approaches for chronic pain, however, cannot be provided as the evidence base for the cost-

effectiveness of established pain treatments is rather weak and the comparability of results across

studies is limited due to very heterogeneous methods across trials [70].

Limitations



months. Therefore, no conclusions regarding the long-term cost-effectiveness can be drawn. Third,

costs were assessed via self-report. However, as the questionnaire used in this study is a valid

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instrument to recall periods up to three months [71], the impact of this bias on results is limited.

Finally, the usage of multiple imputation techniques is frequently recommended (e.g. predictive mean

matching [72]. We used a single imputation approach as it was done in the main (effectiveness)

analysis [25] that might not truly reflect missing data uncertainty. However, the comparison with cost

and QALY outcomes of complete case analysis revealed only small differences, indicating that the risk

of implausible values due to single imputation in this evaluation is low [73]. Furthermore, by using the

non-parametric bootstrapping, sampling was considered.





that both versions of ACTonPain have the potential of being cost-effective, with the unguided version

even leading to lower costs (compared to WLC). The decision whether to choose the guided or

unguided version is a public health issue and strongly depends on whether to mainly focus on patients´

health or societies´ resources. Under health economic aspects ACTonPainunguided should be the

preferred intervention, especially when considering the intention of treatment implementation into the

health care system and scaling up mental health care for pain patients.

Future research should especially focus on conducting methodologically sound studies that are

powered to statistically test health economic differences. Furthermore, long-term follow-up studies

and evaluation of (comparative) cost-effectiveness of different guidance formats of IMIs, particularly

of ACTonPain, and established pain treatments are needed. Moreover, future studies should examine

ACTonPain as integrated part of multi-component pain programs and aim to dismantle the ingredients

that are effective and cost-effective in those complex approaches.

DECLARATIONS

Funding

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and the Albert-Ludwigs University Freiburg in the funding programme Open Access Publishing.

Competing interests















Acknowledgements


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Figure Legends









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73. Vroomen JM, Eekhout I, Dijkgraaf MG, van Hout H, Rooij SE de, Heymans MW, Bosmans JE.

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effects (treatment response: a, b, c; QALYs: d, e, f).

122x63mm (300 x 300 DPI)

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422x274mm (300 x 300 DPI)

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Additional file 1 – CHEERS checklist

Section/item Item

No


No

Title and abstract

Title 1 Identify the study as an economic evaluation or

use more specific terms such as “cost-

effectiveness analysis”, and describe the

interventions compared.

Page 1

Abstract 2 Provide a structured summary of objectives,

perspective, setting, methods (including study

design and inputs), results (including base case

and uncertainty analyses), and conclusions.

Page 2 and 3 (the

sensitivity analysis

is not mentioned

in the abstract

due to limited

words)

Introduction

Background and

objectives

3 Provide an explicit statement of the broader

context for the study.

Present the study question and its relevance for

health policy or practice decisions.

Page 4 and 5

Methods

Target population

and subgroups

4 Describe characteristics of the base case

population and subgroups analysed, including

why they were chosen.

Page 5

Setting and location 5 State relevant aspects of the system(s) in which

the decision(s) need(s) to be made.

Page 5

Study perspective 6 Describe the perspective of the study and relate

this to the costs being evaluated.

Page 5, 8 and 9

Comparators 7 Describe the interventions or strategies being

compared and state why they were chosen.

Page 6

Time horizon 8 State the time horizon(s) over which costs and

consequences are being evaluated and say why

appropriate.

Page 6 and 7

Discount rate 9 Report the choice of discount rate(s) used for

costs and outcomes and say why appropriate.

Page 9

Choice of health

outcomes

10 Describe what outcomes were used as the

measure(s) of benefit in the evaluation and their

relevance for the type of analysis performed.

Page 6 and 7

Measurement of

effectiveness

11a Single study-based estimates: Describe fully the

design features of the single effectiveness study

and why the single study was a sufficient source

of clinical effectiveness data.

Page 4 and 5

11b Synthesis-based estimates: Describe fully the

methods used for identification of included

studies and synthesis of clinical effectiveness

data.

N/A

Measurement and

valuation of

preference based

outcomes

12 If applicable, describe the population and

methods used to elicit preferences for outcomes.

Page 7

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Section/item Item

No


No

Estimating costs and

resources


Describe approaches used to estimate resource

use associated with the alternative

interventions. Describe primary or secondary

research methods for valuing each resource item

in terms of its unit cost. Describe any

adjustments made to approximate to

opportunity costs.

Page 7 and 8,

Table 1

13b Model-based economic evaluation: Describe

approaches and data sources used to estimate

resource use associated with model health

states. Describe primary or secondary research

methods for valuing each resource item in terms

of its unit cost. Describe any adjustments made

to approximate to opportunity costs.

N/A

Currency, price date

and conversion

14 Report the dates of the estimated resource

quantities and unit costs. Describe methods for

adjusting estimated unit costs to the year of

reported costs if necessary. Describe methods for

converting costs into a common currency base

and the exchange rate.

Page 7 and 8

Choice of model 15 Describe and give reasons for the specific type of

decision-analytical model used. Providing a figure

to show model structure is strongly

recommended.

N/A

Assumptions 16 Describe all structural or other assumptions

underpinning the decision-analytical model.

N/A

Analytical methods 17 Describe all analytical methods supporting the

evaluation. This could include methods for

dealing with skewed, missing, or censored data;

extrapolation methods; methods for pooling

data; approaches to validate or make

adjustments (such as half cycle corrections) to a

model; and methods for handling population

heterogeneity and uncertainty.

Page 9, 10 and 11

Results

Study parameters 18 Report the values, ranges, references, and, if

used, probability distributions for all parameters.

Report reasons or sources for distributions used

to represent uncertainty where appropriate.

Providing a table to show the input values is

strongly recommended.

Page 11-16, Table

2 and 4

Incremental costs

and outcomes

19 For each intervention, report mean values for the

main categories of estimated costs and outcomes

of interest, as well as mean differences between

the comparator groups. If applicable, report

incremental cost-effectiveness ratios.

Page 12 and 13;

Table 3

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Section/item Item

No


No

Characterising

uncertainty


Describe the effects of sampling uncertainty for

the estimated incremental cost and

incremental effectiveness parameters, together

with the impact of methodological assumptions

(such as discount rate, study

perspective).

Page 15 and

Figure 1

20b Model-based economic evaluation: Describe the

effects on the results of uncertainty for all input

parameters, and uncertainty related to the

structure of the model and assumptions.

N/A

Characterising

heterogeneity

21 If applicable, report differences in costs,

outcomes, or cost-effectiveness that can be

explained by variations between subgroups of

patients with different baseline characteristics or

other observed variability in effects that are not

reducible by more information.

N/A

Discussion

Study findings,

limitations,

generalisability, and

current knowledge

22 Summarise key study findings and describe how

they support the conclusions reached. Discuss

limitations and the generalisability of the findings

and how the findings fit with current knowledge.

Page 16-18

Other

Source of funding 23 Describe how the study was funded and the role

of the funder in the identification, design,

conduct, and reporting of the analysis. Describe

other non-monetary sources of support.

Page 18

Conflicts of interest 24 Describe any potential for conflict of interest of

study

contributors in accordance with journal policy. In

the absence of a journal policy, we recommend

authors comply with International Committee of

Medical Journal Editors recommendations.

Page 19

N/A, Not applicable

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Journal: BMJ Open



Date Submitted by the Author: 22-Oct-2018

Complete List of Authors: Paganini, Sarah; Albert-Ludwigs University Freiburg, Department of Sports and Sport Science, Sport Psychology; Albert-Ludwigs University Freiburg, Department of Rehabilitation Psychology and Psychotherapy, Institute of PsychologyLin, Jiaxi; Albert-Ludwigs University Freiburg, Department of Sports and Sport Science, Sport PsychologyKählke, Fanny; Friedrich-Alexander University of Erlangen-Nuremberg, Department of Clinical Psychology and PsychotherapyBuntrock, Claudia; Friedrich-Alexander-Universitat Erlangen-Nurnberg, Clinical Psychology and PsychotherapyLeiding, Delia; RWTH Aachen University, Department of Psychiatry, Psychotherapy and PsychosomaticsEbert, David; Friedrich-Alexander University Erlangen Nuremberg, Clinical Psychology and PsychotherapyBaumeister, Harald; Universitat Ulm, Institut of Psychology and Education, Department of Clinical Psychology and Psychotherapy





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1

A guided and unguided internet- and mobile-based intervention for chronic pain: Health economic evaluation alongside a randomized controlled trial

S. Paganini 1, 2a, J. Lin1, F. Kählke3, C. Buntrock3, D. Leiding4, D.D. Ebert3, H. Baumeister5

1Department of Sports and Sport Science, Sport Psychology, University of Freiburg, Germany, [email protected], [email protected]

2Department of Rehabilitation Psychology and Psychotherapy, Institute of Psychology, University of Freiburg, Germany

3Department of Clinical Psychology and Psychotherapy, Friedrich-Alexander University of Erlangen-Nuremberg, Germany, [email protected], [email protected], [email protected]

4Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Germany, [email protected]

5Department of Clinical Psychology and Psychotherapy, Institute of Psychology and Education, University of Ulm, Germany, [email protected]

a Corresponding author: Sarah Paganini, Department of Sports and Sport Science, Sport Psychology, University of Freiburg, Germany, Schwarzwaldstr. 175, 79117 Freiburg, Phone: +49 (0)761 / 203-4514, Email: [email protected]

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ABSTRACT

Objective: This study aims at evaluating the cost-effectiveness/cost-utility of a guided and unguided

internet-based intervention for chronic pain patients (ACTonPainguided/ACTonPainunguided) compared to a

waitlist control(WLC) condition as well as the comparative cost-effectiveness of the interventions.

