Abstract
Objectives:
Multisite pain remains significantly understudied following lower-limb loss (LLL), especially among females. This study aimed to explore sex-specific differences in the presentation of multisite pain post-LLL. Hypotheses were multisite pain would be more prevalent among females post-LLL as compared to males, and female sex would be significantly associated with multisite pain prevalence.
Methods:
In this cross-sectional study, participants answered standardized questions regarding the presence of amputation-specific (i.e., phantom limb, residual limb) and secondary (i.e., contralateral limb, low back) pain. Multisite pain was defined as pain in ≥2 locations. Sex-specific differences in pain prevalence were evaluated using chi-square tests (p≤.050). Using logistic regression, the association between sex and multisite pain was examined after controlling for covariates (age, body mass index, time since amputation, amputation etiology and level).
Results:
The sample included 303 adults (33% females) ≥1-year post-unilateral LLL. More females than males reported pain in the residual limb (53.0% versus 38.4%), low back (56.0% versus 39.9%), contralateral knee (37.0% versus 24.1%), and contralateral hip (25.0% versus 12.3%) [p<.050]. More females than males were classified as having multisite pain (72.0% versus 54.7%; p=.004). While patterns of multisite pain were similar (i.e., pain affected both amputation-specific and secondary sites) between sexes, being female was independently associated with higher odds of having multisite pain (odds ratio: 2.40, 95% confidence interval: 1.40–4.12).
Discussion:
Female sex appears to be associated with multisite pain ≥1-year after LLL. Future work is needed to identify mechanisms underlying sex-specific differences in pain presentation and evaluate the impact of sex on pain-related outcomes post-amputation.
Keywords: amputation, lower limb pain, phantom limb pain, low back pain, persistent pain
Introduction
Of the nearly two million Americans living with lower-limb loss (LLL)1, up to 95% experience bothersome pain in at least one body region, which is associated with depression, worse mobility, and reduced quality-of-life2. Post-LLL, pain may be amputation-specific (i.e., directly involving the amputated limb region) or may occur in secondary sites, such as the non-amputated limb or low back3–6. As in other postoperative patient populations, acute pain may serve an important, protective role in facilitating amputated limb healing7; however, extensive pain site involvement and persistence of pain beyond the healing stage may be pathological.
To date, pain-related research among adults with LLL has largely focused on identifying single-site pain prevalence, as well as the bothersomeness of individual pain sites, among largely male participants2–4,8,9. Furthermore, studies evaluating chronic pain among adults with LLL have predominantly focused on amputation-specific pain3 or have included participants within the first year of their amputation2,6, which may inflate prevalence rates.
Multisite pain, defined as pain in two or more anatomical locations10, remains especially understudied among adults with LLL. While adults with LLL commonly report pain in multiple locations2,3,6, demographic and amputation-related characteristics associated with multisite pain remain unknown. Additionally, descriptions of multisite pain involvement are lacking. Further classification of multisite pain patterns post-LLL is warranted to identify the extent of pain involvement and inform future studies investigating underlying factors contributing to multisite pain (e.g., compensatory loading of secondary pain sites, heightened sensitization to whole-body pain signals).
While female sex is a well-established risk factor for multisite pain development in the general population10,11, there is currently a dearth of evidence regarding whether females experience disproportionate rates of multisite pain among adults with LLL. Females comprise the minority of the LLL population (i.e., 33%1) and remain a significantly understudied group12. Recently, researchers have highlighted the importance of directing research efforts toward females with LLL, as there may be unique considerations for sex-specific prosthetic needs, treatment interventions, and psychosocial stressors12. To assist with this initiative, it is imperative to investigate relationships between sex and post-LLL pain presentation to determine if future, longitudinal pain studies among adults with LLL should consider sex-related differences.
The objectives of this study were two-fold: to explore sex-specific differences multisite pain presentation and investigate associations between female sex and multisite pain ≥1-year post-LLL. The hypotheses were: (1) multisite pain would be more prevalent among females ≥1-year post-LLL as compared to their male counterparts, and (2) female sex would be significantly associated with multisite pain prevalence ≥1-year post-LLL, after controlling for other potential contributing factors [e.g., age, body mass index (BMI), time since amputation, amputation level and etiology].
Materials and Methods
Data were combined from six cross-sectional, observational research studies completed in the Delaware Limb Loss Studies laboratory at the University of Delaware between September 2013 and February 2020. Across all studies, participants were recruited via the University of Delaware Multidisciplinary Amputee Clinic, local prosthetic clinics, and national limb loss conferences and events (e.g., the Amputee Coalition’s National Conference and Limb Loss Education Days). Studies were considered for analysis if standardized pain data was collected among adults with LLL, and participants had signed a written, informed consent permitting use of de-identified data for future research studies.
