Phenotypic Characteristics of Chronic Pain and Pain-Related Factors in Gender Minority Persons: A Cross-Sectional Study

Introduction

Although gender minority (GM) persons account for roughly 1.4 million adults in the United States, they remain an understudied population; however, research in this group has been steadily growing.[36] The GM population includes persons with a gender identity or expression that differs from the sex they were assigned at birth. Existing data show higher rates of chronic pain syndromes in GM persons as well as sexual minority persons (those who have non-heterosexual sexual orientations) when compared to heterosexual and cisgender populations.[3, 44, 71] Chronic pain is one of the most prevalent diseases worldwide and leads to substantial disability and enormous socioeconomic costs.[23] Management of chronic pain can be complex and challenging, requiring approaches that address the full burden of the condition to optimize outcomes for patients in primary care and beyond.[50]

Without taking gender into account, patients assigned female sex at birth have been described to experience a higher incidence of most chronic pain syndromes compared to patients assigned male sex at birth.[43, 66] Sex-related pain discrepancies may be explained by differences in sex steroid levels, receptors, and sites of action between persons assigned male or female at birth.[4, 18] In males, higher levels of androgens appear to be protective against chronic pain, and testosterone has been found to have analgesic effects on experimental pain.[5, 12, 34] Conversely, estrogens have been shown to have both analgesic and hyperalgesic effects in humans and animals.[4, 60] The effect of exogenous sex hormone therapy on chronic pain in GM patients receiving gender-affirming hormone therapy (GHT) has yet to be rigorously studied. GHT is a treatment that aims to induce physical changes in patients that align with their gender identity by maintaining hormone levels in the normal physiological range for the target gender.[32] For example, a patient assigned female at birth who identifies as a transgender man and wishes to experience masculinization of their body may undergo masculinizing GHT through the use of testosterone and testosterone-related compounds. Notably, the GM population is made up of a variety of persons with unique gender identities and expressions, all of whom have unique goals for therapy.

There are numerous gaps in the medical literature regarding chronic pain, pain characteristics and phenotype, and the association of chronic pain with gender identity and GHT. To fill these gaps, we sought to conduct a cross-sectional study in GM persons through rigorous pain phenotyping using a validated battery of questionnaires that assess clinical pain, types of chronic pain syndromes, and other pain-related outcome measures, including sleep, physical functioning, and fatigue. Our goal was to identify the prevalence, characteristics, and types of chronic pain in GM individuals and how this may be associated with gender identity and GHT use.

Methods

This cross-sectional study was conducted at the University of Kansas Medical Center from November 2022 to May 2023. Prior to patient enrollment, all study procedures and experimental protocols were approved by the Institutional Review Board at the University of Kansas Medical Center. All participants who met eligibility criteria and were willing to participate in the study provided informed consent electronically to participate in the study.

Participants

Participants were recruited at the Gender Diversity clinic at the University of Kansas Medical Center and the JayDoc Free Health Clinic Gender Affirming Night clinic. Inclusion criteria were GM patients aged 18 years and older who were able to read and understand English and agreed to enrollment and participation in online surveys. Exclusion criteria included non-English reading or speaking and those who declined participation. After screening, informed consent, and enrollment into the study, study participants completed the questionnaires described below via REDCap online survey sent by secure and personalized email link.

Study Procedures and Outcome Measures

Enrolled participants completed questionnaires regarding demographics, GHT usage, concomitant medications, clinical pain assessments, and several self-reported patient outcome measures pertaining to chronic pain and pain-related outcomes.

Self-Reported Patient Outcome Questionnaires

Demographic questionnaire.

The demographic questionnaire obtained information regarding sex assigned at birth, gender identity, age, race/ethnicity, marital status, education level, and history of gender-affirming surgeries. Participants were asked to self-select their gender identity from the following list: “Man”, “Woman”, or “Prefer to self-describe as _______ (e.g., gender fluid, non-binary, agender)”. For analysis purposes, we denoted those who self-selected “man” as transgender men (TGM), those who self-selected “woman” as transgender women (TGW), and the term “gender-expansive” for those participants who self-selected the “Prefer to self-describe as” category and represent those whose gender identity, expression, or experience extends beyond the traditional male–female binary.

Gender Affirming Hormone Therapy (GHT) questionnaire.

The GHT questionnaire collected information on whether or not the participant is currently taking GHT. If the participant answered that they are currently taking GHT, then they were prompted to specify what GHT they are taking (testosterone, estrogen, anti-androgens) and the duration of therapy. For analysis purposes, we recorded participants’ self-listed medications and created two variables based on their answers. We categorized participants into either receiving GHT that is masculinizing therapy (e.g., testosterone) or feminizing therapy (e.g. estrogen, progesterone, anti-androgens).

