SPECIAL TOPIC SERIES

Subgrouping of Low Back Pain Patients for Targeting Treatments Evidence from Genetic, Psychological, and Activity-related Behavioral Approaches Ivan P.J. Huijnen, PhD,*wz Adina C. Rusu, PhD,y8 Sarah Scholich, MSc,y Carolina Beraldo Meloto, PhD,z and Luda Diatchenko, PhD, MDz

Introduction: Many patients with low back pain (LBP) are treated in a similar manner as if they were a homogenous group. However, scientific evidence is available that pain is a complex perceptual experience influenced by a wide range of genetic, psychological, and activity-related factors. The leading question for clinical practice should be what works for whom. Objectives: The main aim of the present review is to discuss the current state of evidence of subgrouping based on genetic, psychosocial, and activity-related factors in order to understand their contribution to individual differences. Results: Based on these perspectives, it is important to identify patients based on their specific characteristics. For genetics, very promising results are available from other chronic musculoskeletal pain conditions. However, more research is warranted in LBP. With regard to subgroups based on psychosocial factors, the results underpin the importance of matching patients’ characteristics to treatment. Combining this psychosocial profile with the activityrelated behavioral style may be of added value in tailoring the patient’s treatment to his/her specific needs. Conclusions: For future research and treatment it might be challenging to develop theoretical frameworks combining different subgrouping classifications. On the basis of this framework, tailoring treatments more specifically to the patient needs may result in improvements in treatment programs for patients with LBP. Key Words: low back pain, psychological subgroups, genetics, physical activity

(Clin J Pain 2015;31:123–132)

Received for publication February 28, 2014; revised March 11, 2014; accepted March 10, 2014. From the *Department of Rehabilitation Medicine, Research School CAPHRI, Maastricht University; zAcademic Hospital Maastricht, Department of Rehabilitation Medicine, Maastricht; wAdelante, Centre of Expertise in Rehabilitation and Audiology, Hoensbroek, The Netherlands; yDepartment of Medical Psychology and Medical Sociology, Ruhr-University of Bochum, Bochum, Germany; 8Department of Psychology, Royal Holloway, University of London, London, UK; and zThe Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada. Huijnen and Rusu shared first authorship. The work of A.C.R. for this manuscript has been partially supported by a grant from the Research Committee of the University of Bochum, Bochum, Germany. The authors declare no conflict of interest. Reprints: Ivan P.J. Huijnen, PhD, Department of Rehabilitation Medicine, Research School CAPHRI, Maastricht University, P.O. Box 616, Maastricht 6200 MD, The Netherlands (e-mail: [email protected]). Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/AJP.0000000000000100

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ow back pain (LBP), especially chronic low back pain (CLBP) is a major public health problem with high direct and especially indirect costs such as increased disability. The tradition in medicine is that for a specific diagnosis a specific treatment or set of treatments will be prescribed preferably to cure the disease or at least to alleviate some if not all of the symptoms. There remain many unresolved questions in diagnosis and treatment of LBP. Even when different patients receive identical treatments for the same diagnosis, responses to treatment seem to be very variable.1 Patients with CLBP have been treated, for instance, with steroid injections, physical therapy modalities, chiropractic manipulations, and in multidisciplinary pain clinics with varying emphases ranging from programs based on operant conditioning2 to those with heavy emphasis on physical conditioning.3 The biopsychosocial model is widely accepted as the most heuristic approach to the understanding and treatment of CLBP.4 Within this approach, cognitive-behavior therapy (CBT) is the most commonly used approach, which often involves multicomponent treatments in a multidisciplinary context. Despite its popularity, systematic reviews of randomizedcontrolled trials showed that effects on pain and disability are rather modest with room for further improvements.5 The lack of universal success may explain why so many treatments have been prescribed for this group of patients and it seems that the choice for a special treatment becomes empirical, delivered on a trial-and-error basis depending on health care providers’ experience.6 For many years the patient uniformity myth—that all patients with the same diagnosis are treated and provided in a similar manner as if they were a homogenous group, was adopted. Therefore it seems that the advantage of multicomponent treatments, to all patients with CLBP is that some component(s) will prove effective, but perhaps different ones for patients with different characteristics. However, several possible explanations have been offered for the above-mentioned medium effect sizes of CBT treatment in CLBP, such as large variations in dose and quality and lack of focus in content and identified treatment outcomes.1 In particular, the lack of specificity of CBT is surprising, covering a broad range of techniques, including the modification of maladaptive beliefs and coping strategies, attentional control as well as, more recently, mindfulness and acceptance. Consequently, it seems important to develop individual treatments adapted to the needs of a patient. Identifying the characteristics of patients who improve and those who fail to improve when treated with the same intervention seems to predict improved www.clinicalpain.com |

