___________________________________________________________

Interuniversitaire opleiding

Master in de verzekeringsgeneeskunde en de medische expertise Eindverhandeling

__________________________________________________________________________

Return to work of patients treated with spinal cord stimulation for chronic pain:

a systematic review and meta-analysis

Maarten MOENS

Promotor: Prof. dr. Jan Verlooy

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Academiejaar 2017-2018

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This thesis has been accepted for publication in Neuromodulation: Technology at the Neural Interface.

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Return to work of patients treated with spinal cord stimulation for chronic pain: a systematic review and meta-analysis

Maarten Moens MD, PhD1,2,3,4; Lisa Goudman MSC1,4; Raf Brouns MD, PhD5,6; Alexis Valenzuela Espinoza7; Mats De Jaeger MSC1 ; Eva Huysmans MSC7,8; Koen Putman PhD7; Jan Verlooy MD, PhD9

1Department of Neurosurgery, UZ Brussel, Brussels, Belgium 2Department of Radiology, UZ Brussel, Brussels, Belgium 3Center for Neurosciences (C4N), Vrije Universiteit Brussel, Belgium 4Department of Manual Therapy (MANU), Vrije Universiteit Brussel, Brussels, Belgium 5Department of Neurology, ZorgSaam Hospital, Terneuzen, The Netherlands 6Faculty of Medicine and Pharmacy, Vrije Unversiteit Brussel, Belgium 7Department of Public Health (GEWE), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium8Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education & Physiotherapy (KIMA), Vrije Universiteit Brussel, Brussels, Belgium

9Department of Epidemiology and Social Medicine (ESOC), Universiteit Antwerpen, Antwerpen, Belgium

Abstract Background Chronic pain has a substantial negative impact on work-related outcomes, which underscores the importance of interventions to reduce the burden. Spinal cord stimulation (SCS) efficiently causes pain relief in specific chronic pain syndromes. The aim of this review was to identify and summarize evidence on returning to work in patients with chronic pain treated with SCS.

Methods A systematic literature review was performed including studies from PubMed, EMBASE, SCOPUS, and Web of Science (up till October 2017). Risk of bias was assessed using a modified version of the Downs & Black checklist. Where possible, we pooled data using random-effects meta-analysis. The study protocol was registered prior to initiation of the review process (PROSPERO CRD42017077803).

Results Fifteen full-text articles (total articles screened: 2,835) were included. Risk of bias for these articles was scored low. Seven trials provided sufficient data and were judged similar enough to be pooled for meta-analysis on binary outcomes. SCS intervention results in a higher prevalence of patients at work compared with before treatment (OR 2,15; 95% CI, 1,44 to 3,21; I2 = 42%; p < 0,001). SCS treatment results also in high odds to return to work (OR 29,06; 95% CI, 9,73 to 86,75; I2 = 0%; p < 0,001).

Conclusions Based on available literature, SCS proved to be an effective approach to stimulate return to work in patients with specific chronic pain syndromes.

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Background Spinal cord stimulation (SCS) is a well-known safe and effective treatment for many chronic

pain syndromes, including failed back surgery syndrome (FBSS), low back and lower

extremity pain, complex regional pain syndrome, and other neuropathic conditions(1-4).

Despite the extreme complexity of chronic pain, pain relief is the principal desired outcome

for SCS(1). The high socioeconomic burden and healthcare utilization associated with

chronic pain are therefore often reduced to secondary outcomes (5-7). When pain becomes

chronic, return to work (RTW) is negatively associated with a delay in referral to treatment,

socioeconomic status, attorney involvement, and worker’s compensation are(8). Several

studies have shown that unemployment and absenteeism are “negatively associated with

quality of life, depression and generally poor health outcomes”(9-11).

Currently, it is well accepted that SCS is an effective treatment for reducing pain and

improving quality of life, but little is known about the impact of SCS on occupational

outcome parameters such as RTW. Therefore, we conducted a systematic review and meta-

analysis to identify not only the prevalence of RTW by SCS in patients with chronic pain but

also the odds of working with SCS.

Methods Search strategy and selection criteria

This systematic review and meta-analysis were conducted in accordance with the PRISMA

(Preferred Reporting Items for Systematic Review and Meta-Analyses) guidance(12). The

electronic databases of PubMed, Embase, SCOPUS, and Web of Science were searched from

inception to October 20th, 2017 to identify potentially relevant studies.

The search strategy was, based on the PICO (evidence based search strategy focusing on

Patient/Population, Intervention, Comparison and Outcome) Framework (13). Our search

was not limited to randomized controlled trials (RCTs) but also included case series. A

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language restriction of English, French, German, and Dutch was applied. We included

studies that met the following criteria: (1) population – adult (³18 years old) chronic pain

patients eligible for SCS; (2) intervention – SCS; (3) outcome – RTW, employment status and

sick leave. We excluded studies enrolling patients receiving other types of neuromodulation

and publications available only in abstract form or meeting reports.

Data extraction and quality assessment

After combining search results from different databases and removing duplicates by using

EndNote reference manager, two investigators (MM and LG) independently reviewed all the

retrieved abstracts and full texts to remove ineligible studies. In case of disagreement,

consensus was sought through consultation and discussion with a third party (RB). The two

reviewers (MM and LG) independently extracted data from included studies, using an a

priori determined data extraction form comprising the following items (1) first author (2)

year of publication, (3) country, (4) sample size in relation to RTW outcome, (5) study

design, (6) diagnosed population, (7) type of SCS and (8) all predefined outcomes. The

quality of the included studies was evaluated using the risk of bias Downs and Black

checklist (modified version) (14). We assigned a value of 0 or 1 to the different

subcategories of the following items: reporting, external validity and internal validity. A total

score < 10/16 was considered to be low quality, while scores ³ 10/16 were presumed to be

high quality. Discrepancies were identified and resolved through discussion.

Outcome and statistical analysis

The primary goal of this study was to identify the prevalence of work resumption after

implantation of SCS. Subgroup analyses were performed to evaluate the occupational status

at last follow-up point. The results from all relevant studies were merged to estimate the

pooled odds ratio (OR) and associated 95% confidence intervals (CI’s) for dichotomous

outcomes. The outcomes were pooled using a random effects model. All p< 0,05 were

considered statistically significant. Heterogeneity was tested with I2 statistics. This statistic

can be interpreted as the proportion of the total variation in the estimated treatment effect

due to the heterogeneity among studies(15). To explore the robustness and the potential

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influence of various factors on our primary outcome, we performed a subgroup analysis

based on pathology (back and leg pain versus mixed). The Dixon’s Q test for the rejection of

extreme values (at the 5 and 1% levels) was performed to identify outliers(16). Publication

bias was evaluated by visual inspection of the funnel plot. All statistical analyses were

performed using RStudio (version 0.99.903, RStudio, Inc).

Results Study selection

A flowchart of the search strategy and the reasons for exclusion are shown in figure 1. The

initial search identified a total of 2,835 citations. After combining the results, removing

duplicates and selections based on the title and abstract, 54 full-text studies remained.

Thirty-nine studies were excluded after reviewing the full text: 10 because of inappropriate

outcome parameters (no RTW mentioned), 28 were excluded because of unsuitable study

design or conference meeting abstract and, one because no full text was available even

after communication with the first author. Thus, 15 full-text studies were read for further

evaluation. Of those 15 studies, 6 were excluded because they did not provide sufficient

information on the occupational status at last follow-up point(17-22), 1 was excluded

because the studied population was reported in another study(23, 24), and 1 study did not

pass the outlier test(25). This study from Harke et al. was considered an outlier at the level 5

and at the 1%(25). Finally, the remaining seven, which enrolled 824 patients, were included

in the meta-analysis(23, 26-31).

Study characteristics and quality

The main characteristics and predefined outcome data of the included studies for the

systematic review are described in table 1. These studies were published between 1978 and

2017, with sample sizes ranging from 20 to 410. One RCT was included, five retrospective

case series and one prospective cohort study. One study evaluated high-frequency SCS,

while the other studies reported on the use of conventional SCS (29). The mean follow-up

period varied from 1 year to 7.1 years. Three studies were included with a study population

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suffering from back and/or leg pain (FBSS with axial back pain and unilateral limb pain),

while four other studies described a more heterogeneous study population (i.e., FBSS,

multiple sclerosis, spinal cord injury, vascular disease, cancer, occipital neuralgia, trauma,

and peripheral neuropathy). The risk of bias Downs and Black checklist score for each

citation varied across the studies, ranging from 10 to 16 out of 17.