Presence of Clinical Pain questionnaire.

This questionnaire assessed for the presence of chronic pain by asking, “Do you have pain that is present and has been present for more than half the days in 3 months in one or more locations?”.

The Brief Pain Inventory.

The Brief Pain Inventory was administered to participants who answered “Yes” to the “Presence of Clinical Pain” question to assess pain severity and functional interference due to pain. It is validated for chronic, non-malignant forms of pain, and asks patients to rate their current pain numerical rating scale severity (NRS), as well as their worst, least and average pain in the last 7 days (0-10 on the scale) and has been recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials for the assessment of pain in clinical research.[26]

Location of Chronic Pain and Widespreadedness of Pain.

To assess this outcome, participants used the Michigan Body Map[11] to identify the regions of their body that have chronic pain or to report the absence of chronic pain. We calculated the proportion of participants who reported chronic pain in a total of seven body regions including: A) Left shoulder, left upper arm, left lower arm; B) right shoulder, right upper arm, right lower arm; C) left hip/left buttocks, left upper leg, left lower leg; D) right hip/right buttocks, right upper leg, right lower leg; E) neck, upper back, lower back; F) chest, abdomen; and G) right jaw and left jaw.[40] Furthermore, we identified the proportion of participants who had chronic pain in ≥ 3 regions of the body, the threshold used to define the presence of widespread pain.[40]

Presence of Chronic Overlapping Pain Conditions (COPC) Screener.

The COPC Screener has been recently developed as clinical findings suggest that substantial overlap in rates of co-occurrence and underlying mechanism may exist between common chronic pain conditions, including chronic low back pain, endometriosis, fibromyalgia, irritable bowel syndrome, painful bladder syndrome/chronic prostatitis, myalgic encephalomyelitis/chronic fatigue syndrome, migraine, tension-type headache, temporomandibular disorder, and vulvodynia.[46] The National Institutes of Health recognize these conditions as COPCs. The COPC Screener takes at most 10 minutes to complete and provides data on whether the participant met validated diagnostic criteria for any of the ten COPCs, as well as providing information on the total number of COPCs each participant met criteria for.

2016 American College of Rheumatology Fibromyalgia Diagnostic Criteria Survey Score.

This score is calculated by combining the scores on the Widespread Pain Index and Symptom Severity Scale from the 2016 American College of Rheumatology Fibromyalgia Diagnostic Criteria Survey. This derives a continuous metric indicative of the degree of fibromyalgia-like symptomatology in a given individual and is often used as a surrogate measure of the degree of central sensitization/nociplastic pain in an individual.[68]

The Childhood Traumatic Events Scale.

The Childhood Traumatic Events Scale assesses for a history of early life trauma, including physical and sexual abuse, along with other forms of early trauma, such as a prolonged childhood illness, neglect, or death of a parent.[53] Trauma exposure was assessed with attention to whether participants had disclosed their experience to others. Participants were classified as “trauma with confiding” if they reported sharing details of the event with another person, or as “trauma without confiding” if they reported not disclosing the event. This distinction was made to capture potential differences in coping, social support, and psychological processing associated with disclosure.

PainDETECT.

The PainDETECT[30] is a brief 9-item measure of sensory descriptors, spatial characteristics, and temporal characteristics with demonstrated utility in identifying “central” neuropathic components of pain in low back pain and in osteoarthritis.[33] This tool is useful for distinguishing neuropathic pain from musculoskeletal pain, and is often used as a surrogate marker for the presence of neuropathic pain components. High scores are strongly associated with fibromyalgia.[7]

Patient-Reported Outcomes Measurement Information System (PROMIS).

The PROMIS tools are a valid and reliable way to measure additional pain-related factors associated with chronic pain. PROMIS scores were calculated by taking the raw score and finding the T-score, which can be found at http://www.healthmeasures.net/explore-measurement-systems/promis. The PROMIS-29 v2.0 tools were used to assess pain-related domains of physical functional status, sleep-related impairment, sleep disturbance, fatigue, depression, social participation, and anxiety.[35]

Stress and Catastrophizing.

Two traits known to be associated with pain severity and the progression of chronic pain are stress and catastrophizing. The 10-item Perceived Stress Scale is a validated tool to measure a person’s perceived stress levels, including the degree to which a respondent finds circumstances in their life to be unpredictable, uncontrollable, and/or overwhelming. Higher scores on this scale indicate higher levels of perceived stress.[16] Pain catastrophizing was assessed using the 6-item catastrophizing scale from the Coping Strategies Questionnaire.[56]

The Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults.

The Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults is a 27-item questionnaire validated in both TGM and TGW and was used to assess gender incongruency and associated stress related to gender identity.[20]

The UCLA Loneliness Scale.