Design: This is a health-economic evaluation alongside a three-armed randomized controlled trial from a

societal perspective. Assessments were conducted at baseline, nine weeks and six months after

randomization.

Setting: Participants were recruited through online and offline strategies and in collaboration with a health

insurance company.

Participants: 302 adults (≥18 years, pain for at least six months) were randomly allocated to one of the

three groups(ACTonPainguided,ACTonPainunguided,WLC).



Primary and secondary outcome measures: Main outcomes of the cost-effectiveness and the cost-utility

analyses were meaningful change in pain interference (treatment response) and quality-adjusted life years

(QALYs). Economic evaluation estimates were incremental cost-effectiveness/cost-utility ratios

(ICER/ICUR).

Results: At 6-month follow-up treatment response and QALYs were highest in ACTonPainguided(44% and

0.280; mean costs=€6,945), followed by ACTonPainunguided(28% and 0.266; mean costs=€6,560) and

WLC(16% and 0.244; mean costs=€6,908). ACTonPainguided vs. WLC revealed an ICER/ICUR of 171 and

3,033, respectively, while ACTonPainunguided dominated WLC. At a willingness-to-pay of €0 the

probability of being cost-effective was 50% for ACTonPainguided and 66% for ACTonPainunguided. This

probability rose to 95% when society´s willingness-to-pay is 91,000€(ACTonPainguided) and

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€127,000(ACTonPainunguided) per QALY. ACTonPainguided vs. ACTonPainunguided revealed an ICER/ICUR

of 2,949 and 198,377.

Conclusions:

Depending on society´s willingness-to-pay ACTonPain is a potentially cost-effective adjunct to

established pain treatment, with ACTonPainunguided (vs.WLC) even leading to lower costs at better health

outcomes. However, uncertainty has to be taken into account. Direct comparison of the two interventions

indicates a preference for ACTonPainunguided under health economic aspects.

Trial Registration: German Clinical Trial Registration:DRKS00006183,





This is the first study that evaluates the (comparative) cost-effectiveness of a guided and an


In this study state-of-the-art statistical methods such as seemingly unrelated regression equations

models or non-parametric bootstrapping techniques were applied.

Results should be interpreted cautiously, as the study was not powered to statistically test health

economic differences.

As the costs and effects were evaluated over six months, no conclusions regarding the long-term

cost-effectiveness can be drawn.

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BACKGROUND

Chronic pain is highly prevalent [1–4] and associated with substantial decreases in quality of life [1, 5, 6]

and high economic costs for society [3, 7–9]. Evidence supports psychological interventions as one

approach for effectively treating patients with chronic pain [10]. Treatment based on cognitive-behavioral

therapy (CBT) or third-wave therapies, like the Acceptance and Commitment Therapy (ACT, a particular

form of CBT) have been shown to be effective for chronic pain patients [11, 12] and could show

acceptable results concerning cost-effectiveness [13]. However, accessibility and availability of treatment

is often restricted and up to 40% of individuals with chronic pain do not receive adequate pain

management [1, 14]. Internet- and mobile- based interventions (IMIs) are an effective, acceptable and

feasible way for providing psychological interventions [15, 16]. IMIs for chronic pain have been shown to

effectively improve pain interference compared to different control groups, such as standard (medical)

care, text-based material and mostly waitlist control condition (standardized mean difference (SMD)=.4

[17], SMD=−0.50 [18]).

IMIs can not only facilitate the access to psychological treatment, they also have the potential to reduce

treatment costs [19, 20], particularly by saving therapist resources. IMIs can be delivered as guided or

unguided self-help interventions, with both versions usually necessitating less therapist time compared to

traditional on-site therapies [21]. A relevant health care policy question is what amount of professional

human guidance is necessary in order to improve patients´ health, with guided IMIs being seemingly more

effective than unguided IMIs [21, 22]. However, as unguided IMIs can be delivered at lower costs per

participant, they might as well be an attractive option particularly given their high scalability on a

population level.

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cost-effectiveness of a guided and unguided IMI for chronic pain. However, Boer and colleagues found

that an IMI for chronic pain was cost-effective compared to a face-to-face group intervention (concerning

a one-point-improvement in a pain catastrophizing scale) [23]. Lin and colleagues recently finalized a

three arm RCT comparing a guided and unguided version of an Acceptance and Commitment Therapy

based IMI for chronic pain (ACTonPain) against a waitlist control group [24, 25]. Compared to the

waitlist control condition, ACTonPainguided showed significantly lower pain interference at nine weeks and

six months after randomization (d=0.58). Differences between ACTonPainunguided and the control group

and between both ACTonPain groups were not statistically significant [25].

The present paper provides the cost-effectiveness and cost-utility of ACTonPainguided/unguided compared to

the waitlist control condition as well as the comparative cost-effectiveness of ACTonPainguided/unguided.

METHODS


This health-economic evaluation was conducted with a 6-month time horizon from the societal perspective

alongside a three-armed RCT to investigate the cost-effectiveness and cost-utility of ACTonPain. Full

details of the trial design can be found in the study protocol and the main outcome paper of this trial [24,

25]. The economic evaluation was conducted and reported in agreement with the Consolidated Health

Economic Evaluation Reporting Standards (CHEERS) statement [26] and the International Society For

Pharmacoeconomics and Outcomes Research (ISPOR) guidelines [27].

The study has been registered in the German Clinical Trial Register (DRKS00006183) and was approved

by the ethics committee of the University of Freiburg (reference: 387/14). In total, 302 participants were

recruited from 10/2014 until 08/2015 in German pain clinics, largescale organizations for chronic pain

(e.g. self-help groups), on websites and with assistance of a German health insurance company. Inclusion

criteria were 1) age 18 years or older, 2) chronic pain for at least six months, with 3) considerable intensity

(=at least Grade II in the Chronic Pain Grade [28]), 4) being medically suitable for participation in a

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chronic pain IMI, 5) sufficient knowledge of the German language, 6) sufficient computer and internet

literacy, and 7) having internet access. Exclusion criteria were 1) cancer-related pain, 2) ongoing or

planned psychological pain intervention within the forthcoming three months and 3) elevated risk of

suicide.

Randomization

All eligible participants who provided informed consent were asked to fill out the baseline assessment and

were randomly allocated to one of the three conditions ACTonPainguided, ACTonPainunguided and


independent researcher not otherwise involved in the study using an automated, web-based randomization

program.

Interventions



information, metaphors, assignments, and mindfulness exercises. Both treatment conditions differ only in

the provision of guidance. Participants were advised to work on one module every week (~60 minutes). In

both intervention groups, participants had the option to receive daily automated text messages that

repeated content, reminded and motivated participants.

In ACTonPainguided trained and supervised eCoaches (psychologists) provided written feedback for each

module, which aimed at increasing participants' motivation and adherence. The total time of an eCoach

spent per participant was approximately 1.75 hours. Participants in the waitlist condition received the offer

to use ACTonPainunguided after the last follow-up assessment. Participants of all three trial arms had

unrestricted access to care-as-usual.

Outcome measures

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Assessment took place at baseline (T0), post-treatment (T1; nine weeks after randomization) and 6-month

follow-up (T2; six months after randomization). Outcomes were assessed by means of an online self-

report assessment using a secured internet-based platform (AES, 256-bit encrypted).

Treatment response

Main clinical outcome in the cost-effectiveness analysis was treatment response. This outcome was not

defined in the protocol paper. However, it was chosen to calculate a reliable and meaningful change in

pain interference according to the recommendations of the Initiative on Methods, Measurement, and Pain

Assessment in Clinical Trials (IMMPACT) [30] instead of a one-point change on the MPI, that would be

difficult to interpret.



Inventory MPI [31, 32]) and an anchor-based approach (Patient Global Impression of Change scale PGIC

[33]) [30]. First, participants with a change of 0.6 points (based on the scale’s standard deviation) on the

Pain Interference Scale of the MPI (range of the scale: 0-6) were identified as having minimal clinically

important changes [30]. Second, participants were identified, that rated their global improvement in the

PGIC [33] as “minimally, much or very much improved”. Participants who fulfilled both criteria were

classified as having achieved a clinically important change [30], defined as “treatment response”.



AQoL-8D [34] in the main analysis and the EQ5D-3L [35] in the sensitivity analysis. Utility scores are a

preference-based measure of quality of life that is normed by the value 1 meaning complete health and 0

meaning death [36].

The AQoL-8D comprises 35 items, which load on three physical (independent living, pain, senses) and

five psycho-social (mental health, happiness, coping, relationships, self-worth) dimensions [34]. The

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utility scores are scaled by SPSS algorithm for AQoL-8D utility model [34]. The AQoL-8D has been

shown as a reliable and valid instrument, suitable when psychosocial elements of health are the focus of

research [34], whereas utility weights are derived from the Australian adult population [37].


anxiety/depression), each of which is rated as causing ‘no’, ‘some’ or ‘extreme problems,’ and is a well

validated instrument [35, 38, 39]. Theoretically, the EQ-5D-3L generates 243 different health states.

Utility scores were calculated using the UK tariffs [40].




QALY health gains for the 6-months period were estimated by calculating the area under the curve (AUC)

of linearly interpolated AQoL-8D and EQ-5D-3L utility scores [42].


The Trimbos and iMTA questionnaire for costs associated with psychiatric illness (TiC-P) [43, 44] was

adapted to the German health care system and to the healthcare use of individuals with chronic pain. It

was used to assess the direct and indirect costs of the past three month at T0 and T2. Costs were expressed

in Euros (€) for the reference year 2015 (index factor 1.003 and 1.01 for outpatient medical service,

respectively) referring to the German consumer price index [45] (list of unit cost prices see Table 1). To

calculate the 6-month accumulated per-participants costs, the area under curve (AUC) method was used

by linearly interpolating 3-month costs (measured at T0 und T2) to cover the full period of six months

[42].