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outcomes and reduction in costs. Thus, the leading question for clinical practice is to determine what works for whom in which context.7,8 In the last decade there has been a growing recognition that pain is a complex perceptual experience influenced by a wide range of psychological factors, as well as activityrelated and genetic factors.9 Thus, psychosocial factors may interact with activity-related and genetic ones in such a way that considering them in isolation will provide an inadequate understanding. The present review aims to discuss the current state of evidence of subgrouping based on genetic, psychosocial, and activity-related factors for understanding their contribution to individual differences. We argue that these considerations might be helpful for the development of new treatment options.

SUBGROUPS BASED ON GENETIC FACTORS LBP is a complex and multifactorial disease to which both environmental and genetic factors are contributors. A growing body of evidence on musculoskeletal diseases suggests that a multiplicity of risk factors (such as disk degeneration, physical and psychosocial stress, overweight, and smoking), interact with an individual’s genetic background to produce conditions such as LBP, and these genetic factors represent multiple allelic variants, majority of which are of modest effect size.10 Therefore, clustering such a heterogeneous group into more homogeneous subgroups based on genetic background holds great promise in developing new mechanistic diagnostic protocol for treatment decisions. Several studies have demonstrated familial predisposition to LBP11–13 and around 50% of the risk of developing chronic pain conditions is estimated to be driven by a genetic background.10 However, there is only 1 study about the genetics of LBP,14 and a few studies related to LBP treatment outcomes.15,16 On the basis of evidences that interleukin (IL-1) may be involved in the pathogenesis of LBP, as well as on the fact that the production of IL-1 might be influenced by potential risk factors for LBP. Solovieva et al14 hypothesized that polymorphisms in the IL-1 gene family, namely IL-1a, IL-1b, and IL-1 receptor antagonist (IL-1-RN), could be positively related to different aspects of LBP. When evaluating this hypothesis it was found that the IL1b (C3954-T) and the IL-1RN (G1812-A) polymorphisms correlated with the last 12-month occurrence of either radiating or local LBP, number of days with pain, and number of days with limitations in daily activities due to pain. Furthermore, an association of the IL-1a (C889-T) polymorphism with pain intensity was also revealed.17,18 On the basis of their findings, the authors suggested a mechanism for the association between LBP and the IL-1 gene cluster polymorphisms, in which enhanced release of IL-1 connected with local inflammation in the back or an increased basal IL-1 level, due to the net effect of the IL-1 gene cluster would lead to increased release of the IL-1 in the glia within the spinal cord and brain. This, in turn, would exert an exaggerated pain facilitatory effect through inducing the synthesis of prostaglandin E2, possibly indicating an efficient target pathway for LBP treatment. Moreover, based on previous evidence that modic changes (MC)—vertebral endplate and adjacent bone marrow changes visible in MRI—are associated with LBP, the same group investigated the association of the IL-1 gene cluster polymorphisms with MC in the same subgroup of

