Typology of patients with fibromyalgia: cluster analysis of duloxetine study patients

Fibromyalgia (FM) has been defined by the American College of Rheumatology (ACR) as pain in all 4 quadrants and axial skeletal pain, together with at least 11 of 18 tender point sites (1990 ACR criteria [1]), although revised criteria are being proposed [2], and new preliminary diagnostic criteria for FM were published in 2010 [3]. About 2% of the US general population suffers from FM. Patients often also suffer from concomitant symptoms such as fatigue, headache, and sleep disturbance [3]. Mood disorders are also commonly diagnosed in these patients with approximately 25% to 40% of FM patients reporting symptoms of current major depressive disorder (MDD) [4, 5].

Fibromyalgia symptoms may be in part due to deficiencies in serotonin (5-HT) and norepinephrine (NE), 2 neurotransmitters that have been implicated in the mediation of endogenous analgesic mechanisms via the descending inhibitory pain pathways in the brain and spinal cord [6, 7]. Recent evidence suggests that in pathological pain states, these endogenous pain inhibitory mechanisms may be dysfunctional. An imbalance in these inhibitory mechanisms may contribute to the central sensitization and hyperexcitability of the spinal and supraspinal pain transmitting pathways, and may manifest as persistent/chronic pain [8]. These mechanisms of central sensitization and inhibition of the descending anti-nociceptive pathways due to a diminished availability of 5-HT and NE seem to play a key role in the pathogenesis of FM [9–11].

Duloxetine hydrochloride, hereafter referred to as duloxetine, is a potent, selective, and balanced serotonin and norepinephrine reuptake inhibitor (SNRI) in vitro and in vivo. It is approved by the Food and Drug Administration for the treatment of MDD [12, 13], generalized anxiety disorder [12, 14], FM [15, 16], diabetic peripheral neuropathic pain [17, 18], and chronic musculoskeletal pain [17]. With its dual reuptake activity achieved at the recommended dose of 60 mg/day (with minimal or no titration), duloxetine has a relatively early onset of action both in terms of pain and mood components of FM. Duloxetine’s analgesic effects in the supraspinal and descending inhibitory spinal pain pathways are essentially independent of its central antidepressant effects, explaining perhaps its therapeutic effect in distinct mood and pain syndromes as well as syndromes with considerable co-morbidity, such as FM.

In one Phase II study and three Phase III studies, patients with FM (with or without MDD) were effectively treated with duloxetine in various doses compared to placebo [4, 5, 16, 19]. An additional Phase III study evaluated the safety and tolerability of duloxetine during an extended period of up to 60 weeks and showed that long-term treatment is safe and well tolerated [20, 21].

Results in these studies have been described mainly in terms of average scores and mean changes on different symptom and functioning rating scales. Following on from previous studies that examined subgroups of FM patients [21, 22], and to obtain a better understanding of the frequency and extent of changes at an individual patient level, we used data from these registration studies in a cluster analysis to identify distinct subgroups of FM patients based on measures of pain, mental and physical impairment, global impression, and overall functioning. Descriptive rules were derived to classify patients into outcome categories in terms of their overall health status. The relationship between and relative importance of the pain, mood, and functioning domains in FM were also explored. Finally, changes in outcome categories over time were examined in an attempt to predict response after treatment with duloxetine, depending on patient characteristics at the start of treatment.

Since FM is a complex and heterogeneous condition, the European League against Rheumatism (EULAR) recommends a comprehensive assessment of pain, function, and psychosocial context [36]. One main goal of the pooled analysis presented here was to support the validity of distinct subgroups of FM patients suggested by previous cross-sectional studies. We also explored the usefulness of these subgroups for the clinician in positioning the FM patient along the spectrum of different symptom and functioning domains and in predicting outcome and differential response to treatment, which may provide guidance on the level and type of care and support for the patient’s needs.

One major difference between this analysis and previous studies of FM patients [22, 37, 38] is that the clustering was not based on patient characteristics at baseline but on a wide range of post-baseline efficacy measures collected after 12 weeks of treatment with duloxetine. This allowed the definition of the “best” Cluster 5 that included patients with low pain levels and nearly normal mental and physical status.

Cluster 5 reflects a pronounced positive development over time such that patients in this cluster seem to be mostly recovered from FM. Clusters 1 to 4 correspond to some extent with the 3 subgroups of FM patients described by Giesecke et al. [37]. Giesecke identified a group of patients with a high severity of pain combined with a high degree of mental impairment, which would correspond to Cluster 1 (worst) in the present analysis, and a group with a moderate degree of these symptom domains, similar to Cluster 4 (moderate). The third, smaller group identified by Giesecke et al. included patients with a low degree of mood disturbances but with a high tenderness on evoked pain testing, which might overlap to some extent with our Cluster 2 (physically poor). Our cluster analysis results differentiated between 2 distinct symptom domains characterized by either physical impairment (Cluster 2) or mental impairment (Cluster 3), while these 2 resulting clusters were otherwise similar in terms of pain intensity. Similarly, based on 3 symptom factor scores (musculoskeletal, non-musculoskeletal, and cognitive/psychological symptoms), Wilson et al. identified 4 clusters of FM patients where Groups 2 and 3 differ with regard to more pronounced physical and cognitive/psychological symptoms, respectively, similar to our Clusters 2 and 3 [22]. De Souza et al. emphasize anxiety and depression as a differentiating factor, based on a 2-cluster model of the FIQ items [38]. This was confirmed in the present cluster analysis, which differentiated between mental and pain/physical complaints and impairments in patients situated between the worst and moderate levels of overall symptom severity. The comparable results of these other studies and the present findings seem to add validity to the concept of distinct homogenous subgroups within the broad range of FM patients, despite the fact that underlying outcome measures varied between studies and a different construct, based on post-baseline efficacy data, was applied in the present cluster analysis.

