European Journal of Pain

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1 European Journal of Pain 13 (29) Contents lists available at ScienceDirect European Journal of Pain journal homepage: More is not always better: Cost-effectiveness analysis of combined, single behavioral and single physical rehabilitation programs for chronic low back pain Rob J. Smeets a,b, *, Johan L. Severens c,d, Saskia Beelen a, Johan W. Vlaeyen e,f, J. André Knottnerus b a Rehabilitation Centre Blixembosch, P.O. Box 1355, 562 BJ Eindhoven, The Netherlands b School for Public Health and Primary Care (CAPHRI Research Institute), Maastricht University, The Netherlands c Department of Health Organisation, Policy and Economics (CAPHRI Research Institute), Maastricht University, The Netherlands d Department of Clinical Epidemiology and MTA, University Hospital Maastricht, The Netherlands e Department of Medical, Clinical and Experimental Psychology, Maastricht University, The Netherlands f Department of Psychology, University of Leuven, Belgium article info abstract Article history: Received 2 December 27 Received in revised form 14 February 28 Accepted 29 February 28 Available online 22 April 28 Keywords: Low back pain Randomized controlled trial Cost-effectiveness Rehabilitation Disability Several treatment principles for the reduction of chronic low back pain associated disability have been postulated. To examine whether a combination of a physical training and operant-behavioral graded activity with problem solving training is cost-effective compared to either alone one year post-treatment, a full economic analysis alongside a randomized controlled trial was conducted. In total 172 patients with chronic disabling non-specific low back pain referred for rehabilitation treatment, were randomized to 1 weeks of aerobic training and muscle strengthening of back extensors (active physical treatment; APT), 1 weeks of gradual assumption of patient relevant activities based on operant-behavioral principles and problem solving training (graded activity plus problem solving training; GAP), or APT combined with GAP (combination treatment; CT). Total costs, existing of direct health and non-health costs and indirect costs due to absence of paid work were calculated by using cost diaries and treatment attendance lists. The Roland Disability Questionnaire was used to calculate the cost-effectiveness to reduce disability and the gain in quality adjusted life year (QALY) by using the EuroQol-5D. APT, followed by CT showed, although not significant, higher total costs than GAP. Reduction of disability and gain in QALY did not differ significantly between CT and the single treatment modalities. Based on the incremental cost effectiveness ratios (ICERs) and cost-effectiveness acceptability curves CT is not cost-effective at all. However, GAP is cost-effective regarding the reduction of disability and gain in QALY, and to a lesser degree APT is more cost-effective than CT in reducing disability. Ó 28 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. 1. Introduction Since chronic non-specific low back pain (CLBP) and its resulting disability have become an enormous epidemic health and socioeconomic problem (Meerding et al., 1998; van Tulder et al., 1995), most treatments aim at increasing patients activity level and functional abilities. Physical treatments try to restore functional abilities by increasing muscle strength and aerobic capacity (Mayer et al., 1998; Verbunt et al., 23). Fordyce (Fordyce, 1976), however, postulated that contingency management techniques and graded activity based on operant learning processes can increase health behaviors at the cost of dysfunctional illness behaviors. Others assumed that CLBP * Corresponding author. Address: Rehabilitation Centre Blixembosch, P.O. Box 1355, 562 BJ Eindhoven, The Netherlands. Tel.: ; fax: address: rsmeets@iae.nl (R.J. Smeets). patients tend to persevere in their attempt to solve an unsolvable problem, namely pain, despite experiencing repeated failure (Aldrich et al., 2). This perseverance keeps them stuck in a vicious circle, which can be altered by helping patients to identify and deal with the consequences of pain. Problem solving training provides a variety of response alternatives for a problem, and helps patients to select the most effective response available (D Zurilla and Goldfried, 1971). This treatment has successfully been applied in CLBP (van den Hout et al., 23; Linton et al., 25). Muscle strengthening combined with aerobic exercises, operant-behavioral graded activity, problem solving training, and multidisciplinary treatment are superior to no treatment (Abenhaim et al., 2; Guzman et al., 22; Linton and Andersson, 2; Linton et al., 25; Morley et al., 1999; Ostelo et al., 25; van den Hout et al., 23; van Tulder et al., 2a). Nevertheless, evidence is lacking that one of these treatments is more effective than the other. And even more problematic, hardly any information about /$34. Ó 28 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. doi:1.116/j.ejpain

2 72 R.J. Smeets et al. / European Journal of Pain 13 (29) the cost-effectiveness of these treatment is available (Guzman et al., 22; Hayden et al., 25a; Hayden et al., 25b; Liddle et al., 24; Morley et al., 1999; Ostelo et al., 25; Smeets et al., 26b; van Tulder et al., 2b). Just recently, the one year post-treatment major clinical findings of a randomized controlled trial evaluating the effectiveness of a treatment based on physiologic training principles (reconditioning/strengthening exercises), a cognitive-behavioral based treatment (graded activity with problem solving training), and a combination treatment combining the physical and cognitivebehavioral treatment were published (Smeets et al., 28). Since the combination treatment addresses physical reconditioning as well as increasing health behavior and problem solving skills, it was hypothesized that this combination treatment would be more effective in reducing disability and than the single component treatments. Contrary to this hypothesis the results regarding functional disability and other secondary outcome measures showed that the combination treatment was not more effective than the single treatments. However, since work absenteeism accounts for 93% of the total costs for LBP (van Tulder et al., 1995), and to facilitate the decision process regarding treatment selection for practitioners as well as policy makers, a full economic evaluation (cost-effectiveness analysis for disability from a societal perspective and a cost-utility analysis using quality adjusted life year (QALY)) should be used to fully test the hypothesis (Ijzerman et al., 23; Korthals-de Bos et al., 24; van Velden et al., 25). We therefore performed a full economic evaluation alongside this RCT and present the cost-effectiveness and cost-utility results. 