𝐴𝑈𝐶 = (𝐶𝑜𝑠𝑡𝑠 𝑇0

3 +𝐶𝑜𝑠𝑡𝑠 𝑇2

32 ) ∗ 3 + 𝐶𝑜𝑠𝑡𝑠 𝑇2

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Out

patie

nt m

edic

al se

rvic

e /

outp

atie

nt se

ctor

Euro/contact

PhysicianGynecologistOrthopedistSpecialists for internal medicineOphthalmologistDermatologistETN specialistSurgeonUrologistNeurologistPsychotherapistDentist

20.81 31.62 25.82 64.25 36.96 19.58 28.12 44.59 25.20 47.02 79.42 55.24

remedies Logopedics / speech therapyPhysiotherapyErgotherapy / occupational therapyPodiatry / podologyMean remedies

41.02 17.50 39.45 29.13 31.77

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hospitals Euro/day

Completely stationary normal wardCompletely stationary intensive careCompletely stationary psychiatrySemi-stationary general hospitalSemi-stationary psychiatry

648.11 1,424.60 348.26 421.27 226.37

rehabilitation Euro/day OutpatientInpatient

49.43 138.19

opportunitiy costs Euro/houropportunity costs (free time) opportunity costs (work)substitution costs for informal care

21.77 31.89 18.97

Note: Prices for outpatient medical service/outpatient sector were calculated fort the year 2013; all other prices for the year 2014 [46, 47] and adjusted by the German consumer price index for 2015 [45]. ETN specialist, Ear, nose, and throat specialist.


Healthcare costs (e.g. out- and inpatient care) were calculated according to the German guideline of Bock

and colleagues [46, 47]. The costs of therapeutic appliances (that were not listed in Bock and colleagues

[46, 47]) and medication were obtained from the Lauer-Taxe [48].



domestic help) were assessed. Participants reported the cost of travelling by bus or taxi. If not stated, each

kilometer was valued at €0.30. Opportunity costs (i.e., time spent at the practitioners waiting room) were

estimated at €21.77 per hour. Costs of informal care were valued using a shadow price of €18.97 per hour

[47].

Indirect costs

Indirect costs included productivity losses caused by absenteeism and presenteeism. Absenteeism costs

were calculated according to the human capital approach [49]. Self-reported lost work days were

multiplied by the corresponding gross average of participants’ income per day. To calculate presenteeism

costs, participants reported the number of days of reduced efficiency at work. These days were weighted

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by an inefficiency score. Productivity losses from unpaid work (i.e. domestic help from family members)

were valued using a shadow price of €18.97 per hour [47].

Intervention costs

Intervention costs of ACTonPainguided (€299) and ACTonPainunguided (€69) were based on actual market

prices for (un)guided interventions with a similar amount of modules that contain all costs for developing

and hosting the intervention (https://geton-institut.de/).


This study was not powered to statistically test differences in health economic outcomes. Therefore, we

took a probabilistic decision-making approach for health-economic inferences [50], that aims at informing

decision makers on probabilities rather than statistical significance. There was no need to discount costs or

outcomes as the time frame for the study was six months.

All analyses were conducted according to the intention-to-treat principle. All participants completed T0.

Missing clinical outcome data was imputed using the expectation maximization algorithm in Statistical

Package for the Social Sciences (SPSS, version 20). Analyses of clinical outcomes were conducted and

reported elsewhere [25] in accordance with the CONSORT 2010 Statement [51].


Predictors of cost data and dropout were identified by logistic regression analysis and were used to obtain

the most likely values of the missing cost data. At baseline, AQoL-utilities differed between groups

(ACTonPainguided: M=0.496, SD=0.16; ACTonPainunguided: M=0.485, SD=0.17; waitlist: M=0.463,

SD=0.14). Therefore, baseline adjustments were made in further calculations.

We tested group differences in treatment response using the chi-squared test and the Kruskall-Wallis test

for QALYs both followed by post-hoc comparisons (Bonferroni and Dunn´s test, respectively).

In the cost-effectiveness analyses, the outcome estimate is the incremental cost-effectiveness ratio (ICER),

where incremental costs over the 6-month period are divided by incremental effects (treatment response or

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QALYs): ICER=(CostsIG–CostsCG)/(EffectsIG–EffectsCG) subscripted with IG for the two intervention

groups and CG for the comparison groups. Different to the protocol [24], ICERs are reported for a 6-

month horizon (baseline data; T0 and 6-month follow-up; T2) and not based on pre-post (T0 and post-

treatment; T1). As participants are asked for their health care utilization during the last three months, the

TiC-P can only be evaluated appropriately at T0 and T2 (as T1 assessments are conducted nine weeks

after randomization).

Non-parametric bootstrapping by resampling patient-level data with 5,000 replications was used to take

into account the sampling uncertainty of the ICER estimates. Seemingly unrelated regression equations

models were bootstrapped to allow for correlated residuals of the cost and effect equations. Bootstrapping

was used to obtain 95% confidence intervals for the ICERs based on the percentile method, since

parametric techniques are inappropriate for use on skewed variables and ratios [50].


acceptability curve was graphed to assess the probability that the intervention is cost-effective relative to

the comparator condition given varying willingness-to-pay (WTP) ceilings. In order to increase readability

of the direct comparison ACTonPainguided vs. ACTonPainunguided the inverse cost-effectiveness acceptability

curve (ACTonPainunguided vs. ACTonPainguided) was additionally plotted. All analyses were performed using

Stata version 13 [52].


We tested the robustness of the outcomes of the main analysis in a sensitivity analysis. Therefore, we used

the EQ-5D-3L as a widely used instrument for calculating QALYs. As baseline EQ5D-utilities differed

between groups (ACTonPainguided: M=0.469, SD=0.32; ACTonPainunguided: M=0.436, SD=0.31; waitlist:

M=0.494, SD=0.3), baseline adjustment was made in the sensitivity analyses.


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effects were assessed as well as the satisfaction with the intervention (for results, see [25]). The results of

the research will be disseminated to those study participants who wished to be notified.

RESULTS



follow-up (ACTonPainguided: 33/100; ACTonPainunguided: 35/101; waitlist: 10/101). At 6-month follow up,

dropout rates differed significantly between groups (χ2(2)=20.17, p<.001). Pairwise comparison revealed

significant differences for ACTonPainguided vs. waitlist (t(1)=-3.85, p<.001) and ACTonPainunguided vs.

waitlist (t(1)=-4.14, p<.001). Study dropout was not associated with baseline pain interference or socio-

demographic factors.

The average participant was female, 52 years of age, with an above average level of education, employed

and was already treated for chronic pain. Detailed participants’ characteristics and the CONSORT

flowchart have already been reported elsewhere [25].

Outcomes

Table 2 shows treatment response and QALY outcomes as well as group differences. At 6-month follow-

up, treatment response differed significantly between groups (ACTonPainguided: 44/100; ACTonPainunguided:

28/101; waitlist: 16/101). Pairwise comparison revealed significant differences for ACTonPainguided vs.

waitlist and ACTonPainguided vs. ACTonPainunguided but not for ACTonPainunguided vs. waitlist. Between-

group differences in AQoL-8D QALY gains were statistically significant. Pairwise comparison revealed

significant differences only for ACTonPainguided vs. waitlist. Incremental EQ5D-3L QALY gains did not

differ significantly between study groups.

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Table 2. Treatment response and quality-adjusted life-year (QALY) outcomes and group differences at 6-month follow up.

ACTonPain guided (n = 100)

ACTonPain unguided (n = 101)

WLC group (n = 101) Test statistic

Mean (SD) Mean (SD) Mean (SD) χ2 (df=2) Post-hoc test c: pTreatment response (pain interference) 0.44 (0.05) 0.277 (0.04) 0.158 (0.04) 19.44 a <001ACTonPain guided vs. WLC group t(1)=4.52 <.001ACTonPain unguided vs. WLC group t(1)=1.91 .17ACTonPain guided vs. unguided t(1)=2.61 .03QALYAQoL-8D 0.280 (0.08) 0.266 (0.09) 0.244 (0.08) 9.45 b .009ACTonPain guided vs. WLC group Z=-3.07 .003ACTonPain unguided vs. WLC group Z=-1.61 .16ACTonPain guided vs. unguided Z=-1.47 .21EQ5D-3L 0.274 (0.12) 0.255 (0.12) 0.253 (0.13) 2.17 b .34WLC group, waitlist control group; SD, standard deviation; df, degrees of freedom; QALY, quality-adjusted life-yeara Chi-squared test b Kruskall-Wallis H testc Post-hoc test for treatment response: Bonferroni pairwise comparison; Post-hoc test for QALY: Dunn´s test

Costs

At baseline, mean total costs were €3,233 in ACTonPainguided, €3,724 in ACTonPainunguided and €3,570 in

the waitlist group. The 6-month accumulated per-participants costs by study condition are presented in

Table 3. ACTonPainguided showed the highest mean total costs (€6,945), followed by the waitlist group

(€6,908) and ACTonPainunguided (€6,560). Mean direct costs were the highest in the guided group, followed

by the unguided group and waitlist. The opposite order was found for the indirect costs. Medication,

domestic help and opportunity costs were major cost drivers. Productivity losses produced the highest cost

differences between the intervention groups and waitlist of -€871 (ACTonPainguided vs. waitlist) and -€721

(ACTonPainunguided vs. waitlist).

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Table 3. 6-month accumulated per-participants costs (in €) by condition (based on intention-to-treat sample, N = 302).



