Pain Phenotypes in Adults Living With Cerebral Palsy

Abstract

Background and Objectives

To identify pain phenotypes among adults living with cerebral palsy (CP) and compare phenotypes of pain intensity, anxiety and depressive symptoms, and self-reported perceived stress.

Methods

Seventy-one adults with CP presented to the University of Michigan (mean age = 39.3 ± 16.2; 43 women, 28 men). The median of 6 on the American College of Rheumatology fibromyalgia survey was used to classify patients for nociplastic pain centralization. The painDETECT Score was used to classify patients for neuropathic pain. These measures were then used to cross-classify each patient into 1 of 4 possible pain categories: neuropathic, nociplastic, mixed neuropathic/noclipastic, or nociceptive pain (-neuropathic/-nociplastic pain).

Results

Twenty-eight adults with CP (39.4%) were classified as nociceptive, 24 (33.8%) as nociplastic, 8 (11.3%) as neuropathic, and 11 (15.5%) as mixed neuropathic/nociplastic. Subgroups differed significantly on average scores on the Brief Pain Inventory pain intensity scale, the Perceived Stress Scale, and on the Patient-Reported Outcomes Measurement Information System measures of anxiety and depression; the nociceptive pain subgroup reported lower pain and emotional distress compared with the other groups.

Discussion

Findings suggest that type of pain is variable among adults with CP and may arise through multiple mechanisms.

There is a lack of clinical follow-up for patients with cerebral palsy (CP) after they transition from pediatric to adult primary care and insufficient cohort data to track clinical outcomes longitudinally.¹ In particular, pain is the most commonly reported somatic symptom in CP throughout the lifespan, and yet chronic pain is perhaps the least understood, emphasized, and studied physical comorbidity of CP.^2-4 Pain in CP may arise from nociceptive mechanisms associated with chronic muscle spasticity, joint misalignment, and invasive and repetitive surgical procedures.⁵ Alternatively, neuropathic pain could be a consequence of periventricular leukomalacia, which causes dysfunction of non-nociceptive sensory tract neurons in most patients with CP.

There is an excellent review of the assessment and treatment of pain among children with significant impairment of the CNS⁶; however, there have been virtually no investigations to understand the pain phenotype distribution among adults living with CP. The chronic pain literature describes different pain subtypes, depending on pain etiology: (1) neuropathic pain or pain due to damage to the somatosensory system, (2) nociplastic pain or pain due to central sensitization, and (3) nociceptive pain or pain due to direct tissue damage.⁷ The category of nociplastic pain has been developed more recently than nociceptive or neuropathic pain and has had other names, more specifically centralized pain or central hyperalgesia, where there is amplification of the pain processing or pain experience in the CNS.⁸ Fibromyalgia (FM), chronic migraine headaches, irritable bowel syndome, and interstitial cystitis are examples of nociplastic pain conditions. In the case of nociplastic pain conditions, many of the conditions co-occur (either simultaneously or sequentially) and the term chronic overlapping pain conditions has been developed to categorize the grouping of nociplastic diagnoses.⁹ Musculoskeletal pain is a common cause of nociceptive pain.

Given that pain perception may arise from multiple mechanisms, understanding the phenotypes of chronic pain among adults with CP is crucial for prescribing the most appropriate and effective pain management interventions. The purpose of this study was to identify pain phenotypes among adults with CP based on putative mechanisms and compare phenotypes of pain intensity, anxiety and depressive symptoms, and perceived stress.

Methods

Data were prospectively collected from the Michigan Genomics Initiative (MGI) (michigangenomics.org) and the Analgesic Outcomes Study. The MGI is an ongoing institutional biorepository data collection effort at the University of Michigan, which started in 2012. The Analgesic Outcomes Study is a prospective, observational cohort study of acute and chronic postsurgical pain that has previously published outcomes data.^10,11 Patients were excluded if they did not speak English, were unable to provide written informed consent, or were incarcerated.