This 20-item scale is designed to measure one’s subjective feelings of loneliness and social isolation.[57] Recent research has shown that these two variables may play a role in chronic pain and its outcomes.[42, 67]

The Medical Mistrust Index.

This 17-item survey has been validated to measure mistrust of healthcare organizations and is a robust predictor of underutilization of health services.[41]

Pain Phenotype Differences after April 27, 2023 Missouri Attorney General Emergency Order

On April 27, 2023, the Attorney General of Missouri promulgated an “emergency declaration” that restricted access to gender-affirming medical care for minors and adults in the state of Missouri. Geographically, the University of Kansas Medical Center exists near the state line where Kansas and Missouri border one another. The University of Kansas Medical Center serves a large population of patients residing in either Kansas or Missouri. Thus, the emergency order enacted in Missouri is relevant as our institution is located in the State of Kansas, which does not have an order restricting access to gender-affirming medical care for adults. After the Missouri order was enacted, patients from across the state sought care at our institution. As this event occurred during the enrollment period for our study, we sought to investigate whether this restrictive policy had any effect on the outcomes of interest in our study related to pain and pain phenotype. A variable indicating if the participant completed the survey before or after the Attorney General order was created.

Statistical Analysis Methods

All statistical analyses were performed using SAS Version 9.4 (SAS Institute, Inc, Cary, NC). Differences in demographic and pain characteristics by gender identity were evaluated using Chi-square or Fisher’s exact tests for categorical variables, and ANOVA for continuous variables. A multivariable logistic regression model was used to identify unique phenotypic differences between those with and without a history of chronic pain. Sensitivity analyses were performed to identify if pain characteristics differed based on type of GHT (masculinizing therapy vs feminizing therapy). Differences in pain before and after the Missouri Attorney General order were evaluated using Chi-square/Fisher’s exact and independent samples t-tests for categorical and continuous variables, respectively. Cases with missing data were excluded from analyses involving those variables. The proportion of missing data was minimal (<6%), and no systematic pattern of missingness was observed.

Results

Participants

A total of 178 persons were assessed for eligibility. All were eligible for enrollment into the study; 103 participants signed the informed consent and completed online questionnaires. Demographic characteristics of our cohort stratified by Gender Identity are described in Table 1. The study cohort consisted of 29 TGM, 50 TGW, and 24 gender-expansive persons (all assigned female at birth). Enrolled participants were predominantly white and non-Hispanic. Most (n=96, 93.2%) of the study cohort were taking GHT at the time of survey, with a mean duration of GHT of 799 days. 15.5% of all participants reported previous gender-affirming surgeries, and there were no statistically significant differences in a history of gender-affirming surgery between gender identity groups (p=.57). Bivariate analyses between gender identity groups revealed that age, race, education, and relationship status were statistically significantly different. Directionalities of statistically significant differences between gender identity groups are presented in Table 1.

Table 1.

Demographic Characteristics by Gender Identity.

	Transgender Men (N=29)	Transgender Women (N=50)	Gender-Expansive (N=24)	P-value
Age (mean ± SD)	26.1 ± 7.9	34.7 ± 12.8	24.9 ± 5.5	<.000*a
Ethnicity (N(%))				.055
Not Hispanic or Latinx	27 (93)	47 (94)	24 (100)
Hispanic or Latinx	1 (3.5)	2 (4)	0 (0)
Unknown	1 (3.5)	1 (2)	0 (0)
Race (N(%))				<.000*b
White	28 (96.5)	47 (94)	18 (75)
Black or African American	0 (0)	1 (2)	2 (8.3)
Native Hawaiian or Other Pacific Islander	1 (3.5)	0 (0)	0 (0)
Asian	0 (0)	0 (0)	1 (4.2)
Other	0 (0)	1 (2)	3 (12.5)
Unknown	0 (0)	1 (2)	0 (0)
Education (N(%))				<.000*c
Some High School	0 (0)	1 (2)	1 (4.2)
High School Graduate or GED	8 (27.6)	10 (20)	5 (20.8)
Some College	10 (34.5)	15 (30)	8 (33.3)
Technical/Associates Degree	5 (17.2)	6 (12)	2 (8.4)
Bachelor’s Degree	4 (13.8)	13 (26)	8 (33.3)
Advanced Degree	2 (6.0)	5 (10)	0 (0)
Relationship Status (N(%))				<.0001*d
Married	5 (17.2)	14 (28)	4 (16.7)
Never Married	14 (48.3)	20 (40)	9 (37.5)
Divorced	0 (0)	6 (12)	0 (0)
Separated	0 (0)	1 (2)	1 (4.2)
Widowed	0 (0)	1 (2)	0 (0)
Committed Partnership	10 (34.5)	7 (14)	5 (20.8)
Prefer not to answer	0 (0)	1 (2)	5 (20.8)
Gender affirming surgery – Yes (N(%))	6 (20.7)	6 (12.0)	4 (16.7)	0.57

p-values from Chi-square or Fisher’s exact tests for categorical variables and ANOVA for continuous variables