2. Methods 2.1. Patients Between April 22 and December 24, patients for the first time referred by general practitioners or medical specialists to three Dutch outpatient rehabilitation centers were seen by a rehabilitation physician. When this physician judged that a rehabilitation treatment was necessary to resolve or reduce the functional limitations due to chronic low back pain, the patient was invited to participate in this trial. For this judgment, to facilitate generalisation of our findings to current practice, no specific criteria other that the ones used in daily practice (motivation, back pain related disability, and agreement that the aim of treatment is reducing disability and not pain) were used. Next, the research assistant checked the inclusion criteria: age between 18 and 65 years, non-specific low back pain for more than three months resulting in disability (Roland Disability Questionnaire score [RDQ] > 3) (Roland and Morris, 1983), and ability to walk at least 1 m. The exclusion criteria were: vertebral fracture, spinal inflammatory disease or infection, malignancy, current nerve root pathology, spondylolysis, spondylolisthesis, lumbar spondylodesis, medical co-morbidity making exercising impossible (e.g., cardiovascular disease), clear treatment preference, not proficient in Dutch, pregnancy, and substance abuse interfering with treatment. The Symptom Checklist (SCL-9) (Arrindell and Ettema, 1986) and the Dutch Personality Questionnaire (NPV) (Luteijn et al., 1985) were used to exclude patients based on scores suggesting psychopathology that might hamper individual or group processes; patients scoring very high (compared to normative psychiatric population) on one of the SCL-9 scales Insufficient thinking and behaviour, Distrust and interpersonal sensitivity, Hostility or Total, or high (compared to average Dutch population) on the NPV scales Rigidity, Hostility, as well as Self-satisfaction/egoism, were excluded (Smeets et al., 28). Patients meeting the inclusion criteria were informed about the purpose and procedures of the study and were enrolled after giving informed consent. The Medical Ethics Committee of the Rehabilitation Foundation Limburg and the Institute for Rehabilitation Research in Hoensbroek, The Netherlands approved the study protocol. The trial was assigned an international trial identification number ( ISRCTN ) Randomization Each cluster of four consecutive patients was assigned to one of the three active treatments or a waiting list, using block randomization. Opaque, sequentially numbered, sealed envelopes were prepared for each rehabilitation centre before enrollment started. The envelope contained a sheet of paper indicating one of the four treatments. After the patient completed the baseline measurement, the research assistant handed over the envelope Masking The research assistants collecting data were blinded to treatment allocation. Patients and therapists were not blinded to treatment allocation Interventions The overall goal of the three active treatments was to improve functioning (decrease of functional limitations/disability). Emphasis was put on the responsibility of the patient for making plans to keep on being active after the treatment (generalization). Each treatment lasted 1 weeks and started with the explanation of the rationale of that particular treatment. Patients were allowed to continue medication prescribed at baseline, but other co-interventions were discouraged. In the fourth and 1th week, the rehabilitation physician responsible for the whole treatment, together with the patient evaluated the treatment and checked the generalization plans Active physical treatment Active physical treatment (APT) was based on the assumption that an increased aerobic capacity and muscle reconditioning, especially of the deep lumbar extensor muscles (multifidus muscle), are needed for better functioning (Smeets et al., 26b). The duration and intensity of APT were chosen according to the physiologic principles of training (ACSM, 1998). In a group of maximum four, patients were invited to perform 3 min of aerobic training on a bicycle (65 8% heart rate maximum) and 75 min of strength and endurance training of their lower back and upper leg muscles (three series of repetitions in a dynamic-static manner with a training intensity of 7% of the 1-Repetition Maximum, which was reassessed every fifth session), three times a week during 1 weeks. Two physiotherapists supervised the training Graded activity with problem solving training Graded activity with problem solving training (GAP) was based on the assumption that how individuals with CLBP behave is a resultant of learning, both through environmental contingencies as through information processing (Morley et al., 1999). It is assumed that CLBP patients tend to persevere in their attempt to solve an unsolvable problem, namely pain, despite the experience of repeated failure, keeping them hypothetically stuck in a vicious circle of chronic pain (Aldrich et al., 2). Problem solving training can help patients to redefine their problem(s) and focus more on their individually relevant daily life goals that can be achieved by using graded activity techniques.