Standard Protocol Approvals, Registrations, and Patient Consents

The institutional review board of the University of Michigan, Ann Arbor, approved this study, and all participants provided written informed consent. Patients consented to the use of their health data for future unspecified research. Preoperative patient characteristic data were obtained using validated self-report measures of pain, mood, affect, and function.

Sample Selection

We obtained access to data for all patients with CP, aged 18 years and older, during the period from 2012 to present. Patients were included if they had an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) or International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes for a CP diagnosis (all ICD-9 and ICD-10 codes are provided in Table 1).

Table 1.

ICD-9 and ICD-10 Codes for Identifying Cerebral Palsy

Assessment of Pain Characteristics

Validated pain measures common to the MGI and Analgesic Outcomes Study were used in this study.

Neuropathic Pain

Neuropathic pain was assessed using the painDETECT questionnaire (PD-Q), a 13-item survey to determine the presence/severity of pain of neuropathic origin.¹² The PD-Q assesses current, average, and worst pain intensity over the past 4 weeks (rated on an 11-point numeric rating scale of 0–10) and the presence of neuropathic pain qualities (e.g., burning sensation and tingling/prickling sensations, rated on a Likert scale from 0 [never] to 5 [very strongly]). Pain duration/pattern and radiation of pain are also assessed. The total score ranges from −1 to 38, with higher scores indicative of higher likelihood of neuropathic pain origin. Scores ≤12 indicate that a neuropathic component of pain is unlikely, scores between 13 and 18 are ambiguous, and scores ≥19 indicate that a neuropathic component of pain is likely.

Nociplastic Pain

The degree of centrally enhanced pain processing was assessed using the American College of Rheumatology 2011 FM Survey Criteria including widespread body pain and comorbid somatic symptoms (higher scores indicating greater centralized pain).^13,14 This survey includes the number of painful body regions using the Michigan Body Map (0–19) and related symptoms such as problems thinking, fatigue, and sleep difficulties (0–12). This continuously scaled metric (ranging between 0 and 31) can be used as a proxy index for central sensitization or can be used to indicate likely FM with a cut-point of >13.¹⁴ This survey has been previously used to quantify centralized pain in other clinical populations,^15,16 correlates strongly to functional neuroimaging findings in nociplastic pain,^17,18 and is highly associated with both pain and disability.^19-21 For this study, we defined central sensitization as scores that were greater than the median, as previously described.¹⁶

Pain Intensity

Pain severity was measured with the Brief Pain Inventory (BPI), which assessed the overall current pain and average, least, and worst body pain in the past 24 hours (11-point Likert-type scale, total represents the average score across all responses, and ranges from 0 to 10 with higher scores indicating greater pain severity).²²

Stress, Anxiety, and Depression

Stress was measured using the patient-completed Perceived Stress Scale,²³-a 14-item scale that assesses perceived stress of life situations in adults and has well-established validity in relation to physiologic stress responses²⁴ and anxiety and depressive disorders.²⁵ Anxiety and depression were measured using the Patient Reported Outcomes Measurement Information System (PROMIS) short-form measures of anxiety and depression (score range, 4–20, with ≥8 indicating positive for anxiety or depression).²⁶

Statistical Analysis

Demographic and clinical characteristics of the sample were summarized as mean (SD) and/or median (Interquartile range [IQR]) for continuous variables and frequency and proportion for categorical variables. Chi-squared tests were used to compare the frequency of overlapping pain conditions and depression and anxiety by pain subtype group. One-way analysis of variance (ANOVA) was used to compare mean PROMIS pain intensity T-scores and reported depression or anxiety by different pain subtype groups. In cases where the omnibus ANOVA test was significant, post hoc multiple comparison Tukey Honest Significant Difference tests were conducted to examine pair-wise comparisons of pain intensity and depression or anxiety across the pain subtypes. Standardized effect sizes (Hedges g) were calculated to further characterize statistically significant pair-wise group differences. Hierarchical linear regressions were used to examine the effects of scoring positive for nociplastic (based on FM Survey median, dummy coded) or neuropathic pain (based on painDETECT median, dummy coded) on depression, anxiety, and stress outcomes, controlling for pain intensity (BPI).

