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

Abstract and Introduction


Chronic pain is highly prevalent in multiple sclerosis (MS). Pain heterogeneity may contribute to poor treatment outcomes. The aim of this study was to characterize pain phenotypes distributions in persons with MS and compare pain phenotypes in terms of pain intensity, frequency of chronic overlapping pain conditions, and use and analgesic effects of different classes of pain medications. Data were collected through a national web-based survey with measures of neuropathic (painDETECT) and nociplastic pain (Fibromyalgia Survey Criteria), chronic overlapping pain conditions, and pain medication use and pain relief. In a sample of N = 842 adults with chronic pain and MS, the largest proportion (41%) showed evidence of nociceptive pain, 27% had mixed neuropathic/nociplastic pain, 23% had nociplastic pain, and 9% had neuropathic pain. Nociplastic pain was associated with significantly higher pain intensity and frequency of chronic overlapping pain conditions. Across all pain types, high frequency of pain medication use along with poor-modest pain relief was reported. Cannabis use for pain was more common, and pain relief ratings were higher among those with nociplastic pain, relative to nociceptive pain. Although NSAID use was highest among those with nociplastic pain (80%), pain relief ratings for NSAIDs were highest among those with nociceptive pain. These findings underscore the need for multidimensional assessment of pain in MS with greater emphasis on the identification of pain phenotype. An improved characterization of pain as a multifaceted condition in MS could inform therapeutic approaches.


Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that affects approximately 1 million people in the United States and is the leading cause of nontraumatic disability in young adults.[39,40,64,65] Chronic pain is one of the most common and disabling symptoms in MS.[1,14–16,18,24,25,30,36,38,44,46] Unfortunately, current pain treatments do not provide sufficient or durable pain relief.[55,56]

Poor analgesic outcomes may result from pain heterogeneity in MS.[17,18,53,54,56] Many studies have focused on the prevalence of specific pain syndromes in MS (eg, migraine, trigeminal neuralgia, and Lhermitte's sign),[43,53,62] but an approach that focuses on describing pain subtypes with common underlying mechanisms could have greater therapeutic potential.[2,13,43,55] Attempts to characterize pain subtypes often use time- and resource-intensive approaches to identifying pain mechanisms (eg, quantitative sensory testing and imaging).[2,13] Alternatively, survey-based assessments have provided useful information about putative underlying pain mechanisms in populations outside of MS.[7,8,23,28,41,63]

The International Association for the Study of Pain (IASP) has defined 3 categories of mechanistically based pain types.[42,61] Neuropathic pain results from lesion or disease of the somatosensory nervous system.[52] Given the axonal injury associated with MS, pain is often assumed to be neuropathic in origin.[27] Nociceptive pain, by contrast, arises from activation of nociceptors in the periphery due to actual or threatened tissue damage (including inflammation) as opposed to dysfunction in the somatosensory nervous system;[26] nociceptive pain is not well characterized in MS. Nociplastic pain arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain. This type of pain, often termed "centralized pain" or "central sensitization," is believed to be due to CNS alterations in pain processing, as opposed to ongoing inflammation (nociceptive) or damaged neural pathways (neuropathic).[31,52,61]

To date, the majority of work on pain in persons with MS has focused on pain associated with focal demyelinating lesions,[43] with little attention given to concomitant nociceptive/inflammatory or nociplastic mechanisms, or differences in perceived treatment effects related to pain mechanisms. One study of the natural history of pain in MS indicated that those with chronic pain went on to develop more widespread pain over time (a characteristic of central sensitization),[73] but an examination of nociplastic pain in MS has not been undertaken. Work to identify subgroups with different underlying pain mechanisms will likely improve pain outcomes in MS by providing opportunity to tailor therapies to an individual's specific type(s) of pain.[2]

To address gaps in knowledge about pain phenotypes in MS, we conducted a nationwide survey to (1) characterize distribution of neuropathic, nociceptive, nociplastic, and mixed neuropathic/nociplastic pain in those with chronic pain and MS; (2) examine whether level of pain intensity and prevalence of chronic overlapping pain conditions[37] differ between pain subtypes, with the expectation that both would be higher in those with nociplastic pain;[66] and (3) compare use and perceived pain relief from commonly used pharmacological analgesic treatments.