3 R.J. Smeets et al. / European Journal of Pain 13 (29) GAP consisted of operant behavioral graded activity training (GA) (Fordyce, 1976; Sanders, 1996) and problem solving training (PST) (van den Hout et al., 23). During GA, a skilled physiotherapist or occupational therapist focused on a time contingent increase or pacing of three activities being important and relevant for the patient s personal situation. In order to create as much contrast as possible with the APT, no physical training element (e.g., muscle strength or aerobic exercises) was incorporated. GA started with three group sessions followed by a maximum of 17 individual sessions of 3 min. The frequency of the sessions gradually decreased from three to one session a week. PST started with three sessions in which the rationale and the skill of positive problem orientation were discussed. Sessions 4 1 focused on problem definition and formulation, generation of alternatives, decision-making, implementation and evaluation. Patients received a course book with a summary of each session and homework assignments. A clinical psychologist or social worker, specifically trained to guide this intervention, provided ten sessions of 1.5 h to a maximum of four patients at a time Combination treatment Combination treatment (CT) aimed at restoring functional ability through increased fitness, the reinforcement of healthy behaviors and the modification of problem solving abilities. For CT, all three treatment modules (APT, GA and PST) were integrated and in the treatment rationale, the patient was told that benefits may be expected from redefining his problems and focusing more on other individually relevant daily life goals (activities), which can be achieved by using graded activity techniques. However, parallel increase in aerobic fitness and strength is expected to facilitate the application of the graded activity in daily life. The CT started with APT and PST, both offered in the same frequency and duration as in APT and GAP, respectively. GA started in the third week with the selection of three patient specific activities. By the end of the fourth week, the gradual increase of these three activities was started. A total of 19 GA-sessions were delivered. All therapists were trained in one specific treatment module (APT, GA or PST), and delivered this module in CT as well. However, the therapists were explicitly informed about the integrative aspects of CT Waiting list (WL) Patients were requested to wait ten weeks after which they were offered regular individual rehabilitation treatment. For these patients only data were collected before and immediately after the ten weeks of no treatment and were not included in the cost-effectiveness analysis Data collection During the pre-treatment assessment, data were collected on age, gender, level of education, employment status, duration of complaints and disability, previous treatment(s), level of radiating pain, traumatic onset, pain-related fear (Tampa Scale for Kinesiophobia) (Goubert et al., 24; Goubert et al., 2; Roelofs et al., 24), and physical activity (Baecke Physical Activity Questionnaire) (Baecke et al., 1982; Jacob et al., 21). Immediately after the explanation of the treatment rationale, treatment credibility and expectancy were assessed (Credibility/Expectancy Questionnaire) (Devilly and Borkovec, 2) Outcome measures Assessments for collecting the outcome measures were carried out before treatment and immediately after ten weeks of active treatment, and 26 and 52 weeks after completion of treatment. For the cost-effectiveness analysis, only the Roland Disability Questionnaire (RDQ), the primary outcome measure, was used. It is a valid, and responsive outcome measure (Beurskens et al., 1996; Gommans et al., 1997; Roland and Morris, 1983). Utility (health related quality of life) was measured by the Euro- Qol (EQ-5D) (EuroQol Group, 199). QALY were calculated by multiplying the utility based on EuroQol scores with the amount of time a patient spent in this particular health status ( calculating the area under the curve ) (Dolan, 1997). In this study, this means that the presented QALYs were calculated for a total time period of 62 weeks (1 weeks of treatment and 52 weeks of follow-up posttreatment) Economic evaluation Costs were collected from a societal viewpoint. Intervention costs of the allocated treatment were calculated by collecting checklists filled out by therapists and treating physician after each treatment session, documenting the number of patients being present and involved therapists. The volumes of treatment time spent for each patient were calculated by dividing the total time spent during each session by the number of attending patients and by multiplying this with the number of involved therapists. For example, in case a group of four patients was guided during a physical training session by two therapists during 1.5 h, the actual time spent for each patient was.75 h ((1.5/4) 2 =.75). The total amount of treatment hours was multiplied by the cost price for one hour of treatment in a Dutch rehabilitation centre in the year 23, which was 83 (Oostenbrink et al., 24). Other direct healthcare (not related to the allocated treatment), direct non-healthcare and indirect costs due to absenteeism from paid work were collected by costs diaries (each diary covering 4 weeks) filled out by patients during the period of treatment (1 weeks), 1 12 weeks, weeks, weeks and weeks post-treatment (Goossens et al., 2). Costs were calculated by multiplying the volumes with the estimated prices. Table 1 summarizes the cost categories, and the prices and sources used for valuing these categories. Indirect costs of absenteeism from paid work were calculated according to the human capital approach, which estimates the value of the potential production lost during the entire period of absenteeism (Oostenbrink et al., 24). The mean income of the Dutch population was used as presented by Statistics Netherlands (CBS, 22). As the cost data were collected during the period of 22 24, the 23 value of all costs was used Content of treatment Treatment content was also validated by the checklists filled out by therapists after each treatment session. Patient attending at least 2/3 of all assigned treatment sessions for each training element, were classified as having sufficient treatment compliance Sample size A difference of 2.5 points in RDQ score between treatment groups was considered to be clinically relevant (Roland and Fairbank, 2). Based on a two-sided a of.5 and a 1 b of.9, with a standard deviation (SD) of the RDQ change of 4, 55 patients per group were needed to test the hypothesis that CT is more effective than APT and GAP, respectively Statistical analyses Distribution of baseline characteristics was calculated to determine the prognostic similarity of treatment groups.

