Post-Amputation Pain: Comparing Pain Presentations between Adults with and without Increased Amputated-Region Sensitivity

Abstract

Objective:

Among adults with persistent post-amputation pain, increased amputated-region pain sensitivity may reflect peripheral sensitization or indicate underlying central sensitization. To determine whether underlying central sensitization may contribute to increased pain sensitivity in this population, this study compared clinical signs and symptoms associated with central sensitization between adults with post-amputation pain who demonstrate or lack increased amputated-region sensitivity (as compared to reference data).

Design:

Cross-sectional.

Subjects:

99 adults (60 with a unilateral, transtibial amputation and post-amputation pain, 39 pain-free controls with intact limbs).

Methods:

Participants underwent pain-pressure threshold testing of amputated-region and secondary (non-amputated-region) sites and completed outcome measures assessing central sensitization symptoms (Patient-Reported Outcomes Measurement Information System® pain intensity and interference domains, Central Sensitization Inventory). Among the full sample, the presence and frequency of specific central sensitization symptoms were evaluated. Participants with post-amputation pain were then grouped based on whether normalized, amputated-region pain-pressure thresholds fell below (i.e., sensitive) or above (i.e., non-sensitive) the 25^th percentile of sex-specific reference data. Between-group differences in normalized secondary-site sensitivity were evaluated using a multivariate analysis of variance; central sensitization symptom scores were compared using a Kruskal-Wallis test.

Results:

Noteworthy symptoms associated with central sensitization (e.g., fatigue, sleep disturbance, cognitive difficulty) were reported by 33–62% of participants. Secondary-site pain sensitivity was greater among individuals with increased amputated-region sensitivity (n=24) compared to peers without increased amputated-region sensitivity [(n=36), mean difference >1.33 standard deviation (SD), p<.001]. Central sensitization symptom scores, however, were similar between groups (p>0.187).

Conclusions:

Participants with increased amputated-region sensitivity demonstrate generalized, secondary-site pain hypersensitivity, potentially indicating underlying central sensitization. Central sensitization symptom scores, however, were similar between groups, suggesting differences in physiological pain sensitivity may not manifest in subjective post-amputation pain descriptions.

Introduction

Persistent post-amputation pain affects over 50% of adults with lower-limb loss¹ and includes both phantom (i.e., pain perceived as coming from the amputated portion of the limb) and residual limb pain (i.e., pain in the remaining portion of the limb).² While the exact mechanisms underlying phantom and residual limb pain remain unknown, persistent post-amputation pain has been attributed to maladaptive physiological changes in the peripheral and central nervous systems, resulting in increased transmission, perception, and maintenance of pain signals from the amputated region.³ Peripheral sensitization, i.e., increased sensitivity of peripheral neural structures, may be a consequence of surgical nerve resection within the amputated limb.^{3, 4} Relatedly, central sensitization⁵ describes the amplification and reduced inhibition of pain signals at the level of the spinal cord and/or brain and may be contribute to post-amputation pain persistence.^{6, 7}

The degree to which peripheral and/or central sensitization contribute to persistent post-amputation pain remains unclear.³ Sustained abnormalities in peripheral nerve signaling may drive pain persistence, without additional contributions from the central nervous system.⁷ Prolonged peripheral sensitization, however, may also give rise to overarching changes in central nervous system function,⁴ resulting in centrally-maintained pain even after aberrant peripheral input has normalized. Prior studies have investigated post-amputation pain contributions from either peripheral^8–10 or central^11–13 sources in isolation, without considering the potential interaction of the peripheral and central nervous systems in maintaining persistent post-amputation pain.

Persistent post-amputation pain appears to have peripheral contributions, as individuals with post-amputation pain demonstrate greater amputated-region pain sensitivity than pain-free peers with and without limb loss.¹⁴ Furthermore, phantom limb pain has been shown to improve following dorsal root ganglion injections,⁸ and associations have been identified between pre-amputation limb pressure sensitivity and early post-amputation pain severity.¹⁵ What is less known, however, is whether amputated-region sensitivity reflects patterns of peripheral sensitization in isolation, or if it may reflect underlying central sensitization among individuals with post-amputation pain.

