Approximately 50% of patients with diabetes develop polyneuropathy (DN), which is painful (pDN) in up to one-third of cases. While the pathophysiology of DN itself is already diverse—with metabolic, vascular, and immunologic causes—the pathophysiology of pain in the setting of pDN is likely even more diverse. Neuropathic pain in pDN is caused by a combination of heightened activation of peripheral nociceptors (e.g., through methylglyoxal), central nociceptive sensitization, or inefficient pain control; other types of pain from joints, bones or muscles are often overlooked (1). On the other hand, specific drug trials for neuropathic pain include patients based on their diagnosis (pDN) without accounting for individual pain mechanisms, resulting in only moderate and very heterogeneous pain relief (2). In the case of pDN, this is fatal because drug selection recommendations in guidelines are often based on data from studies where pDN is used as a disease-defined model for neuropathic pain (e.g., 2).
In chemotherapy-induced neuropathy (CIN), we found that ∼60% of patients with painful CIN had musculoskeletal pain components. These patients differed in sensory findings and had higher anxiety and depression scores than patients with neuropathic pain only (3). Previous human research on pain mechanisms in DN concentrated on the differences between nonpainful DN (npDN) and pDN. pDN is characterized by more severe neuropathy, higher depression and anxiety scores, and more impaired quality of life (1). However, none of these studies included distinction between neuropathic and musculoskeletal pain.
We therefore consecutively investigated 69 subjects (25 women) aged 66 ± 1.3 years with DN caused by type 2 diabetes. Forty-one had pDN, and the remaining 28 had npDN. Subjects with neuropathies other than diabetic (n = 6), as well as those with prediabetes or type 1 diabetes (n = 8), additional chronic pain syndromes (n = 8), or cerebrovascular disease (n = 1), were excluded. Analgesic intake was more frequent in pDN (29.3%) compared with npDN (3.6%, P < 0.01). Demographic and diabetes-specific data were not different. Toward a personalized assessment of pain, we performed in-depth phenotyping using standardized clinical examinations including myofascial pain assessment, nerve conduction study, sensory phenotyping by quantitative sensory testing (QST), and testing of pain tolerance and pain control (cold pressor test [CPT]). Additionally, patient-reported outcomes (polyneuropathy-related impairment, anxiety, and depression [Hospital Anxiety and Depression Scale (HADS)]) were assessed. All results are given as mean±SEM.
Clinical DN was confirmed in all patients by nerve conduction study and QST. All subjects with pDN met the criteria of “definite neuropathic pain” (4). Confirming findings of previous studies (1), polyneuropathy was more severe in pDN (Fig. 1A). Myofascial pain is characterized by active muscle trigger points (MTrPs) that, on direct palpation, reproduce local and referred pain occurring spontaneously or during physical load (5). Active MTrPs were identified in 22% (9 of 41) of the pDN group (myo+pDN) but never in the npDN group. They were in the anterior or posterior calf muscles and the small plantar muscles. They occurred bilaterally in 8 of 9 patients (89%) and involved mirror-image muscles in 7 of 9 (78%).
Our main findings relate to the presence of myofascial pain: participants with a myofascial pain component (myo+pDN) had higher mean (NRS 54.4 ± 5.0 vs. 33.0 ± 3.7) and maximum (NRS 76.6 ± 6.6 vs. 51.9 ± 5.3; both P < 0.01) pain intensity, showed worse pain tolerance and control (CPT) (Fig. 1B), presented with higher HADS scores (Fig. 1C), and reported more severe neuropathy-related impairment (Fig. 1D) than their counterparts without myofascial pain (myo-pDN). Otherwise, neuropathy was indistinguishable between myo+DN and myo-pDN.
In summary, myofascial pain is easy to assess and is common (22%) in pDN. Its presence probably characterizes a subgroup of pDN. Since the present results support our previous findings with an almost identical percentage of MTrPs (25%) in painful CIN (3), we conclude that they might be transferable to painful neuropathies in general. Pathophysiological and therapeutic implications for pain in DN may arise: studies searching for biomarkers or pathophysiology of pDN may be compromised by unrecognized myofascial pain as a potential confounder that could be easily recognized and addressed. We recommend routine screening for myofascial pain in pDN not only for individual treatment but also for stratification in future treatment trials with pain as the primary outcome.
F.B. and C.G. share senior authorship.
Acknowledgments. The authors thank Cheryl Ernest (Department of Neurology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany) for proofreading the manuscript.
Funding. This study was funded by an intramural grant of University Medical Centre Mainz, and German Research Foundation (DFG Bi 579/10).
Duality of Interest. No potential conflicts of interest relevant to this article were reported.
Author Contributions. F.B. and C.G. designed the study. F.B.-S. and C.G. conducted the experiments. F.E.-L., F.B.-S., and C.G. calculated the statistics. F.E.-L. and C.G. wrote the manuscript. H.K., F.B., and C.G. revised the manuscript. C.G. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.