4 74 R.J. Smeets et al. / European Journal of Pain 13 (29) Table 1 Prices used in the economic evaluation (year 23) Costs Cost ( ) Direct healthcare costs Rehabilitation treatment (per hour) a 83 General practitioner (consultation) a 2.2 Medical specialist including radiology (consultation) a 56 Occupational physician (consultation) a 2.2 Therapist (physiotherapist, manual therapist, Cesar or Mensendieck therapist) (consultation) a 22.9 Psychologist (consultation) b 6.5 Medication c Hospitalization general hospital (per day) a 337 Day care general hospital (per day) a 229 Medical procedure a Direct non-healthcare costs Alternative therapist d Paid housekeeping (per hour) 21.7 Unpaid help from partner or friends (per hour) 8.3 Travel expenses (per km).16 Over the counter medication e Equipment aids e Indirect costs Absenteeism from paid work (per hour) f a b c d e f Price according to Dutch guidelines for economic evaluation in health care. Price according to Dutch professional organisation of psychologists. Price per tablet according to the Royal Dutch Society of Pharmacy and for each recepy 6.45 is added. Mean price of value of prices of alternative health care visits registered by patients in cost diaries. According to cost diaries. Costs based on mean income of Dutch population according to age and sex. For this economic evaluation, the clinical outcomes at 52 weeks post-treatment were used. For the RDQ, the difference between the baseline score and the 52 weeks post-treatment score were calculated for each individual. These change scores were used to compare CT with APT and GAP, respectively, using the Student t-test for statistical significance. Group differences and two-tailed 95% confidence intervals (95% CI) were calculated. To adjust for possible baseline differences, a multiple linear regression analysis for RDQ was used, with the change scores as dependent variable, treatment as independent variable, and baseline score of the RDQ and possible prognostic variables as co-variables. The adjusted results hardly changed the outcome, and therefore we present only the unadjusted results. Utility scores were used to calculate QALY as described previously. Student t-test was used for testing statistical significance between the single treatment groups and CT. In case of imbalance of the utility baseline scores between the treatment groups (significant difference or absolute difference >.3), it was decided to use a utility based regression correction in which the follow-up utility is the dependent variable as the primary analysis, and perform a sensitivity analysis for the non-corrected utilities (Manca et al., 25). The formula for this regression model is: U 1 = a U + b U U, where U 1 is the follow-up utility, U is the baseline utility and a U,b U are the regression coefficients. Bootstrapping (1 replications) was used for pair wise comparison and calculation of confidence intervals for the mean differences in costs between APT and CT, and GAP and CT, respectively. Incremental cost-effectiveness ratios (ICERs) in which the mean difference in total costs is compared to the mean difference in improvement of the outcome measure between CT and the two single treatment groups respectively, were calculated using an intention to treat principle. The cost-effectiveness planes were constructed using bootstrapping method with 1 replications of the trial data. These estimates were then used to generate the cost effectiveness acceptability curves, representing the probability that an intervention is most cost-effective over a range of cost-effectiveness thresholds (Fenwick et al., 21; Fenwick et al., 24). These curves show the posterior probability that each treatment is better than the other two across the range of values that health policy or other decision makers might pay to achieve an additional increment in outcome (RDQ or QALY). Patients, who did not return at least three cost diaries, were excluded from further analysis. In case maximal 13 cost diaries were missing, the missing values were substituted by the overall (of all treatment groups together) mean score for the direct healthcare (not related to the allocated treatment), direct non-healthcare and indirect costs of each particular cost diary that was missing. For example, in case the results of the fourth cost diary were missing, the overall mean score for the costs reported in all available fourth cost diaries of the other patients was used (Little and Rubin, 22). Missing outcome variables at follow-up were substituted by the overall mean score of that assessment point during the study. All statistical analyses were performed using SPSS statistical software, version 12. (SPSS, Inc., Chicago, IL). 3. Results 3.1. Recruitment and follow-up Of the 39 eligible patients, 82 patients were excluded. Reasons for exclusion are shown in Fig. 1. Eighteen patients were excluded due to psychopathology that could hamper individual or group processes. Additionally, four patients were excluded before start of treatment because of another medical diagnosis preventing participation (1 in APT, 2 in GAP, 1 in CT). A total of 223 patients were randomly assigned to either APT (n = 53), GAP (n = 58), CT (n = 61), or WL (n = 51). The unequal number of patients in each treatment group is the result of the block randomization carried out for each rehabilitation centre, separately. Since no 26 and 52 weeks post-treatment data for WL were collected, only the results of the patients allocated to an active treatment will be further discussed (n = 172). Follow-up rates for the questionnaires and cost-diaries were rather high (see Fig. 1). For all patients the baseline scores of the RDQ and utility, as well as the total costs of the allocated treatment were available. A total of 137 patients (79.7%) filled out all questionnaires and returned all