Clinically, identifying the source(s) of heightened pain sensitivity may aid decision-making regarding appropriate therapeutic interventions. For example, patients who demonstrate increased amputated-region sensitivity in isolation, without concomitant signs and symptoms of central sensitization, may benefit from locally-targeted treatment in isolation (e.g., desensitization exercises).¹⁶ In contrast, patients with post-amputation pain who demonstrate signs of peripheral and central sensitization may benefit most from multidisciplinary, locally- and centrally-targeted treatment (e.g., desensitization exercises¹⁶ combined with pain neuroscience education,¹⁷ graded exercise and activity,¹⁸ or pharmacological agents targeting reduced nervous system sensitivity¹⁹).

Direct evaluation of central neuronal sensitivity is not feasible in humans, making identification of central sensitization difficult.⁶ Pain-pressure thresholds (.e., thresholds at which applied pressure becomes painful²⁰), however, may be used as clinical, surrogate measures of neuronal sensitivity, and patterns may differentiate peripheral versus central sensitization. In comparison to pain sensitivity values from healthy control populations, peripheral sensitization may be suggested by increased pain sensitivity within primary (i.e., amputated-region) sites, while central sensitization may be suggested by generalized pain sensitivity in both primary and secondary (i.e., non-amputated-region) sites.²¹ Furthermore, self-reported outcome measures evaluating symptoms associated with underlying central nervous system hypersensitivity may help identify central sensitization. For example, the Central Sensitization Inventory (CSI²²) evaluates the frequency of symptoms associated with central sensitization (e.g., fatigue, sleep disturbance, widespread pain) and has been shown to discriminate between patients with and without clinical diagnoses hallmarked by central sensitization (e.g., fibromyalgia, chronic fatigue syndrome).²³ While a potentially useful tool for identifying patients with post-amputation pain associated with central sensitization, the psychometric properties of the CSI have not yet been evaluated among individuals with post-amputation pain.

The objective of this study was to compare (a) physiological signs of central sensitization (i.e., increased secondary-site pain sensitivity) and (b) self-reported symptoms of central sensitization (i.e., increased pain intensity and interference, higher CSI scores) between adults with post-amputation pain who have and do not have increased amputated-region sensitivity (as compared to a reference sample without limb loss). When compared to peers without increased amputated-region sensitivity, we hypothesized adults with post-amputation pain and increased amputated-region sensitivity would demonstrate (a) greater secondary-site pain sensitivity and (b) higher pain intensity, pain interference, and CSI scores, indicating underlying central sensitization. A secondary objective of this study was to evaluate the frequency of CSI symptoms and establish CSI test-retest reliability among adults with post-amputation pain. We hypothesized CSI symptoms would be reported frequently by adults with post-amputation pain and test-retest reliability would be good-to-excellent.

Methods

This study was a secondary analysis of a cross-sectional study conducted from February of 2018 to December of 2020. Participants were recruited via the University of Delaware Multidisciplinary Limb Loss Clinic, local community events and prosthetic clinics, and the 2018 and 2019 Amputee Coalition National Conferences.

Participants included 60 adults ≥1-year post-unilateral, transtibial amputation who experienced persistent post-amputation pain. To create a reference group for evaluating normative limb sensitivity, 39 age-matched, pain-free controls (i.e., adults with intact limbs without pain in the low back, legs, ankles, or feet) were also recruited. Exclusion criteria for all participants included presence of a significant neuromuscular condition affecting sensation (e.g., Multiple Sclerosis, Parkinson’s Disease), impaired skin integrity, and acute illness. Finally, as this analysis was part of a larger study evaluating sensory testing and mobility following limb loss, exclusion criteria specific to participants with lower-limb loss included <8 hours of prosthesis use per day and use of more than a single cane for mobility. All participants signed written informed consent documents approved by the University of Delaware Institutional Review Board for Human Subjects Research.

Standardized interviews were conducted by trained examiners to obtain pain-related, demographic, and amputation-specific characteristics. Participants were asked about the presence of phantom and/or residual limb pain; if present, participants were asked to rate their current pain intensity, as well as lowest and highest pain intensity in the previous 24 hours, on a numeric pain rating scale (0=no pain, 10=worst pain imaginable²⁴).

Pain-related Outcome Measures

Participants independently completed pain-related outcome measures including the CSI and Patient-Reported Outcomes Measurement Information System®−29 item v2.0 (PROMIS-29).⁶ Pain-related outcome measures were completed prior to PPT testing to reduce ordering bias.