Data Availability

Anonymized data will be shared by request from any qualified investigator.

Results

Of the 120 adult patients with CP, n = 71 had complete pain inventory data (mean age = 39.3 ± 16.2; 43 women, 28 men).

Distribution of Pain Subtypes

Neither sex nor age distribution differed by pain phenotype. On the American College of Rheumatology 2011 FM Survey Criteria (measure of centralized pain), the sample mean was 7.03 ± 4.72 and the median was 6.00 (IQR = 4.00, 9.00; Figure 1). Using the cut-point of ≥6, 24 (33.8%) of the sample scored positive for central sensitization (nociplastic type), and using the cut-point of ≥13, 10 (14.1%) of the sample scored positive for high nociplastic. For the measure of neuropathic pain, the painDETECT, the sample mean was 8.06 ± 6.70 and the median = 7.00 (IQR = 2.00, 13.00; Figure 2). Most of the sample did not show strong evidence of neuropathic pain, with 8 (11.3%) scoring in the likely neuropathic range on the scale (labeled “neuropathic type”). The largest subgroup showed low scores on measures of both neuropathic and nociplastic pain (n = 28, 39.4%) and was labeled “nociceptive type” (-neuropathic/-nociplastic). Eleven adults with CP (15.5%) were classified as combination neuropathic/nociplastic and were labeled as having a “mixed neuropathic/nociplastic type” (Figure 3).

Figure 1. Distribution of Fibromyalgia Survey Criteria Scores (N = 71).

Figure 2. Distribution of painDETECT Scores (N = 71).

Figure 3. Distribution of Pain Types Based on Surveys of Neuropathic and Nociplastic Pain (N = 71).

Pain Intensity

The pain subtypes differed significantly in BPI pain intensity scores.

(F [3, 60] = 10.38, p < 0.001). The nociceptive type had the lowest (mean = 1.98 ± 2.19) and the mixed neuropathic/nociplastic type had the highest (mean = 5.86 ± 2.44) average pain intensities. The neuropathic (mean = 5.19 ± 2.44) and nociplastic (mean = 4.77 ± 2.30) types had similar average pain scores. Post hoc multiple comparison tests revealed that the average nociceptive pain type intensity was significantly lower than all other in pain intensity scores (all p < 0.001), and large differences in mean pain scores were observed between the nociceptive and neuropathic (Hedges g = 1.35), nociplastic (Hedges g = 1.24), and mixed neuropathic/nociplastic type subtypes (Hedges g = 1.72). Pain intensity scores between nociplastic, neuropathic, and mixed neuropathic/nociplastic pain subtypes demonstrated no clinically meaningful differences.

Stress, Anxiety, and Depression

The pain subtypes also differed on the Perceived Stress Scale (F [3, 65] = 3.11, p = 0.03), as well as the PROMIS measures of depression (F [3, 65] = 3.86, p = 0.01) and anxiety (F [3, 65] = 3.61, p = 0.02) (Table 2). Post hoc multiple comparison tests revealed that the nociplastic (Mean = 7.76 ± 2.77) pain type had higher average PROMIS depression scores than the nociceptive (Mean = 5.50 ± 2.37) pain type (p = 0.03). Moreover, the mixed neuropathic/nociplastic pain subtype had higher average PROMIS anxiety scores (mean = 11.09 ± 3.36) than the nociceptive (mean = 7.12 ± 3.56) pain subtype (p = 0.02). Large differences in average Perceived Stress Scale scores were observed between the mixed neuropathic/nociplastic type and the neuropathic pain type (Hedges g = 1.31) and between the nociplastic type and the neuropathic pain types (Hedges g = 1.03). Large differences in the average PROMIS measures of depression were found between the mixed neuropathic/nociplastic type and nociceptive pain type (Hedges g = 1.02) and between nociplastic type and nociceptive pain type (Hedges g = 0.88). Large differences in the average PROMIS measures of anxiety were found between the mixed neuropathic/nociplastic type and both the nociceptive (Hedges g = 1.13) and neuropathic (Hedges g = 1.13) pain types. Finally, a medium difference was observed between the mixed neuropathic/nociplastic type and the nociplastic pain type (Hedges g = 0.70).