WLC group (n = 101)

Incremental costs

Difference, €

Mean, € (SD) Mean, € (SD) Mean, €

(SD)

ACTonPain guided vs. WLC

ACTonPain unguided vs. WLC

ACTonPain guided vs. unguided

Intervention 299 (-) 69 (-) 0 (-) 299 69 230Direct medical costsHealth care costs Medical specialist 576 (478) 511 (381) 511 (382) 65 0 65 Mental health care 212 (431) 181 (397) 258 (455) -46 -77 31 Other medical specialist a

369 (515) 357 (435) 406 (576) -37 -49 12

In-patient care (hospital)

198 (479) 173 (369) 141 (420) 57 32 25

Day care 147 (687) 122 (381) 306 (1,584) -159 -184 25 Rehabilitation 190 (794) 134 (507) 191 (773) -1 -57 56 Medication 1,092 (2,748) 784 (1,438) 660 (1,638) 432 124 308 Therapeutic appliances 65 (139) 86 (222) 46 (96) 19 40 -21Direct non-medical costs Patient and family costs Travel 131 (229) 105 (150) 101 (100) 30 4 26 Domestic help 1,297 (4,064) 1,147 (1,936) 840 (1,490) 457 307 150 Opportunity costs b 1,553 (1,965) 1,925 (3,251) 1,759 (3,116) -206 166 -372Indirect costsProductivity losses Absenteeism 517 (1,647) 647 (1,979) 1,133 (3,333) -616 -486 -130 Presenteeism 300 (740) 320 (774) 555 (1,360) -255 -235 -20

Total direct costs 5,829 (7,129) 5,525 (4,959) 5,220 (5,133) 611 306 305Total indirect costs 817 (1,978) 966 (2,283) 1,688 (3,735) -871 -721 -150Total societal costs 6,945 (7,327) 6,560 (5,549) 6,908 (6,279) 39 -346 385WLC group, waitlist control groupa i.e. physiotherapist, occupational therapistb i.e. for waiting time before treatment




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AnalysisACTonPain guided vs. WLC group

Incremental costs, €(95% CI)

Incremental effects(95% CI)

MeanICER(95% CI)

Distribution over the ICER planeNE NW SE SW

Cost-effectiveness, treatment response (MPI and PGIC)

6(-916-953)

0.14(0.08-0.2)

171(-6,671-8,260)

50% - 50% -

Cost-utilityAQoL QALYs

6(-916-953)

0.01(0.005- 0.015)

3,033(-92,924- 114,325)

50% - 50% -

Sensitivity analysis EQ5D QALYs 6

(-916-953)0.014(0.004- 0.024)

4726 (-69,407- 122,314)

50% - 50% -

AnalysisACTonPain unguided vs. WLC group



MeanICER(95% CI)



-352(-1,968-1,272)

0.12(0.006-0.232)

ACTonPain unguided dominates WLC

32% 1% 66% 1%

Cost-utility AQoL QALYs

-352(-1,968-1,272)

0.013(0.002-0.024)


32% 1% 66% 1%

Sensitivity analysis EQ5D QALYs -352

(-1,968-1,272)

0.017 (-0.005- 0.04)


30% 4% 64% 3%

AnalysisACTonPain guided vs. ACTonPain unguided



MeanICER(95% CI)



388(-1,416-2,185)

0.164(0.034-0.29)

2,949(-11,097-25,276)

65% - 35% -


388(-1,416-2,185)

0.008(-0.003-0.019)

198,377a

60% 5% 33% 2%


(-1,416-0.01 (-0.01- 0.031)

114,858 a

53% 12% 31% 4%

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2,158)WLC group, waitlist control group; MPI, Pain Interference Scale of the Multidimensional Pain Inventory; PGIC, Patient Global Impression of Change scale; 95% CI, 95% confidence interval; EQ-5D QALYs, Quality-adjusted life years based on EuroQol; ICER, incremental cost-effectiveness ratio; NE, northeast quadrant; NW, northwest quadrant; SE, southeast quadrant; SW, southwest quadrant.aA dependably accurate 95% confidence interval for this distribution cannot be defined because there is no line through the origin that excludes α/2 of the distribution[53].

Cost-effectiveness

The cost-effectiveness planes and acceptability curves, representing the 5,000 bootstrap replications, are

shown in Figure 1(a,b,c) and 2(a,b). ACTonPainguided showed the same and ACTonPainunguided a higher

potential of being cost-effective compared to waitlist at a WTP of €0 (ACTonPainguided 50%,



treatment response, and for ACTonPainunguided to 70% at a WTP of €660 and to 95% at a WTP of €13,460.

The probability that ACTonPainguided is more cost-effective than ACTonPainunguided was 35% at a WTP of

€0 for an additional treatment response. When society’s WTP increases up to €5,535 or €17,170 this

probability rises to 70% or 95%, respectively. The break even point (where ACTonPainguided and

ACTonPainunguided have the same possibility of being cost-effective at same costs) is at €2,188 (see Figure

2b).

- Figure 1-

- Figure 2-

Cost-utility

Cost-effectiveness planes and acceptability curves that refer to cost-utility are shown in figure 1(d,e,f) and

2(c,d). ACTonPainguided showed the same and ACTonPainunguided a higher potential of being cost-effective

compared to waitlist at a WTP of €0 (50% and 66%, respectively). The interventions’ probability of being

more cost-effective compared to waitlist increased up to 70% and to 95% at a WTP of €24,415 and

€91,000, respectively, in ACTonPainguided and €6,130 (70%) and €127,000 (95%) in ACTonPainunguided for

one additional QALY. The probability that ACTonPainguided is more cost-effective than ACTonPainunguided

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was 31% at a WTP of €0 for one additional QALY. When society’s WTP increases up to €113,550 this

probability rises to 70% and stagnates on this level. The break-even point is at €41,350 (see Figure 2d).


After non-parametric bootstrapping, using the EQ-5D-3L resulted in larger incremental QALY gains in all

comparisons compared to the results using the AQoL-8D (see table 4).

At a WTP of €0 the probability of ACTonPainguided of being cost-effective compared to waitlist was 50%.

The probability of ACTonPainunguided of being cost-effective compared to waitlist was 64% at a WTP of

€0. ACTonPainguided vs. ACTonPainunguided resulted in a probability of being cost-effective of 31% at a

WTP of €0.

DISCUSSION




However, when assuming that an intervention should reach a likelihood of being cost-effective of 95% or

greater it has to be considered that the WTP would have to be €13,460 for treatment response and

€127,000 for a QALY gain. Therefore, the judgement of whether the intervention is cost-effective or not

ultimately depends on the society’s WTP for treatment response or a QALY gain, respectively.

ACTonPainguided also causes better results in the main outcome parameters, but at (slightly) higher costs

with ICERs of 171 (treatment response) and 3,033 (AQoL QALY gains). The probability of being cost-

effective at a WTP of €0 compared to waitlist is higher in ACTonPainunguided, for both, treatment response

and QALYs gained (66%) than in ACTonPainguided (50%).

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However, when comparing the costs that would have to be invested by using ACTonPainguided (compared

to waitlist) for a QALY gained (€3,033) to the only official WTP threshold stated by the National Institute

for Health and Clinical Excellence (NICE) of £20,000 to £30,000 [54] (~ €22,647 - €33,971; conversion

according to the European Central bank [55]), this intervention would also be categorized as a potentially

cost-effective treatment. Here again, uncertainty has to be considered as well as the required WTP for a

likelihood of being cost-effective of 95% of €6,490 (treatment response) and €91,000 (QALY gain).

The direct comparison of ACTonPainguided and ACTonPainunguided shows more treatment responders and

higher QALY gains for the guided version, but at higher costs. According to the NICE guidelines costs are

far above the WTP threshold for a QALY gain and would thus be judged as probably not cost-effective. In

terms of QALYs gained, the guided version only reaches a probability of 31% of being cost-effective at a

WTP of €0 and even with rising WTP threshold, the probability does not increase much.



Estimated EQ-5D utility scores for one year ranged from 0.50 to 0.54, what appears rather low compared

to national EQ-5D estimates for (back) pain from other countries (e.g. 0.74-0.79 [56, 57]). Lower

estimates in the current study could have occurred due to the sociodemographic properties of this study

sample, as participants were predominately women (84%), reported comorbid medical or mental

conditions (57% and 39%, respectively) and the back was the most often reported pain location (34%)

[25]. Several studies showed that the mentioned characteristics (female sex, musculoskeletal and mental

disorders) are associated with lower quality of life scores [56–58]. Furthermore, Burström et al. (2001)

reported in their study that participants with low back pain showed quality of life weights of 0.55 [58],

what is comparable to the sample in the current study.

The conclusion of ACTonPain being cost-effective are in line with a recent study and a review about the

cost-effectiveness of IMIs for depression [23, 59]. The guided IMI for chronic pain of Boer and colleagues

revealed an ICER of 40 (defined as cost savings of €40) for an one-point improvement in a pain

catastrophizing scale compared to a face-to-face group intervention, while QALYs were not reported [23].

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ACTonPainguided reached higher ICERs for the clinical outcome pain interference (171 compared to

waitlist group and 2,949 compared to the unguided group). However, these values were calculated for

treatment response in terms of pain interference and therefore, a meaningful change and not for a one-

point improvement on the scale. In a systematic review, IMIs that were classified as cost-effective were all

guided and showed probabilities of being cost-effective between 28% and 49% at a WTP of €0 for a

QALY gained, whereas ACTonPainguided and the unguided version even reached higher probabilities at

this WTP level (50% and 66%, respectively). Thus, integrating psychological e-health approaches in pain

management programs might even be more promising from an economical point of view when compared

to the well-established area of depression e-health care.

The higher direct costs over a 6-month period in both intervention groups compared to waitlist might be

explained by higher or stable health care utilization similar to findings in a previous study on the costs of

established depression treatments [60]. However, research indicates that indirect rather than direct costs

represent the majority of overall costs [61, 62], where ACTonPain seemingly has its core advantage. Mean

indirect costs over the 6-month period were almost half as high in the intervention groups compared to

waitlist, regarding both absenteeism and presenteeism.