The CSI is comprised of two Parts: Part A, which is scored, and Part B, which is not scored (and was consequently not evaluated as part of this study). Part A is a 25-item assessment of the frequency of central sensitization-related symptoms (0=never to 4=always), and the maximum score is 100 points.²⁵ Previously, scores ≥40 points have been shown to identify patients with underlying central sensitization.²⁶ More recently, the following central sensitization symptom severity sub-classifications have been proposed: 0–29 = subclinical, 30–39 = mild, 40–49 = moderate, 50–59 = severe, and ≥60 = extreme.²⁷

The PROMIS-29 is a reliable [intraclass correlation coefficient (ICC)=0.82–0.87] and valid norm-based measure evaluating various domains of self-reported mental, physical, and social function.^{28, 29} The PROMIS-29 Pain Interference domain, an assessment of the degree to which pain interferes with daily activities,²⁸ was evaluated for this study and is scored on a T-score scale (mean T-score of the general population=50; standard deviation=10). Finally, the PROMIS-29 Pain Intensity domain was assessed, which asks participants to rate their average pain in the past 7 days on a scale of 0=no pain to 10=worst imaginable pain.²⁸

Pain-pressure Threshold Assessment

Trained examiners assessed PPTs using a calibrated Pain Test^™ FDX Algometer (Wagner Instruments, Greenwich, CT). Reliability and validity (against force plate measurements) have been previously reported for algometer-based PPT assessments.³⁰ Standardized testing procedures³¹ were used at each site, where examiners increased pressure at a rate of 1.00 kilograms-of-force per cubic-centimeter (kgf/cm³) per second until the participant first experienced pain, signaled by the participant saying “stop.” Participants were blinded to algometer output to reduce testing bias, and testing order was randomized by limb to reduce procedural bias. Procedures were repeated 3 times per site, with approximately 10 seconds of rest between trials, and trials were averaged at each of the 10 total sites: bilateral (a) greater trochanters, (b) lateral thighs, i.e., 5 inches distal to the greater trochanter; (c) lateral femoral epicondyles; (d) patellar tendons; and (e) lateral humeral epicondyles.

Central Sensitization Inventory Test-Retest Reliability

After completing the in-person evaluation, participants with lower-limb loss were provided with a second copy of the CSI and instructed to repeat the questionnaire within 7–10 days of their evaluation. To facilitate questionnaire return, questionnaires were provided in a postage-paid and addressed return envelope. Participants who did not return their repeat questionnaire were contacted up to three times in the attempt to minimize missing data.

Statistical Analysis

Prior to performing statistical analyses, questionnaire and PPT data were examined for missing data. Participants who did not return CSI questionnaires (n=14) were excluded from test-retest reliability assessments. For participants missing ≤25% of the total CSI items (i.e., <5 missing items), person-mean imputation³² was used, where the participant’s missing items were inferred as the mean of all non-missing items for that same participant. For PPT data, participants missing ≥2 of the 3 trials for any given site were excluded from analyses, whereas valid trials were averaged for participants with 2–3 trials at each site.

All statistical analyses were conducted using SPSS Statistics 26 (IBM Corp., Armonk, NY, USA). Descriptive statistics were used to identify the frequency of the most prevalent CSI items among adults with post-amputation pain (n=59), using data from the first administration of the questionnaire. CSI test-retest reliability was evaluated by determining ICCs and corresponding 95% confidence intervals (CIs) using a two-way, mixed effects (3, 1) model with absolute agreement, based on guidelines recommended by Koo and Li.³³ ICCs were interpreted as follows: ≤0.50=poor, 0.51–0.75=moderate, 0.76–0.90=good, ≥0.91=excellent.³³ The standard error of measurement (SEM), a measure of the expected variation in scores due to measurement error,³⁴ was calculated, and a Bland-Altman plot was generated.