The heterogeneity across the clusters also allowed us to establish patient categories that approximate the clusters with high sensitivity and specificity, using distinct descriptive rules based on only 3 key outcome variables (BPI pain interference; FIQ items 14 [interference with work] and 20 [depression]). Using such rules, any given patient can be classified into one of these categories, as long as data on the 3 outcome variables are available. In the present analysis, pain impact severity seemed to be the most important parameter driving classification of a patient into the 2 best categories or the 3 worst categories. For patients with moderate pain interference, the level of depression was decisive for Category 2 versus 3. For patients with low pain interference, “interference with work” determined the split between Category 4 versus 5. These findings may help guide the clinician’s treatment strategy for the individual FM patient.

The SDS has been used as a validated measure of functional improvement and remission for patients suffering from major depression and generalized anxiety disorders [39]. In the present study, the SDS-based remission criterion discriminated very well between clusters with poor outcome (Clusters 1–3) and those with better outcome (Clusters 4–5), but provided little discrimination among Clusters 1–3 (Table 1). Moreover, 91% of patients in Cluster 5 achieved a functional remission based on the SDS criterion, highlighting its utility in patients with FM.

Duloxetine and placebo were compared based on category frequencies at baseline and after 12 weeks of treatment, confirming the results seen in the individual studies [4, 5, 16, 19]. While frequencies per category were similar between treatment groups at baseline, more duloxetine than placebo patients fell into the 2 best categories after 12 weeks. This was confirmed in the analysis of transition probabilities.

Mentally poor patients (Cluster 3) were more likely to deteriorate to Cluster 1 than physically poor patients (Cluster 2), suggesting that mental impairment is the more detrimental co-morbidity compared to physical impairment influencing outcome category. Furthermore, a better treatment effect on the change in categories from baseline to Week 12 was observed in physically impaired patients. This supports the independent analgesic properties of duloxetine and suggests that it is a beneficial treatment for FM patients, irrespective of the presence of mental impairment.

Aside from the most predictive factors, i.e. treatment and baseline category, previous use of antidepressants was identified as a modestly significant predictor of outcome category. Results indicated that duloxetine-treated patients with previous antidepressant use were doing moderately better. However, it is not clear if duloxetine is protecting against a history of depression and/or if it is an indication that duloxetine as an SNRI has a positive effect on both pain and emotional problems in FM, in contrast to the most commonly used antidepressants, i.e. selective serotonin reuptake inhibitors (SSRIs). Future studies would be needed to confirm this hypothesis in FM, to support the literature reporting the beneficial role of duloxetine in patients with MDD and painful physical symptoms who were switched from failed initial treatment with SSRIs or other SNRIs [40, 41].

A sustained effect of duloxetine was seen when classification rules were applied to the long-term study. The “best” outcome category at 14 weeks was maintained at 24 weeks in almost 75% of patients. About 64% of patients with “moderate” outcome either maintained their status or improved to the “best” category. Considering that the remainder of patients in this category worsened (36%), the presence of mild residual symptoms may indicate a risk for relapse. On the other hand, more than half of the patients in the “worst” category at Week 14 were able to improve their status with duloxetine treatment up to Week 26.

This cluster analysis confirms earlier findings that FM patients are heterogeneous with different levels of impairment [37, 38], emphasizing the need for treatments tailored to the individual patient while also taking into account both the mental and physical symptoms of the patient. Some patients with minor impairment could be treated in primary care with advice and pharmacological or non-pharmacological support. The more complex patients with a high level of physical and/or mental impairment are better treated in tertiary care with a tailored multidisciplinary approach, as also suggested by Van Koulil [42, 43]. According to the individual patient’s co-morbidity, such treatment should not only focus on pain medication, but also on education, treatment of secondary depressive/anxiety disorders, functional rehabilitation, and psychotherapy. A meta-analysis by Häuser provided strong evidence that multi-component therapy has beneficial short-term effects on the main symptoms of FM, but has no effect in the long term [44]. Häuser therefore underlined the need to develop strategies to maintain a long-term benefit. This process may need to focus on teaching self-management strategies and addressing perpetuating personality factors such as perfectionism, and on treating mental impairment, as this seems to be one of the more negative prognostic factors.

Limitations of the described analyses and results were as follows:

These analyses show that FM patients are heterogeneous and can be classified into distinct subgroups based on overall symptom and impairment severity, and on the basis of the predominance of mental versus physical symptoms for patients with intermediate overall severity level. Treatment with duloxetine showed higher improvement rates than with placebo, and the majority of patients on duloxetine in any category either maintained or improved their health status beyond 12 weeks. The results underline the need for further research into FM patient subgroups and the importance of a comprehensive patient assessment as a first step towards a tailored treatment.