Table 2.

Comparison of Scores for Perceived Stress, Depression, and Anxiety by Pain Subtype

Hierarchical regression results showed that scoring positive for nociplastic pain did not independently predict worse anxiety but did predict significantly worse self-reported depression (β = 0.27, t = 2.16) and perceived stress (β = 0.31, t = 2.31) above and beyond the effects of pain intensity (BPI; all p < 0.04). In contrast, scoring positive for neuropathic pain type did not significantly predict any depression, anxiety, or perceived stress after accounting for pain intensity (BPI; all p > 0.05).

Discussion

The principal finding of this study was that more than 60% of the subjects with CP experienced neuropathic, nociplastic, or mixed neuropathic/nociplastic pain, with 34% demonstrating nociplastic pain, 11% presenting with neuropathic pain (i.e., “pain caused by a lesion or disease of the somatosensory nervous system”^27,28), and roughly 16% with a combination of neuropathic and nociplastic pain. The remainder of adults with CP (39%) experienced chronic pain that is characteristic of nociceptive pain (i.e., peripheral pain “that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors”^27,28). This is one of the first studies to document the elevated burden of neuropathic and nociplastic pain experienced by adults living with CP. Understanding the pain phenotype is vitally important when assessing and treating pain. In 2017, the International Association for the Study of Pain defined “nociplastic pain” as “Pain that 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 pain²⁸” after the 2016 proposition of Kosek et al.²⁹ Moreover, it can present clinically as a combination of widespread pain and elevated somatic symptom burden (e.g., the presence of depressive symptoms, headaches, fatigue, and difficulty sleeping), as noted by the FM survey questionnaire. Indeed, our results showed that scoring positive for nociplastic pain predicted significantly worse self-reported depression and perceived stress above and beyond the effects of pain intensity. In contrast, scoring positive for neuropathic pain type did not significantly predict any health-related quality of life outcomes after accounting for pain intensity. Scoring positive for the mixed neuropathic/nociplastic type represented the highest scores for perceived stress, as well as depression and anxiety. These findings indicate that nociplastic pain may explain some of the elevated burden of pain, fatigue, and depression noted in studies of adults with CP and that abnormal pain processing in CP may be consistent with centralized pain, including multisite hyperalgesia and impaired endogenous pain modulation. However and importantly, although nociplastic pain is characterized by the absence of musculoskeletal alterations, the absence of these structural abnormalities does not exclude a tissue origin, and mixed presentation in CP are likely common.³⁰ Moreover, as noted by Freynhagen et al.,⁷ “mixed pain is a complex overlap of the different known pain types (nociceptive, neuropathic, and nociplastic) in any combination, acting simultaneously and/or concurrently to cause pain in the same body area. Either mechanism may be more clinically predominant at any point of time. Mixed pain can be acute or chronic.” Future efforts are needed to better understand the mechanisms of chronic centralized pain the CP, and the optimal interventions needed to help patients manage pain experiences.