^*Denotes statistical significance

^aPairwise comparisons found transgender women were significantly older than transgender men and gender-expansive participants (Tukey-adjusted p <0.05)

^bStandardized residuals identified that individuals in the gender-expansive group were significantly underrepresented among White participants and over-represented among those identifying as other race

^cExamination of standardized residuals indicated that no individual cell differed significantly from expected counts

^dStandardized residuals identified that transgender men were more likely to report living with a partner, transgender women were more likely to be divorced, and participants in the gender-expansive group were more likely choose “prefer not to answer.”

Pain Phenotype and Patient Characteristics by Gender Identity

Table 2 details the data on phenotypic pain characteristics between different gender identities. About 59% (n=17) of TGM, 54% (n=13) of gender-expansive persons, and 40% (n=20) of TGW reported having the presence of chronic pain, however this did not significantly differ between groups (p=.23). Worst pain severity scores as measured by the Brief Pain Inventory was found to be statistically significantly different between gender identity groups, with TGM having higher pain severity ratings than TGW (p=.007). Pain interference as measured by the Brief Pain Inventory was found to be notably higher in TGM and gender-expansive persons when compared to TGW (p=.007). Fibromyalgianess, as measured by the 2016 Fibromyalgia Diagnostic Criteria Survey score, and perceived stress levels, as measured by the Perceived Stress Scale, were significantly higher in TGM and gender-expansive persons compared to TGW (p=.008 and p=.03, respectively). PainDETECT measurements of neuropathic pain were significantly higher in TGM as compared to TGW (p=.01). Pain catastrophizing scores from the 6-item catastrophizing scale from the Coping Strategies Questionnaire were not significantly different amongst gender identity groups (p=.18).

Table 2.

Chronic Pain and Pain-Related Phenotypic Characteristics by Gender Identity

	Transgender Men (N=29)	Transgender Women (N=50)	Gender-Expansive (N=24)	P-value
Presence of Clinical Pain – Yes	17 (59)	20 (40)	13 (54)	.23
Pain Severity – Worst	7.1 ± 2.3	5.1 ± 1.8	6.6 ± 1.1	.007*a
Pain Interference	2.9 ± 2.7	1.4 ± 1.9	2.8 ± 2.3	.007*a,b
FM Criteria Survey Score	11.8 ± 6.5	7.7 ± 6.0	11.5 ± 6.7	.008*a,b
PainDETECT	11.3 ± 9.7	5.7 ± 6.8	8.3 ± 7.3	.01*a
Perceived Stress Scale	24.2 ± 8.7	20 ± 7.6	24.3 ±7.1	.03*a,b
Pain Catastrophizing	11.2 ± 9.2	7.7 ± 8.7	10.7 ± 9.3	.18
Medical Mistrust	43.7 ± 7.3	43.9 ± 3.1	44.5 ± 2.8	.8
UCLA Loneliness Scale	48.0 ± 13.1	51.5 ± 12.5	49.7 ± 9.4	.65
Childhood Traumatic Events Scale
Score	16.2 ± 11.8	10.6 ± 9.16	12.2 ± 8.7	.06
Category (N (%))				<.0001*c
No Trauma	5 (17.2)	5 (10)	1 (4.2)
Mild Trauma	4 (13.8)	21 (42)	9 (37.5)
Trauma, with confiding	5 (17.2)	1 (2)	0 (0)
Trauma, without confiding	15 (51.8)	23 (46)	14 (58.3)
GIDYQ-AA	1.9 ± .3	2.0 ± .4	2.4 ± .4	<.0001 *a,b,d
PROMIS Depression	60.4 ± 8.9	58.3 ± 9.1	60.9 ± 6.6	.39
PROMIS Anxiety	64.4 ± 8.5	60.2 ± 8.9	61.5 ± 6.71	.098
PROMIS Physical Functioning	46.2 ± 8.03	49.5 ± 8.7	45.3 ± 6.9	.07
PROMIS Sleep-Related Impairment	63.2 ± 8	54.6 ± 10.2	61.1 ± 6.7	.0001*a,b
PROMIS Sleep Disturbance	59.3 ± 7.6	53.2 ± 7.3	57.2 ± 6.6	.001*a
PROMIS Fatigue	61.0 ± 9.4	53.3 ± 10.5	60.2 ± 7.2	.001*a,b
PROMIS Social Participation	45.8 ± 10.8	48.2 ± 9.1	44.4 ± 7.8	.23