Primary Outcome

Occupational status

The number of patients working after SCS was mentioned in all seven studies. The pooled

analysis showed that SCS increases the odds to work after SCS (7 studies; n = 824, OR 2,15;

95% CI, 1,44 to 3,21; I2 = 42%; p = 0,0001). Given the moderate heterogeneity, a subgroup

based on the type of population was also evaluated. The type of population (chronic back

and/or leg pain versus mixed pain syndromes) was defined to be a factor influencing

heterogeneity (figure 2).

In general, both subgroups analyses confirmed similar OR of working status among groups.

The funnel plot shows no publication bias (available upon request).

Return to work %RTW, defined as the percentage of patients going back to work who were unemployed

before treatment, was reported or could be calculated in all seven studies. The %RTW

varied between 10 and 47 (mean 14). The pooled analysis showed that SCS increases the

odds to return to work after SCS in patients with absenteeism before treatment (7 studies;

n = 701, OR 29,06; 95% CI, 9,73 to 86,75; I2 = 0%; p < 0,0001). The funnel plot shows no

publication bias (available upon request).

Secondary outcomes

The types of employment after returning to work were not reported in all seven studies.

Three studies described the number of patients with part-time and full-time employment

after SCS implantation at the last follow-up(29, 30, 32). Two studies also mentioned the

numbers of patients who increased working time after SCS implantation(26, 30). One study

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presented the percentage of patients with SCS working at various follow-up points(31). Yet

another study reported the median time of unemployment(28).

Discussion In the past two decades, SCS for pain relief has evolved to include many new methods of

current delivery by neurostimulation devices(3). This resulted in several studies presenting

excellent results on pain reduction. Although the status of “remission,” or achieving almost

complete pain relief by SCS, for some patients has been reported, occupational outcomes,

such as RTW, are rarely an outcome parameter in neuromodulation studies(33). SCS has

shown superior efficacy to conventional medical management in an FBSS population and

SCS leads to long-term health care cost savings(28, 34). These data support the long-term

cost utility of SCS in the treatment of FBSS patients(34). However, in a chronic pain

population, it is well known that two thirds of the total health care costs are represented by

indirect costs (loss of productivity or working days lost)(35).

Our epidemiological meta-analysis included seven studies with 824 patients investigated

occupational outcomes. Despite the clinical heterogeneity of the subgroup “chronic back

and leg pain”, the results for this subgroup appeared to be statistically homogenous and this

in contrast to the subgroup with mixed diagnoses. This can be explained by the fact that the

mixed group consists of various diagnoses with variable evidence for SCS, while SCS for

chronic low back pain has proven to be effective and has reached a recommendation in the

recent European Academy of Neurology (EAN) guidelines(36).

This meta-analysis showed that, among chronic pain patients, SCS improves the odds of

returning to work and that SCS results in more patients at work, compared with the same

population before SCS.

In terms of %RTW, the percentage of patients going back to work who were unemployed

before treatment, SCS seems to allow chronic pain patients to work again. Since SCS

candidates are refractory to conventional pain therapy and therefore difficult to treat, a

mean of 14% of unemployed patients returning to work should be born in mind. However,

no information is available in these studies on the type of work the patients are returning

to. Although three studies reported the number of patients returning to work on a part-time

basis, the relevant number of hours worked daily was not mentioned(24, 26, 30). Young et

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al. considered returning to household duties or to studying as returning to gainful

employment(31). It is generally accepted that patients at working age or defined as patients

under the age of 65 are more likely to return to work. This specific subdivision of patients

receiving SCS was reported only in a minority of the reviewed studies(28-30).

The number of patients found in this meta-analysis is similar to the findings of the

systematic review of Frey et al. in 2009(37). They summarized a 13% entry in gainful

employment and return to work in 16 to 31% of FBSS patients(37).

Researchers agree that both job loss and continuing “worklessness” impact adversely on

people’s health with increased levels of both mental and physical problems(38).

Notwithstanding the evidence of using classical pain relief, functionality, and quality of life

as outcome measurements in chronic pain studies, RTW as a central determinant of

(mental) health, should also be considered as an important clinical outcome measure.

Additionally, Elfering et al. reported that only measuring global work status and %RTW as

work-related outcome parameters, lack specificity(39). In-depth and detailed analyses, clear

definitions, disjunctive classes of categories and adequate time frames might upgrade this

specificity. Job description and educational level, type of employment (full time, part time or

casual), reasons for unemployment, work-related attitudes (e.g. job satisfaction, work-

related expectations, ...) and other risk factors for chronic disability may also be taken in

consideration(39, 40).

Strengths and limitations To diminish bias, the study selection, data extraction, and evaluation of study quality were

performed by two independent reviewers. We comprehensively analyzed the odds of

working and the odds of RTW after SCS treatment in studies with different designs.

There were also several potential limitations regarding our meta-analysis. First, some well-

designed studies were excluded because they lacked essential information about the work

status of all patients. Second, the sample size was small as only seven studies were included.

Third, the bias of the publications might have affected the validity of our conclusions, such

as lack of comparison (e.g. best medical treatment, other types of therapies, …). And finally,

the search method was limited to Medline, Embase, Web of Science and Scopus. We did not

search the “grey literature” (trial registries nor backward references).

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Conclusion

In summary, based on available data, this meta-analysis demonstrates that SCS treatment

results in more patients at work and also more patients returning to work. More, large-scale

studies are warranted to analyze in detail the work status of the included patients (type of

job, full time, part-time, % patients at working age, etc).

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Figure legend Table 1 Characteristics of included studies.

Abbreviations: RTW: return to work; mo: months; y: year(s); CLBP: chronic low back pain; FBSS: failed back surgery syndrome; PT/FT: part time/full time; SCS: spinal cord stimulation Explanation: Country (C): presented in ISO3166-1 alpha-2 codes (US: United States of America; GB: Great Britain; CA: Canada; IE: Ireland) Study Type: RCT: randomized controlled trial; retro case series: retrospective case series; prosp cohort study: prospective cohort study N: total sample size for return to work analysis Population: type of population eligible to SCS: Mixed: a mixed group of patients with different diagnoses; CLBP: chronic low back pain patients; FBSS: patients with failed back surgery syndrome Mean postoperative sick leave duration: Presents the median time of unemployment before SCS treatment Follow-up points: either a fixed follow-up moment, or a mean of follow-up. %RTW (No of patients): X% of the patients has returned to work PT/FT: number of patients returned to work (part-time / full-time) Working at baseline: number of patients at work at baseline Working after SCS: number of patients at work after SCS at the latest follow-up point Figure 1: Flow chart of study selection in meta-analysis of occupational outcome after SCS treatment Figure 2: Forest plot of working status with SCS compared with before treatment

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14

15

Pre-SCSSCSTotalTotal WorkingWorking

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Appendix A: PICO Free terms MeSH-terms Population “Chronic pain patients”;

“chronic pain”; “persistent pain” “intractable pain”; AND "Causalgia"; "Reflex sympathetic dystrophy"; “failed back surgery syndrome”; “post laminectomy syndrome”; “postlaminectomy syndrome”; “failed neck surgery syndrome”; “CRPS”; “complex regional pain syndrome”; “complex regional pain syndromes”; “FBSS”; “FNSS”; “peripheral neuropathy”; “neuropathic pain”; “angina pectoris”; “peripheral vascular disease”; "peripheral vascular diseases"; "Peripheral nervous system diseases"

Chronic pain; Pain, Intractable; AND Failed back surgery syndrome; Causalgia; Complex regional pain syndromes; Reflex sympathetic dystrophy; peripheral nervous system diseases; neuropathic pain; angina pectoris; peripheral vascular diseases;

Intervention “Spinal cord stimulation”; "Neurostimulation"; "Neuromodulation"; “Dorsal column stimulation”; "Neurostimulator"; “Spinal cord stimulator”; “Dorsal column stimulator”; “electrical stimulation”; “pain stimulator”; “pain stimulation”;

spinal cord stimulation; Implantable neurostimulators; Electric stimulation therapy; Electric stimulation;

Control / / Outcome “occupation”;

“re-employment”; “professional situation”; “return-to-work”; “back to work”; “back-to-work”; “work activity”; “employment status”;

Return to work; Employment; Sick leave

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Resume; Reintegration; Reinsertion; Incapacity AND Work; “labour market”; “labor market”; Professional; Occupation; occupational “disability leave”; “Sick day”; “sick days”; “illness day”; “illness days”; “disability pension”; “occupational disability”; “work disability”