Next to the questions of whether ACTonPain is cost-effective compared to waitlist and whether it should

rather be provided guided or unguided, it would be of interest how ACTonPain performs compared to

established medical, psychological, physiotherapeutical, and surgical treatments that result in high direct

costs [63–66]. However, surprisingly little is known about the cost-effectiveness of these established pain

treatments. In two reviews it was highlighted, that interdisciplinary pain rehabilitation programs are more

cost-effective or produce lower costs than interventions such as surgery and conservative care [67, 68].

For individuals with low back pain it was concluded that interdisciplinary rehabilitation, exercise,

acupuncture, spinal manipulation and CBT are potentially cost-effective [69]. A further systematic review

focused on economic evaluations of third-wave CBT therapies (including ACT), were available ICERs

ranged from -€19,300 (National Health Service perspective, converted into Euro [55]) to €56,637 (societal

perspective) per QALY gained [13]. When compared to waitlist the ICERs based on the AQoL-8D in this

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study were €3,033 and a negative ICER (indicating dominance of the unguided intervention over WLC)

per QALY gained. Thus, it seems safe to argue that ACTonPain, as an example of an innovative IMI for

the treatment of chronic pain, is effective [25] and could be an cost-effective intervention. A comparison

across treatment approaches for chronic pain, however, cannot be provided as the evidence base for the

cost-effectiveness of established pain treatments is rather weak and the comparability of results across

studies is limited due to very heterogeneous methods across trials [70].

Limitations

First, when interpreting the results, it has to be considered that the study was not powered to statistically

test health economic differences. Second, the costs and effects were evaluated over six months. Therefore,

no conclusions regarding the long-term cost-effectiveness can be drawn. Furthermore, costs between

randomization and three months after randomization were calculated with the area under the curve

method. This is just an estimate and not a representation of the actual costs incurred during this period.

Fourth, costs were assessed via self-report. However, as the questionnaire used in this study is a valid

instrument to recall periods up to three months [71], the impact of this bias on results is limited. Finally,

the usage of multiple imputation techniques is frequently recommended (e.g. predictive mean matching

[72]. We used a single imputation approach as it was done in the main (effectiveness) analysis [25] that

might not truly reflect missing data uncertainty. However, the comparison with cost and QALY outcomes

of complete case analysis revealed only small differences, indicating that the risk of implausible values

due to single imputation in this evaluation is low [73]. Furthermore, by using the non-parametric

bootstrapping, sampling was considered.


For patients with chronic pain, IMIs might become an important alternative to established interventions.

IMIs can expand treatment options for people, whose physical impairment or location makes access to

relevant care difficult [19]. Findings from this health economic evaluation study show that both versions

of ACTonPain have the potential of being cost-effective, with the unguided version even leading to lower

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costs (compared to WLC). However, uncertainty should be taken into account. The decision whether to

choose the guided or unguided version is a public health issue and strongly depends on whether to mainly

focus on patients´ health or societies´ resources. Under health economic aspects ACTonPainunguided should

be the preferred intervention, especially when considering the intention of treatment implementation into

the health care system and scaling up mental health care for pain patients.

Future research should especially focus on conducting methodologically sound studies that are powered to

statistically test health economic differences. Furthermore, long-term follow-up studies and evaluation of

(comparative) cost-effectiveness of different guidance formats of IMIs, particularly of ACTonPain, and

established pain treatments are needed. Moreover, future studies should examine ACTonPain as integrated

part of multi-component pain programs and aim to dismantle the ingredients that are effective and cost-

effective in those complex approaches.

DECLARATIONS

Funding


profit sectors. The article processing charge was funded by the German Research Foundation (DFG) and

the Albert-Ludwigs University Freiburg in the funding programme Open Access Publishing.

Competing interests

Two of the authors of the manuscript were involved in the development of ACTonPain (JL and HB). HB

and DDE are consultants for several stakeholders (insurance companies, ministries, psychotherapy

chambers, companies). DDE is part of the GET.ON Institut GmbH, which aims at implementing evidence-

based internet- and mobile based interventions into routine care. SP, CB, FK and DL declare that they

have no competing interests.


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The datasets used and/or analyzed during the current study are available from the corresponding author on

reasonable request.


JL and HB initiated the randomized control trial for this health economic evaluation. SP, FK, CB, DL and

DDE contributed to the design of this health economic evaluation. SP, DL, FK and CB contributed to the

data analysis. SP had full access to all the data in the study and had responsibility for the decision to

submit for publication. SP wrote the draft of the manuscript. All authors contributed to the further writing

and approved the final version of the manuscript.

Acknowledgements


Figure Legends









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Additional file 1 – CHEERS checklist Section/item Item

No Recommendation Reported on page

No

Title and abstract

Title 1 Identify the study as an economic evaluation or use more specific terms such as “cost-effectiveness analysis”, and describe the interventions compared.

Page 1

Abstract 2 Provide a structured summary of objectives, perspective, setting, methods (including study design and inputs), results (including base case and uncertainty analyses), and conclusions.

Page 2 and 3 (the sensitivity analysis is not mentioned in the abstract due to limited words)

Introduction

Background and objectives

3 Provide an explicit statement of the broader context for the study. Present the study question and its relevance for health policy or practice decisions.

Page 4 and 5

Methods

Target population and subgroups

4 Describe characteristics of the base case population and subgroups analysed, including why they were chosen.

Page 5

Setting and location 5 State relevant aspects of the system(s) in which the decision(s) need(s) to be made.

Page 5

Study perspective 6 Describe the perspective of the study and relate this to the costs being evaluated.

Page 5, 8, 9 and 10

Comparators 7 Describe the interventions or strategies being compared and state why they were chosen.

Page 6

Time horizon 8 State the time horizon(s) over which costs and consequences are being evaluated and say why appropriate.

Page 6 and 7

Discount rate 9 Report the choice of discount rate(s) used for costs and outcomes and say why appropriate.

Page 10

Choice of health outcomes

10 Describe what outcomes were used as the measure(s) of benefit in the evaluation and their relevance for the type of analysis performed.

Page 6, 7 and 8

Measurement of effectiveness

11a Single study-based estimates: Describe fully the design features of the single effectiveness study and why the single study was a sufficient source of clinical effectiveness data.

Page 4 and 5

11b Synthesis-based estimates: Describe fully the methods used for identification of included studies and synthesis of clinical effectiveness data.

N/A

Measurement and valuation of preference based outcomes

12 If applicable, describe the population and methods used to elicit preferences for outcomes.

Page 7

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Section/item Item No

Recommendation Reported on page No

Estimating costs and resources

13a Single study-based economic evaluation: Describe approaches used to estimate resource use associated with the alternative interventions. Describe primary or secondary research methods for valuing each resource item in terms of its unit cost. Describe any adjustments made to approximate to opportunity costs.

Page 8, 9 and 10, Table 1

13b Model-based economic evaluation: Describe approaches and data sources used to estimate resource use associated with model health states. Describe primary or secondary research methods for valuing each resource item in terms of its unit cost. Describe any adjustments made to approximate to opportunity costs.

N/A

Currency, price date and conversion

14 Report the dates of the estimated resource quantities and unit costs. Describe methods for adjusting estimated unit costs to the year of reported costs if necessary. Describe methods for converting costs into a common currency base and the exchange rate.

Page 8

Choice of model 15 Describe and give reasons for the specific type of decision-analytical model used. Providing a figure to show model structure is strongly recommended.

N/A

Assumptions 16 Describe all structural or other assumptions underpinning the decision-analytical model.

N/A

Analytical methods 17 Describe all analytical methods supporting the evaluation. This could include methods for dealing with skewed, missing, or censored data; extrapolation methods; methods for pooling data; approaches to validate or make adjustments (such as half cycle corrections) to a model; and methods for handling population heterogeneity and uncertainty.

Page 10, 11 and 12

Results

Study parameters 18 Report the values, ranges, references, and, if used, probability distributions for all parameters. Report reasons or sources for distributions used to represent uncertainty where appropriate. Providing a table to show the input values is strongly recommended.

Page 12-17, Table 2 and 4

Incremental costs and outcomes

19 For each intervention, report mean values for the main categories of estimated costs and outcomes of interest, as well as mean differences between the comparator groups. If applicable, report incremental cost-effectiveness ratios.

Page 13; Table 3

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Characterising uncertainty

20a Single study-based economic evaluation: Describe the effects of sampling uncertainty for the estimated incremental cost and incremental effectiveness parameters, together with the impact of methodological assumptions (such as discount rate, study perspective).

Page 16 and 17 and Figure 1 and 2

20b Model-based economic evaluation: Describe the effects on the results of uncertainty for all input parameters, and uncertainty related to the structure of the model and assumptions.

N/A

Characterising heterogeneity

21 If applicable, report differences in costs, outcomes, or cost-effectiveness that can be explained by variations between subgroups of patients with different baseline characteristics or other observed variability in effects that are not reducible by more information.

N/A

Discussion

Study findings, limitations, generalisability, and current knowledge

22 Summarise key study findings and describe how they support the conclusions reached. Discuss limitations and the generalisability of the findings and how the findings fit with current knowledge.

Page 17-21

Other

Source of funding 23 Describe how the study was funded and the role of the funder in the identification, design, conduct, and reporting of the analysis. Describe other non-monetary sources of support.

Page 21

Conflicts of interest 24 Describe any potential for conflict of interest of study contributors in accordance with journal policy. In the absence of a journal policy, we recommend authors comply with International Committee of Medical Journal Editors recommendations.