Participants were included in this study if they were ≥18 years of age, able to read and speak English (due to completion of questionnaires and interviews in English), had undergone a unilateral lower-limb amputation at the partial-foot level or higher ≥1-year prior to their research participation, and reported all pain prevalence data of interest. Exclusion criteria included any major amputation of the contralateral limb (i.e., Syme’s-level or higher).
Overview of Procedures
Across all studies, participants underwent the informed consent process. Demographic and amputation-specific characteristics were captured during standardized interviews, either led by trained examiners or in standardized text. Height and weight (with the prosthesis donned) were collected for the calculation of BMI.
When available, prosthesis-related data were extracted for participant characterization. Prosthesis-related data included participants’ Houghton Scale score, which assesses prosthesis use and stability when using a prosthesis13, and Socket Comfort Score, which assesses current prosthetic socket comfort14. The Houghton Scale, scored from 0–12 points, has been reported to have excellent test-retest reliability [intraclass correlation coefficient (ICC)=0.9613] and criterion validity for differentiating community, limited community, and household ambulation categories post-LLL15. Specifically, scores ≥9 points may suggest the individual is a community ambulator13. For the Socket Comfort Score, 0 represents “the most uncomfortable fit” and 10 represents “the most comfortable fit imaginable”14. Test-retest reliability (ICC=0.7716) and criterion validity14 have been previously reported for the Socket Comfort Score.
To capture pain prevalence data, participants answered standardized pain questions. Phantom limb pain was defined as “pain perceived as coming from the amputated portion of the limb2,” while residual limb pain was defined as “pain in the remaining portion of the amputated limb2,3,6.” As individuals with LLL commonly report pain in the contralateral limb and/or low back3–6, secondary pain sites of interest included the contralateral hip, knee, foot, and ankle, as well as the low back.
Data Analysis
Prior to statistical analyses, participants’ identifying information was cross-checked between studies to ensure individual participants were included only once. Pain-related responses were verified with additional evaluation material (e.g., pain body diagrams, diagnosis codes), when available, to ensure pain prevalence data was accurately captured. The total number of pain sites was calculated for each participant, with a maximum of 7 possible pain sites (i.e., phantom limb, residual limb, low back, contralateral hip, contralateral knee, contralateral ankle, contralateral foot).
Multisite pain was defined as the presence of pain in two or more locations. For participants classified as having multisite pain, multisite pain presentation was further categorized into the following patterns: amputation-specific multisite pain (i.e., pain in both the phantom and residual limb, without involvement of secondary sites), secondary multisite pain (i.e., pain in two or more secondary sites, without pain involvement in the amputated limb), or mixed multisite pain (i.e., pain in two or more sites, including both the amputated limb and at least one secondary site).
All statistical analyses were performed using SPSS Statistics 26 (SPSS, Inc., IBM, Armonk, NY). Participant demographics and amputation-specific data were analyzed using descriptive statistics. For each pain type and pattern of interest, pain prevalence was examined by sex, and sex differences were evaluated using chi square tests (p≤.050). Univariate logistic regression was used to test the unadjusted association of sex and multisite pain presence. Next, sequential logistic regression modeling was used to test the association of sex and multisite pain after adjusting for covariates that may influence pain development2,11,17, which were entered into the first block. Covariates included potential confounders to control for: age, BMI, time since LLL, and LLL etiology and level. LLL etiology was dichotomized as non-traumatic versus traumatic, as traumatic etiology has been associated with amputation-specific pain2. Furthermore, LLL level was dichotomized as at or below the transtibial level (i.e., partial foot, Syme’s, or transtibial) versus at or above the knee disarticulation level (i.e., knee disarticulation, transfemoral, or hip disarticulation), as more proximal amputation levels have been associated with amputation-specific pain18. Sex (i.e., 0=male, 1=female) was added independently in the second block.
Results
Figure 1 depicts inclusion of participants for the analyses. In total, 541 unique participants completed research studies during the period of interest. Five of the six research studies included data for all pain sites of interest, resulting in 402 participants with complete pain data (i.e., phantom, residual, contralateral limb, and low back pain presence data). Of the 402 participants, 29 reported major bilateral amputations, and 63 had experienced their initial amputation within the past year, resulting in exclusion. Finally, of the remaining 310 participants, seven were missing BMI data, resulting in a total sample of 303 participants with complete pain and covariate data for the analyses.
Figure 1.