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Appendix B: Systematic literature search for PubMed

SEARCH 20/10/2017 PubMed

POPULATION

"Chronic pain patients" 2488

“chronic pain” 33327

“persistent pain” 4259

“intractable pain” 7309

“failed back surgery syndrome” 720

“post laminectomy syndrome” 30

“failed neck surgery syndrome” 4

“postlaminectomy syndrome” 32

“CRPS” 1886

“complex regional pain syndrome” 2415

“complex regional pain syndromes" 1245

“FBSS” 257

“FNSS” 23

“peripheral neuropathy” 15580

“neuropathic pain” 15952

“angina pectoris” 40590

“peripheral vascular disease” 8305

"Causalgia" 906

"Reflex sympathetic dystrophy" 3999

"peripheral vascular diseases" 12965

"Peripheral nervous system diseases" 21388

"Chronic Pain"[Mesh] 8555

"Pain, Intractable"[Mesh] 5987

"Failed back surgery syndrome"[Mesh] 233

"Causalgia"[Mesh] 666

"Complex regional pain syndromes"[Mesh] 5154

"Reflex sympathetic dystrophy"[Mesh] 3499

"peripheral nervous system diseases"[Mesh] 133020

19

"neuralgia"[Mesh] 27216

"angina pectoris"[Mesh] 41824

"peripheral vascular diseases"[Mesh] 49171

(((((((((((((((((((((((((((("Chronic pain patients") OR “chronic pain”) OR “persistent pain”) OR “intractable pain”) OR “failed back surgery syndrome”) OR “post laminectomy syndrome”) OR “failed neck surgery syndrome”) OR “postlaminectomy syndrome”) OR “CRPS”) OR “complex regional pain syndrome”) OR “complex regional pain syndromes") OR “FBSS”) OR “FNSS”) OR “peripheral neuropathy”) OR “neuropathic pain”) OR “angina pectoris”) OR “peripheral vascular disease”) OR "Causalgia") OR "Pain, Intractable"[Mesh]) OR "Failed back surgery syndrome"[Mesh]) OR "Causalgia"[Mesh]) OR "Complex regional pain syndromes"[Mesh]) OR "Reflex sympathetic dystrophy"[Mesh]) OR "angina pectoris"[Mesh]) OR "peripheral vascular diseases"[Mesh]) OR neuralgia) OR "peripheral nervous system diseases"[Mesh]) OR "Peripheral nervous system diseases") OR "peripheral vascular diseases"

297580

(((((((((((((((((((("Chronic pain patients") OR “chronic pain”) OR “persistent pain”) OR “intractable pain”) OR “failed back surgery syndrome”) OR “post laminectomy syndrome”) OR “failed neck surgery syndrome”) OR “postlaminectomy syndrome”) OR “CRPS”) OR “complex regional pain syndrome”) OR “complex regional pain syndromes") OR “FBSS”) OR “FNSS”) OR “peripheral neuropathy”) OR “neuropathic pain”) OR “angina pectoris”) OR “peripheral vascular disease”) OR "Causalgia") OR "Reflex sympathetic dystrophy") OR "peripheral vascular diseases") OR "Peripheral nervous system diseases"

150948

((((((((("Chronic Pain"[Mesh]) OR "Pain, Intractable"[Mesh]) OR "Failed back surgery syndrome"[Mesh]) OR "Causalgia"[Mesh]) OR "Complex regional pain syndromes"[Mesh]) OR "Reflex sympathetic dystrophy"[Mesh]) OR "peripheral nervous system diseases"[Mesh]) OR neuralgia) OR "angina pectoris"[Mesh]) OR "peripheral vascular diseases"[Mesh]

245267

((((("Chronic pain patients") OR “chronic pain”) OR “persistent pain”) OR “intractable pain”) OR "Chronic Pain"[Mesh]) OR "Pain, Intractable"[Mesh]

42953

(((((((((((((((((((((((("Causalgia") OR "Reflex sympathetic dystrophy") OR “failed back surgery syndrome”) OR “post laminectomy syndrome”) OR “failed neck surgery syndrome”) OR “postlaminectomy syndrome”) OR “CRPS”) OR “complex regional pain syndrome”) OR “complex regional pain syndromes") OR “FBSS”) OR “FNSS”) OR “peripheral neuropathy”) OR “neuropathic pain”) OR “angina pectoris”) OR “peripheral vascular disease”) OR "peripheral vascular diseases") OR "Peripheral nervous system diseases") OR "Failed back surgery syndrome"[Mesh]) OR "Causalgia"[Mesh]) OR "Complex regional pain syndromes"[Mesh]) OR "Reflex sympathetic dystrophy"[Mesh]) OR "peripheral nervous system diseases"[Mesh]) OR neuralgia) OR "angina pectoris"[Mesh]) OR "peripheral vascular diseases"[Mesh]

260924

(((((((((((((((((((((((((("Causalgia") OR "Reflex sympathetic dystrophy") OR “failed back surgery syndrome”) OR “post laminectomy syndrome”) OR “failed neck surgery syndrome”) OR “postlaminectomy syndrome”) OR “CRPS”) OR “complex regional pain syndrome”) OR “complex regional pain syndromes") OR “FBSS”) OR “FNSS”) OR “peripheral neuropathy”) OR “neuropathic pain”) OR “angina pectoris”) OR “peripheral vascular disease”) OR "peripheral vascular diseases") OR "Peripheral nervous system diseases") OR "Failed back surgery syndrome"[Mesh]) OR

6030

20

"Causalgia"[Mesh]) OR "Complex regional pain syndromes"[Mesh]) OR "Reflex sympathetic dystrophy"[Mesh]) OR "peripheral nervous system diseases"[Mesh]) OR neuralgia) OR "angina pectoris"[Mesh]) OR "peripheral vascular diseases"[Mesh])) AND (((((("Chronic pain patients") OR “chronic pain”) OR “persistent pain”) OR “intractable pain”) OR "Chronic Pain"[Mesh]) OR "Pain, Intractable"[Mesh])

INTERVENTION

“Spinal cord stimulation” 2565

"Neurostimulation" 1985

"Neuromodulation" 7171

“Dorsal column stimulation” 195

"Neurostimulator" 385

“Spinal cord stimulator” 321

“Dorsal column stimulator” 18

“electrical stimulation” 41302

“pain stimulator” 12

“pain stimulation” 452

"spinal cord stimulation"[Mesh] 568

"implantable neurostimulators"[Mesh] 9204

"electric stimulation therapy"[Mesh] 68867

"electric stimulation"[Mesh]

122883

((((((((((((("electric stimulation"[Mesh]) OR "electric stimulation therapy"[Mesh]) OR "implantable neurostimulators"[Mesh]) OR "spinal cord stimulation"[Mesh]) OR “pain stimulation”) OR “pain stimulator”) OR “electrical stimulation”) OR “Dorsal column stimulator”) OR “Spinal cord stimulator”) OR "Neurostimulator") OR “Dorsal column stimulation”) OR "Neuromodulation") OR "Neurostimulation") OR “Spinal cord stimulation”)

216118

POPULATION AND INTERVENTION

(((((((((((((((((((((((((((("Causalgia") OR "Reflex sympathetic dystrophy") OR “failed back surgery syndrome”) OR “post laminectomy syndrome”) OR “failed neck surgery syndrome”) OR “postlaminectomy syndrome”) OR “CRPS”) OR “complex regional pain syndrome”) OR “complex regional pain syndromes") OR “FBSS”) OR “FNSS”) OR “peripheral neuropathy”) OR “neuropathic pain”) OR “angina pectoris”) OR “peripheral vascular disease”) OR "peripheral vascular diseases") OR "Peripheral nervous system diseases") OR "Failed back surgery syndrome"[Mesh]) OR "Causalgia"[Mesh]) OR

830

21

"Complex regional pain syndromes"[Mesh]) OR "Reflex sympathetic dystrophy"[Mesh]) OR "peripheral nervous system diseases"[Mesh]) OR neuralgia) OR "angina pectoris"[Mesh]) OR "peripheral vascular diseases"[Mesh])) AND (((((("Chronic pain patients") OR “chronic pain”) OR “persistent pain”) OR “intractable pain”) OR "Chronic Pain"[Mesh]) OR "Pain, Intractable"[Mesh]))) AND (((((((((((((("electric stimulation"[Mesh]) OR "electric stimulation therapy"[Mesh]) OR "implantable neurostimulators"[Mesh]) OR "spinal cord stimulation"[Mesh]) OR “pain stimulation”) OR “pain stimulator”) OR “electrical stimulation”) OR “Dorsal column stimulator”) OR “Spinal cord stimulator”) OR "Neurostimulator") OR “Dorsal column stimulation”) OR "Neuromodulation") OR "Neurostimulation") OR “Spinal cord stimulation”)