FM: Fibromyalgia; GIDYQ-AA: The Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults; COPCs: Chronic Overlapping Pain Conditions

Values are frequency and percent for Presence of Clinical Pain and Childhood Traumatic Events Scale category; mean and standard deviation for all other variables.

p-values from Chi-square or Fisher’s exact tests for categorical variables and ANOVA for continuous variables

^*Denotes statistical significance

^aStatistically significant difference between transgender men and transgender women

^bStatistically significant difference between transgender women and gender-expansive group

^cTransgender men had significantly less mild trauma than expected, and significantly more trauma with confiding than expected

^dStatistically significant difference between transgender men and gender-expansive group

Medical mistrust, as measured by the Medical Mistrust Index, and loneliness, measured by the UCLA Loneliness Scale, were not found to be statistically significantly different between gender identity groups. Gender incongruence as measured by the Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults was found to be statistically significantly different by gender identity (p=<.0001), with differences found between TGM and TGW, TGW and gender-expansive persons, and TGM and gender-expansive persons. Amongst these comparisons, TGM had higher levels of gender incongruence compared to TGW and gender-expansive persons and TGW had higher levels of gender incongruence compared to gender-expansive persons. Mean scores for the Childhood Traumatic Events Scale were not found to be statistically significantly different among gender identity groups. However, categorically the scores were significantly different among gender identity groups, with TGM having significantly less mild trauma than expected and significantly more trauma with confiding than expected (p=<.0001).

PROMIS measures for depression, anxiety, physical functioning, and social participation were not found to differ between gender identity groups. Increased sleep-related impairment and fatigue scores as measured by PROMIS were identified in TGM and gender-expansive persons compared to TGW (p=.0001 and p=.001, respectively). TGM reported higher levels of sleep-related disturbance than TGW (p=.001).

Pain Regions and Widespreadedness of Pain by Gender Identity

Chronic pain in the spine region (neck, upper back, and lower back) was the most prevalent region of pain that patients in this cohort identified, with TGM reporting 48.3% (n=14), TGW reporting 52% (n=26), and gender-expansive persons reporting 58.3% (n=14). There was no significant difference between gender identity groups for pain reported in the neck, upper back, and lower back (p=.76). Widespread pain, defined as pain in 3 or more regions of the body, was noted in 37.9% of TGM, 36% of TGW, and 45.8% of gender-expansive persons and was not found to be significantly different between gender identity groups. There was a meaningful difference in the prevalence of jaw pain between gender identity groups, with TGM and gender-expansive persons having a higher prevalence of jaw pain compared to TGW (p=.003). All other regions of pain had nonsignificant differences between gender identity groups (Table 3).

Table 3.

Chronic Pain Reported by Body Region, Stratified by Gender Identity.

Body Regions (N(%))	Transgender Men (N=29)	Transgender Women (N=50)	Gender-Expansive (N=24)	P-value
Left shoulder, upper arm, lower arm	10 (34.4)	13 (26)	7 (29.2)	.73
Right shoulder, upper arm, lower arm	7 (24.1)	13 (26)	8 (33.3)	.73
Left hip/buttocks, upper leg, lower leg	8 (27.6)	20 (40)	8 (33.3)	.53
Right hip/buttocks, upper leg, lower leg	9 (31)	12 (24)	8 (33.3)	.65
Neck, upper back, lower back	14 (48.3)	25 (52)	14 (58.3)	.76
Chest, abdomen	7 (24.1)	16 (32)	11 (45.8)	.24
Right jaw, left jaw	5 (17.2)	3 (6)	9 (37.5)	.003*a
Widespread pain	11 (37.9)	18 (36)	11 (45.8)	.71

p-values from Chi-square or Fisher’s exact tests

^*Denotes statistical significance

^aTransgender women and gender-expansive group had more pain than expected

Chronic Overlapping Pain Conditions by Gender Identity

The mean total number of COPCs present, as measured by the COPC Screener, differed significantly between gender identity groups, with TGM and gender-expansive persons having higher numbers of COPCs compared to TGW (p=.01). The prevalence of meeting criteria for 2 or more COPCs was higher among TGM and gender-expansive persons compared to TGW (p= 0.05).