Inclusion Flow Diagram
Participant characteristics are provided in Table 1. Consistent with previously-reported statistics regarding the LLL population1, roughly one-third of participants (n=100) were female. Median age and BMI were 56 years and 29.0 kg/m2, respectively. Seventy-three percent of participants had a transtibial amputation, and median time since LLL was 6 years. While demographic and LLL characteristics were largely similar between sexes (p>.050), LLL etiology was significantly different between males and females (p=.006). A post-hoc chi square test indicated more females (17.0%) than males (4.4%) reported cancer-related LLA (p<.001); however, no significant between-group differences were found for other etiologies. Finally, nearly all participants used a prosthesis and were community-ambulators based on Houghton Scale scores15.
Table 1.
Participant Characteristics by Sex
| n (%) | ||||
|---|---|---|---|---|
| Domain | Full Sample (n=303) | Males (n=203) | Females (n=100) | p† |
|
Demographic | ||||
| Age, years* | 56 (46, 65) 18–94 |
57 (46, 65) 18–94 |
55 (46, 65) 21–84 |
0.568 |
| Body Mass Index, kg/m2* | 29.0 (25.1, 33.3) 14.4–55.7 |
29.5 (25.5, 33.5) 17.5–52.0 |
27.4 (23.8, 32.7) 14.4–55.7 |
0.056 |
|
Amputation-Specific | ||||
| Amputation Level | ||||
| Partial Foot | 1 (0.3%) | 1 (0.5%) | 0 (0.0%) | 0.914 |
| Transtibial | 222 (73.3%) | 148 (72.9%) | 74 (74.0%) | |
| Van Ness Rotationplasty | 1 (0.3%) | 1 (0.5%) | 0 (0.0%) | |
| Knee Disarticulation | 3 (1.0%) | 2 (1.0%) | 1 (1.0%) | |
| Transfemoral | 75 (24.8%) | 50 (24.6%) | 25 (25.0%) | |
| Hip Disarticulation | 1 (0.3%) | 1 (0.5%) | 0 (0.0%) | |
| Amputation Etiology | ||||
| Dysvascular (i.e., DM, PVD) | 81 (26.7%) | 58 (28.6%) | 23 (23.0%) | 0.006 |
| Trauma | 110 (36.3%) | 81 (39.9%) | 29 (29.0%) | |
| Cancer | 26 (8.6%) | 9 (4.4%) | 17 (17.0%) | |
| Congenital | 11 (3.7%) | 8 (3.9%) | 3 (3.0%) | |
| Gangrene/Infection | 41 (13.5%) | 27 (13.3%) | 14 (14.0%) | |
| Other/Multiple Reasons | 34 (11.2%) | 20 (9.9%) | 14 (14.0%) | |
| Time since Amputation, years* | 6 (2, 16) 1–76 |
5 (2, 16) 1–66 |
7 (2, 20) 1–76 |
0.542 |
|
Prosthesis Use | ||||
| Current Prosthesis Use | 295 (97.4%) | 199 (98.0%) | 96 (96.0%) | 0.300 |
| Houghton Scale, 0–12* |
n=284 10 (9, 12) 2–12 |
n=192 11 (9, 12) 2–12 |
n=92 10 (9, 12) 4–12 |
0.208 |
| Current Socket Comfort Score, 0–10* |
n=292 8 (6, 9) 0–10 |
n=197 8 (6, 9) 0–10 |
n=95 8 (5, 9) 0–10 |
0.642 |
Continuous data presented as median (25th, 75th percentiles) and range.
P-value denoted for between-group differences (males versus females).
Abbreviations: kg=kilogram; m=meter; DM=Diabetes Mellitus; PVD=Peripheral Vascular Disease
Pain prevalence by site is presented in Table 2. While phantom limb pain prevalence was similar between sexes, residual limb pain was more common among females as compared to males (53.0% versus 38.4%; χ2=5.80, p=.016). Secondary site pain was also more prevalent among females; specifically, more females than males reported low back pain (56.0% vs. 39.9%), contralateral knee pain (37.0% vs. 24.1%), and contralateral hip pain (25.0% vs. 12.3%) [χ2=5.45–7.82, p<.050]. Altogether, males were more likely than females to report 0 painful sites (20.7% versus 11.0%, χ2= 4.36, p=.037), while females were more likely than males to report pain in all 7 possible sites (9.0% vs. 1.0%, χ2= 12.30, p=.001).
Table 2.