POPULATION OR INTERVENTION

((((((((((((((("electric stimulation"[Mesh]) OR "electric stimulation therapy"[Mesh]) OR "implantable neurostimulators"[Mesh]) OR "spinal cord stimulation"[Mesh]) OR “pain stimulation”) OR “pain stimulator”) OR “electrical stimulation”) OR “Dorsal column stimulator”) OR “Spinal cord stimulator”) OR "Neurostimulator") OR “Dorsal column stimulation”) OR "Neuromodulation") OR "Neurostimulation") OR “Spinal cord stimulation”)) OR ((((((((((((((((((((((((((("Causalgia") OR "Reflex sympathetic dystrophy") OR “failed back surgery syndrome”) OR “post laminectomy syndrome”) OR “failed neck surgery syndrome”) OR “postlaminectomy syndrome”) OR “CRPS”) OR “complex regional pain syndrome”) OR “complex regional pain syndromes") OR “FBSS”) OR “FNSS”) OR “peripheral neuropathy”) OR “neuropathic pain”) OR “angina pectoris”) OR “peripheral vascular disease”) OR "peripheral vascular diseases") OR "Peripheral nervous system diseases") OR "Failed back surgery syndrome"[Mesh]) OR "Causalgia"[Mesh]) OR "Complex regional pain syndromes"[Mesh]) OR "Reflex sympathetic dystrophy"[Mesh]) OR "peripheral nervous system diseases"[Mesh]) OR neuralgia) OR "angina pectoris"[Mesh]) OR "peripheral vascular diseases"[Mesh])) AND (((((("Chronic pain patients") OR “chronic pain”) OR “persistent pain”) OR “intractable pain”) OR "Chronic Pain"[Mesh]) OR "Pain, Intractable"[Mesh]))

221318

OUTCOME

“Return to work” 8113

Employment 109212

“Sick leave” 7334

“work activity” 666

“employment status” 7132

“Re-employment” 165

“professional situation” 89

“return-to-work” 8113

“back to work” 498

22

“back-to-work” 498

“disability leave” 41

“sick day” 102

“sick days” 335

“illness day” 40

“illness days” 57

“disability pension” 1121

“occupational disability” 268

“work disability” 1758

Incapacity 2764

Resume 6599

Reintegration 2641

Reinsertion 10339

professional 272333

“labour market” 1418

“labor market” 2082

Work 854476

Occupation 71922

Occupational 297058

(((((work) OR "labour market") OR “labor market”) OR occupation) OR occupational) OR professional)

1363359

(((reinsertion) OR reintegration) OR resume) OR incapacity 22247

((((((("labour market") OR work) OR occupational) OR occupation) OR professional) OR "labor market")) AND ((((reinsertion) OR reintegration) OR resume) OR incapacity)

3246

(((((((((((((((((return to work) OR employment) OR sick leave) OR "work activity") OR "employment status") OR "re-employment") OR "professional situation") OR "return-to-work") OR "back to work") OR "disability leave") OR "sick day") OR "sick days") OR "illness day") OR "illness days") OR "disability pension") OR "occupational disability") OR "work disability") OR occupation

181732

(((((((((((((((((((return to work) OR employment) OR sick leave) OR "work activity") OR "employment status") OR "re-employment") OR "professional situation") OR "return-to-work") OR "back to work") OR "disability leave") OR "sick day") OR "sick days") OR "illness day") OR "illness days") OR "disability pension") OR "occupational disability") OR "work disability") OR occupation)) OR (((((((work) OR "labour market") OR occupation) OR

183898

23

occupational) OR professional)) AND ((((reinsertion) OR reintegration) OR resume) OR incapacity))

((((((((((((((((return to work) OR employment) OR sick leave) OR "work activity") OR "employment status") OR "re-employment") OR "professional situation") OR "return-to-work") OR "back to work") OR "disability leave") OR "sick day") OR "sick days") OR "illness day") OR "illness days") OR "disability pension") OR "occupational disability") OR "work disability"

126726

((((((((((((((((((return to work) OR employment) OR sick leave) OR "work activity") OR "employment status") OR "re-employment") OR "professional situation") OR "return-to-work") OR "back to work") OR "disability leave") OR "sick day") OR "sick days") OR "illness day") OR "illness days") OR "disability pension") OR "occupational disability") OR "work disability")) OR (((((((work) OR "labour market") OR occupation) OR occupational) OR professional)) AND ((((reinsertion) OR reintegration) OR resume) OR incapacity))

129050

((((((((("labour market") OR work) OR occupational) OR occupation) OR professional) OR "labor market")) AND ((((reinsertion) OR reintegration) OR resume) OR incapacity))) OR ((((((((((((((((((return to work) OR employment) OR sick leave) OR "work activity") OR "employment status") OR "re-employment") OR "professional situation") OR "return-to-work") OR "back to work") OR "disability leave") OR "sick day") OR "sick days") OR "illness day") OR "illness days") OR "disability pension") OR "occupational disability") OR "work disability") OR occupation)

183900

((((((((("labour market") OR work) OR occupational) OR occupation) OR professional) OR "labor market")) AND ((((reinsertion) OR reintegration) OR resume) OR incapacity))) OR (((((((((((((((((return to work) OR employment) OR sick leave) OR "work activity") OR "employment status") OR "re-employment") OR "professional situation") OR "return-to-work") OR "back to work") OR "disability leave") OR "sick day") OR "sick days") OR "illness day") OR "illness days") OR "disability pension") OR "occupational disability") OR "work disability")

129052

No “occupation” free

POPULATION OR INTERVENTION AND OUTCOME

((((((((((((((((("electric stimulation"[Mesh]) OR "electric stimulation therapy"[Mesh]) OR "implantable neurostimulators"[Mesh]) OR "spinal cord stimulation"[Mesh]) OR “pain stimulation”) OR “pain stimulator”) OR “electrical stimulation”) OR “Dorsal column stimulator”) OR “Spinal cord stimulator”) OR "Neurostimulator") OR “Dorsal column stimulation”) OR "Neuromodulation") OR "Neurostimulation") OR “Spinal cord stimulation”)) OR ((((((((((((((((((((((((((("Causalgia") OR "Reflex sympathetic dystrophy") OR “failed back surgery syndrome”) OR “post laminectomy syndrome”) OR “failed neck surgery syndrome”) OR “postlaminectomy syndrome”) OR “CRPS”) OR “complex regional pain syndrome”) OR “complex regional pain syndromes") OR “FBSS”) OR “FNSS”) OR “peripheral neuropathy”) OR “neuropathic pain”) OR “angina pectoris”) OR “peripheral vascular disease”) OR "peripheral vascular diseases") OR "Peripheral nervous system diseases") OR "Failed back surgery syndrome"[Mesh]) OR "Causalgia"[Mesh]) OR "Complex regional pain syndromes"[Mesh]) OR "Reflex sympathetic dystrophy"[Mesh]) OR "peripheral nervous system diseases"[Mesh]) OR neuralgia) OR "angina pectoris"[Mesh]) OR "peripheral vascular diseases"[Mesh])) AND (((((("Chronic pain patients") OR “chronic pain”) OR “persistent pain”) OR “intractable

389

24

pain”) OR "Chronic Pain"[Mesh]) OR "Pain, Intractable"[Mesh])))) AND (((((((((("labour market") OR work) OR occupational) OR occupation) OR professional) OR "labor market")) AND ((((reinsertion) OR reintegration) OR resume) OR incapacity))) OR ((((((((((((((((((return to work) OR employment) OR sick leave) OR "work activity") OR "employment status") OR "re-employment") OR "professional situation") OR "return-to-work") OR "back to work") OR "disability leave") OR "sick day") OR "sick days") OR "illness day") OR "illness days") OR "disability pension") OR "occupational disability") OR "work disability") OR occupation))