The COPC Screener utilizes branching logic from the Michigan Body Map to guide participants to take specific COPC diagnostic criteria based on the area of the body map where they indicated pain. As such, we were unable to report true prevalence data for each COPC among the cohort. For the 102 participants who took the chronic low back pain diagnostic criteria, 40.2% met criteria for the diagnosis (n=41) and when stratified by gender identity, TGM and gender-expansive persons had increased presence of chronic low back pain compared to TGW; however, this did not reach statistical significance (p=.13). The entire cohort of participants took the 2016 Fibromyalgia Diagnostic Criteria survey. A total of 15.5% (n=16) of all participants met criteria for the diagnosis of fibromyalgia, with a statistically significant difference between gender identity groups, where gender-expansive persons and TGM had higher diagnosis of fibromyalgia than TGW (p=.015). Of all COPCs other than fibromyalgia, only temporomandibular disorder was found to be significantly higher in TGM and gender-expansive persons compared to TGW. Interestingly, among participants who took the validated questionnaire for myalgic encephalomyelitis/chronic fatigue syndrome, 92.9% of TGM, 62.5% of gender-expansive persons, and 87.5% of TGW were found to meet the criteria for this diagnosis, however there were no significant differences between gender identity groups (Table 4). The total number of COPCs each participant had was also found to be significantly higher in TGM and gender-expansive persons compared to TGW. Additional data and analyses from the COPC Screener are reported in Table 4.

Table 4.

Presence and Frequency of Chronic Overlapping Pain Conditions by Gender Identity.

Chronic Overlapping Pain Condition (N(%))	Transgender Men (N = 29)	Transgender Women (N = 50)	Gender-Expansive (N = 24)	P-value
Chronic Low Back Pain	16 (55.7)	16 (32)	9 (39.1)	.13
Endometriosis	1 (33.3)	0 (0)	2 (66.7)	N/A
Fibromyalgia	5 (17.2)	5 (10)	6 (25)	.015*a
Irritable Bowel Syndrome	8 (42.1)	6 (21.4)	6 (37.5)	.23
Interstitial Cystitis/Painful Bladder Syndrome	6 (54.6)	5 (38.5)	5 (45.5)	.73
Chronic Prostatitis	0 (0)	2 (15.4)	0 (0)	N/A
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome	13 (92.9)	7 (87.5)	5 (62.5)	.17
Migraine Headache	6 (20.7)	5 (10)	5 (21.7)	.30
Tension Type Headache	1 (3.45)	1 (2)	1 (4.35)	.84
Temporomandibular Disorder	6 (20.7)	2 (4)	7 (30.4)	.007*a
Vulvodynia	2 (15.4)	0 (0)	4 (36.4)	.24
Total Number of COPCs (mean ± SD)	2.2 ± 2.3	1.0 ± 1.5	2.1 ± 2.2	.01*b
Number of COPCs (N (%))				.05
0	7 (24.1)	27 (54)	7 (29.1)
1	8 (27.6)	12 (24)	7 (29.2)
2-10	14 (48.3)	11 (22)	10 (41.7)

COPC: Chronic Overlapping Pain Condition

p-values from Chi-square or Fisher’s exact tests for categorical variables and ANOVA for continuous variables

N/A p-values are a result of row or column sums of 0, therefore Chi-square tests are unable to be computed.

^*Denotes statistical significance

^aTransgender women had significantly less than expected, gender-expansive had significantly more than expected

^bStatistically significant difference between transgender men and transgender women

Predictors of the Presence of Chronic Pain

Results from a multivariable logistic regression model conducted to assess the unique phenotypic differences between those with the presence of chronic pain and those without are presented in Table 5. In this model, gender identity, use of GHT, perceived stress levels as measured by the Perceived Stress Scale, medical mistrust as measured by the Medical Mistrust Index, and loneliness as measured by the UCLA Loneliness Scale were included with the presence of chronic pain as the outcome. Of these variables, higher levels of perceived stress were associated with the presence of chronic pain (OR = 1.10 [95% CI 1.03-1.18], p = .007).

Table 5.

Multivariable Logistic Model Used to Assess the Unique Phenotypic Differences Between Those With A History of Chronic Pain and Those Without

Variable	Chronic Pain (N=50)	No Chronic Pain (N=53)	Standard Error	OR (95% CI)	P-value
Gender Identity [n (%)]
Expansive	13 (26.0)	11 (20.8)	.4	.88 (.20-3.81)	.87
TGW	20 (40.0)	30 (56.6)	.5	.75 (.08-6.87)	.80
TGM (ref)	17 (34.0)	12 (22.6)		-
GHT1 [n (%)]
Feminizing	24 (50.0)	15 (31.2)	.5	.73 (.10-5.22)	.75
Masculinizing (ref)	24 (50.0)	33 (68.8)		-
Perceived Stress Scale [mean ± SD2]	24.8 ± 7.7	19.7 ± 7.6	.04	1.1 (1.03-1.18)	.007*
UCLA Loneliness Scale [mean ± SD2]	52.7 ± 10.2	48.2 ± 13.2	.02	1.01 (.97-1.06)	.63
Medical Mistrust Index [mean ± SD2]	43.3 ± 5.6	44.6 ± 3.4	.07	.93 (.81-1.07)	.30

OR=Odds Ratio; CI=Confidence Interval; TGW=transgender woman; TGM=transgender man; GHT=gender-affirming hormone therapy

¹n=7 missing type of GHT

²Unit increase=1

^*Denotes statistical significance

p-values from multivariable logistic regression models

Pain Phenotype Differences by GHT Type

Findings from these analyses in participants who reported that they were currently taking GHT were similar in nature to the findings presented above, which is logical given our TGM and gender-expansive groups were all assigned female at birth and taking masculinizing therapy and our TGW group was taking feminizing therapy. These sensitivity analyses and results are presented in Supplemental Tables 1-3.