5 R.J. Smeets et al. / European Journal of Pain 13 (29) Patients referred by physicans (n = 39) Not randomly assigned (n = 82) Refused participation before first contact (n = 14) Not Hip pathology meeting inclusion (n=1) criteria (n = 31) Preference Collitis ulcerosa specific (n=1) treatment (n = 2) Rheumatoid Logistic problems Arthritis (n = (n=1) 15) Waiting Spondylodesis time between (n=1) inclusion and randomisation too long (n = 2) Excluded before start treatment (n = 4) Hip pathology (n = 1) Collitis ulcerosa (n = 1) Rheumatoid arthritis (n = 1) Spondylodesis (n = 1) Randomly assigned (n = 223) Waiting list (n = 51) Only short term results Allocated to Active Physical Treatment (n = 53) Allocated to Graded Activity with Problem Solving Training (n = 58) Allocated to Combination Treatment (n = 61) Excludedduetonocostdiarydata (n = 1) Exluded due to no cost diary data (n = 6) Excludedduetonocostdiarydata (n = 5) Outcome data Post-treatment (complete n = 52, no imputation) 26 weeks (complete n = 5, imputation n = 2) 52 weeks (complete n = 51, imputation n = 1) Cost diaries 52 weeks post-treatment (complete n = 49, imputation n = 3) Outcome data Post-treatment (complete n = 51, imputation n = 1) 26 weeks (complete n = 51, imputation n = 1) 52 weeks (complete n = 51, imputation n = 1) Cost diaries 52 weeks post-treatment (complete n = 39, imputation n = 11) Outcome data Post-treatment (complete n = 55, imputation n = 1) 26 weeks (complete n = 53, imputation n = 3) 52 weeks (complete n = 53, imputation n = 3) Cost diaries 52 weeks post-treatment (complete n = 45, imputation n = 9) Fig. 1. Flow chart describing the progress of patients through the trial. cost-diaries. Twenty-three patients (13.3%) did not return all, but at least three cost diaries. Overall mean score of the besides the allocated treatment used (non-)healthcare utilities and hours of paid work absenteeism for each cost diary separately were used to impute the missing values. Of these 23 patients with missing cost diary data, 18 had complete data regarding follow-up scores of the RDQ and utility. Compared to the patients with complete cost data, these 18 patients, showed no statistically significant differences regarding all collected baseline values, change of RDQ during follow-up, and QALY. For the other five patients (one in APT, one in GAP, three in CT), the overall mean RDQ and utilityscore at 52 weeks post-treatment was used to impute the missing value. For two additional patients (one in GAP, one in CT) the utility-score at post-treatment, and for six patients (two in APT, one in GAP, three in CT) the utility-score at 26 weeks post-treatment were missing and had to be imputed by the mean overall score. Of 11 patients no cost data and no follow-up outcome measures were available, and for one patient the complete outcome measures but no cost data at all, were available. These 12 patients (7%; one in APT, six in GAP, five in CT) were excluded from further analysis. The reasons for not responding were not clearly related to the type of treatment: other medical problem (one in APT, one in CT), psychosocial problems needing other treatment (two in CT), clear treatment preference (one in CT), logistic reasons (two in

6 76 R.J. Smeets et al. / European Journal of Pain 13 (29) GAP, one in CT), still searching for medical solution/pain relief (three in GAP), and lack of understanding of the assessment (one in GAP). The non-responders were significantly younger (mean, 34.7 versus 42.5 years, P =.8) and showed significantly lower sufficient treatment compliance (8% versus 74%, P <.1) Comparability at baseline Baseline status of patients, including distribution of baseline RDQ and utility-score, did not differ significantly between treatment groups and are shown in Table 2. Although the differences of the baseline utility-score did not differ significantly between the treatment groups, they exceeded the predefined threshold of.3 (.9 between GAP and CT, and.4 between APT and CT). Therefore we decided to correct for these baseline differences and performed a sensitivity analysis for the unadjusted utility-scores Treatment compliance In APT the percentage of patients with sufficient treatment compliance was 85%, in GAP 85% for graded activity and 83% for the problem solving training. In CT, the percentage with sufficient compliance for the physical training part was 8%, and 68% for graded activity and problem solving training Effectiveness of the interventions Disability change from baseline to 52 weeks post-treatment and the QALY during that period are presented in Table 3. No statistically significant differences regarding disability and QALY between CT and the single treatment groups were found. All groups showed a substantial reduction of disability over the course of follow-up. The observed change on the RDQ was 3.21 ± 4.77 for APT, 3.25 ± 4.3 for GAP, and 1.98 ± 4.55 for CT, respectively Healthcare utilisation and absenteeism from work Table 4 shows the utilisation of healthcare resources other than the resources used according to the allocated treatment protocol, and the hours of absence from paid work. In all groups, several patients received additional health care, especially treatment sessions with a therapist ranging from four to nine sessions per patient during the study period (62 weeks). During the trial treatment (first 1 weeks), no patients were hospitalized, and during the 1-year follow-up, seven patients (four in APT, two in GAP, and one in CT) were hospitalized (either day care or inpatient) for disc surgery (n = 1), lumbar spondylodesis (n = 2), and pain reducing procedures (n = 4, in total five procedures). GAP showed slightly higher costs for paid and unpaid help. Absentee- Table 2 Baseline variables for the total population and the three therapy groups Variables Total (n = 16) APT (n = 52) GAP (n = 52) CT (n = 56) Age (years) 42.5 ± ± ± 9.7) 41.5 ± 1. Gender (% male) Education (%) Low Middle high Work status (%) Full time Partly absence Full absence No job Duration of LBP (months) 61.6 ± ± ± ± 7.2 Duration of functional limitations (months) 39.5 ± ± ± ± 55.8 Radiation of pain (%) No radiation Above knee Below knee Previous back surgery (%) Trauma preceding LBP (%) Treatment credibility (3 27) 19.9 ± ± ± ± 3.6 Treatment expectancy (3 27) 16.3 ± ± ± ± 4.6 TSK (17 68) 39.4 ± ± ± ± 6.9 RDQ ( 24) 13.9 ± ± ± ± 3.6 Current pain ( 1) 48. ± ± ± ± 23.7 Utility (EuroQol).49 ± ± ± ±.26 Values presented are means ± SD or percentage. APT, active physical treatment; GAP, graded activity plus problem solving training; CT, combination treatment; LBP, low back pain; TSK, Tampa Scale for Kinesiophobia; RDQ, Roland Disability Questionnaire. Table 3 Mean improvement from baseline until 52 weeks post-treatment, and differences of mean improvement between APT-CT and GAP-CT, respectively in RDQ and QALY Outcome measure Mean (SD) improvement Difference (95% CI) a APT (n = 52) GAP (n = 52) CT (n = 56) CT versus APT CT versus GAP RDQ 3.21 ± ± ± ( 3.1 to.55) 1.27 ( 2.96 to.42) QALY.693 ± ± ± (.94 to.66).45 (.119 to.29) APT, active physical treatment; GAP, graded activity plus problem solving training; CT, combination treatment. a 95% confidence intervals obtained by Student t-testing.