POPULATION AND INTERVENTION AND OUTCOME

((((((((((((((((("electric stimulation"[Mesh]) OR "electric stimulation therapy"[Mesh]) OR "implantable neurostimulators"[Mesh]) OR "spinal cord stimulation"[Mesh]) OR “pain stimulation”) OR “pain stimulator”) OR “electrical stimulation”) OR “Dorsal column stimulator”) OR “Spinal cord stimulator”) OR "Neurostimulator") OR “Dorsal column stimulation”) OR "Neuromodulation") OR "Neurostimulation") OR “Spinal cord stimulation”)) AND ((((((((((((((((((((((((((("Causalgia") OR "Reflex sympathetic dystrophy") OR “failed back surgery syndrome”) OR “post laminectomy syndrome”) OR “failed neck surgery syndrome”) OR “postlaminectomy syndrome”) OR “CRPS”) OR “complex regional pain syndrome”) OR “complex regional pain syndromes") OR “FBSS”) OR “FNSS”) OR “peripheral neuropathy”) OR “neuropathic pain”) OR “angina pectoris”) OR “peripheral vascular disease”) OR "peripheral vascular diseases") OR "Peripheral nervous system diseases") OR "Failed back surgery syndrome"[Mesh]) OR "Causalgia"[Mesh]) OR "Complex regional pain syndromes"[Mesh]) OR "Reflex sympathetic dystrophy"[Mesh]) OR "peripheral nervous system diseases"[Mesh]) OR neuralgia) OR "angina pectoris"[Mesh]) OR "peripheral vascular diseases"[Mesh])) AND (((((("Chronic pain patients") OR “chronic pain”) OR “persistent pain”) OR “intractable pain”) OR "Chronic Pain"[Mesh]) OR "Pain, Intractable"[Mesh])))) AND (((((((((("labour market") OR work) OR occupational) OR occupation) OR professional) OR "labor market")) AND ((((reinsertion) OR reintegration) OR resume) OR incapacity))) OR ((((((((((((((((((return to work) OR employment) OR sick leave) OR "work activity") OR "employment status") OR "re-employment") OR "professional situation") OR "return-to-work") OR "back to work") OR "disability leave") OR "sick day") OR "sick days") OR "illness day") OR "illness days") OR "disability pension") OR "occupational disability") OR "work disability") OR occupation))

15

Bold: term used in the final systematic search with corresponding number of search results

25

Appendix C: Risk of bias assessment Reporting External validity Internal validity

Hyp

othe

sis

Mai

n ou

tcom

es

Patie

nt c

hara

cter

istic

s

Inte

rven

tions

Find

ings

Estim

ates

of

rand

om v

aria

bilit

y

Adve

rse

even

ts

Char

acte

ristic

s of

patie

nts L

TFU

Actu

al

prob

abili

ty v

alue

s

Repr

esen

tativ

enes

s of

pa

tient

s ask

ed

Repr

esen

tativ

enes

s of

in

clud

ed p

atie

nts

Repr

esen

tativ

enes

s of

tr

eatm

ent a

ccom

mod

atio

n

Data

dre

dgin

g

Appr

opria

tene

ss o

f st

atis

tics

Com

plia

nce

with

in

terv

entio

n

Out

com

e m

easu

res

va

lid/r

elia

ble

Loss

es o

f pat

ient

s

take

n in

to a

ccou

nt

Tota

l

North (1993) 1 1 1 1 1 0 1 1 1 0 0 0 1 1 1 1 1 13

Young (1978) 1 0 1 1 1 0 1 1 1 0 0 0 0 0 1 1 1 10

Kumar (2006) 1 1 1 1 1 0 1 1 1 1 0 0 1 1 1 1 1 14

Harke (2005) 1 1 1 1 1 1 1 1 1 1 0 0 0 1 1 1 1 14

Gopal (2016 1 1 1 1 1 0 1 1 1 1 0 0 1 1 1 1 1 14

Al-Kaisy (2017) 1 1 1 1 1 1 1 1 1 0 0 0 1 1 1 1 1 14

Kumar (2008) 1 1 1 1 1 1 1 1 1 1 1 0 1 1 1 1 1 16

North (1991) 1 1 1 1 1 1 1 1

1 1 0 0 1 1 1 1 1 15 Total 8 7 8 8 8 4 8 8 8 5 1 0 6 7 8 8 8 LTFU: loss to follow-up

26

North (1993)

Kumar (2008)

Gopal (2016)

North (1991)

Al-Kaisy (2017)Young (1978)

Kumar (2006)

Funnel plot: working status with SCS compared with before treatment

27

Funnel plot: return to work due to SCS compared with before treatment

Al-Kaisy (2017)Kumar (2008)

Young (1978)North (1991)

Gopal (2016)North (1993)

Kumar (2006)

28

01-May-2018 Dear Professor Moens: It is a pleasure to accept your manuscript entitled "Return to work of patients treated with spinal cord stimulation for chronic pain: a systematic review and meta-analysis" in its current form for publication in the Neuromodulation: Technology at the Neural Interface. Your article cannot be published until the publisher has received the appropriate signed license agreement. Once your article has been received by Wiley for production the corresponding author will receive an email from Wiley’s Author Services system which will ask them to log in and will present them with the appropriate license for completion. In addition, WIKISTIM.org is a searchable, free, collaborative website supported by the neuromodulation community. WIKISTIM lists publications that present primary data and provides datasheets for extrapolating SCS, DRG, DBS, PNS, and SNS data. Citations and completed datasheets can be downloaded to create evidence tables, answer clinical questions, and aid in reimbursement and payment decisions. We congratulate you on the acceptance of your paper and invite you to submit a companion completed data sheet to WIKISTIM. Links to the datasheets are provided below. We thank you for your fine contribution. On behalf of the Editors of the Neuromodulation: Technology at the Neural Interface, we look forward to your continued contributions to the Journal. Many thanks, Dr Robert Levy Editor in Chief, Neuromodulation: Technology at the Neural Interface rlevy@neuromodulation.com WIKISTIM DATASHEET LINKS: SCS: http://www.wikistim.org/wp-content/uploads/2015/05/SCS-datasheet-with-examples.csv DRG: http://www.wikistim.org/wp-content/uploads/2015/05/DRG-datasheet-with-examples.csv DBS: http://www.wikistim.org/wp-content/uploads/2015/05/DBS-datasheet-with-examples.csv PNS: http://www.wikistim.org/wp-content/uploads/2015/05/PNS-datasheet-with-examples-.csv SNS: http://www.wikistim.org/wp-content/uploads/2015/05/SNS-datasheet-with-examples.csv GES: http://www.wikistim.org/wp-content/uploads/2015/09/GES-datasheet-with-examples-.csv

29

For Peer Review

Return to work of patients treated with spinal cord

stimulation for chronic pain:

a systematic review and meta-analysis

Journal: Neuromodulation: Technology at the Neural Interface

Manuscript ID NER-2413-03-2018.R2

Manuscript Type: Review Article

Date Submitted by the Author: n/a

Complete List of Authors: Moens, Maarten; Universitair Ziekenhuis Brussel, Neurosurgery

Goudman, Lisa; Universitair Ziekenhuis Brussel, Neurosurgery Brouns, Raf Valenzuela Espinoza, Alexis; Vrije Universiteit Brussel Faculteit Geneeskunde en Farmacie, Department of Public Health (GEWE) De Jaeger, Mats Huysmans, Eva Putman, Koen; Vrije Universiteit Brussel Faculteit Geneeskunde en Farmacie, Department of Public Health (GEWE) Verlooy, Jan; Universiteit Antwerpen Faculteit geneeskunde en gezondheidswetenschappen, Department of Epidemiology and Social Medicine (ESOC)

Keywords: Spinal Cord Stimulation, return to work, Review article, Meta-analysis,

Chronic Pain

Neuromodulation Proof

Neuromodulation Proof

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For Peer Review

Return to work of patients treated with spinal cord stimulation for chronic pain:

a systematic review and meta-analysis

Maarten Moens MD, PhD1,2,3,4

; Lisa Goudman MSC1,4

; Raf Brouns MD, PhD5,6

; Alexis

Valenzuela Espinoza7; Mats De Jaeger MSC

1 ; Eva Huysmans MSC

7,8; Koen Putman PhD

7; Jan

Verlooy MD, PhD9

1Department of Neurosurgery, UZ Brussel, Brussels, Belgium

2Department of Radiology, UZ Brussel, Brussels, Belgium

3Center for Neurosciences (C4N), Vrije Universiteit Brussel, Belgium

4Department of Manual Therapy (MANU), Vrije Universiteit Brussel, Brussels, Belgium

5Department of Neurology, ZorgSaam Hospital, Terneuzen, The Netherlands

6Faculty of Medicine and Pharmacy, Vrije Unversiteit Brussel, Belgium

7Department of Public Health (GEWE), Faculty of Medicine and Pharmacy, Vrije Universiteit

Brussel, Brussels, Belgium

8Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical

Education & Physiotherapy (KIMA), Vrije Universiteit Brussel, Brussels, Belgium

9Department of Epidemiology and Social Medicine (ESOC), Universiteit Antwerpen,

Antwerpen, Belgium

Abstract

Background

Chronic pain has a substantial negative impact on work-related outcomes, which

underscores the importance of interventions to reduce the burden. Spinal cord stimulation

(SCS) efficiently causes pain relief in specific chronic pain syndromes. The aim of this review

was to identify and summarize evidence on returning to work in patients with chronic pain

treated with SCS.