Page 21

N/A, Not applicable

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Journal: BMJ Open



Date Submitted by the Author: 19-Dec-2018

Complete List of Authors: Paganini, Sarah; Albert-Ludwigs University Freiburg, Department of Sports and Sport Science, Sport Psychology; Albert-Ludwigs University Freiburg, Department of Rehabilitation Psychology and Psychotherapy, Institute of PsychologyLin, Jiaxi; Albert-Ludwigs University Freiburg, Department of Sports and Sport Science, Sport PsychologyKählke, Fanny; Friedrich-Alexander University of Erlangen-Nuremberg, Department of Clinical Psychology and PsychotherapyBuntrock, Claudia; Friedrich-Alexander-Universitat Erlangen-Nurnberg, Clinical Psychology and PsychotherapyLeiding, Delia; RWTH Aachen University, Department of Psychiatry, Psychotherapy and PsychosomaticsEbert, David; Friedrich-Alexander University Erlangen Nuremberg, Clinical Psychology and PsychotherapyBaumeister, Harald; Universitat Ulm, Institut of Psychology and Education, Department of Clinical Psychology and Psychotherapy



Keywords: Chronic pain, Internet-and mobile-based intervention, Health economic evaluation, Cost-effectiveness, Cost-utility, eHealth


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A guided and unguided internet- and mobile-based intervention for chronic pain: Health economic evaluation alongside a randomized controlled trial

S. Paganini 1, 2a, J. Lin1, F. Kählke3, C. Buntrock3, D. Leiding4, D.D. Ebert3, H. Baumeister5

1Department of Sports and Sport Science, Sport Psychology, University of Freiburg, Germany, [email protected], [email protected]

2Department of Rehabilitation Psychology and Psychotherapy, Institute of Psychology, University of Freiburg, Germany

3Department of Clinical Psychology and Psychotherapy, Friedrich-Alexander University of Erlangen-Nuremberg, Germany, [email protected], [email protected], [email protected]

4Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Germany, [email protected]

5Department of Clinical Psychology and Psychotherapy, Institute of Psychology and Education, University of Ulm, Germany, [email protected]

a Corresponding author: Sarah Paganini, Department of Sports and Sport Science, Sport Psychology, University of Freiburg, Germany, Schwarzwaldstr. 175, 79117 Freiburg, Phone: +49 (0)761 / 203-4514, Email: [email protected]

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ABSTRACT

Objective: This study aims at evaluating the cost-effectiveness/cost-utility of a guided and unguided

internet-based intervention for chronic pain patients (ACTonPainguided/ACTonPainunguided) compared to

a waitlist control(WLC) condition as well as the comparative cost-effectiveness of the interventions.

Design: This is a health-economic evaluation alongside a three-armed randomized controlled trial

from a societal perspective. Assessments were conducted at baseline, nine weeks and six months after

randomization.

Setting: Participants were recruited through online and offline strategies and in collaboration with a

health insurance company.

Participants: 302 adults (≥18 years, pain for at least six months) were randomly allocated to one of

the three groups(ACTonPainguided,ACTonPainunguided,WLC).



Primary and secondary outcome measures: Main outcomes of the cost-effectiveness and the cost-

utility analyses were meaningful change in pain interference (treatment response) and quality-adjusted

life years (QALYs). Economic evaluation estimates were incremental cost-effectiveness/cost-utility

ratios (ICER/ICUR).

Results: At 6-month follow-up treatment response and QALYs were highest in ACTonPainguided(44%

and 0.280; mean costs=€6,945), followed by ACTonPainunguided(28% and 0.266; mean costs=€6,560)

and WLC(16% and 0.244; mean costs=€6,908). ACTonPainguided vs. WLC revealed an ICER/ICUR of

45 and 604, respectively, while ACTonPainunguided dominated WLC. At a willingness-to-pay of €0 the

probability of being cost-effective was 50% for ACTonPainguided and 66% for ACTonPainunguided. This

probability rose to 95% when society´s willingness-to-pay is 91,000€(ACTonPainguided) and

€127,000(ACTonPainunguided) per QALY. ACTonPainguided vs. ACTonPainunguided revealed an

ICER/ICUR of 2,374 and 45,993.

Conclusions:

Depending on society´s willingness-to-pay ACTonPain is a potentially cost-effective adjunct to

established pain treatment, with ACTonPainunguided (vs.WLC) even leading to lower costs at better

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health outcomes. However, uncertainty has to be taken into account. Direct comparison of the two

interventions indicates a preference for ACTonPainunguided under health economic aspects.

Trial Registration: German Clinical Trial Registration:DRKS00006183,


183

Keywords: Chronic pain; internet- and mobile-based intervention; eHealth; health economic

evaluation; cost-effectiveness; cost-utility


This is the first study that evaluates the (comparative) cost-effectiveness of a guided and an


In this study state-of-the-art statistical methods such as seemingly unrelated regression

equations models or non-parametric bootstrapping techniques were applied.

Results should be interpreted cautiously, as the study was not powered to statistically test


As the costs and effects were evaluated over six months, no conclusions regarding the long-


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BACKGROUND





(ACT, a particular form of CBT) have been shown to be effective for chronic pain patients [11, 12]

and could show acceptable results concerning cost-effectiveness [13]. However, accessibility and

availability of treatment is often restricted and up to 40% of individuals with chronic pain do not

receive adequate pain management [1, 14]. Internet- and mobile- based interventions (IMIs) are an

effective, acceptable and feasible way for providing psychological interventions [15, 16]. IMIs for

chronic pain have been shown to effectively improve pain interference compared to different control

groups, such as standard (medical) care, text-based material and mostly waitlist control condition

(standardized mean difference (SMD)=.4 [17], SMD=−0.50 [18]).










cost-effectiveness of a guided and unguided IMI for chronic pain. However, Boer and colleagues

found that an IMI for chronic pain was cost-effective compared to a face-to-face group intervention

(concerning a one-point-improvement in a pain catastrophizing scale) [23]. Lin and colleagues

recently finalized a three arm RCT comparing a guided and unguided version of an Acceptance and

Commitment Therapy based IMI for chronic pain (ACTonPain) against a waitlist control group [24,

25]. Compared to the waitlist control condition, ACTonPainguided showed significantly lower pain

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interference at nine weeks and six months after randomization (d=0.58). Differences between

ACTonPainunguided and the control group and between both ACTonPain groups were not statistically

significant [25].




METHODS


















Randomization


and were randomly allocated to one of the three conditions ACTonPainguided, ACTonPainunguided and

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independent researcher not otherwise involved in the study using an automated, web-based

randomization program.

Interventions












Outcome measures

Assessment took place at baseline (T0), post-treatment (T1; nine weeks after randomization) and 6-



Treatment response

Main clinical outcome in the cost-effectiveness analysis was treatment response. This outcome was

not defined in the protocol paper. However, it was chosen to calculate a reliable and meaningful

change in pain interference according to the recommendations of the Initiative on Methods,

Measurement, and Pain Assessment in Clinical Trials (IMMPACT) [30] instead of a one-point change

on the MPI, that would be difficult to interpret.

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Inventory MPI [31, 32]) and an anchor-based approach (Patient Global Impression of Change scale

PGIC [33]) [30]. First, participants with a change of 0.6 points (based on the scale’s standard

deviation) on the Pain Interference Scale of the MPI (range of the scale: 0-6) were identified as having

minimal clinically important changes [30]. Second, participants were identified, that rated their global

improvement in the PGIC [33] as “minimally, much or very much improved”. Participants who

fulfilled both criteria were classified as having achieved a clinically important change [30], defined as

“treatment response”.



AQoL-8D [34] in the main analysis and the EQ5D-3L [35] in the sensitivity analysis. Utility scores

are a preference-based measure of quality of life that is normed by the value 1 meaning complete

health and 0 meaning death [36].





focus of research [34], whereas utility weights are derived from the Australian adult population [37].








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was adapted to the German health care system and to the healthcare use of individuals with chronic

pain. It was used to assess the direct and indirect costs of the past three month at T0 and T2. Costs

were expressed in Euros (€) for the reference year 2015 (index factor 1.003 and 1.01 for outpatient

medical service, respectively) referring to the German consumer price index [45] (list of unit cost

prices see Table 1). To calculate the 6-month accumulated per-participants costs, the area under curve

(AUC) method was used by linearly interpolating 3-month costs (measured at T0 und T2) to cover the

full period of six months [42].

𝐴𝑈𝐶 = (𝐶𝑜𝑠𝑡𝑠 𝑇0

3 +𝐶𝑜𝑠𝑡𝑠 𝑇2

32 ) ∗ 3 + 𝐶𝑜𝑠𝑡𝑠 𝑇2

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Out

patie

nt m

edic

al se

rvic

e /

outp

atie

nt se

ctor

Euro/contact

PhysicianGynecologistOrthopedistSpecialists for internal medicineOphthalmologistDermatologistETN specialistSurgeonUrologistNeurologistPsychotherapistDentist

20.81 31.62 25.82 64.25 36.96 19.58 28.12 44.59 25.20 47.02 79.42 55.24

remedies Logopedics / speech therapyPhysiotherapyErgotherapy / occupational therapyPodiatry / podologyMean remedies

41.02 17.50 39.45 29.13 31.77

hospitals Euro/day

Completely stationary normal wardCompletely stationary intensive careCompletely stationary psychiatrySemi-stationary general hospitalSemi-stationary psychiatry

648.11 1,424.60 348.26 421.27 226.37

rehabilitation Euro/day OutpatientInpatient

49.43 138.19

opportunitiy costs Euro/houropportunity costs (free time) opportunity costs (work)substitution costs for informal care

21.77 31.89 18.97

Note: Prices for outpatient medical service/outpatient sector were calculated fort the year 2013; all other prices for the year 2014 [46, 47] and adjusted by the German consumer price index for 2015 [45]. ETN specialist, Ear, nose, and throat specialist.


Healthcare costs (e.g. out- and inpatient care) were calculated according to the German guideline of






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each kilometer was valued at €0.30. Opportunity costs (i.e., time spent at the practitioners waiting


€18.97 per hour [47].

Indirect costs







Intervention costs












conducted and reported elsewhere [25] in accordance with the CONSORT 2010 Statement [51].