Pain Phenotype Differences after April 27, 2023 Missouri Attorney General Emergency Order

While most phenotypic characteristics showed no significant differences in participants who took the questionnaire before or after the Attorney General ruling, there were a few notable differences (Supplemental Table 4). The PainDETECT score was noted to be significantly higher after the Attorney General order when compared to before (p=.02), indicating higher levels of neuropathic pain symptoms. Anxiety as measured by PROMIS was noted to be statistically significantly higher after the Attorney General order when compared to before (p=.03).

Discussion

Our findings show a high burden of chronic pain in our study population of GM adults with prevalence that ranges from 40-59%, exceeding the chronic pain prevalence in the general population which has been reported at ~20% of adults in the United States.[55, 69]

Extant literature supports high rates of chronic pain syndromes in the GM population, although very few studies exist.[3, 24, 44] A recent study by Tabernacki et al estimating incidence rates of chronic pain in GM persons from a large aggregate of EMR data (N=56,470 TGM and 41,882 TGW) showed significantly higher rates of chronic pain syndromes among GM persons compared with cisgender counterparts.[61] Overall, the study found that both TGM and TGW, whether naïve to or on GHT, showed higher chronic pain prevalence compared to cisgender controls. However, the study did not investigate the difference in the likelihood of chronic pain occurrence between TGM and TGW, nor did the authors stratify chronic pain by specific body regions or types of chronic pain conditions. [61]

In the analysis of body regions where our participants reported chronic pain, we noted that approximately 50% experienced pain in the spine region, including the cervical, thoracic, and lumbar spine areas. This data is similar to the findings in The PRIDE Study, where pain in the spine region was found to be of highest prevalence, with approximately 50% of participants endorsing spine pain.[13] Compared to the total lifetime prevalence of chronic spine pain in the general population at ~13%[59], our data suggest a higher burden of chronic spine-related pain in GM persons. An increased burden of spine pain in gender minorities may reflect differences in biopsychosocial and structural determinants of health. Chronic exposure to stigma, discrimination, and identity-related stress may activate neuroendocrine and inflammatory pathways that heighten pain sensitivity and promote central sensitization.[22, 25, 28] Barriers in accessing healthcare can contribute to delayed diagnosis and undertreatment of spine conditions, which could reinforce chronicity. Although the biomechanics of spine pain in gender minorities remain understudied, hormonal influences on bone density, ligament laxity, and muscle mass have been documented in transgender populations and may plausibly impact spinal integrity.[19, 63, 65]

Common chronic pain syndromes reported in the GM population include COPCs such as migraine headaches, fibromyalgia, and chronic pelvic pain as well as other conditions such as chronic breast pain, musculoskeletal pain, and abdominal pain.[3] In a study of 115 GM participants by Levit et al, 17 (14.8%) fulfilled criteria for diagnosis of fibromyalgia, where the rate amongst TGM was 19.4% and 6.98% in TGW.[44] These findings are comparable to the findings in our study, where we found that 17.2% of TGM, 25% of gender-expansive persons, and 10% of TGW met criteria for the diagnosis of fibromyalgia. Similarly, the difference in the presence of FM in our cohort between gender identity groups was found to be higher in TGM and gender-expansive persons compared to TGW. Our study is the first to report on the presence of other COPCs besides fibromyalgia in the GM population using the validated COPC Screener. One caveat of using the COPC Screener is that true incidence data for each COPC could not be calculated from the COPC Screener, as its branching logic administered the validated diagnostic criteria for specific COPC only to persons who marked pain in certain regions of the body associated with each COPC.