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Finnish men a few years later.19 As an additional inclusion criterion, 14 participants were excluded due to poor technical quality of MR images, and this study counted with 104 participants. They found the minor allele of the SNP IL-1a (C889-T) to be associated with an increased risk of MC, which remained significant after adding the alleles of the other loci investigated as covariates in the logistic regression analysis. Therefore, it is plausible that the genetics of the IL-1 gene cluster is involved in the pathomechanisms of MC, and ultimately further implicated in the pathophysiology of LBP. These data, however, need to be confirmed in larger and independent studies. In 2006, Tegeder et al15 identified a rate-limiting enzyme in the synthesis cascade of 6(R)-L-erythro-5,6,7,8tetrahydrobiopterin (BH4)—GTP cyclohydrolase—to be involved in neuropathic and inflammatory pain. BH4 is an essential cofactor for the synthesis of catecholamine, serotonin, and nitric oxide, and given the vital roles of these neurotransmitters, alterations in BH4 concentrations may profoundly impact pain signaling. Thus, the authors hypothesized that polymorphisms in the human gene encoding for GCH1 might be associated with a distinct pain phenotype, and genotyped 168 white adults, who participated in a prospective observational study of surgical discectomy for persistent lumbar root pain caused by intervertebral disk herniation, for 15 single SNPs in the GCH1 gene. Five SNPs (rs8007267, rs3783641, rs8007201, rs4411417, and 752688) were independently associated with low scores of persistent leg pain over the first postoperative year (prespecified as the primary outcome), and that combination of these SNPs form a GCH1 haplotype with an allelic frequency of 15.4% highly associated with low scores for the same outcome.15 In the same study, these findings were further validated in 2 independent cohorts of pain-free volunteers, in which individuals carrying 2 copies of the pain-protective haplotype were significantly less sensitive to mechanical pain and tended to be less sensitive to heat and ischemic pain.15 With these results, Tegeder et al15 demonstrated that SNPs in the gene for the rate-limiting BH4-producing enzyme—GTP cyclohydrolase—alter both responses in healthy humans to noxious stimuli and the susceptibility of patients to the development of persistent neuropathic pain. Based on the results of animal and cellular studies, Tegeder et al15 proposed that a treatment strategy that could reduce excess de novo synthesis of BH4 in the dorsal root ganglion, might prevent the establishment or maintenance of chronic pain for the subgroup of patients not carrying the painprotective allele. In addition, the identification of a predictor of the intensity and chronicity of pain will be a useful tool to assess an individual’s risk for developing chronic pain. The effect of the pain-protective haplotype on both experimental and persistent pain, and the involvement of BH4 in both inflammatory and neuropathic pain, may explain why sensitivity to acute experimental pain is a predictor of postsurgical and eventually chronic pain. Using a similar approach, found a potassium channel modulatory subunit gene (KCNS1, also called Kv9.1) to be downregulated in distinct neuropathic pain models.16 Thus, they genotyped 7 SNPs encompassing the entire KCNS1 gene in 151 patients that had undergone surgical discectomy for lumbar root pain by intervertebral disk herniation and found one of the alleles of 2 SNPs, rs734784 and rs13043825, to be associated with greater pain. The same study replicated these results for SNP rs734784 in 3

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independent neuropathic pain cohorts, and also found it to be associated with greater sensitivity to painful stimuli in a cohort of healthy volunteers. Thus, in this study, the authors provide substantial evidence that a KCNS1 genotype strongly associates with pain following nerve injury and should prove useful in shaping treatment strategies. Individuals at higher risk for developing neuropathic pain, need special effort to avoid nerve damage at surgery, as well as aggressive early treatment in the presence of an unavoidable nerve lesion, to prevent a transition from acute to chronic pain. Although there are very limited data available from genetic studies of LBP, we may learn from genetic studies of other chronic musculoskeletal pain diseases. LBP is highly comorbid with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorders (TMDs),20 thereby strongly suggesting that they may share common pathophysiological pathways. In that regard, 2 pathways of vulnerability at the genetic level have been repeatedly identified so far— adrenergic and serotonergic. The adrenergic pathway is implicated mainly through the COMT gene, which encodes for the enzyme catechol-Omethyltransferase that catabolizes and inactivates catechol neurotransmitters, such as epinephrine, norepinephrine, and dopamine. A large number of studies have implicated the SNP rs4680 (Val158Met), which encodes for a less active form of the enzyme, with an increased risk of chronic pain.21–25 Other studies have found this functional SNP to be one of the polymorphisms comprising 3 major COMT haplotypes that modify expression and activity of the enzyme.26 Moreover, the haplotype associated with the highest enzymatic activity, was related to reduce responses to experimental pain stimuli and was protective against chronic TMD pain.26–28 In addition, 2 SNPs in the b2 adrenergic receptor gene (ADRB2), rs1042713 (Arg16Gly) and rs1042714 (Gln27Glu), that regulate its expression and internalization were associated with an increased risk of fibromyalgia and chronic widespread pain,21,29,30 as well as with differences in susceptibility to chronic pain.29,31 SNPs in the 5-hydroxytryptamine receptor 2A and 5HT transporter genes (HTR2A and SLC6A4, respectively) implicate the serotonin pathway in musculoskeletal diseases. In the first case, the silent 102 T > C polymorphism in the HTR2A has been repeatedly shown to increase risk of fibromyalgia32,33 and TMD.34 In the second case, the “short” allele of a 44 bp insertion/deletion polymorphism in the promoter region of SLC6A4 has been found to increase the risk of fibromyalgia,35–37 although the “long” allele has been associated with a higher risk of TMD in a Japanese cohort.38 A study on a Turkish population also found a variable number tandem-repeat polymorphism in intron 2 of SLC6A4 to play a role in the genetic predisposition to TMD.39 Subgrouping patients according to genotypic markers of chronic pain has substantial value for targeting treatments. A concrete example of how the results from human genetic associations can contribute to the process of understanding and development of treatments for a common pain condition is the results obtained with the study of the variations in COMT gene. As previously mentioned, genetic variants of COMT coding for lower enzymatic activity have been consistently proved to be associated with higher pain sensitivity and risk of developing clinical pain in multiple studies.40 The primary genetic association findings encouraged animal studies that showed that the Copyright