Pain Involvement and Multisite Pain Patterns by Sex
| n (%) | ||||
|---|---|---|---|---|
| Pain Involvement | Full Sample (n=303) | Males (n=203) | Females (n=100) | p* |
|
Amputation-Specific Pain | ||||
| Phantom Limb | 159 (52.5%) | 100 (49.3%) | 59 (59.0%) | 0.110 |
| Residual Limb | 131 (43.2%) | 78 (38.4%) | 53 (53.0%) | 0.016 |
|
Secondary Pain | ||||
| Low Back | 137 (45.2%) | 81 (39.9%) | 56 (56.0%) | 0.008 |
| Contralateral Hip | 50 (16.5%) | 25 (12.3%) | 25 (25.0%) | 0.005 |
| Contralateral Knee | 86 (28.4%) | 49 (24.1%) | 37 (37.0%) | 0.020 |
| Contralateral Ankle | 40 (13.2%) | 23 (11.3%) | 17 (17.0%) | 0.170 |
| Contralateral Foot | 60 (19.8%) | 35 (17.2%) | 25 (25.0%) | 0.111 |
|
Total # of Painful Sites | ||||
| 0 | 53 (17.5%) | 42 (20.7%) | 11 (11.0%) | .037 |
| 1 | 67 (22.1%) | 50 (24.6%) | 17 (17.0%) | .132 |
| 2 | 75 (24.8%) | 51 (25.1%) | 24 (24.0%) | .831 |
| 3 | 50 (16.5%) | 29 (14.3%) | 21 (21.0%) | .139 |
| 4 | 26 (8.6%) | 15 (7.4%) | 11 (11.0%) | .291 |
| 5 | 11 (3.6%) | 6 (3.0%) | 5 (5.0%) | .514 |
| 6 | 10 (3.3%) | 8 (3.9%) | 2 (2.0%) | .506 |
| 7 | 11 (3.6%) | 2 (1.0%) | 9 (9.0%) | .001 |
|
Multisite Pain | ||||
| Multisite Pain Present | 183 (60.4%) | 111 (54.7%) | 72 (72.0%) | .004 |
| Multisite Pain Pattern | ||||
| Amputation-specific** | 20/183 (10.9%) | 15/111 (13.5%) | 5/72 (6.9%) | .164 |
| Secondary† | 20/183 (10.9%) | 12/111 (10.8%) | 8/72 (11.1%) | .949 |
| Mixed‡ | 143/183 (78.2%) | 84/111 (75.7%) | 59/72 (82.0%) | .316 |
P-value denoted for between-group differences (males versus females).
Amputation-specific multisite pain defined as pain in both the phantom and residual limb, without pain involvement in secondary sites (i.e., contralateral limb, low back).
Secondary multisite pain defined as pain in ≥2 secondary sites, without pain involvement in the amputated limb.
Mixed multisite pain defined as pain in ≥2 sites, including both the amputated limb and ≥1 secondary site.
Sixty percent of the sample reported multisite pain, which was more prevalent among females (72.0%) as compared to males (54.7%; χ2=8.40, p=.004). Despite overall prevalence differences in multisite pain, multisite pain patterns did not significantly differ between sexes (p=.164-.949). Of the participants classified as having multisite pain, the majority of males (75.7%) and females (82.0%) reported mixed multisite pain.
In the unadjusted model, female sex was significantly associated with a higher odds of reporting multisite pain [χ2= 8.63, p=.003, Odds Ratio (OR) =2.13]. Results from the sequential logistic regression analysis are presented in Table 3. Block 1 was not significant (χ2= 8.37, p=.137). The addition of sex in Block 2 significantly improved the model (χ2= 19.09; p = 0.004). With the addition of sex, BMI became significantly associated with multisite pain [Odds Ratio (OR)=1.04, p=.044]. Holding all other variables constant, being female was associated with higher odds of reporting multisite pain (odds ratio: 2.40, 95% confidence interval: 1.40–4.12; p=.001).
Table 3.
Logistic Regression Model: Relationship between Sex and Multisite Pain (n=303)
| Block | Variable | β | SE | p | Odds Ratio (95% CI) | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Age, years | 0.013 | 0.008 | 0.113 | 1.01 (1.00–1.03) | |||||
| Body Mass Index, kg/m2 | 0.032 | 0.019 | 0.096 | 1.03 (0.99–1.07) | ||||||
| Time since Amputation, years | −0.008 | 0.009 | 0.364 | 0.99 (0.98–1.01) | ||||||
| Amputation Etiology, Trauma | −0.146 | 0.262 | 0.576 | 0.86 (0.52–1.44 | ||||||
| Amputation Level, KD or Higher | 0.378 | 0.280 | 0.178 | 1.46 (0.84–2.53) | ||||||
| χ2 = 8.37; p = 0.137 | ||||||||||
| 2 | Age, years | 0.016 | 0.009 | 0.067 | 1.02 (0.99–1.03) | |||||
| Body Mass Index, kg/m2 | 0.040 | 0.020 | 0.044 | 1.04 (1.00–1.08) | ||||||
| Time since Amputation, years | −0.011 | 0.009 | 0.231 | 0.99 (0.97–1.01) | ||||||
| Amputation Etiology, Trauma | −0.036 | 0.269 | 0.894 | 0.97 (0.57–1.64) | ||||||
| Amputation Level, KD or Higher | 0.407 | 0.286 | 0.154 | 1.50 (0.86–2.63) | ||||||
| Sex | 0.876 | 0.275 | 0.001 | 2.40 (1.40–4.12) | ||||||
| χ2 = 19.09; p = 0.004 | ||||||||||
Abbreviations: SE = standard error; CI = confidence interval; kg=kilogram; m=meter; KD=knee disarticulation
Discussion
More than 1-year post-amputation, 60.4% of adults with LLL from a large, heterogeneous sample reported multisite pain. When compared to male peers, females with LLL reported significantly higher rates of residual limb, low back, and contralateral knee and hip pain. Further, females disproportionately experienced multisite pain. While numerous studies have investigated amputation-specific and secondary pain separately2–4,8,9,19–21, few have characterized multisite pain among adults living with LLL. Our study characterizes multisite pain presentation post-LLL and presents the first evidence, to our knowledge, of sex-specific differences in multisite pain long-term post-LLL.