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obtain the most likely values of the missing cost data. At baseline, AQoL-utilities differed between

groups (ACTonPainguided: M=0.496, SD=0.16; ACTonPainunguided: M=0.485, SD=0.17; waitlist:

M=0.463, SD=0.14). Therefore, baseline adjustments were made in further calculations.























We tested the robustness of the outcomes of the main analysis in a sensitivity analysis. Therefore, we

used the EQ-5D-3L as a widely used instrument for calculating QALYs. As baseline EQ5D-utilities

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differed between groups (ACTonPainguided: M=0.469, SD=0.32; ACTonPainunguided: M=0.436,

SD=0.31; waitlist: M=0.494, SD=0.3), baseline adjustment was made in the sensitivity analyses.




effects were assessed as well as the satisfaction with the intervention (for results, see [25]). The results

of the research will be disseminated to those study participants who wished to be notified.

RESULTS



follow-up (ACTonPainguided: 33/100; ACTonPainunguided: 35/101; waitlist: 10/101). At 6-month follow








Outcomes






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Table 2. Treatment response and quality-adjusted life-year (QALY) outcomes and group differences at 6-month follow up.



WLC group (n = 101) Test statistic

Mean (SD) Mean (SD) Mean (SD) χ2 (df=2) Post-hoc test c: pTreatment response (pain interference) 0.44 (0.05) 0.277 (0.04) 0.158 (0.04) 19.44 a <001ACTonPain guided vs. WLC group t(1)=4.52 <.001ACTonPain unguided vs. WLC group t(1)=1.91 .17ACTonPain guided vs. unguided t(1)=2.61 .03QALYAQoL-8D 0.280 (0.08) 0.266 (0.09) 0.244 (0.08) 9.45 b .009ACTonPain guided vs. WLC group Z=-3.07 .003ACTonPain unguided vs. WLC group Z=-1.61 .16ACTonPain guided vs. unguided Z=-1.47 .21EQ5D-3L 0.274 (0.12) 0.255 (0.12) 0.253 (0.13) 2.17 b .34WLC group, waitlist control group; SD, standard deviation; df, degrees of freedom; QALY, quality-adjusted life-yeara Chi-squared test b Kruskall-Wallis H testc Post-hoc test for treatment response: Bonferroni pairwise comparison; Post-hoc test for QALY: Dunn´s test

Costs









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Table 3. 6-month accumulated per-participants costs (in €) by condition (based on intention-to-treat sample, N = 302).



WLC group (n = 101)

Incremental costs

Difference, €

Mean, € (SD) Mean, € (SD) Mean, €

(SD)

ACTonPain guided vs. WLC

ACTonPain unguided vs. WLC

ACTonPain guided vs. unguided

Intervention 299 (-) 69 (-) 0 (-) 299 69 230Direct medical costsHealth care costs Medical specialist 576 (478) 511 (381) 511 (382) 65 0 65 Mental health care 212 (431) 181 (397) 258 (455) -46 -77 31 Other medical specialist a

369 (515) 357 (435) 406 (576) -37 -49 12

In-patient care (hospital)

198 (479) 173 (369) 141 (420) 57 32 25

Day care 147 (687) 122 (381) 306 (1,584) -159 -184 25 Rehabilitation 190 (794) 134 (507) 191 (773) -1 -57 56 Medication 1,092 (2,748) 784 (1,438) 660 (1,638) 432 124 308 Therapeutic appliances 65 (139) 86 (222) 46 (96) 19 40 -21Direct non-medical costs Patient and family costs Travel 131 (229) 105 (150) 101 (100) 30 4 26 Domestic help 1,297 (4,064) 1,147 (1,936) 840 (1,490) 457 307 150 Opportunity costs b 1,553 (1,965) 1,925 (3,251) 1,759 (3,116) -206 166 -372Indirect costsProductivity losses Absenteeism 517 (1,647) 647 (1,979) 1,133 (3,333) -616 -486 -130 Presenteeism 300 (740) 320 (774) 555 (1,360) -255 -235 -20

Total direct costs 5,829 (7,129) 5,525 (4,959) 5,220 (5,133) 611 306 305Total indirect costs 817 (1,978) 966 (2,283) 1,688 (3,735) -871 -721 -150Total societal costs 6,945 (7,327) 6,560 (5,549) 6,908 (6,279) 39 -346 385WLC group, waitlist control groupa i.e. physiotherapist, occupational therapistb i.e. for waiting time before treatment




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AnalysisACTonPain guided vs. WLC group



MeanICER(95% CI)



6(-916-953)

0.14(0.08-0.2)

45(-6,671-8,260)

50% - 50% -

Cost-utilityAQoL QALYs

6(-916-953)

0.01(0.005- 0.015)

604(-92,924- 114,325)

50% - 50% -


(-916-953)0.014(0.004- 0.024)

438 (-69,407- 122,314)

50% - 50% -

AnalysisACTonPain unguided vs. WLC group



MeanICER(95% CI)



-352(-1,968-1,272)

0.12(0.006-0.232)


32% 1% 66% 1%


-352(-1,968-1,272)

0.013(0.002-0.024)


32% 1% 66% 1%

Sensitivity analysis EQ5D QALYs -352

(-1,968-1,272)

0.017 (-0.005- 0.04)


30% 4% 64% 3%

AnalysisACTonPain guided vs. ACTonPain unguided



MeanICER(95% CI)



388(-1,416-2,185)

0.164(0.034-0.29)

2,374 (-11,097-25,276)

65% - 35% -


388(-1,416-2,185)

0.008(-0.003-0.019)

45,993a 60% 5% 33% 2%


(-1,416-2,158)

0.01 (-0.01- 0.031)

37,327a 53% 12% 31% 4%

WLC group, waitlist control group; MPI, Pain Interference Scale of the Multidimensional Pain Inventory; PGIC, Patient Global Impression of Change scale; 95% CI, 95% confidence interval; EQ-5D QALYs, Quality-adjusted life years based on EuroQol; ICER, incremental cost-effectiveness ratio; NE, northeast quadrant; NW, northwest quadrant; SE, southeast quadrant; SW, southwest quadrant.

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aA dependably accurate 95% confidence interval for this distribution cannot be defined because there is no line through the origin that excludes α/2 of the distribution[53].

Cost-effectiveness


are shown in Figure 1 (a, b, c) and 2 (a, b). ACTonPainguided showed the same and ACTonPainunguided a





€13,460.





Figure 2b).

- Figure 1-

- Figure 2-

Cost-utility

Cost-effectiveness planes and acceptability curves that refer to cost-utility are shown in figure 1 (d, e,

f) and 2 (c, d). ACTonPainguided showed the same and ACTonPainunguided a higher potential of being

cost-effective compared to waitlist at a WTP of €0 (50% and 66%, respectively). The interventions’





WTP increases up to €113,550 this probability rises to 70% and stagnates on this level. The break-

even point is at €41,350 (see Figure 2 d).

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After non-parametric bootstrapping, using the EQ-5D-3L resulted in larger incremental QALY gains

in all comparisons compared to the results using the AQoL-8D (see table 4).

At a WTP of €0 the probability of ACTonPainguided of being cost-effective compared to waitlist was

50%. The probability of ACTonPainunguided of being cost-effective compared to waitlist was 64% at a

WTP of €0. ACTonPainguided vs. ACTonPainunguided resulted in a probability of being cost-effective of

31% at a WTP of €0.

DISCUSSION




However, when assuming that an intervention should reach a likelihood of being cost-effective of 95%

or greater it has to be considered that the WTP would have to be €13,460 for treatment response and

€127,000 for a QALY gain. Therefore, the judgement of whether the intervention is cost-effective or

not ultimately depends on the society’s WTP for treatment response or a QALY gain, respectively.

ACTonPainguided also causes better results in the main outcome parameters, but at (slightly) higher

costs with ICERs of 45 (treatment response) and 604 (AQoL QALY gains). The probability of being

cost-effective at a WTP of €0 compared to waitlist is higher in ACTonPainunguided, for both, treatment

response and QALYs gained (66%) than in ACTonPainguided (50%).

However, when comparing the costs that would have to be invested by using ACTonPainguided

(compared to waitlist) for a QALY gained (€604) to the only official WTP threshold stated by the

National Institute for Health and Clinical Excellence (NICE) of £20,000 to £30,000 [54] (~ €22,647 -

€33,971; conversion according to the European Central bank [55]), this intervention would be

categorized as a potentially cost-effective treatment (with a probability of around 70%). This threshold

might serve as a reference, but it has to be considered, that it might differ for the German population.

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Here again, uncertainty has to be considered as well as the required WTP for a likelihood of being

cost-effective of 95% of €6,490 (treatment response) and €91,000 (QALY gain).

The direct comparison of ACTonPainguided and ACTonPainunguided shows more treatment responders

and (slightly) higher QALY gains for the guided version, but at higher costs. In terms of QALYs

gained, the guided version only reaches a probability of 31% of being cost-effective at a WTP of €0

and even with rising WTP threshold, the probability does not increase much.



Estimated EQ-5D utility scores for one year ranged from 0.50 to 0.54, what appears rather low

compared to national EQ-5D estimates for (back) pain from other countries (e.g. 0.74-0.79 [56, 57]).

Lower estimates in the current study could have occurred due to the sociodemographic properties of

this study sample, as participants were predominately women (84%), reported comorbid medical or

mental conditions (57% and 39%, respectively) and the back was the most often reported pain location

(34%) [25]. Several studies showed that the mentioned characteristics (female sex, musculoskeletal

and mental disorders) are associated with lower quality of life scores [56–58]. Furthermore, Burström

et al. (2001) reported in their study that participants with low back pain showed quality of life weights

of 0.55 [58], what is comparable to the sample in the current study.