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pharmacological inhibition of COMT increases nociception behavior, which is reversed by the administration of both the nonselective b-adrenergic antagonist propranolol and the combination of selective b2-adrenergic and b3-adrenergic antagonists.41 On the basis of this finding, it was reasonable to speculate that propranolol, a nonselective b-adrenergic antagonist widely used clinically for treatment of hypertension, would be effective in the treatment of chronic pain conditions depending upon the patient’s COMT haplotypes. Therefore, a double-blind, placebo-controlled, 2-period crossover pilot study of efficacy of propranolol was conducted in 40 female patients with TMD and showed that it reduces a composite measure of clinical pain.42 Most importantly, after stratifying this clinical effect according to COMT haplotype, it is clear that effect is driven by patients carrying the COMT haplotypes coding for low enzymatic activity. The results described above provide an excellent illustration of how a genetic marker can define a specific clinical subgroup of shared pathway of genetic vulnerability and be predictive for efficacy of response to specific drugs. Although the initial clinical pharmacogenomic studies have been conducted on a TMD population, b2/b3-adrenergic receptor antagonists will probably be effective in treating other musculoskeletal pain conditions, such as LBP, in a COMT genotype specific manner. Therefore, this approach could represent a general example of how genetic markers can be useful for identification of clinical subgroups of human musculoskeletal pain conditions and treatment decision in the near future.

SUBGROUPS BASED ON PSYCHOSOCIAL FACTORS A number of studies have identified subgroups of patients according to psychosocial and behavioral characteristics.43–47 Several studies found that patients classified into different subgroups on the basis of their psychosocial and behavioral responses responded differently to identical treatments.48,49 Subgroups of chronic pain patients characterized by a number of psychosocial and behavioral characteristics seem to be fairly consistently observed across different pain syndromes (eg, LBP, fibromyalgia syndrome, TMDs, headaches, cancer, spinal cord injuries, and whiplash-associated disorders45,50,51) suggesting the independence of psychosocial factors from the physical pathology. Distinctiveness of the psychosocial profiling implies that patients in different subgroups may exhibit differential responses to treatment, which has been demonstrated in several outcome studies. Turk and Rudy43 performed a cluster analysis on patients’ responses to the West Haven-Yale Multidimensional Pain Inventory (MPI),52 a frequently used measure in the chronic pain literature53 that has been shown to be reliable, valid, and sensitive to change.54,55 The MPI consists of a set of empirically derived scales designed to assess the perceptions of (1) pain severity; (2) interference with family and marital functioning, work, and social and recreational activities; (3) support received from significant others; (4) life control incorporating perceived ability to solve problems and feelings of personal mastery and competence; (5) affective distress; and (6) performance of activities. Turk and Rudy43 identified 3 relatively homogenous groups and labeled 1 subgroup characterized by severe

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pain, compromised life activities and enjoyment, reduced sense of control, and high level of emotional distress as “dysfunctional” (DYS). Another subgroup, also marked with relatively high degrees of pain and affective distress but further characterized by low levels of perceived support from significant others, was labeled “interpersonally distressed” (ID). The third group consisted of chronic pain patients who appeared to be coping relatively well despite their long-standing pain. This group, which experienced low levels of pain, functional limitations, and emotional distress, was labeled “adaptive copers” (AC). Reliable, external scales supported the uniqueness of each of the 3 subgroups of patients. The subgroups have been replicated in several studies.55–57 Using external measures of relevant constructs, Turk and Rudy43 found that: (1) the DYS patients reported significantly higher levels of pain than AC patients; (2) the DYS and ID groups reported significantly higher levels of depressed mood and perceived disability; and (3) the ID patients rated their interpersonal relationships with significant others to be significantly lower in quality compared with the DYS and AC patients. These data provide convergent validity for the 3 subgroups. Comparing the taxonomic structure and profiles of distinct chronic pain groups can help to establish the generalizability of the MPI taxonomy. The 3 MPI subgroups have been replicated with a number of different pain populations. Turk and Rudy45 directly compared the power and stability of the MPI taxonomy by studying samples of patients with CLBP, headache, and TMDs. The scale interrelationships for the 3 diagnostic groups were equivalent. All 3 syndrome groups were represented in each of the subgroups. Thus, it is possible that patients with CLBP, headache, and TMD who are classified within the same subgroup may be psychologically more similar to each other than patients with the same diagnosis but who are classified within different subgroups. Studies comparing the MPI subgroups have yielded evidence supporting differential response to the same intervention.48,58,59 For instance, when a rehabilitation pain management program for fibromyalgia patients was tested, the DYS group improved in most areas, whereas the ID patients, who reported levels of pain and disability comparable with the DYS group, failed to respond to the treatment.60 There was little change in the AC patients, owing possibly to a floor effect. Strategier et al61 reported similar results with a sample of patients with LBP. Both these studies found that the AC group improvements were intermediate between the DYS and ID. The results further support the need for different treatments targeting characteristics of subgroups and suggest that psychosocial characteristics of patients with chronic pain are important predictors of treatment responses and may be used to customize treatment. For example, DYS patients are characterized by high levels of emotional distress, feelings of little control, and high levels of inactivity and may warrant treatment with the focus on cognitive factors associated with their maladaptive beliefs (eg, cognitive restructuring), whereas the ID patients may require additional treatment components addressing clinical needs specific to this group (eg, interpersonal skills) and some components of the standard interdisciplinary treatment may not be essential for the AC patients. From a clinical view, patient attrition is a major problem in pain rehabilitation programs. It is possible that