To date, research investigating multisite pain has predominantly focused on adults with intact limbs, where female sex has been consistently identified as a risk factor10,11. In support of our hypothesis, females with LLL experienced greater rates of multisite pain than their male peers, suggesting females with and without LLL may share several biological, social, and psychological mechanisms that help explain sex-specific pain experiences. Biologically, hormonal influences have been shown to increase pain sensitivity and inflammation in females, predisposing females to more extensive pain involvement22. Furthermore, sex differences in pain-related immune responses have been documented in both animals23 and humans24, suggesting males and females may process and experience pain differently. Socially, cultural roles and coping strategies may differ based on sex, influencing how females and males perceive and report pain22. While pain sensitivity has not been assessed among individuals with LLL, sex-specific differences in pain-related, psychological functioning have been identified in a sample of adults with predominantly traumatic LLL25. Specifically, females with LLL reported greater pain catastrophizing and endorsed the use of maladaptive coping strategies more so than male peers25, suggesting poor psychological functioning may contribute to the development of extensive, multisite pain post-LLL. While the secondary nature of this study does not allow for specific identification of underlying peripheral or central mechanisms contributing to sex-related differences, future research studies might explore whether unique factors associated with LLL (e.g., prosthesis use, psychosocial response to LLL, pre-, peri-, and post-operative pain medication use) also contribute to observed sex-specific differences in multisite pain prevalence.
Among participants who reported multisite pain, patterns of pain were similar between males and females, with the majority of males (75.7%) and females (82.0%) experiencing mixed multisite pain. The lack of sex-related differences in multisite pain patterns indicates there may be potential central contributions26 to multisite pain among both males and females with LLL. Specifically, multisite pain may reflect a state of globally heightened pain sensitivity, due to sensitization at the spinal or cortical level in response to the loss of a limb27. Although general patterns of multisite pain were similar, more females (9.0%) than males (1.0%) reported pain in all 7 sites. Furthermore, a post-hoc analysis examining the number of pain sites as a cumulative outcome confirmed our logistic regression findings, in that female sex and BMI were the only significant predictors of greater pain site involvement. Altogether, findings suggest extensive multisite pain may be more common among females post-LLL as compared to their male counterparts.
To our knowledge, this is the first study to identify a higher prevalence of secondary pain among females with LLL as compared to male peers; specifically, prevalence rates for low back and contralateral hip or knee pain were approximately 1.5 to 2 times higher among females as compared to males. Beyond the abovementioned factors that may be involved in multisite pain development, females with LLL may face unique, prosthesis-related challenges resulting in a predisposition to secondary pain. Historically, prosthetic componentry has been largely designed to accommodate male build and body mass12. While we did not find significant differences in self-reported socket comfort between males and females at the time of the evaluation (Z=−0.466, p=0.642), other prosthesis-related issues (e.g., heavy weight, poor suspension, malalignment) may be more prevalent among females28 and may increase demands on the intact limb or low back. Further investigation into relationships among pain, sex, and prosthetic fit and functionality may help identify mechanisms underlying sex-specific differences in secondary pain prevalence.
Phantom limb pain prevalence was similar between males (49.3%) and females (59.0%) in our sample, adding to a pool of conflicting evidence regarding the relationship between biological sex and phantom limb pain. For example, prior studies have mirrored our findings2,18, while others have identified higher prevalence rates of phantom limb pain among females17,29 or males25. Conflicting evidence may be due, in part, to the diverse definitions used across studies, including varied descriptions of phantom limb pain location (e.g., “the missing part”2,17, “the amputated part”18), quality (e.g., “bothersome”25, “so intense that it is experienced as pain”18, “any painful sensations”17), and frequency (e.g., “persistent”25, “in the last four weeks”2, or an undefined frequency2,18). Standardizing phantom limb pain language would reduce inconsistencies and allow comparisons across studies, which may improve our understanding of phantom limb pain.