The conclusion that ACTonPain has the potential of being cost-effective are in line with a recent study

and a review about the cost-effectiveness of IMIs for depression [23, 59]. The guided IMI for chronic

pain of Boer and colleagues revealed an ICER of 40 (defined as cost savings of €40) for an one-point

improvement in a pain catastrophizing scale compared to a face-to-face group intervention, while

QALYs were not reported [23]. ACTonPainguided reached (slightly) higher ICERs for the clinical

outcome pain interference (45 compared to waitlist group and 2,374 compared to the unguided group).

However, these values were calculated for treatment response in terms of pain interference and

therefore, a meaningful change and not for a one-point improvement on the scale. In a systematic

review, IMIs for depression that were classified as cost-effective were all guided and showed

probabilities of being cost-effective between 28% and 49% at a WTP of €0 for a QALY gained,

whereas ACTonPainguided and ACTonPainunguided even reached higher probabilities at this WTP level

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(50% and 66%, respectively). However, it has to be considered that in terms of QALY gain society has

to invest quite high sums of money for high probabilities (95%) of being cost-effectiveness.

Nevertheless, integrating psychological e-health approaches in pain management programs might be

promising from an economical point of view when compared to the well-established area of

depression e-health care.

The higher direct costs over a 6-months period in both intervention groups compared to waitlist might

be explained by higher or stable health care utilization similar to findings in a previous study on the

costs of established depression treatments [60]. However, research indicates that indirect rather than

direct costs represent the majority of overall costs [61, 62], where ACTonPain seemingly has its core

advantage. Mean indirect costs over the 6-month period were almost half as high in the intervention

groups compared to waitlist, regarding both absenteeism and presenteeism.

Next to the questions of whether ACTonPain is cost-effective compared to waitlist and whether it

should rather be provided guided or unguided, it would be of interest how ACTonPain performs

compared to established medical, psychological, physiotherapeutical, and surgical treatments that

result in high direct costs [63–66]. However, surprisingly little is known about the cost-effectiveness

of these established pain treatments. In two reviews it was highlighted, that interdisciplinary pain

rehabilitation programs are more cost-effective or produce lower costs than interventions such as

surgery and conservative care [67, 68]. For individuals with low back pain it was concluded that

interdisciplinary rehabilitation, exercise, acupuncture, spinal manipulation and CBT are potentially

cost-effective [69]. A further systematic review focused on economic evaluations of third-wave CBT

therapies (including ACT), were available ICERs ranged from negative ICERs indicating dominance

over the control group (National Health Service perspective) to €56,637 (societal perspective) per

QALY gained [13]. When compared to waitlist the ICERs based on the AQoL-8D in this study were

604 and a negative ICER (indicating dominance of the unguided intervention over WLC) per QALY

gained. Thus, it can be concluded that ACTonPain, as an example of an innovative IMI for the

treatment of chronic pain, is effective [25] and could be a cost-effective intervention. A comparison

across treatment approaches for chronic pain, however, cannot be provided as the evidence base for

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the cost-effectiveness of established pain treatments is rather weak and the comparability of results

across studies is limited due to very heterogeneous methods across trials [70].

Limitations



months. Therefore, no conclusions regarding the long-term cost-effectiveness can be drawn.

Furthermore, costs between randomization and three months after randomization were calculated with

the area under the curve method. This is just an estimate and not a representation of the actual costs

incurred during this period. Fourth, costs were assessed via self-report. However, as the questionnaire

used in this study is a valid instrument to recall periods up to three months [71], the impact of this bias

on results is limited. Finally, the usage of multiple imputation techniques is frequently recommended

(e.g. predictive mean matching [72]. We used a single imputation approach as it was done in the main

(effectiveness) analysis [25] that might not truly reflect missing data uncertainty. However, the

comparison with cost and QALY outcomes of complete case analysis revealed only small differences,

indicating that the risk of implausible values due to single imputation in this evaluation is low [73].





that depending on the society´s willingness-to-pay, both versions of ACTonPain have the potential of

being cost-effective, with the unguided version even leading to lower costs (compared to WLC).

However, uncertainty has to be taken into account. The decision whether to choose the guided or

unguided version is a public health issue and strongly depends on whether to mainly focus on patients´

health or society´s resources. Under health economic aspects ACTonPainunguided should be the preferred

intervention, especially when considering the intention of treatment implementation into the health

care system and scaling up mental health care for pain patients.

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Future research should especially focus on conducting methodologically sound studies that are

powered to statistically test health economic differences. Furthermore, long-term follow-up studies

and evaluation of the (comparative) cost-effectiveness of different guidance formats of IMIs,

particularly of ACTonPain, and established pain treatments are needed. Moreover, future studies

should examine ACTonPain as integrated part of multi-component pain programs and aim to

dismantle the ingredients that are effective and cost-effective in those complex approaches.

DECLARATIONS

Funding



and the Albert-Ludwigs University Freiburg in the funding programme Open Access Publishing.

Competing interests















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Acknowledgements


Figure Legends









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Additional file 1 – CHEERS checklist Section/item Item

No Recommendation Reported on page

No

Title and abstract

Title 1 Identify the study as an economic evaluation or use more specific terms such as “cost-effectiveness analysis”, and describe the interventions compared.

Page 1

Abstract 2 Provide a structured summary of objectives, perspective, setting, methods (including study design and inputs), results (including base case and uncertainty analyses), and conclusions.

Page 2 and 3 (the sensitivity analysis is not mentioned in the abstract due to limited words)

Introduction

Background and objectives

3 Provide an explicit statement of the broader context for the study. Present the study question and its relevance for health policy or practice decisions.

Page 4 and 5

Methods

Target population and subgroups

4 Describe characteristics of the base case population and subgroups analysed, including why they were chosen.

Page 5

Setting and location 5 State relevant aspects of the system(s) in which the decision(s) need(s) to be made.

Page 5

Study perspective 6 Describe the perspective of the study and relate this to the costs being evaluated.

Page 5, 8, 9 and 10

Comparators 7 Describe the interventions or strategies being compared and state why they were chosen.

Page 6

Time horizon 8 State the time horizon(s) over which costs and consequences are being evaluated and say why appropriate.

Page 6 and 7

Discount rate 9 Report the choice of discount rate(s) used for costs and outcomes and say why appropriate.

Page 10

Choice of health outcomes

10 Describe what outcomes were used as the measure(s) of benefit in the evaluation and their relevance for the type of analysis performed.

Page 6, 7 and 8

Measurement of effectiveness

11a Single study-based estimates: Describe fully the design features of the single effectiveness study and why the single study was a sufficient source of clinical effectiveness data.

Page 4 and 5

11b Synthesis-based estimates: Describe fully the methods used for identification of included studies and synthesis of clinical effectiveness data.

N/A

Measurement and valuation of preference based outcomes

12 If applicable, describe the population and methods used to elicit preferences for outcomes.

Page 7

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Estimating costs and resources

13a Single study-based economic evaluation: Describe approaches used to estimate resource use associated with the alternative interventions. Describe primary or secondary research methods for valuing each resource item in terms of its unit cost. Describe any adjustments made to approximate to opportunity costs.

Page 8, 9 and 10, Table 1

13b Model-based economic evaluation: Describe approaches and data sources used to estimate resource use associated with model health states. Describe primary or secondary research methods for valuing each resource item in terms of its unit cost. Describe any adjustments made to approximate to opportunity costs.

N/A

Currency, price date and conversion

14 Report the dates of the estimated resource quantities and unit costs. Describe methods for adjusting estimated unit costs to the year of reported costs if necessary. Describe methods for converting costs into a common currency base and the exchange rate.

Page 8

Choice of model 15 Describe and give reasons for the specific type of decision-analytical model used. Providing a figure to show model structure is strongly recommended.

N/A

Assumptions 16 Describe all structural or other assumptions underpinning the decision-analytical model.

N/A

Analytical methods 17 Describe all analytical methods supporting the evaluation. This could include methods for dealing with skewed, missing, or censored data; extrapolation methods; methods for pooling data; approaches to validate or make adjustments (such as half cycle corrections) to a model; and methods for handling population heterogeneity and uncertainty.

Page 10, 11 and 12

Results

Study parameters 18 Report the values, ranges, references, and, if used, probability distributions for all parameters. Report reasons or sources for distributions used to represent uncertainty where appropriate. Providing a table to show the input values is strongly recommended.

Page 12-17, Table 2 and 4

Incremental costs and outcomes

19 For each intervention, report mean values for the main categories of estimated costs and outcomes of interest, as well as mean differences between the comparator groups. If applicable, report incremental cost-effectiveness ratios.

Page 13; Table 3

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Characterising uncertainty

20a Single study-based economic evaluation: Describe the effects of sampling uncertainty for the estimated incremental cost and incremental effectiveness parameters, together with the impact of methodological assumptions (such as discount rate, study perspective).

Page 16 and 17 and Figure 1 and 2

20b Model-based economic evaluation: Describe the effects on the results of uncertainty for all input parameters, and uncertainty related to the structure of the model and assumptions.

N/A

Characterising heterogeneity

21 If applicable, report differences in costs, outcomes, or cost-effectiveness that can be explained by variations between subgroups of patients with different baseline characteristics or other observed variability in effects that are not reducible by more information.

N/A

Discussion

Study findings, limitations, generalisability, and current knowledge

22 Summarise key study findings and describe how they support the conclusions reached. Discuss limitations and the generalisability of the findings and how the findings fit with current knowledge.

Page 17-21

Other

Source of funding 23 Describe how the study was funded and the role of the funder in the identification, design, conduct, and reporting of the analysis. Describe other non-monetary sources of support.

Page 21

Conflicts of interest 24 Describe any potential for conflict of interest of study contributors in accordance with journal policy. In the absence of a journal policy, we recommend authors comply with International Committee of Medical Journal Editors recommendations.

Page 21

N/A, Not applicable

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