Characterizing Chronic Pain Phenotypes in Multiple Sclerosis

A Nationwide Survey Study

Anna L. Kratz; Daniel Whibley; Kevin N. Alschuler; Dawn M. Ehde; David A. Williams; Daniel J. Clauw; Tiffany J. Braley


Pain. 2021;162(5):1426-1433. 

In This Article


This is the first study to characterize pain phenotypes in MS within the IASP-defined mechanistically based framework and to compare pain phenotypes in terms of pain intensity, chronic overlapping pain conditions, and use of perceived analgesia of commonly used pharmacological therapies. The pattern we identified in MS is similar to that seen with other autoimmune disorders,[12,45] where nociceptive pain is the most common underlying pain descriptor, but a sizable proportion of individuals also have nociplastic or mixed neuropathic/nociplastic pain types. In this sample, it was relatively uncommon for individuals to score high solely on the measure of neuropathic pain while not also scoring high on the measure of nociplastic pain. This suggests that identification of neuropathic pain alone may be insufficient to fully characterize pain for many individuals with MS, who may also demonstrate features of co-occurring nociplastic pain.

Nociceptive pain has been recognized as 1 pain subtype in MS, often associated with postural problems, deconditioning, and/or muscle spasms.[51,56] However, the prominent focus on neuropathic pain in MS has contributed to lack of understanding of the scope and nature of nociceptive pain in MS. Given the relatively high prevalence of nociceptive pain in our sample (41%; indicated by neither neuropathic nor nociplastic pain characteristics), it is critical to gain a better understanding of nociceptive pain with an eye toward optimizing treatment for this pain subtype. Identification of patients with primarily nociceptive pain could enhance the chance of analgesic success. It is important to note that, because of our process of identifying nociceptive pain by process of elimination from the other pain categories, we may have underestimated the proportion of our sample with of pain of nociceptive origin; it is likely that mixed pain in MS also includes overlap of nociceptive pain with neuropathic and/or nociplastic in the same individual.[19,21,60]

Nearly 60% of the sample had evidence of predominantly nociplastic pain, neuropathic pain, or a combination of both. This finding is not surprising, given the widespread CNS damage associated with MS and associated changes to the somatosensory system and pain processing. Yet, although neuropathic pain is commonly studied in MS, there have been no known investigations of centralized (nociplastic) pain, as it is currently defined, in MS. However, allodynia, perceived pain in response to a nonpainful stimuli and a common feature of centralized pain, has been previously identified in patients with MS and chronic pain.[57,58] Further examination of 2 likely scenarios of nociplastic pain in MS—nociplastic pain occurring before the onset of MS or nociplastic pain developing after onset of MS—is warranted; in particular, examination of possible contributions of MS CNS lesions to central sensitization and pain centralization is needed to better understand and treat pain in MS.

Results for pain intensity and overlapping pain conditions were consistent with our expectations. We found a graded increase in pain intensity when going from the group with nociceptive pain to those with elements of nociplastic pain. This is expected because nociplastic pain is believed to be due to CNS pain sensitization/amplification, and this same finding is noted when phenotyping based on pain mechanisms in rheumatic and other autoimmune disorders.[5,7] Also as expected, chronic overlapping pain conditions were reported more frequently in those with nociplastic pain type. Although these pain conditions are diagnostically distinct, they share many similar characteristics (eg, fatigue, mental fog, and sleep problems), frequently co-occur, and are considered to be different manifestations of a common cause—pain amplification due to central sensitization.[37,66] This consideration highlights an understudied overlap between characteristics of MS and chronic overlapping pain conditions, including FM. Significant problems with chronic pain, fatigue, cognitive dysfunction, depressed mood, and poor sleep are shared features of both MS and FM. The measure of pain centralization, the ACR FM Survey Criteria, includes a number of these symptoms—fatigue, sleep, and cognition—in the calculation of the total score. This overlap could complicate the interpretation of FM Survey Criteria scores in a sample of people with MS. It is possible that classification of degree of central sensitization and classification of "positive" FM cases are overestimated because of this similarity in symptomology. It is also plausible that a significant proportion of people with MS truly have nociplastic pain, with some of these having a diagnosis of comorbid FM. Given our de-emphasis of identifying specific syndromes, we would argue for more of a focus on detecting elements of central sensitization mechanisms rather than on the FM diagnosis per se.[68]