Previously, amputations at or above the transfemoral level have been cited as risk factors for post-amputation pain, due to their potential for greater nerve damage, larger neuroma development, and poorer prosthetic fit18. Based on our logistic regression model, a relationship between amputation level and multisite pain was not found. Furthermore, age, time since LLL, and traumatic etiology were not independently associated with multisite pain. Altogether, findings seem to suggest multisite pain similarly affects a diverse group of individuals with LLL. Given our findings, future studies are warranted to investigate relationships between multisite pain and other potentially-influential risk factors, such as poor psychological functioning (e.g., anxiety, depression), post-operative complications (e.g., infection, revision surgeries), and/or social and environmental factors (e.g., assistive device use, social support).
Importantly, only 17.5% of all participants reported 0 painful sites, with the proportion of pain-free females (11.0%) being significantly smaller than pain-free males (20.7%). Results from this study indicate the rarity of having a pain-free experience post-LLL and emphasize the importance of including comprehensive, multisite pain assessments in clinical prosthetic evaluations, especially among females. While clinical practice guidelines are available for assessing low back30, hip31, and knee pain32 in other patient populations, recommendations for evaluating secondary pain post-LLL have not yet been developed. Furthermore, amputation-specific pain remains extraordinarily challenging to assess and treat, largely due to its unclear etiology and numerous clinical presentations. Recently, clinical practice guidelines from the Department of Veterans Affairs and Department of Defense highlighted the importance of evaluating and tracking pain post-LLL using standardized questionnaires and measurement tools (e.g., Visual Analogue Scale for pain intensity, McGill Pain Questionnaire for pain quality and descriptors)33; however, research informing the use of pain-related outcome measures among adults with LLL is limited. To determine which pain-related measures may be most appropriate for a given patient with LLL, further research, including reliability and validity studies, is necessary.
Study Limitations
While novel findings regarding sex differences in pain presentation and the prevalence of multisite pain post-LLL are presented, several study limitations are acknowledged. First, as this study was a secondary analysis of existing datasets, data were extracted from available participant records without a priori determination of sample size. Post-hoc analyses, however, indicate the number of covariates selected was appropriate based on the equation N=10k/p (N=number of participants, k=number of predictors, and p=proportion of positive cases)34, suggesting ≤15 predictors be considered when evaluating the presence of multisite pain among our sample of 303 participants.
Second, pain prevalence data was captured using a combination of survey and in-person interview methods. While standardized pain site definitions were used across all pain sites, regardless of administration method (i.e., in-person interview versus written questions), differences in administration of pain questions may have affected respondents’ answers. Pain evaluations were also limited due to study priorities. For example, pain intensity was not consistently assessed at each site of interest and, therefore, not considered in the analyses. Standardized secondary pain site definitions did not include temporal components of pain (e.g., duration or frequency of symptoms); consequently, we are unable to conclude whether assessments of secondary pain capture chronic pain, as defined by the International Association for the Study of Pain (IASP) Task Force for the Classification of Chronic Pain as “persistent or recurrent pain lasting longer than ≥3 months.”35 Additionally, as the analyses only evaluated presence versus absence of pain, we are unable to compare our findings to prior studies evaluating “bothersome” or “problematic” pain. Finally, pain assessments did not include evaluations of upper-extremity, neck, or head pain, as data from these sites were not collected in a uniform manner across all studies; future studies may consider including pain body diagrams to more comprehensively capture pain.
Conclusion
More than 1-year after LLL, over 60% of adults report multisite pain, which appears to be more prevalent and extensive among females. This study emphasizes the importance of including comprehensive, clinical pain assessments during prosthetic evaluations and highlights various knowledge gaps for future pain-related research post-LLL. Importantly, the majority of adults with multisite pain post-LLL appear to experience pain in both amputation-specific and secondary sites, regardless of sex. Future studies may consider identifying objective measurement strategies for amputation-specific and secondary pain to improve clinical assessment of multisite pain among adults with LLL. Additionally, as female sex appears to be associated with multisite pain, investigators should prioritize initiatives to identify mechanisms underlying sex-specific differences in pain prevalence and evaluate the impact of sex on pain-related outcomes post-LLL.
Acknowledgements:
The authors wish to thank the Delaware Limb Loss Studies lab assistants, particularly Chesca Basilio and Ryan Hogan, who assisted with extracting and analyzing data for this study. The authors also wish to thank the participants of this study, as well as those from the University of Delaware and Independence Prosthetics-Orthotics, Inc., who assisted with data collections at the University of Delaware and the 2017–2019 Amputee Coalition National Conferences.