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patients who receive a treatment that does not match with their specific needs (patterns of coping and adapting) would be more likely to terminate treatment. In 1 small-scale treatment study, Carmody62 observed that ID (47%) and DYS (33%) patients were significantly more likely to dropout of group rehabilitation treatments than the AC group (11%). Data such as these reinforce the idea that treatments that are prescribed need to be congruent with patient characteristics. If patients are not satisfied with the treatment they are receiving and do not believe that the treatment components are addressing their particular concerns, especially when rehabilitation treatments can be very demanding, they will not be committed to the treatment. Clinicians will need to spend time developing tailored interventions to match patient needs and expectations. Moreover, they will need to expend extra effort motivating patients by educating them regarding the relevance of the components of the treatments being offered. Research by Vlaeyen et al63 has emphasized the prominent role played by fear of injury and pain in patients with chronic pain. The presence of high levels of fearavoidance might serve as a target for treatment. However, researchers have noted limitations in the application of the Fear-Avoidance Model to subgroups of patients where pain-related disability is associated with high task performance or overuse.64 In particular, there is evidence for the role of endurance-related responses (ERs) as predictors of chronic pain in patients.65–68 The Avoidance-Endurance Model (AEM; for review see69,70) provides testable hypotheses specifically about subgroups of patients with ERs. The AEM of pain postulates opposite pathways into chronic pain: 1 via pain-related fear-avoidance responses (FAR), and at least another one other via ER. FAR including misinterpreting pain as a sign of serious injury, increasing fear, hypervigilance, and avoidance behavior may lead to physical deconditioning and disability.71 ER behavior despite severe pain is suggested to lead to chronic pain by physical overload of physical structures.72,73 Thought suppression (TS) represents a cognitive ER where patients suppress the perception of pain or the interruption of daily activities normally demanded by pain.74 A rebound effect was suggested which leads to more frequently occurring pain-related thoughts accompanied by the perception of failure and increased depression. To identify pain patients at risk for developing chronic pain and disability at an early stage and to develop individually targeted treatments, it is important to identify specific subgroups of patients with homogenous and highly rigid responses pattern to pain.75 In a study in chronic back pain patients, Rusu and Hasenbring,76 investigated whether ER play a significant role in the phenomenology of the MPI subgroups. Although it is assumed that the DYS group is associated with DYS coping,43 only a few studies have investigated the relationship between DYS group and FAR. These studies have consistently shown that the DYS group reported significantly more catastrophizing, pain-related anxiety, avoidance, less control, and positive future thinking.77–79 However, little is known about the interrelation of the DYS group, ER, and pain communication. Investigating the interrelationships between the MPI subgroups with regard to pain-related FAR, ER, and pain communication (as measured by the Kiel Pain Inventory),80 the authors found that, even after controlling for pain intensity and depression, patients classified as DYS reported more anxiety/ depression, helplessnes/hopelessness, and catastrophizing