Methods

A systematic literature review was performed including studies from PubMed, EMBASE,

SCOPUS, and Web of Science (up till October 2017). Risk of bias was assessed using a

modified version of the Downs & Black checklist. Where possible, we pooled data using

random-effects meta-analysis. The study protocol was registered prior to initiation of the

review process (PROSPERO CRD42017077803).

Results

Fifteen full-text articles (total articles screened: 2,835) were included. Risk of bias for these

articles was scored low. Seven trials provided sufficient data and were judged similar

enough to be pooled for meta-analysis on binary outcomes. SCS intervention results in a

higher prevalence of patients at work compared with before treatment (OR 2,15; 95% CI,

1,44 to 3,21; I2

= 42%; p < 0,001). SCS treatment results also in high odds to return to work

(OR 29,06; 95% CI, 9,73 to 86,75; I2

= 0%; p < 0,001).

Conclusions

Based on available literature, SCS proved to be an effective approach to stimulate return to

work in patients with specific chronic pain syndromes.

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Background

Spinal cord stimulation (SCS) is a well-known safe and effective treatment for many chronic

pain syndromes, including failed back surgery syndrome (FBSS), low back and lower

extremity pain, complex regional pain syndrome, and other neuropathic conditions(1-4).

Despite the extreme complexity of chronic pain, pain relief is the principal desired outcome

for SCS(1). The high socioeconomic burden and healthcare utilization associated with

chronic pain are therefore often reduced to secondary outcomes (5-7). When pain becomes

chronic, return to work (RTW) is negatively associated with a delay in referral to treatment,

socioeconomic status, attorney involvement, and worker’s compensation are(8). Several

studies have shown that unemployment and absenteeism are “negatively associated with

quality of life, depression and generally poor health outcomes”(9-11).

Currently, it is well accepted that SCS is an effective treatment for reducing pain and

improving quality of life, but little is known about the impact of SCS on occupational

outcome parameters such as RTW. Therefore, we conducted a systematic review and meta-

analysis to identify not only the prevalence of RTW by SCS in patients with chronic pain but

also the odds of working with SCS.

Methods

Search strategy and selection criteria

This systematic review and meta-analysis were conducted in accordance with the PRISMA

(Preferred Reporting Items for Systematic Review and Meta-Analyses) guidance(12). The

electronic databases of PubMed, Embase, SCOPUS, and Web of Science were searched from

inception to October 20th

, 2017 to identify potentially relevant studies.

The search strategy was, based on the PICO (evidence based search strategy focusing on

Patient/Population, Intervention, Comparison and Outcome) Framework (13). Our search

was not limited to randomized controlled trials (RCTs) but also included case series. A

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language restriction of English, French, German, and Dutch was applied. We included

studies that met the following criteria: (1) population – adult (≥18 years old) chronic pain

patients eligible for SCS; (2) intervention – SCS; (3) outcome – RTW, employment status and

sick leave. We excluded studies enrolling patients receiving other types of neuromodulation

and publications available only in abstract form or meeting reports.

Data extraction and quality assessment

After combining search results from different databases and removing duplicates by using

EndNote reference manager, two investigators (MM and LG) independently reviewed all the

retrieved abstracts and full texts to remove ineligible studies. In case of disagreement,

consensus was sought through consultation and discussion with a third party (RB). The two

reviewers (MM and LG) independently extracted data from included studies, using an a

priori determined data extraction form comprising the following items (1) first author (2)

year of publication, (3) country, (4) sample size in relation to RTW outcome, (5) study

design, (6) diagnosed population, (7) type of SCS and (8) all predefined outcomes. The

quality of the included studies was evaluated using the risk of bias Downs and Black

checklist (modified version) (14). We assigned a value of 0 or 1 to the different

subcategories of the following items: reporting, external validity and internal validity. A total

score < 10/16 was considered to be low quality, while scores ≥ 10/16 were presumed to be

high quality. Discrepancies were identified and resolved through discussion.

Outcome and statistical analysis

The primary goal of this study was to identify the prevalence of work resumption after

implantation of SCS. Subgroup analyses were performed to evaluate the occupational status

at last follow-up point. The results from all relevant studies were merged to estimate the

pooled odds ratio (OR) and associated 95% confidence intervals (CI’s) for dichotomous

outcomes. The outcomes were pooled using a random effects model. All p< 0,05 were

considered statistically significant. Heterogeneity was tested with I2

statistics. This statistic

can be interpreted as the proportion of the total variation in the estimated treatment effect

due to the heterogeneity among studies(15). To explore the robustness and the potential

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influence of various factors on our primary outcome, we performed a subgroup analysis

based on pathology (back and leg pain versus mixed). The Dixon’s Q test for the rejection of

extreme values (at the 5 and 1% levels) was performed to identify outliers(16). Publication

bias was evaluated by visual inspection of the funnel plot. All statistical analyses were

performed using RStudio (version 0.99.903, RStudio, Inc).

Results

Study selection

A flowchart of the search strategy and the reasons for exclusion are shown in figure 1. The

initial search identified a total of 2,835 citations. After combining the results, removing

duplicates and selections based on the title and abstract, 54 full-text studies remained.

Thirty-nine studies were excluded after reviewing the full text: 10 because of inappropriate

outcome parameters (no RTW mentioned), 28 were excluded because of unsuitable study

design or conference meeting abstract and, one because no full text was available even

after communication with the first author. Thus, 15 full-text studies were read for further

evaluation. Of those 15 studies, 6 were excluded because they did not provide sufficient

information on the occupational status at last follow-up point(17-22), 1 was excluded

because the studied population was reported in another study(23, 24), and 1 study did not

pass the outlier test(25). This study from Harke et al. was considered an outlier at the level 5

and at the 1%(25). Finally, the remaining seven, which enrolled 824 patients, were included

in the meta-analysis(23, 26-31).

Study characteristics and quality

The main characteristics and predefined outcome data of the included studies for the

systematic review are described in table 1. These studies were published between 1978 and

2017, with sample sizes ranging from 20 to 410. One RCT was included, five retrospective

case series and one prospective cohort study. One study evaluated high-frequency SCS,

while the other studies reported on the use of conventional SCS (29). The mean follow-up

period varied from 1 year to 7.1 years. Three studies were included with a study population

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suffering from back and/or leg pain (FBSS with axial back pain and unilateral limb pain),

while four other studies described a more heterogeneous study population (i.e., FBSS,

multiple sclerosis, spinal cord injury, vascular disease, cancer, occipital neuralgia, trauma,

and peripheral neuropathy). The risk of bias Downs and Black checklist score for each

citation varied across the studies, ranging from 10 to 16 out of 17.

Primary Outcome

Occupational status

The number of patients working after SCS was mentioned in all seven studies. The pooled

analysis showed that SCS increases the odds to work after SCS (7 studies; n = 824, OR 2,15;

95% CI, 1,44 to 3,21; I2

= 42%; p = 0,0001). Given the moderate heterogeneity, a subgroup

based on the type of population was also evaluated. The type of population (chronic back

and/or leg pain versus mixed pain syndromes) was defined to be a factor influencing

heterogeneity (figure 2).

In general, both subgroups analyses confirmed similar OR of working status among groups.

The funnel plot shows no publication bias (available upon request).

Return to work

%RTW, defined as the percentage of patients going back to work who were unemployed

before treatment, was reported or could be calculated in all seven studies. The %RTW

varied between 10 and 47 (mean 14). The pooled analysis showed that SCS increases the

odds to return to work after SCS in patients with absenteeism before treatment (7 studies;

n = 701, OR 29,06; 95% CI, 9,73 to 86,75; I2

= 0%; p < 0,0001). The funnel plot shows no

publication bias (available upon request).