PPTs were log-transformed to meet parametric assumptions (as PPTs were non-parametrically distributed per significant Shapiro-Wilk tests). Then, for adults with post-amputation pain, PPTs at each site were normalized (i.e., z-transformed) based on their relative standing within sex-specific control groups. This conversion has been previously published¹⁴ and allowed comparison of participants with lower-limb loss to sex-specific reference data (as it is well-established that females demonstrate greater pain sensitivity as compared to males³⁵). Amputated-region pain sensitivity was computed as the average of normalized residual patellar tendon and residual lateral femoral epicondyle PPTs. Secondary-site pain sensitivity was computed as followed: upper-extremity sensitivity (i.e., average of bilateral lateral humeral epicondyles PPTs), intact limb sensitivity (i.e., average of intact greater trochanter, thigh, lateral femoral epicondyle, and patellar tendon PPTs), and remote residual limb sensitivity (i.e., average of residual greater trochanter and thigh PPTs).

Group classification (i.e., pain with versus without increased amputated-region sensitivity) was decided based on amputated-region pain sensitivity values (see Figure 1). Increased amputated-region sensitivity was defined as normalized amputated-region PPT<−0.67, representing scores below the 25^th percentile of the control group; normalized amputated-region PPT≥−0.67 were considered non-sensitive. In prior pain research, PPTs falling below the 25^th percentile of a healthy, reference sample have been considered to indicate the lower limit of pain hypersensitivity.^{36, 37}

Figure 1.

(A) Theoretical depictions of pain-pressure threshold data are presented for males and female controls, respectively, where mean pain-pressure thresholds are lower among females as compared to males. Conversion of pain-pressure threshold data to a standardized z-score scale (B) allows evaluation of increased pain sensitivity among the post-amputation pain sample, while considering sex-related differences in pain sensitivity. In (C), a z-score of 0 represents both male and female control means; a z-score of −0.67 represents the 25^th percentile. Thus, among adults with lower-limb loss (regardless of sex), individuals with average amputated-region z-scores <−0.67 were classified as having “pain with increased amputated-region sensitivity.”

Finally, descriptive statistics were used to characterize groups (i.e., pain with versus without increased amputated-region sensitivity). Two, separate models were used to compare (1) normalized, secondary-site PPT and (2) pain-related outcome measure scores between groups (p<.025). After ensuring data met parametric assumptions, a multivariate analysis of variance (MANOVA) was used to evaluate between-group differences in normalized secondary-site PPT; where upper-extremity, intact limb, and remote residual limb sensitivity were entered separately as dependent variables. Post-hoc univariate ANOVAs were conducted to identify between-group differences for individual variables. As pain-related outcome measure data did not meet parametric assumptions required for MANOVA, a Kruskal-Wallis test was used to compare PROMIS-29 Pain Interference T-scores, PROMIS-29 pain intensity scores, and CSI scores between groups.

Results

In total, of the 234 participants with lower-limb loss contacted, 64 were eligible and enrolled (see Figure 2). Among the 64 enrolled participants, four participants were removed (three were missing PPT data, and one reported misunderstanding testing directions after completing his evaluation and was consequently removed). Ultimately, 60 participants with lower-limb loss were included in between-group comparisons (36 without increased amputated-region sensitivity, 24 with increased amputated-region sensitivity). Of the 52 control participants with intact limbs contacted, 40 were eligible and enrolled (for establishing normative reference values only). One control participant was missing PPT data and was consequently removed, leaving a total of 39 control participants for comparison.

Figure 2.

Participant inclusion flow diagram.

CSI Reliability and Descriptive Data

Of the 60 participants with post-amputation pain, 14 did not return their second questionnaires, leaving a total sample of 46 participants for analyses. After performing preliminary data analyses, one participant’s data were removed from the reliability dataset as their responses were substantially and inexplicably different between the first (2 points) and second administration (61 points). Under typical circumstances (i.e., without interference from a traumatic, significant, or unexpected event), it is unlikely that an individual would report “rarely” experiencing only two central sensitization symptoms, then report experiencing 25 central sensitization symptoms just 10–14 days later, many at a frequency of “often” or “always.” In terms of symptom severity sub-classifications, the score jump from 2 to 61 points reflects a change from subclinical to extreme severity, indicating that if results were valid, the participant demonstrated a significant change in status and should not be considered for a reliability analysis. Consequently, a total of 45 participants were included in reliability analyses.

The Bland-Altman plot representing test-retest distributions, as well as the ICC, 95% CI, and SEM data, are presented in Figure 3. Mean CSI values were 24 and 27 points for the first and second administration, respectively, and no significant differences were found between administrations (p>0.050). Overall, test-retest reliability was considered good, with an ICC of 0.80 (95% CI: 0.62–0.89) and SEM of 5.2 points.