Funding: This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health [grant numbers T32HD007490 and R03HD088668]; an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health [grant number: U54GM104941, PI: Binder-Macleod] and the State of Delaware; Promotion of Doctoral Studies I and II scholarships from the Foundation for Physical Therapy Research; the Orthotics and Prosthetics Education and Research Foundation, Inc. [grant number 15A01561]; and a Post-Doctoral Research Fund from Independence Prosthetics-Orthotics, Inc. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding institutions.
Footnotes
Disclosure: This work has been accepted for virtual presentation as a poster at the American Physical Therapy Association’s Combined Sections Meeting in February of 2021.
Ethics statement: All studies included in this work were approved by the University of Delaware Institutional Review Board for Human Subjects and carried out in accordance with the Declaration of Helsinki for research among human subjects.
The authors have no other conflicts of interest relevant to this work to declare.
References
- 1.Ziegler-Graham K, MacKenzie EJ, Ephraim PL, Travison TG, Brookmeyer R. Estimating the prevalence of limb loss in the United States: 2005 to 2050. Arch Phys Med Rehabil. 2008;89(3):422–429. [DOI] [PubMed] [Google Scholar]
- 2.Ephraim PL, Wegener ST, MacKenzie EJ, Dillingham TR, Pezzin LE. Phantom pain, residual limb pain, and back pain in amputees: results of a national survey. Arch Phys Med Rehabil. 2005;86(10):1910–1919. [DOI] [PubMed] [Google Scholar]
- 3.Ehde DM, Czerniecki JM, Smith DG, et al. Chronic phantom sensations, phantom pain, residual limb pain, and other regional pain after lower limb amputation. Arch Phys Med Rehabil. 2000;81(8):1039–1044. [DOI] [PubMed] [Google Scholar]
- 4.Ehde DM, Smith DG, Czerniecki JM, Campbell KM, Malchow DM, Robinson LR. Back pain as a secondary disability in persons with lower limb amputations. Arch Phys Med Rehabil. 2001;82(6):731–734. [DOI] [PubMed] [Google Scholar]
- 5.Highsmith MJ, Goff LM, Lewandowski AL, et al. Low back pain in persons with lower extremity amputation: a systematic review of the literature. Spine J. 2019;19(3):552–563. [DOI] [PubMed] [Google Scholar]
- 6.De Witt Jansen B, Brazil K, Passmore P, et al. Nurses’ experiences of pain management for people with advanced dementia approaching the end of life: a qualitative study. J Clin Nurs. 2017;26(9–10):1234–1244. [DOI] [PubMed] [Google Scholar]
- 7.Gupta A, Kaur K, Sharma S, Goyal S, Arora S, Murthy RS. Clinical aspects of acute post-operative pain management & its assessment. J Adv Pharm Technol Res. 2010;1(2):97–108. [PMC free article] [PubMed] [Google Scholar]
- 8.Jensen MP, Smith DG, Ehde DM, Robinsin LR. Pain site and the effects of amputation pain: further clarification of the meaning of mild, moderate, and severe pain. Pain. 2001;91(3):317–322. [DOI] [PubMed] [Google Scholar]
- 9.Kulkarni J, Gaine WJ, Buckley JG, Rankine JJ, Adams J. Chronic low back pain in traumatic lower limb amputees. Clin Rehabil. 2005;19(1):81–86. [DOI] [PubMed] [Google Scholar]
- 10.Thapa S, Shmerling RH, Bean JF, Cai Y, Leveille SG. Chronic multisite pain: evaluation of a new geriatric syndrome. Aging Clin Exp Res. 2019;31(8):1129–1137. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Coggon D, Ntani G, Palmer KT, et al. Patterns of multisite pain and associations with risk factors. Pain. 2013;154(9):1769–1777. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Randolph BJ, Nelson LM, Highsmith MJ. A Review of Unique Considerations for Female Veterans With Amputation. Mil Med. 2016;181(S4):66–68. [DOI] [PubMed] [Google Scholar]
- 13.Devlin M, Pauley T, Head K, Garfinkel S. Houghton Scale of prosthetic use in people with lower-extremity amputations: Reliability, validity, and responsiveness to change. Arch Phys Med Rehabil. 2004;85(8):1339–1344. [DOI] [PubMed] [Google Scholar]
- 14.Hanspal RS, Fisher K, Nieveen R. Prosthetic socket fit comfort score. Disabil Rehabil. 2003;25(22):1278–1280. [DOI] [PubMed] [Google Scholar]
- 15.Wong CK, Gibbs W, Chen ES. Use of the Houghton Scale to Classify Community and Household Walking Ability in People With Lower-Limb Amputation: Criterion-Related Validity. Arch Phys Med Rehabil. 2016;97(7):1130–1136. [DOI] [PubMed] [Google Scholar]