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than did those classified as AC.76 Furthermore, the DYS group showed more TS compared with AC; however, subgroups did not differ significantly with regard to avoidance of social and physical activity, and endurance behavior. In line with the expectations, DYS as well as ID patients showed more nonverbal pain behavior (measured by self-report) compared with AC, which suggests the special role of operant conditioning. As mentioned above, DYS patients exhibited more TS, which is in line with experimental studies showing that TS produced shorter tolerance time, more pain, and distress in a cold pressor test compared with acceptance-based thoughts.81 Thus, the application of techniques specifically geared toward the reduction of automatic and frequent TS may be an important component in the treatment of DYS patients. Similarly, evidence from a randomized-controlled intervention study for patients with acute sciatic pain has shown that a risk factor–based cognitive-behavioral intervention, which was aimed to specifically target DYS endurance-responses, was more effective compared with a standardized treatment.82 Previous studies have shown evidence for the prospective validity of AEM-based subgroups for back pain, assessed by a short screening instrument including depression, TS, and behavioral endurance (risk screening for back pain).65,67,83 Besides a FAR subgroup, which showed high fear and avoidance, patients of the ER subgroup responded with TS, depression, and endurance behavior (distressendurance pattern DER), whereas a second ER subgroup showed endurance behavior, minimization, and positive mood despite pain (eustress-endurance pattern, EER). A fourth subgroup was found (adaptive responses to pain AR) which was low on depression, TS, and behavioral endurance. Hasenbring65 investigated in a prospective study these 4 subgroups and found that the DER as well as the EER subgroup reported higher pain intensity at the 6-month follow-up, less return to work, and a higher rate of application for early retirement compared with the adaptive group. Consistent results were also reported by Grebner et al67 in 82 patients undergoing lumbar disk surgery, showing that EER and FAR subgroups had a higher rate of early retirement at the 6-month follow-up compared with the adaptive group, and also compared with the DER group. In a recent study replicating and extending these findings, 162 primary care patients with subacute nonspecific back pain were investigated at the start of medical treatment and at a 6month follow-up.84 Back pain patients were classified into the 4 AEM-based subgroups using RISC-BP and predefined cutoff points. Results revealed that both ER subgroups showed higher pain intensity at the 6-month follow-up compared with the adaptive subgroup. In contrast, subgroup analyses revealed that the adaptive group showed prospectively less pain chronicity compared with all other groups and less disability compared with FAR and DER subgroups. Preliminary support for the hypothesis that ER patients reveal a higher level of physical activity and a higher rate of static strain postures indicated by physical overload was found in a cross-sectional study measuring overt physical activity using accelerometry in patients 6 months after lumber disk surgery.72 Future prospective studies should investigate the AEM subgroups in the prediction of long-term adjustment to pain using different outcomes, which are independent from the Kiel Pain Inventory and may better elucidate the conditions under which ERs may become adaptive or maladaptive. Finding further evidence for differences in psychosocial subgroups, whether Copyright

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classified by the MPI or other clinically relevant psychological measures, may improve treatment evaluation as well as the process of patient-therapy matching.

SUBGROUPS BASED ON ACTIVITY-RELATED BEHAVIOR In patients with CLBP avoidance behavior has often been identified as a negative consequence of chronic pain.85 Although the role of fear-avoidance has been confirmed in a wide range of patients with pain,86 the resulting avoidance behavior and lower daily life functioning levels may not be applicable for all patients suffering from CLBP. More recently, an additional activity-related behavior style, defined as persistence behavior, has been proposed. There seems to be a subgroup of patients who, although they feel disabled, have a daily life activity level comparable with pain-free volunteers.87–89 It has been assumed that, next to avoidance behavior, there may be an alternative activity-related style, characterized by persistence in activities. “Persisters” tend to continue their activities despite pain, until completion is reached. After activity completion, pain will increase, which in turn will force persisters to take rest until pain subsides.90,91 In persisters these activity fluctuations are discernable as a saw-tooth pattern in a multiple day activity registration. Several scientific models did already propose this additional activity-related style, characterized by persistence in activities despite pain.92,72,93,64,94,95 However, the characteristics of this persisters group are still under debate. The proposed negative association between fluctuations in activity and a patient’s disability level was confirmed in a study of Huijnen et al.96 This result may support the existence of a subgroup of persisters by showing that some patients have fluctuating levels of daily life activities and that these fluctuations are associated with feeling or being more disabled in daily life functioning. Several studies have evaluated activity-related characteristics of patients with different activity-related behavior styles.97,98,84 In these 3 studies, scores on different questionnaires were used to classify patients in subgroups. Huijnen et al, classified patients with CLBP based on their scores on the avoidance and overdoing subscale of the Patterns of Activity Measure-Pain in different activity-related behavior styles.97 McCracken and Samuel98 developed the Pain and Activity Relations Questionnaire, and classified patients based on their scores on the avoidance, pacing, and confronting. Hasenbring et al84 used the TS and behavioral persistence scales of the avoidance-endurance questionnaire and a measure of depression (Beck Depression Inventory) to form subgroups based on activity-related behavior. In all 3 studies, 4 subgroups were formed, and there seems to be some overlap. One subgroup was defined as an avoider group and 1 subgroup as an adaptive or functional group who report rather low pain intensity and disability levels.97,98,84 Furthermore, in the 3 studies one subgroup showed some overlap in doing activities despite pain; the persisters in Huijnen and colleague’s study, the doers in McCracken and colleague’s study, and the eustress-endurance group in Hasenbring and colleague’s study. Finally, the last group defined in all 3 studies is a subgroup showing a mixed style containing avoidance as well as persistence characteristics.97,98,84 Results of the studies showed that avoiders and the mixed group have relatively high levels of disability,97,98 but similar pain intensity levels compared with patients who persist in activities. These persisters have a longer self-reported and