The findings of higher chronic pain and COPC prevalence, as well as more severe pain phenotypes, in GM persons assigned female at birth compared to TGW are thought-provoking. Although the effects of estradiol and progesterone on pain are relatively complex – both having been described to exert pro-nociceptive and anti-nociceptive effects on pain – testosterone has historically been described as anti-nociceptive and protective against pain in nature.[17] This knowledge may present a conundrum, given the contrary nature of our findings. It has been suggested that the increased prevalence of fibromyalgia in TGM compared to TGW may be attributed to exposure of the central nervous system to female hormones during development in utero.[44] The onset of puberty may also play a role. Before puberty, boys and girls report similar pain prevalence; however, after puberty, rates of chronic pain syndromes rise sharply in girls compared to boys.[43] Ultimately, the results of our study and others require additional prospective work aimed at identifying the true impact of GHT on pain in GM persons, with data interpretations recognizing the contributions of stress, developmental influences, psychosocial factors, and the intersectionality of these constructs.

Minority stress refers to distinct chronic stressors experienced by individuals from marginalized groups due to their identities, and can collectively increase the burden of psychological stress over time.[62] Sustained exposure to these unique stressors has been linked to various adverse health outcomes in GM persons, including mental health disorders and chronic pain conditions.[21, 48, 49, 71] While this investigation did not specifically interrogate the effects of minority stress, our results from the Perceived Stress Scale highlight that the increased prevalence of chronic pain in this population was, at least in part, driven by the compounded effects of experienced stress, as sustained psychological distress can predict chronic pain[9], precipitate stress-induced hyperalgesia[28, 39, 47, 72], and contribute to the development or worsening of chronic pain conditions.[58] GM individuals also experience significantly higher rates of adverse childhood experiences, trauma, and PTSD than the general population[14, 29, 38, 64] – all factors that have been linked to the development of chronic pain conditions.[1, 2, 6, 8, 31, 51, 54, 70] These stressors can disrupt the nervous, immune, and metabolic systems, leading to extensive long-term health consequences.[1, 2, 6, 8, 31, 54, 70]

Fatigue and sleep can impact the experiences of chronic pain. Chronic pain is frequently associated with chronic fatigue, characterized by a profound sense of exhaustion.[37] Fatigue can be multifactorial, involving relationships with lifestyle habits, medical conditions, and psychological stress.[27] There is substantial evidence of a reciprocal relationship between sleep and pain, with studies showing that sleep disturbances predict the onset of new pain and worsening of chronic pain.[10, 45, 52] In males, poorer sleep quality is associated with lower testosterone concentrations.[15] In females, sex steroid levels are characterized by monthly cycles in addition to pregnancy and menopause. The transition to menopause/post-menopause with decreasing hormone levels often leads to worse sleep disturbances.[52] Our finding of increased sleep disturbances in TGM and gender-expansive persons is consistent with prior research, as these individuals were experiencing a decrease/suppression of estrogen/progesterone and a higher than genetically programmed baseline testosterone level.

Limitations

A limitation of the present study includes its cross-sectional design, and as such, we w unable to draw inferences on when the chronic pain developed - either pre- or post-initiation of GHT or gender-affirming surgeries. In addition, our study did not include cohorts of cisgender men and women for comparison with our GM data. Our sampling was limited to GM individuals who accessed care, potentially excluding those unable or unwilling to seek care. Furthermore, we are unable to conclude the true prevalence of each COPC for the cohort due to the nature of the COPC Screener logic. Moreover, besides the GIDYQ-AA questionnaire, the pain phenotype outcome measures used in this study have yet to be validated specifically for the GM population. We are also unable to identify how the type of GHT being used, either masculinizing or feminizing therapy, impacted the presence and characteristics of chronic pain, as 98% of our cohort had been taking GHT for various lengths of time at the time of questionnaire administration.

Another limitation is the inability to assess how the studied phenotypic variables or other additional factors, such as intersectionality, have contributed to chronic pain and widespread pain in our GM population. For example, it remains unclear whether the elevated pain levels observed in GM individuals were attributable to specific stressors, such as minority stress, or to general stress. Moreover, our study did not assess ongoing trauma in adulthood, which may have also impacted the observed outcomes. Grouping all ‘other’ genders into a single category may have obscured important distinctions, particularly between binary and non-binary identities.

While our research team includes persons who identify as cisgender and heterosexual, those who identify as LGBTQIA+, as well as those who do and don’t experience chronic pain, we recognize that the positionalities of our team would be through community engagement and/or the inclusion of persons with lived experience in all aspects of this study. Future work will incorporate these elements to strengthen our commitment to transparently reporting our equity-focused work.

Conclusion

This investigation endorses higher rates of chronic pain, chronic widespread pain, and nociplastic pain conditions in GM persons compared to general US population data, which is presumably mostly cisgender. Our data support the need for comprehensive studies to clarify the mechanisms of increased pain prevalence and nociplastic pain in GM populations. Furthermore, studies on the impact of GHT on pain and pain characteristics in GM persons using a rigorous prospective design are warranted. Future studies are planned to elucidate how a variety of biopsychosocial mechanisms and GHT may influence chronic pain in GM persons.