7 R.J. Smeets et al. / European Journal of Pain 13 (29) Table 4 Utilisation of healthcare resources other than treatment protocol, and absenteeism from work during treatment and follow up of 52 weeks for three interventions for chronic low back pain Type of utilisation APT (n = 52) GAP (n = 52) CT (n = 56) General practice (no of visits) 2.99 (5.58) 3.29 (4.62) 2.12 (2.45) Medical specialist care (no of visits) 1.7 (2.81) 1.12 (1.97) 1.55 (2.63) Radiology (no of visits).6 (.24).16 (.46).26 (1.48) Occupational physician (no of visits).1 (.41).24 (.96).12 (.5) Psychologist (no of visits).57 (3.14).29 (1.26).34 (1.24) Therapist (physiotherapy, manual therapy, Cesar or Mensendieck therapist; no of sessions) 4.41 (9.47) 9.3 (18.34) 7.36 (25.36) Hospital admission including medical procedure (costs) a (942.17) (129.98) (11.3) Alternative therapist (no of visits) 1.85 (6.94) 1.5 (5.96) 3.17 (11.14) Prescribed medication (costs) 19.3 (321.87) (273.85) 58.4 (84.8) Non-prediscribed medication (costs) 2.35 (73.43) 14.2 (49.35) (53.56) Paid housekeeping (hours) (53.54) 27.1 (17.65) (49.9) Help from partner or friends (hours) (17.19) (144.) (82.4) Absenteeism from paid work (hours) (152.64) (887.35) (922.84) Values are means (standard deviation). APT, active physical treatment; GAP, graded activity plus problem solving training; CT, combination treatment. a Costs caused by 7 patients (4 APT, 2 GAP, 1 CT). Table 5 Mean (standard deviation total costs ( ) and costs ( ) and differences in mean total costs (95% confidence intervals) a 1 weeks of treatment and follow up of 52 weeks for three interventions for chronic low back pain Costs Mean (SD) total costs Difference in mean (95% CI) a total costs APT (n = 52) GAP (n = 52) CT (n = 56) CT versus APT CT versus GAP Direct health care costs 322 (1754) 179 (853) 3787 (1279) 766 ( ) 272 ( ) Direct non-health care costs 841 (179) 1268 (2679) 785 (1562) 56 ( 671 to 568) 466 ( 1375 to 293) Total direct costs 3863 (2617) 2987 (387) 4572 (257) 714 ( 162 to 1633) 1587 ( ) Indirect costs 16,153 (18,748) 11,816 (15,84) 14,987 (1562) 1137 ( 676 to 4511) 351 ( 2933 to 8862) Total costs 2,15 (19,675) 14,794 (17,29) 19,559 (14,78) 47 ( 6987 to 59) 4787 ( 984 to 1,54) APT, active physical treatment; GAP, graded activity plus problem solving training; CT, combination treatment. a 95% confidence intervals obtained by bootstrapping (1 replications). ism from work was already substantial and not statistically different between treatment groups at the start of the trial. Overall, the GAP showed the lowest costs due to absenteeism from paid work Costs In Table 5 the mean costs for each intervention are shown. The total direct healthcare costs consisting of the intervention costs and all other direct healthcare costs, were significantly higher for CT compared to the single treatment groups. The direct nonhealthcare costs showed no significant differences. Regarding the total direct costs consisting of direct healthcare and direct nonhealthcare costs, CT appeared to be more expensive than GAP. For the indirect costs due to absence of paid work, no significant differences were found. However, it should be taken into account that the range of these costs was quite large. CT showed a trend of being cheaper than APT. On the other hand GAP was cheaper than CT. Table 6 Cost effectiveness and cost utility ratios ( ) for disability and utility for back pain Outcome measure CT: APT CT: GAP RDQ APT 371 a GAP 3759 c QALY APT 35,6 b GAP 18,857 d APT, active physical treatment; GAP, graded activity plus problem solving training; CT, combination treatment. a Costs 371 to get improvement of one point in RDQ. b Costs 35,6 to get improvement of one QALY. c Costs 3759 less to get improvement of one point in RDQ. d Costs 18,857 less to get improvement of one QALY. Regarding the most important costs, the total costs which included all direct and indirect costs, no significant differences between CT and the single treatment groups were found. APT showed a trend of being a bit more expensive than CT ( 47, 95% CI: 6987 to 59), and GAP being on average 4787 (95% CI: 984 to 1,54) cheaper than CT Cost-effectiveness and cost-utility analyses Table 6 presents the cost-effectiveness and cost-utility ratios of CT versus APT and GAP, respectively. The numbers indicate that in order to gain one extra point of reduction of RDQ, it costs 371 by offering APT instead of CT, or one can save 3759 by offering GAP instead of CT. Fig. 2 represents 1 bootstrap replications of the cost-effectiveness ratio for RDQ comparing CT with APT. More pairs are located in the north-west quadrant (44%) indicating inferiority of CT, compared to only 4% located in the south-east quadrant indicating superiority. However, most pairs were located in the south-west quadrant, meaning that CT is cheaper but resulted in less reduction of RDQ. It can be concluded that CT is not more cost-effective than APT. Fig. 3 shows that CT is slightly inferior regarding cost-utility compared to APT (37% in north-west quadrant versus 31% in south-east quadrant). Furthermore, CT was less cost-effective than GAP (89% in northwest quadrant versus 1% in south-east quadrant) regarding the reduction of RDQ (Fig. 4) and showed a poorer cost-utility (Fig. 5, with 83% in north-west quadrant versus 1% in south-east quadrant). The cost-effectiveness acceptability curve for RDQ (Fig. 6) shows that CT is never cost-effective and the more money one is