Chronic pain has high global prevalence (∼30%;³¹), imposes a significant socioeconomic burden, and contributes to excess mortality.³² The most comprehensive study to date to document pain in adults with CP was a systematic review and meta-analysis with individual participant data from internationally representative samples.³³ In that study of 1,243 participants with CP, the investigative team found that the overall mean pain prevalence ranged from 38% to 89% within individual samples and reported predominantly in the legs. Moreover, they found that pain severity and pain interference were both approximately 4 of 10 on a 0–10 numerical rating scale (moderate pain and pain intensity). Although the largest study to date to examine prevalence of pain among adults with CP, that study was limited in that it did not shed light on pain type or mechanism of pain. Pain is experienced by adults with CP and other pediatric-onset disabilities when completing normal tasks, such as dressing and transferring, or other activities that require medical interventions.^34,35 Previous research has found that nearly 40% of adults with CP commonly experienced pain and severe fatigue.^36,37 When compared to individuals without CP, approximately 70%–75% of adults with CP report chronic pain.^33,34 This study demonstrated that nociplastic pain was >30% prevalent and was associated with increased stress, depression, and anxiety. Thus, these putative pain mechanisms could provide new insight into the pain experience in adults with CP and inform interventions to address pain and associated morbidity (e.g., sleep disturbance, mental health outcomes, and fatigue). Future clinical research is desperately needed to determine the true pain experience and phenotype in these populations, through comprehensive pain screening inventories and assessments of pain processing with quantitative sensory testing with advanced imaging techniques such as fMRI. Future studies are also needed to examine outpatient pharmacy claims and inferred opioid and nonopioid medication prescribing patterns. Although opioids are well known for high risk of addiction and morbidity, many nonopioid pain medications also present risks for morbidity. This is particularly important when considering individuals with CP because recent reports have noted a high level of polypharmacy in this population, with chronic kidney disease and liver disease contributing extensively to morbidity and mortality.³⁸ Thus, understanding the pain phenotype facilitates improved treatment of pain by targeting medications appropriately and avoiding high-risk prescribing patterns and polypharmacy.

Strengths and Weaknesses

A major strength of this study is the robust pain phenotyping information among the adults with CP. It can be challenging to gather granular clinical pain data on clinical subpopulations, and very little is known about pain phenotyping among individuals with CP as they transition throughout adulthood. This is the first and largest study to date to examine pain with different putative underlying mechanisms in adults living with CP. Future research and clinical efforts are needed to not only better understand the healthcare burden associated with these pain subytpes in adults with CP, and across other subpopulations with neurodevelopmental and acquired physical disabilities, but also to understand the health disparities in access and pain progression experienced between privately and federally insured beneficiaries living with disabilities. Moreover, these findings support the need for improved clinical screening tools to accurately identify pain phenotypes and improve pain treatments in patients with CP. The high burden of nociplastic and neuropathic pain in this population indicates the need for validation and uptake of appropriate screening tools for different pain subtypes in adults with CP. Improved understanding of underlying pain mechanisms can provide information on underlying disease processes that may be contributing to the high burden of pain in this population. Current pain treatments are not sufficiently robust or durable in CP³⁹ and focused primarily on site-specific musculoskeletal pain.

Our study also has several limitations that should be acknowledged. First, we were unable to determine the severity of CP through electronic medical data. However, we suspect that our sample may be more reflective of a healthier, higher functioning segment of the CP population because they had to be able to complete numerous surveys related to pain experience, which are not accessible to individuals with either sensory impairments and/or intellectual disabilities (highly comorbid with CP). Our sample was drawn from individuals undergoing a surgery and a single academic medical center, which may further limit generalization of findings to the broader population of adult with CP. Moreover, we were unable to determine whether other competing risks or unmeasured confounding (i.e., other risk factors [e.g., a family history of pain disorders, lack of physical activity, and loss of functional independence]) may have influenced the observed findings. Unmeasured confounding could also be within proxy variables of appropriate care (physical therapy, occupational therapy, etc.), which might mitigate pain morbidity risk (and were not considered). This would lend credence to additional follow-up work to understand the care pathway to success for these patients.

Adults with CP experience a vast array of chronic pain subtypes, spanning nociceptive pain, nociplastic pain, neuropathic pain, and a combination of neuropathic and nociplastic pain. Therefore, increasing clinical awareness and assessment of the heterogeneity of pain subtypes among adults with CP can improve tailoring of pain treatment strategies to individuals and to better analgesic outcomes in this population.

Appendix. Authors

Study Funding

The authors report no targeted funding.

Disclosure

The authors report no disclosures relevant to the manuscript. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.