Figure 3.

The Bland-Altman plot depicts the distribution of Central Sensitization Inventory score differences (1^st administration – 2^nd administration) versus score means (average of 1^st and 2^nd administrations). The intraclass correlation coefficient (ICC), corresponding 95% confidence interval (CI), and standard error of measurement (SEM) are presented.

Table 1 presents frequencies of the most commonly reported CSI items among adults with post-amputation pain. Based on item responses, the most prevalent symptoms (i.e., reported ≥sometimes) were muscular pain (53–62%), sleep disturbances (43–60%), fatigue (45–57%), and cognitive difficulties including impaired concentration and memory (40–45%).

Table 1.

Most Frequently-Reported Central Sensitization Inventory Symptoms among Adults with Post-Amputation Pain

Item	Description	# Reporting Symptom† (n=58)	Frequency
			Never	Rarely	Sometimes	Often	Always
2	“My muscles feel stiff and achy.”	36 (62%)	5 (9%)	17 (29%)	24 (41%)	12 (21%)	0 (0%)
12	“I do not sleep well.”	35 (60%)	7 (12%)	16 (28%)	21 (36%)	12 (21%)	2 (3%)
1	“I feel tired and unrefreshed when I wake from sleeping.”	33 (57%)	8 (14%)	17 (29%)	23 (40%)	8 (14%)	2 (3%)
18	“I have muscle tension in my neck and shoulders.”	31 (53%)	9 (16%)	18 (31%)	17 (29%)	9 (16%)	5 (9%)
8	“I get tired very easily when I am physically active.”	30 (52%)	17 (29%)	11 (19%)	25 (43%)	4 (7%)	1 (2%)
17	“I have low energy.”	26 (45%)	10 (17%)	22 (38%)	23 (40%)	2 (3%)	1 (2%)
13	“I have difficulty concentrating.”	26 (45%)	11 (19%)	21 (36%)	20 (34%)	2 (3%)	4 (7%)
22	“My legs feel uncomfortable and restless when I am trying to go to sleep at night.”	25 (43%)	16 (28%)	17 (29%)	11 (19%)	14 (24%)	0 (0%)
23	“I have difficulty remembering things.”	23 (40%)	14 (24%)	21 (36%)	14 (24%)	7 (12%)	2 (3%)
15	“Stress makes my physical symptoms get worse.”	21 (36%)	23 (40%)	14 (24%)	14 (24%)	6 (10%)	1 (2%)
21	“I have to urinate frequently.”	21 (36%)	24 (41%)	13 (22%)	14 (24%)	6 (10%)	1 (2%)
14	“I have skin problems such as dryness, itchiness, or rashes.”	19 (33%)	25 (43%)	14 (24%)	13 (22%)	5 (9%)	1 (2%)

^†Presented as n (% of sample) for participants reporting the symptom (i.e., sometimes-always).

Between-Group Differences in Signs and Symptoms of Central Sensitization

Table 2 presents participant characteristics, which were similar between participants with post-amputation pain, regardless of amputated-region sensitivity (p>.050). Participants in both groups were largely middle-aged (mean=51–53 years) males, with similar time since amputation (median=3–4 years). Amputation etiology was similar (p=0.472) between participants in both groups (i.e., those with and without increased amputated-region sensitivity), with the majority of participants having experienced an amputation due to trauma. Proportions of phantom and residual limb pain were similar between groups (p=0.282–0.725), as were proportions of pain in secondary pain sites (i.e., intact hip, knee, or ankle/foot; low back; p=0.362–0.746). Few participants reported phantom limb pain at the time of the study (median “current” phantom limb pain intensity = 0 out of 10); however, participants who experienced residual limb pain reported mild pain²⁴ (mean “current” residual limb pain intensity = 2 out of 10) at the time of the study.

Table 2.