This study has important clinical value, laying the foundation for improving our ability to define individual sensory profiles that may predict differential treatment response. A number of efforts are underway to advance personalized pain therapy by phenotyping pain using the painDETECT,[22,50] and painDETECT scores have been shown to predict treatment response in diabetic neuropathy[4] and chronic low back pain.[49] Similarly, previous research has shown that scores on the FM Survey predict outcomes after knee or hip arthroplasty[8] and opioid consumption after surgery.[28,33] Nociplastic pain conditions such as FM are not believed to be responsive to NSAIDs or other anti-inflammatory drugs, and instead preferentially respond to centrally acting analgesics such as gabapentinoids, tricyclics, serotonin-norepinephrine reuptake inhibitors, and cannabinoids.[11] Our findings are partially consistent with these previous observations. We found greater self-reported analgesic effectiveness from NSAIDs for nociceptive pain type and from cannabinoids for mixed pain and neuropathic types. Armed with this information, clinicians may be supported in identifying the most appropriate initial pharmacotherapy treatment plan for the presenting pain picture. For example, successfully identifying pain of nociceptive origin spares the patient medications indicated for neuropathic pain that may offer an unfavorable benefit/risk profile. Given that patients with MS are 5 times more likely to receive a neuropathic pain medication than patients without MS,[9] identifying those for whom this type of pain medication is not indicated seems particularly critical. Across pain phenotypes, survey responses indicate high utilization of multiple classes of analgesic medication to manage chronic pain in MS and ratings that suggest poor to modest pain relief across the medication categories. NSAIDs have been used for musculoskeletal pain or to address pain flares during MS exacerbations, but are more often indicated as comedications with other analgesic categories that target neuropathic pain.[47,56] Higher use of cannabinoids in those with nociplastic pain either alone or along with neuropathic pain (mixed pain) is consistent with previous findings that people with MS who demonstrated sensory disturbances indicative of pain centralization reported higher use of cannabis.[51] Although these initial findings indicate that medications may have different analgesic effects based on pain phenotype, the ability to predict treatment response from survey scores needs to be tested in MS.

This study focused on pharmacological pain treatments, but pain phenotypes could respond differently to physical and psychological therapies as well. The nociceptive-dominant pain subgroup may be driven by a variety of musculoskeletal or inflammatory nociceptive sources of pain that historically respond well to nonpharmacological management approaches, including physical or occupational therapy, that target biomechanical pain generators. There is mounting evidence supporting the effectiveness of psychological therapies to manage symptoms in both MS and FM and demonstrating that psychological interventions can alter how the brain processes sensory information.[29,59] Together these bodies of literature support a shared CNS mechanism of pain in both MS and FM and suggest a need for future research to investigate whether and how nonpharmacological treatments may be effective for nociplastic pain in people with MS and chronic pain.

Study Strengths and Limitations

The large nationwide sample, use of validated measures, good response rate, and low level of missing data from those who started the survey are strengths of this study. The sample was predominantly female and white, which limits generalizability. Use of the National MS Society email listserv to recruit most study participants may also limit the generalizability of the findings. Given the lack of available measures to identify nociceptive pain, this pain type was identified by exclusion, which limited our ability to understand mixed pain characterized by co-occurrence of nociceptive and other pain types. The current IASP definition of pain includes both sensory and emotional aspects of the pain experience; the focus of this article to attempt to characterize the biological and neurobiological mechanisms of chronic pain in MS does not incorporate potential emotional facets of pain phenotypes. Future research that characterizes MS pain phenotypes based on both sensory and emotional characteristics, and in the context of other symptoms, may help to further clarify our understanding of pain in MS and how best to treat it.