- 16.Hafner BJ, Morgan SJ, Askew RL, Salem R. Psychometric evaluation of self-report outcome measures for prosthetic applications. J Rehabil Res Dev. 2016;53(6):797–812. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Bosmans JC, Geertzen JH, Post WJ, van der Schans CP, Dijkstra PU. Factors associated with phantom limb pain: a 31/2-year prospective study. Clin Rehabil. 2010;24(5):444–453. [DOI] [PubMed] [Google Scholar]
- 18.Dijkstra PU, Geertzen JH, Stewart R, van der Schans CP. Phantom pain and risk factors: a multivariate analysis. J Pain Symptom Manage. 2002;24(6):578–585. [DOI] [PubMed] [Google Scholar]
- 19.Buchheit T, Van de Ven T, Hsia HL, et al. Pain Phenotypes and Associated Clinical Risk Factors Following Traumatic Amputation: Results from Veterans Integrated Pain Evaluation Research (VIPER). Pain Med. 2016;17(1):149–161. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Norvell DC, Czerniecki JM, Reiber GE, Maynard C, Pecoraro JA, Weiss NS. The prevalence of knee pain and symptomatic knee osteoarthritis among veteran traumatic amputees and nonamputees. Arch Phys Med Rehabil. 2005;86(3):487–493. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Sherman RA, Sherman CJ. Prevalence and characteristics of chronic phantom limb pain among American veterans. Results of a trial survey. Am J Phys Med. 1983;62(5):227–238. [PubMed] [Google Scholar]
- 22.Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley JL, 3rd. Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain. 2009;10(5):447–485. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Dance A. Why the sexes don’t feel pain the same way. Nature. 2019;567(7749):448–450. [DOI] [PubMed] [Google Scholar]
- 24.North RY, Li Y, Ray P, et al. Electrophysiological and transcriptomic correlates of neuropathic pain in human dorsal root ganglion neurons. Brain. 2019;142(5):1215–1226. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Hirsh AT, Dillworth TM, Ehde DM, Jensen MP. Sex differences in pain and psychological functioning in persons with limb loss. J Pain. 2010;11(1):79–86. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Hsu E, Cohen SP. Postamputation pain: epidemiology, mechanisms, and treatment. J Pain Res. 2013;6:121–136. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Butera KA, Roff SR, Buford TW, Cruz-Almeida Y. The impact of multisite pain on functional outcomes in older adults: biopsychosocial considerations. J Pain Res. 2019;12:1115–1125. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Elnitsky CA, Latlief GA, Andrews EE, Adams-Koss LB, Phillips SL. Preferences for rehabilitation services among women with major limb amputations. Rehabil Nurs. 2013;38(1):32–36. [DOI] [PubMed] [Google Scholar]
- 29.Kooijman CM, Dijkstra PU, Geertzen JH, Elzinga A, van der Schans CP. Phantom pain and phantom sensations in upper limb amputees: an epidemiological study. Pain. 2000;87(1):33–41. [DOI] [PubMed] [Google Scholar]
- 30.Delitto A, George SZ, Van Dillen L, et al. Low back pain. J Orthop Sports Phys Ther. 2012;42(4):A1–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Cibulka MT, Bloom NJ, Enseki KR, Macdonald CW, Woehrle J, McDonough CM. Hip Pain and Mobility Deficits-Hip Osteoarthritis: Revision 2017. J Orthop Sports Phys Ther. 2017;47(6):A1–A37. [DOI] [PubMed] [Google Scholar]
- 32.Brown GA. AAOS clinical practice guideline: treatment of osteoarthritis of the knee: evidence-based guideline, 2nd edition. J Am Acad Orthop Surg. 2013;21(9):577–579. [DOI] [PubMed] [Google Scholar]
- 33.Webster JB, Crunkhorn A, Sall J, Highsmith MJ, Pruziner A, Randolph BJ. Clinical Practice Guidelines for the Rehabilitation of Lower Limb Amputation: An Update from the Department of Veterans Affairs and Department of Defense. Am J Phys Med Rehabil. 2019;98(9):820–829. [DOI] [PubMed] [Google Scholar]
- 34.Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol. 1996;49(12):1373–1379. [DOI] [PubMed] [Google Scholar]
- 35.Treede RD, Rief W, Barke A, et al. A classification of chronic pain for ICD-11. Pain. 2015;156(6):1003–1007. [DOI] [PMC free article] [PubMed] [Google Scholar]