Descriptive Characteristics

Variable	Pain without ↑ Amputated-Region Sensitivity (n=36)	Pain with ↑ Amputated-Region Sensitivity (n=24)	p
Sex, female†	15 (41.7%)	5 (20.8%)	0.094
Age, years‡	51 (14)	53 (17)	0.671
Body Mass Index, kg/m2‡	30.1 (5.9)	30.0 (5.5)	0.917
Amputation Etiology †
Dysvascular	4 (11.1%)	7 (29.2%)	0.472
Trauma	16 (44.4%)	9 (37.5%)
Cancer	3 (8.3%)	2 (8.3%)
Infection	7 (19.4%)	4 (16.7%)
Other	6 (16.7%)	2 (8.3%)
Time since Amputation, years*	3 (2, 9)	4 (2, 5)	0.281
Phantom Limb Pain Present †	29 (80.6%)	21 (87.5%)	0.725
Current Phantom Limb Pain Intensity, 0–10*	n=29 0 (0, 3)	n=21 0 (0, 2)	0.953
Best Phantom Limb Pain Intensity, 0–10*	n=29 0 (0, 0)	n=21 0 (0, 2)	0.272
Worst Phantom Limb Pain Intensity, 0–10*	n=29 4 (2, 7)	n=21 4 (1, 8)	0.272
Residual Limb Pain Present †	24 (66.7%)	12 (50.0%)	0.282
Current Residual Limb Pain Intensity, 0–10‡	n=24 2 (3)	n=12 2 (3)	0.454
Best Residual Limb Pain Intensity, 0–10‡	n=24 1 (2)	n=12 1 (1)	0.404
Worst Residual Limb Pain Intensity, 0–10‡	n=24 5 (4)	n=12 5 (4)	0.918
Other Pain Site Involvement †
Intact Hip	8 (22.2%)	4 (16.7%)	0.746
Intact Knee	10 (27.8%)	4 (16.7%)	0.368
Intact Ankle/Foot	11 (30.6%)	4 (16.7%)	0.362
Low Back	19 (52.8%)	16 (66.7%)	0.423

^†Presented as n (% of sample)

^‡Presented as mean (SD)

^*Presented as median (25^th, 75^th percentile)

Table 3 presents mean secondary-site pain sensitivity data and pain-related outcome measure scores. There was a significant, large multivariate effect of group for normalized secondary-site PPTs [Wilk’s Λ=0.538, F(1,57)=16.01, p<0.001]. Univariate analyses, which are also presented in Table 3, showed a significant effect of group for each region of secondary-site PPTs [F(1,57)=20.90–49.58, p<0.001]; participants with pain and increased amputated-region sensitivity demonstrated significantly greater secondary-site pain sensitivity (i.e., lower normalized upper-extremity, intact limb, and remote residual limb PPTs) compared to peers without increased amputated-region sensitivity. In contrast, the Kruskal Wallis test found no between-group differences in pain-related outcome measures (H=0.35–1.74, p=0.187–0.557).

Table 3.

Between-group differences in Secondary-Site Pain Sensitivity and Pain-Related Outcome Measures

Model 1	Pain without ↑ Amputated-Region Sensitivity (n=36)	Pain with ↑ Amputated-Region Sensitivity (n=24)	df	F	p	partial ƞ2
Normalized Secondary-Site Pain-Pressure Thresholds † *
Upper-Extremity	0.44 (1.13)	−0.89 (1.07)	1	20.90	<0.001	0.265
Intact Lower-Extremity	0.55 (0.76)	−0.87 (0.78)		49.58	<0.001	0.461
Remote Residual Extremity	0.35 (1.04)	−1.24 (1.12)		31.99	<0.001	0.355
Model 2	Pain without ↑ Amputated-Region Sensitivity (n=36)	Pain with ↑ Amputated-Region Sensitivity (n=24)	df	H	p
Self-Reported Pain Outcome Measures
PROMIS-29 Average Pain Intensity, 0–10‡	4 (2, 6)	2 (2, 4)	1	1.44	0.230
PROMIS-29 Pain Interference, T-score‡	53.8 (41.6, 59.9)	55.6 (41.6, 56.7)	1	0.35	0.557
CSI Part A Total, 0–100 points†	n=35 24 (12)	n=23 28 (12)	1	1.74	0.187

^†Presented as mean (SD)

^*Normalized secondary-site pain-pressure thresholds reflect average z-scores as compared to sex-specific reference data, among the following site subgroups: upper-extremity (i.e., bilateral humeral epicondyles), intact lower-extremity (i.e., non-amputated greater trochanter, thigh, lateral femoral epicondyle, and patellar tendon), and remote residual extremity (i.e., regions of the residual lower-limb remote to the area of the amputation and prosthetic socket, including the greater trochanter and thigh).