Secondary outcomes

The types of employment after returning to work were not reported in all seven studies.

Three studies described the number of patients with part-time and full-time employment

after SCS implantation at the last follow-up(29, 30, 32). Two studies also mentioned the

numbers of patients who increased working time after SCS implantation(26, 30). One study

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presented the percentage of patients with SCS working at various follow-up points(31). Yet

another study reported the median time of unemployment(28).

Discussion

In the past two decades, SCS for pain relief has evolved to include many new methods of

current delivery by neurostimulation devices(3). This resulted in several studies presenting

excellent results on pain reduction. Although the status of “remission,” or achieving almost

complete pain relief by SCS, for some patients has been reported, occupational outcomes,

such as RTW, are rarely an outcome parameter in neuromodulation studies(33). SCS has

shown superior efficacy to conventional medical management in an FBSS population and

SCS leads to long-term health care cost savings(28, 34). These data support the long-term

cost utility of SCS in the treatment of FBSS patients(34). However, in a chronic pain

population, it is well known that two thirds of the total health care costs are represented by

indirect costs (loss of productivity or working days lost)(35).

Our epidemiological meta-analysis included seven studies with 824 patients investigated

occupational outcomes. Despite the clinical heterogeneity of the subgroup “chronic back

and leg pain”, the results for this subgroup appeared to be statistically homogenous and this

in contrast to the subgroup with mixed diagnoses. This can be explained by the fact that the

mixed group consists of various diagnoses with variable evidence for SCS, while SCS for

chronic low back pain has proven to be effective and has reached a recommendation in the

recent European Academy of Neurology (EAN) guidelines(36).

This meta-analysis showed that, among chronic pain patients, SCS improves the odds of

returning to work and that SCS results in more patients at work, compared with the same

population before SCS.

In terms of %RTW, the percentage of patients going back to work who were unemployed

before treatment, SCS seems to allow chronic pain patients to work again. Since SCS

candidates are refractory to conventional pain therapy and therefore difficult to treat, a

mean of 14% of unemployed patients returning to work should be born in mind. However,

no information is available in these studies on the type of work the patients are returning

to. Although three studies reported the number of patients returning to work on a part-time

basis, the relevant number of hours worked daily was not mentioned(24, 26, 30). Young et

al. considered returning to household duties or to studying as returning to gainful

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employment(31). It is generally accepted that patients at working age or defined as patients

under the age of 65 are more likely to return to work. This specific subdivision of patients

receiving SCS was reported only in a minority of the reviewed studies(28-30).

The number of patients found in this meta-analysis is similar to the findings of the

systematic review of Frey et al. in 2009(37). They summarized a 13% entry in gainful

employment and return to work in 16 to 31% of FBSS patients(37).

Researchers agree that both job loss and continuing “worklessness” impact adversely on

people’s health with increased levels of both mental and physical problems(38).

Notwithstanding the evidence of using classical pain relief, functionality, and quality of life

as outcome measurements in chronic pain studies, RTW as a central determinant of

(mental) health, should also be considered as an important clinical outcome measure.

Additionally, Elfering et al. reported that only measuring global work status and %RTW as

work-related outcome parameters, lack specificity(39). In-depth and detailed analyses, clear

definitions, disjunctive classes of categories and adequate time frames might upgrade this

specificity. Job description and educational level, type of employment (full time, part time or

casual), reasons for unemployment, work-related attitudes (e.g. job satisfaction, work-

related expectations, ...) and other risk factors for chronic disability may also be taken in

consideration(39, 40).

Strengths and limitations

To diminish bias, the study selection, data extraction, and evaluation of study quality were

performed by two independent reviewers. We comprehensively analyzed the odds of

working and the odds of RTW after SCS treatment in studies with different designs.

There were also several potential limitations regarding our meta-analysis. First, some well-

designed studies were excluded because they lacked essential information about the work

status of all patients. Second, the sample size was small as only seven studies were included.

Third, the bias of the publications might have affected the validity of our conclusions, such

as lack of comparison (e.g. best medical treatment, other types of therapies, …). And finally,

the search method was limited to Medline, Embase, Web of Science and Scopus. We did not

search the “grey literature” (trial registries nor backward references).

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Conclusion

In summary, based on available data, this meta-analysis demonstrates that SCS treatment

results in more patients at work and also more patients returning to work. More, large-scale

studies are warranted to analyze in detail the work status of the included patients (type of

job, full time, part-time, % patients at working age, etc).

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31. Young RF. Evaluation of dorsal column stimulation in the treatment of chronic pain.

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North (1993) US RCS 171 92 Mixed C - mean 7,1 y

Young (1978) US RCS 51 19 Mixed C - 3 m, 6 m, 1 y, 2 y, 3 y, 4y, 5y

Kumar (2006) CA RCS 410 158 Mixed C - mean 97,6 m

Gopal (2016) IE RCS 80 33 Mixed C - 1 m, 12m

Al-Kaisy (2017) GB PCS 20 9 CLBP HF10 - 1y

Kumar (2008) CA RCT 42 17 FBSS C median unemployment: 2,76 y1 m, 3 m, 6 m, 9 m, 12 m, 18 m, 24 m

North (1991) US RCS 50 23 FBSS C - 5y

Study (Year) Study DesignC N Female P Type SCS Mean postop sick leave duration Follow-up intervals

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% RTW (No of patients) PT/FT Working at baseline Working after SCS

15% (24/157) 5/19 64 74

17% (8/48) - 3 11

10% (39/391) - 19 58

47% (8/17) - 63 71

27% (4/15) 2/2 11 15

15% (5/33) - 9 11

25% (10/40) 4/6 10 20

outcome

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Figure 1: Flow chart of study selection in meta-analysis of occupational outcome after SCS treatment

179x213mm (300 x 300 DPI)

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Pre-SCSSCSTotalTotal WorkingWorking

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Figure legend

Table 1

Characteristics of included studies.

Abbreviations:

RTW: return to work; mo: months; y: year(s); CLBP: chronic low back pain; FBSS: failed back

surgery syndrome; PT/FT: part time/full time; SCS: spinal cord stimulation

Explanation:

Country (C): presented in ISO3166-1 alpha-2 codes (US: United States of America; GB: Great

Britain; CA: Canada; IE: Ireland)

Study Type: RCT: randomized controlled trial; retro case series: retrospective case series;

prosp cohort study: prospective cohort study

N: total sample size for return to work analysis

Population: type of population eligible to SCS: Mixed: a mixed group of patients with

different diagnoses; CLBP: chronic low back pain patients; FBSS: patients with failed back

surgery syndrome

Mean postoperative sick leave duration: Presents the median time of unemployment before

SCS treatment

Follow-up points: either a fixed follow-up moment, or a mean of follow-up.

%RTW (No of patients): X% of the patients has returned to work

PT/FT: number of patients returned to work (part-time / full-time)

Working at baseline: number of patients at work at baseline

Working after SCS: number of patients at work after SCS at the latest follow-up point

Figure 1: Flow chart of study selection in meta-analysis of occupational outcome after SCS

treatment

Figure 2: Forest plot of working status with SCS compared with before treatment

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Appendix A: PICO

Free terms MeSH-terms

Population “Chronic pain patients”;

“chronic pain”;

“persistent pain”

“intractable pain”;

AND

"Causalgia";

"Reflex sympathetic dystrophy";

“failed back surgery syndrome”;

“post laminectomy syndrome”;

“postlaminectomy syndrome”;

“failed neck surgery syndrome”;

“CRPS”;

“complex regional pain syndrome”;

“complex regional pain syndromes”;

“FBSS”;

“FNSS”;

“peripheral neuropathy”;

“neuropathic pain”;

“angina pectoris”;

“peripheral vascular disease”;

"peripheral vascular diseases";

"Peripheral nervous system diseases"

Chronic pain;

Pain, Intractable;

AND

Failed back surgery

syndrome;

Causalgia;

Complex regional pain

syndromes;

Reflex sympathetic

dystrophy;

peripheral nervous

system diseases;

neuropathic pain;

angina pectoris;

peripheral vascular

diseases;

Intervention “Spinal cord stimulation”;

"Neurostimulation";

"Neuromodulation";

“Dorsal column stimulation”;

"Neurostimulator";

“Spinal cord stimulator”;

“Dorsal column stimulator”;

“electrical stimulation”;

“pain stimulator”;

“pain stimulation”;

spinal cord stimulation;