8 78 R.J. Smeets et al. / European Journal of Pain 13 (29) Additional costs Additional effects Fig. 2. Cost-effectiveness plane for RDQ after combination treatment (CT) or active physical treatment (APT) Additional costs Additional effects Fig. 3. Cost-effectiveness plane for QALY after combination treatment (CT) or active physical treatment (APT) Additional costs Additional effects Fig. 4. Cost-effectiveness plane for RDQ after combination treatment (CT) or graded activity with problem solving (GAP).

9 R.J. Smeets et al. / European Journal of Pain 13 (29) Additional costs Additional effects Fig. 5. Cost-effectiveness plane for QALY after combination treatment (CT) or graded activity with problem solving (GAP). willing to pay, the more the curves of GAP and APT approach each other. This is largely due to the cost-advantage of GAP, the relative importance of which diminishes as one is prepared to pay more for one point of reduction of the RDQ. The cost-effectiveness acceptability curve for QALY (Fig. 7), shows that GAP is most likely to be cost-effective at all costs one is willing to pay per QALY. As GAP is marginally more effective and is associated with lowest direct and indirect costs compared to CT and APT, it is most likely to be cost-effective at all costs regarding QALY Sensitivity analysis The analysis of the uncorrected utility-scores showed slightly different results. CT compared to APT resulted in.1 more QALY instead of the.1 QALY lower score while using the adjusted scores. In the ICER plot (not presented), more pairs (42%) were located in the south-east quadrant (indicating superiority of CT) than in the north-west quadrant (27%). CT compared to GAP now showed no difference regarding the QALY and thus no difference regarding cost-utility was found. Probability intervention is most cost-effective 1% 8% 6% 4% 2% % Price prepared to pay per one point reduction of RDQ (Euro) Fig. 6. The cost-effectiveness acceptability curve for RDQ. GAP CT APT 35 Probability intervention is most cost-effective 1% 8% 6% 4% 2% % Discussion Price prepared to pay per QALY (Euro) Fig. 7. The cost-effectiveness acceptability curve for QALY. GAP Despite the fact that the mean score of our study population is indicative for a moderate to severe level of disability, comparable to populations being treated in other trials and daily practice in The Netherlands (Roland and Fairbank, 2; VRIN/VRA, 1999), as well as most of these patients received one or more treatments previously, all treatments showed improvement of disability and quality of life. However, no statistically significant differences between the combined treatment and the single treatment modalities were found regarding these outcome measures. Contrary to our hypothesis, the combination treatment was not more costeffective and showed no favourable cost-utility than the single treatment modalities. Even more surprising, and in spite of the lack of statistically significant differences regarding the outcome measures of interest, GAP is cost-effective regarding reduction of disability and gain in QALY. APT is also cost-effective compared to CT regarding reduction of disability, especially if one is prepared to pay more money. Furthermore, it is interesting to note that after 1-year of followup, APT and GAP compared with CT, showed a higher, although statistically insignificant reduction of RDQ: 1.23 [95% CI.55 to 3.1], and 1.27 [95% CI.42 to 2.96], respectively. The fact that several researchers argue that a point additional reduction CT APT

10 8 R.J. Smeets et al. / European Journal of Pain 13 (29) of the RDQ at a group level is worth the effort (Moffett et al., 1999; UK BEAM, 24), combined with the proven superior cost-effectiveness of the single treatment modalities over the combination treatment, urges one to conclude that the combination treatment is definitely not the treatment of choice. The cost data showed that the direct healthcare costs for CT were, as expected due to the combination of the two single treatment modalities, significantly higher during the intervention period. However, once all direct costs, including other direct healthcare and non-healthcare costs were taken into account, only GAP was significantly cheaper during the total study period of 62 weeks. As reported by others (van Tulder et al., 1995), indirect costs due to absenteeism from paid work calculated according the human capital method, accounted for a huge part of the total costs for all three treatments during the total study time of 62 weeks. Taken these indirect costs into account, there were no significant differences regarding the total costs of CT compared to APT and GAP, respectively because of the large range and high standard deviation (not shown) of the total costs. Nevertheless, and especially important for the cost-effectiveness and cost-utility ratios, APT was the most expensive treatment, followed by CT and GAP, of which the latter was the cheapest. Since the sample size calculation was based on a difference of at least 2.5 points in RDQ-change score between the combination treatment and the single treatment groups being clinically relevant, the power for a cost-effectiveness study could be too low. However, since we did not find a tendency of CT being better, it is not likely that a higher powered study would change our conclusion that CT is not cost-effective compared to the single treatments. The same applies for the cost-utility analysis. Although the treatment groups did not differ significantly regarding baseline utility-score, it is known that even minor differences in this score can have a large impact on the cost-utility analysis (Manca et al., 25). Therefore, we decided to adjust for baseline difference in case the treatment group scores differed more than.3, and followed the most recent recommendation by using the utility based regression correction method and used the unadjusted score for a sensitivity