^‡Presented as median (25^th, 75^th percentile)

Abbreviations: CSI = Central Sensitization Inventory, PROMIS-29 = Patient-Reported Outcomes Measurement Information System-29 Item

Discussion

Persistent post-amputation pain is a heterogeneous condition that presents with variable symptoms and often is non-responsive to existing treatment interventions.^38–40 Recommendations for evaluating and treating post-amputation pain are lacking, in part due to the lack of understanding of mechanisms underlying post-amputation pain persistence.³ In this study, adults with post-amputation pain and increased amputated-region sensitivity demonstrated generalized increases in pain sensitivity, potentially reflective of underlying central sensitization. Peripheral sensitization, in isolation, would be indicated by similar, normalized secondary-site PPTs between groups; therefore, findings suggest increased amputated-region sensitivity may not be attributed to peripheral sensitization alone. Based on significant between-group differences in pain sensitivity found in our study, adults with concomitant peripheral and central sensitization may comprise a distinct subgroup of adults with post-amputation pain, for whom comprehensive, locally- and centrally-focused management may be critical. Remarkably, while groups demonstrated clear differences in amputated-region and secondary-site pain sensitivity, there were no between-group differences in pain intensity, pain interference, or symptoms associated with central sensitization. Findings indicate physiological differences in pain sensitivity may not be primary drivers of adverse post-amputation self-reported pain outcomes.

Knowledge regarding best practices for post-amputation pain evaluation and treatment is constantly evolving. While many conservative treatment interventions (e.g., transcutaneous electrical stimulation,⁴¹ graded motor imagery,⁴² mirror therapy,⁴³ virtual reality⁴⁴) demonstrate promise in reducing post-amputation pain severity, there is a dearth of high-quality evidence demonstrating therapy effectiveness.⁴⁵ While rare, some adults demonstrate adverse responses to conservative treatments (e.g., mirror therapy), including increased pain severity and depressive symptoms when focusing attention on the residual limb.⁴⁶ Discrepancies in treatment responses may be, in part, due to nonspecific inclusion criteria for studies investigating the effectiveness of post-amputation pain treatments. Our findings reinforce the heterogeneous nature of post-amputation pain, confirming a critical need to consider pain presentation (e.g., pain severity, concomitant symptoms) and related impairments (e.g., pain sensitivity) holistically when evaluating and treating post-amputation pain.

In patients with other musculoskeletal pain conditions (e.g., osteoarthritis, lateral epicondylalgia), researchers have shifted to identifying pain-group subclassifications to guide interventions and determine when centrally-focused treatment may be beneficial. For example, recent work from Nijs et al. recommends that patients with musculoskeletal pain and signs associated with central sensitization (e.g., disproportionate pain experience, diffuse pain distribution, CSI scores ≥40) may benefit from incorporation of pain neuroscience education and graded activity into treatment.⁴⁷ Similar impairment-based treatment subclassifications may help guide post-amputation pain management. For example, our participants with generalized increases in pain sensitivity may require top-down interventions targeting reductions in nervous system hypersensitivity (e.g., pain neuroscience education,¹⁷ centrally acting medication¹⁹). In contrast, patients with localized pain sensitivity may instead benefit from evaluation of other impairments (e.g., environmental and/or prosthesis-related aggravating factors), which may guide treatment decisions.

Among studies evaluating post-amputation pain treatment, changes in pain intensity are cited as the primary outcome of interest.^{43, 46, 48–51} Changes in other pain-related domains (e.g., pain sensitivity, psychosocial stressors, pain-related disability) are often unassessed. Our findings suggest PPT testing may be useful as objective, surrogate measures of peripheral and central sensitization in post-amputation pain. Furthermore, this study found good test-retest reliability of the CSI, suggesting it may be useful for evaluating symptoms associated with central sensitization among adults with post-amputation pain. Future, longitudinal studies may consider including central sensitization-related measures (e.g., PPT, CSI) to determine if baseline pain sensitivity and CSI scores predict long-term pain-related outcomes.