Implantable

neurostimulators;

Electric stimulation

therapy;

Electric stimulation;

Control / /

Outcome “occupation”;

“re-employment”;

“professional situation”;

“return-to-work”;

“back to work”;

“back-to-work”;

“work activity”;

“employment status”;

Return to work;

Employment;

Sick leave

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Resume;

Reintegration;

Reinsertion;

Incapacity

AND

Work;

“labour market”;

“labor market”;

Professional;

Occupation;

occupational

“disability leave”;

“Sick day”;

“sick days”;

“illness day”;

“illness days”;

“disability pension”;

“occupational disability”;

“work disability”

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Appendix B: Final systematic literature search for PubMed

SEARCH 20/10/2017 PubMed

((((((((((((((((("electric stimulation"[Mesh]) OR "electric stimulation therapy"[Mesh]) OR

"implantable neurostimulators"[Mesh]) OR "spinal cord stimulation"[Mesh]) OR “pain

stimulation”) OR “pain stimulator”) OR “electrical stimulation”) OR “Dorsal column

stimulator”) OR “Spinal cord stimulator”) OR "Neurostimulator") OR “Dorsal column

stimulation”) OR "Neuromodulation") OR "Neurostimulation") OR “Spinal cord

stimulation”)) OR ((((((((((((((((((((((((((("Causalgia") OR "Reflex sympathetic dystrophy")

OR “failed back surgery syndrome”) OR “post laminectomy syndrome”) OR “failed neck

surgery syndrome”) OR “postlaminectomy syndrome”) OR “CRPS”) OR “complex

regional pain syndrome”) OR “complex regional pain syndromes") OR “FBSS”) OR

“FNSS”) OR “peripheral neuropathy”) OR “neuropathic pain”) OR “angina pectoris”) OR

“peripheral vascular disease”) OR "peripheral vascular diseases") OR "Peripheral

nervous system diseases") OR "Failed back surgery syndrome"[Mesh]) OR

"Causalgia"[Mesh]) OR "Complex regional pain syndromes"[Mesh]) OR "Reflex

sympathetic dystrophy"[Mesh]) OR "peripheral nervous system diseases"[Mesh]) OR

neuralgia) OR "angina pectoris"[Mesh]) OR "peripheral vascular diseases"[Mesh])) AND

(((((("Chronic pain patients") OR “chronic pain”) OR “persistent pain”) OR “intractable

pain”) OR "Chronic Pain"[Mesh]) OR "Pain, Intractable"[Mesh])))) AND (((((((((("labour

market") OR work) OR occupational) OR occupation) OR professional) OR "labor

market")) AND ((((reinsertion) OR reintegration) OR resume) OR incapacity))) OR

((((((((((((((((((return to work) OR employment) OR sick leave) OR "work activity") OR

"employment status") OR "re-employment") OR "professional situation") OR "return-

to-work") OR "back to work") OR "disability leave") OR "sick day") OR "sick days") OR

"illness day") OR "illness days") OR "disability pension") OR "occupational disability")

OR "work disability") OR occupation))

389

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Appendix C: Risk of bias assessment

Reporting External validity Internal validity

Hy

po

the

sis

Ma

in o

utc

om

es

Pa

tie

nt

cha

ract

eri

stic

s

Inte

rve

nti

on

s

Fin

din

gs

Est

ima

tes

of

ran

do

m v

ari

ab

ility

Ad

vers

e e

ven

ts

Ch

ara

cte

rist

ics

of

pa

tie

nts

LT

FU

Act

ua

l

pro

ba

bili

ty v

alu

es

Re

pre

sen

tati

ven

ess

of

pa

tie

nts

ask

ed

Re

pre

sen

tati

ven

ess

of

incl

ud

ed

pa

tie

nts

Re

pre

sen

tati

ven

ess

of

tre

atm

en

t a

cco

mm

od

ati

on

Da

ta d

red

gin

g

Ap

pro

pri

ate

ne

ss o

f

sta

tist

ics

Co

mp

lian

ce w

ith

inte

rve

nti

on

Ou

tco

me

me

asu

res

valid

/re

liab

le

Los s

es

of

pa

tie

nts

tak

en

into

acc

ou

nt

To

tal

North (1993) 1 1 1 1 1 0 1 1 1 0 0 0 1 1 1 1 1 13

Young (1978) 1 0 1 1 1 0 1 1 1 0 0 0 0 0 1 1 1 10

Kumar (2006) 1 1 1 1 1 0 1 1 1 1 0 0 1 1 1 1 1 14

Harke (2005) 1 1 1 1 1 1 1 1 1 1 0 0 0 1 1 1 1 14

Gopal (2016 1 1 1 1 1 0 1 1 1 1 0 0 1 1 1 1 1 14

Al-Kaisy (2017) 1 1 1 1 1 1 1 1 1 0 0 0 1 1 1 1 1 14

Kumar (2008) 1 1 1 1 1 1 1 1 1 1 1 0 1 1 1 1 1 16

North (1991) 1 1 1 1 1 1 1 1 1 1 0 0 1 1 1 1 1 15

Total 8 7 8 8 8 4 8 8 8 5 1 0 6 7 8 8 8

LTFU: loss to follow-

up

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Hy

po

the

sis

Ma

in o

utc

om

es

Pa

tie

nt

cha

ract

eri

stic

s

Inte

rve

nti

on

s

Fin

din

gs

Est

ima

tes

of

ran

do

m v

ari

ab

ility

Ad

vers

e e

ven

ts

Ch

ara

cte

rist

ics

of

pa

tie

nts

LT

FU

Act

ua

l

pro

ba

bili

ty v

alu

es

Re

pre

sen

tati

ven

ess

of

pa

tie

nts

ask

ed

Re

pre

sen

tati

ven

ess

of

incl

ud

ed

pa

tie

nts

Re

pre

sen

tati

ven

ess

of

tre

atm

en

t a

cco

mm

od

ati

on

Da

ta d

red

gin

g

Ap

pro

pri

ate

ne

ss o

f

sta

tist

ics

Co

mp

lia

nce

wit

h

inte

rve

nti

on

Ou

tco

me

me

asu

res

valid

/re

lia

ble

Loss

es

of

pa

tie

nts

tak

en

into

acc

ou

nt

To

tal

Devulder (1997) 1 1 1 1 1 0 1 0 1 0 0 0 1 1 1 1 1 12

Hamm-Faber (2012) 1 1 1 1 1 1 1 1 1 0 0 0 1 0 1 1 1 13

Kumar (2003) 1 1 0 1 1 0 1 0 0 0 0 0 0 0 1 1 0 7

Kupers (1994) 1 0 1 1 0 0 1 0 0 0 0 0 0 0 1 0 0 5/6

North (1991) fbss 1 1 1 1 1 1 1 1 1 1 0 0 1 1 1 1 1 15

North (1993) 1 1 1 1 1 0 1 1 1 1 0 0 1 1 1 1 1 14

Young (1978) 1 0 1 1 1 0 1 1 1 0 0 0 0 0 1 1 1 10

North (2005) 1 1 1 1 1 1 1 1 0 1 0 0 0 1 1 1 1 13

Kumar (2006) 1 1 1 1 1 0 1 1 1 1 0 0 1 1 1 1 1 14

Harke (2005) 1 1 1 1 1 1 1 1 1 0 0 0 1 1 1 1 1 14

Gopal (2016 1 1 1 1 1 0 1 1 1 1 0 0 1 1 1 1 1 14

Al-Kaisy (2016) 1 1 1 1 1 1 1 1 1 1 0 0 1 1 1 1 1 15

Kumar (2008) 1 1 1 1 1 1 1 1 1 1 0 0 1 1 1 1 1 15

Sundaraj (2005)

0 1 1 1 1 0 1 1 0 1 0 0 1 1 1 1 1 12

North (1991) scs 1 1 0 1 0 0 1 1 1 1 0 0 1 1 1 1 1 12

Total 14 13 15 15 14 6 15 12 11 7 1 0 11 12 13 13 13

* 9: 1 if correct reported + if not reported due to no testing (shoud be indicated as NA).

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North (1993)

Kumar (2008)

Gopal (2016)

North (1991)

Al-Kaisy (2017)Young (1978)

Kumar (2006)

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Funnel plot: return to work due to SCS compared with before treatment

Al-Kaisy (2017)Kumar (2008)

Young (1978)North (1991)

Gopal (2016)North (1993)

Kumar (2006)

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Neuromodulation Proof

Neuromodulation Proof

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