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objectively registered time between getting up and going to sleep defined as daily uptime. In addition, the self-reported daily life activity level is higher in persisters compared with avoiders.97 However, no difference could be found in the objectively registered actual daily life activity level.97 Persisters and avoiders may be characterized based on differences in daily uptime and their self-reported daily life activity level. Both subgroups also felt more disabled in daily life functioning compared with patients classified as functional performers. Although avoiders perceive their daily life activity level as lower compared with persisters, the actual, objectively assessed characteristics of daily life activities, such as the mean daily life activity level and fluctuations in activity, are not different. An explanation for this discrepancy between the actual and perceived daily life activity level might be that patients with CLBP have difficulties estimating their own daily life activity level resulting in a rather low association between the perceived and actual daily life activity level.99,100 However, there might also be an alternative explanation why no differences in the actual daily life activity level and fluctuations in activity between persisters and avoiders were found. Patients classified as avoiders are especially prone to avoid specific activities or postures that they fear, but they might continue to perform other nonfeared activities. Consequently, a decline in the general level of daily life activities may not be detected as it is simply not there. Although an accelerometry assessment is proven to be a valid method to assess daily life activities,89 this assessment method cannot identify specific activities and postures. A future challenge would be to identify specific postures and activities. As a result of the avoidance of specific fearful activities and postures, this might reveal that an avoider, in contrast to a persister, will have a different distribution of activities and postures overtime. For future research, it is recommended to use an activity monitor, which will enable the identification of different types of activities and postures.87 For example, the distribution of active versus passive postures/activities and the length of periods the patient is physically active during the day may further identify characteristics of patients applying different activity-related behavioral styles. It has been found that the distribution of activities over the day appeared to be different between patients with CLBP and pain-free controls. Patients with CLBP were found to be less physically active during the evening.88,101,102 As discussed earlier patients classified as avoiders have a shorter self-reported and objectively assessed period of daily uptime, compared with persisters.97,98 Whether this shorter daily uptime also means that in avoiders a lower activity level during the evening is present, seems plausible, but should be further explored. Regarding the results of persisters it can be concluded that persisters are active for a longer time period, but no information is available on the intensity of activities during the evening. It may be that, due to fatigue, the intensity of activities will decrease during the day resulting in a lower activity level in the evening. The additional information gathered with an activity monitor, may help to improve the differentiation between persisters and avoiders. This might result in a new diagnostic tool for identifying a patient’s activity-related behavioral styles, which in turn may be helpful in choosing the optimal treatment for each individual patient. It can be concluded that different activity-related styles seem present in a population of patients with CLBP. One of

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the identified styles is a subgroup of patients who persist in activities. Although it was found that the perceived level of physical activity was higher compared with the avoiders, this could not be confirmed based on a registration of actual daily life functioning. A potential explanation might be that a patient’s perception of their own daily life activities is distorted99 or their perception is influenced by their level of activity before they were in pain.103 Regarding the question whether persistence behavior is associated with the disability level and psychological functioning a systematic review and meta-analysis was performed.104 Results of the meta-analysis showed that inconsistent results were found for the association between pain intensity and persistence. Furthermore, higher levels of persistence were found to be weakly associated with a lower perceived disability level and better psychological functioning.104 However, Cane et al105 did find that persistence behavior was associated with higher levels of depression and disability. In addition, in patients with fibromyalgia, higher levels of persistence were associated with more disabilities and lower psychological functioning.106,107 The authors of the systematic review concluded that the associations between persistence and the disability level and psychological functioning level may depend on the measurement instrument used.104 It might be that the definition used for persistence behavior is different between researchers and clinicians. To explore the underlying dimensions of persistence behavior 3 different types were identified by using various self-reports measuring persistence behavior: task-contingent persistence (completing activities despite pain), pain-contingent persistence (performing activities is determined by pain), and excessive persistence (doing too much, not respecting one’s physical limits, and experiencing the rebound effect of heightened activity levels).108 Excessive persistence was the only type of persistence behavior that was found to be related to disability and depression. A remarkable finding was the negative relation between task-contingent persistence behavior and a patient’s disability level.108 It would be of interest to identify these different types of persistence behavior in a sample of patients with CLBP. However, in the 3 studies presenting subgroups based on activity-related behavioral styles the persistence subscale of the used questionnaires contains not only items of one of the types of persistence behavior making the differentiation impossible.97,98,84 More research on the different types of persistence behavior is recommended. An intriguing finding is that there seems to be a style characterized by avoidance and persistence behavior. This mixed group showed higher levels of fear of movement, pain intensity, depression, disability, and a lower selfreported activity level compared with the functional performers.97,98 In this mixed performer group, it might be that it is context-dependent whether a patient persists or avoids activities. Patients in this mixed group seem to be at least as DYS as persisters and avoiders. Future studies should gain more insight in a patient’s decision for using either avoidance or persistence strategies in their daily life activities. This might be especially relevant for daily practice. Until now, avoidance and persistence behavior are often assumed as 2 opposite activity-related styles. For example in a study in patients with fibromyalgia, patients were categorized as persister or avoider based on their scores on avoidance behavior measured by the 5-item scale “resting when in pain” of the Pain Coping Inventory and a