Following amputation, both the peripheral and central nervous system are exposed to factors that may induce sensitization (e.g., nerve injury and resultant changes in nerve structure and activity,⁴ concomitant psychological stress^{52, 53}). Therefore, it is unsurprising that our group with increased amputated-region sensitivity demonstrates concomitant signs of peripheral and central sensitization. What is surprising, however, is that pain-related characteristics were similar between groups in this study, regardless of physiological signs of peripheral and central sensitization. Findings contrast previous studies among adults with other chronic pain conditions, where adults with pain and signs of central sensitization typically demonstrate more severe, extensive, and debilitating pain.^{54, 55} Importantly, our findings indicate physiological measures of underlying nervous system sensitivity may not discriminate between individuals with post-amputation pain who demonstrate symptoms associated with central sensitization (i.e., fatigue, sleep disturbance, impaired memory and concentration); as such, post-amputation pain assessments should include evaluations of both physiological signs and psychosocial symptoms to create a comprehensive understanding of each patient’s pain.

Among participants in this study, 36% were classified as having mild to severe central sensitization per CSI scores (i.e., 24% mild, 7% moderate, 5% severe). Overall, however, mean CSI scores, i.e., 28 and 24 points among adults with and without increased amputated region sensitivity, respectively, were relatively low, with the majority of participants (i.e., 64%) falling under the “subclinical” symptom subclassification.²⁷ When interpreting CSI findings, two considerations are critical: first, limb loss involves not only a significant physical transformation, but also substantial psychological adaptations associated with the grieving process. As such, physiological changes in pain sensitivity may be less influential with respect to the self-reported pain experience in comparison to other psychological factors (e.g., resilience, anxiety/depression, self-efficacy, post-traumatic stress) that were not evaluated in this study. Second, the predominance of research assessing signs and symptoms of central sensitization in other pain conditions has been conducted among care-seeking patients, i.e., those actively pursuing treatment for their pain. This study was a secondary analysis of data collected among community-dwelling participants with overall lower symptom severity, which may explain the lack of between-group differences in pain-related, self-reported outcome measures. Future studies may consider evaluating CSI scores among individuals actively pursuing post-amputation pain treatment to determine whether self-reported symptoms and frequencies differs from findings among non-care-seeking participants in this study.

Study Limitations

This work provides support for clinically evaluating PPT adults with post-amputation pain to help guide treatment-related decision-making; however, several limitations are acknowledged. First, while PPTs are commonly used as surrogate measures of peripheral and central nervous system sensitivity, additional quantitative sensory testing of conditioned pain modulation or temporal summation²⁰ may identify more robust differences in central pain processing. Furthermore, additional evaluation of neuropathic signs and symptoms (e.g., nerve conduction, neuropathic pain descriptors) or other pain assessments (e.g., pinprick-evoked pain) may have allowed assessment of differences in participant characteristics between groups. While this study evaluated signs and symptoms associated with central sensitization among a moderately large sample of participants with post-amputation pain, participants expressed generally mild phantom and/or residual limb pain intensities with subclinical symptoms of central sensitization. Thus, findings may not be generalizable to adults with severe post-amputation pain. Additionally, while amputated-region sensitivity was classified using established parameters and sex-specific reference norms, more conservative PPT cut-points (e.g., 5^th or 10^th percentiles) may provide greater confidence in identifying underlying nervous system sensitization. Also, while the extreme outlier excluded from CSI reliability analyses appears justified based on unexplainable data discrepancies, the exclusion of this participant reduced heterogeneity in CSI data, which must be acknowledged. Finally, while pain medication use may affect pressure-induced pain sensitivity, pain medication data was unavailable; future studies may consider evaluating pain medications to assess their potential impact on pressure sensitivity among individuals with post-amputation pain.

Conclusion

A subgroup of participants with post-amputation pain appears to demonstrate signs associated with central sensitization, as evidenced by generalized increases bodily pain sensitivity. Self-reported pain characteristics (i.e., pain intensity, pain interference, and symptoms associated with underlying central sensitization), however, appear similar between individuals with and without increased amputated-region sensitivity post-amputation. While physiological signs potentially reflecting underlying central nervous system hypersensitivity may inform pain management among adults with post-amputation pain, they may be nondiscriminatory for differentiating between self-reported pain presentations. Results warrant further investigation into whether other factors (e.g., resilience, self-efficacy, pain-related attitudes) may be more closely associated with pain-related self-reported outcomes among adults with post-amputation pain.

Data availability:

The study dataset is available from the corresponding author upon reasonable request.