analysis (Manca et al., 25). The sensitivity analysis indeed showed different, although only slightly different results. Therefore, in future research one should not only adjust for statistically significant, but also absolute differences of baseline utility-scores. The study also has some limitations; it should be noted that these cost-effectiveness and cost-utility results are based on the results of 16 of the 172 randomized patients. For 137 (8%) the data were complete, which is quite a high percentage for a costeffectiveness study. Nevertheless, for 23 patients, missing data were imputed by the overall (of all treatment groups together) mean score for the direct healthcare, direct non-healthcare and indirect costs of the cost diaries that were missing. Missing outcome variables at follow-up were also substituted by the overall mean score of that assessment point during the study, although this was only applicable for a very small number of patients. This type of imputation, as every type of imputation, introduces some kind of uncertainty. Since we found no significant differences regarding the baseline scores and outcome measures during follow-up between the patients with missing cost data and those with complete cost data, it is not very likely that we over or under predicted their total costs. Furthermore, 12 patients were excluded due to complete missing cost data. These patients were younger and showed lower treatment compliance, and so might have responded less (i.e., lower reduction of disability and QALY), as well as having caused higher levels of total costs. However, the reasons for not responding seemed not be related to the type of treatment, and therefore it seems likely that the results of this study are sufficiently reliable and valid. In this trial treatments explicitly based on a supposedly causative factor(s) for the development and maintenance of CLBP associated disability were compared. All treatments showed similar results regarding reduction of disability, as other active treatments, and even treatments that used stronger selection criteria (Guzman et al., 22; Hayden et al., 25a; Hayden et al., 25b; Ostelo et al., 25). Unfortunately, hardly any results regarding cost-utility are available, making a comparison with other studies using comparable treatments impossible. CT consisted of the APT and GAP training combined, and was carried out by the same, welltrained therapists as in the single treatments. Treatment groups did not differ regarding baseline characteristics, treatment credibility and expectancy. The result that CT is not cost-effective compared to the single treatments is puzzling, and suggests opposing rather than synergetic effects, despite the fact specific efforts were made to integrate the different treatment modules into one treatment. Based on the treatment credibility and expectancy scores, patients perceived the combination treatment as a reasonable treatment. Nevertheless, CT required a higher effort and time investment of patients, which might be an explanation for the lower compliance rates. On the other hand, the compliance rate was quite similar to multidisciplinary treatments used in RCTs (Kole- Snijders et al., 1999; Moffett et al., 1999), and daily practice (Woby et al., 24). The rationales of the different CT elements might have been counteractive. The increase of exercise load in APT was based on training physiology, and time-contingent increase of activities was used in GAP. This might have resulted in insufficient generalization of the learned principles. Additionally, proven effective multidisciplinary treatments differ from our combination treatment as they used other cognitive treatment modules as well as functional restoration (Guzman et al., 22). And last but not least, the APT showed longer lasting effectiveness than expected (Hayden et al., 25a; Liddle et al., 24). APT resulted in a similar decrease of pain catastrophizing which also mediated outcome, as did GAP and CT (Smeets et al., 26a). This is in line with the suggestion that not improved physical fitness, but cognitive processes are responsible for the effectiveness of exercise training (Helmhout et al., 24; Mannion et al., 1999). We conclude that the single treatments are cost-effective and have a higher cost-utility than the combination treatment over a period of 1 weeks of treatment and 1 year of follow-up. This means that more is not always better, and these results urge us to investigate whether subgroups of patients can be identified, which show different (cost-)effectiveness for different treatments by using objective, valid and reliable criteria (Vollenbroek- Hutten et al., 24). In our previous study regarding the long-term effectiveness (Smeets et al., 28), we could not detect a significant interaction between the level of disability, pain and pain-related fear and the different treatments. However, due to the relative low number of patients in each treatment group, the power might have been too low to detect subgroups. Future trials should include treatments that target more systematically on putative mechanisms of change, such as pain catastrophizing, pain related fear of perceived pain control (Vlaeyen and Morley, 25). Acknowledgements The authors thank the rehabilitation centers Breda, Leijpark and Blixembosch and the many people who contributed to the successful completion of this study, particularly the participating patients, the rehabilitation centre contact persons, therapists, researchassistants, especially Ria Laros, Frederieke Berendsen, and Anke Veuskens who performed the calculation of the treatment costs. We particularly want to thank Mariëlle Goossens for her advice