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judgment of a therapist.109 Given the fact that a substantial number of patients show high avoidance and high persistence, it can be concluded that classifying patients in persisters and avoiders based on their score on avoidance behavior might not be an adequate method. In clinical practice, these mixed performers report that they avoid some activities, whereas during other activities they will persist in activities despite pain. The underlying mechanisms why patients sometimes avoid and sometimes persist are unknown and should be further explored. Knowledge on this theme will be useful to improve the treatment for patients applying this mixed activity-related style.

Subgrouping of LBP Patients for Targeting Treatments

DISCUSSION

addressing patients’ psychological needs, clinicians are likely to be able to enhance both the cost-effectiveness and the clinical effectiveness of interventions. In addition, early identification of patients’ modes of adapting to subacute pain may lead to the development of interventions that can prevent chronicity and long-term disability. Combining the psychosocial profile with the activity-related behavioral style may be of added value in tailoring the patient’s treatment to his/her specific needs. For future research and treatment it might be challenging to develop theoretical frameworks combining different subgrouping classifications. On the basis of this framework, tailoring treatments more specifically to the patient needs may be offered. Hopefully, this will result in better outcomes of treatment programs for patients with LBP.

In this review on subgrouping patients, 3 different perspectives were discussed. From the genetic perspective, it can be concluded that genetic factors contribute to LBP. Even though only very few studies have been conducted on the genetics of LBP itself, this condition is highly comorbid with other chronic musculoskeletal pain conditions and therefore, it is decidedly likely that they may share common pathophysiological pathways and that genetically targeted treatment options that prove useful to any of these conditions may also benefit LBP patients. In addition, studies identifying subgroups of patients with CLBP based on psychosocial factors were discussed. The results of the studies reported indicate that AEM-based subgroups are useful for the identification of fearavoidance as well as endurance-responses to pain, underline the notion that the differentiation between the 2 endurancerelated subgroups is pivotal and that new therapeutic strategies are strongly needed for patients with endurance-related coping, especially for those with an EER pattern. Finally, studies reporting on subgroups based on activity-related characteristics of patients with different activity-related behavioral styles were discussed. Besides patients showing avoidance behavior, it was found that also a subgroup of patients persist in their activities. It is unclear whether this persistence behavior is present in actual functioning measured with objective registration system as an accelerometer, or is mainly present in a patients’ perception measured with self-reports (questionnaires or diaries). Another remarkable style was the mixed style characterized by higher levels of avoidance and persistence behavior. On the basis of these perspectives, it can be concluded that identifying patients based on their specific characterstics is crucial. For the genetics part, the knowledge gathered from other chronic musculoskeletal pain conditions represents a very useful starting point. However, one cannot assume that these findings are immediately applicable to LBP, and it is needless to say that studies investigating the role of such genetic variants in patients affected by LBP are strongly warranted. There is a great need for discovery and replication studies in the field of genetics of LBP, which should lead to both animal studies aiming to unravel the underlying pathologic mechanisms of this condition, and clinical trials attempting to exploit the usefulness of this knowledge for the treatment of LBP. Ultimately, this shall revert to the development of genetically driven LBP treatment and provide guidance for successful treatment for subgroups of patients carrying specific genetic risk factors. With regard to subgroups based on psychosocial factors, the results support the importance of matching patients’ characteristics to treatment. By specifically

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Subgrouping of low back pain patients for targeting treatments: evidence from genetic, psychological, and activity-related behavioral approaches.

Many patients with low back pain (LBP) are treated in a similar manner as if they were a homogenous group. However, scientific evidence is available t...
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