American Journal Of Biomedical Science & Pharmaceutical Innovation
38
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VOLUME
Vol.05 Issue06 2025
PAGE NO.
38-49
10.37547/ajbspi/Volume05Issue06-09
Personalized Approach to The Diagnosis of Neuropathic
Pain in Metastatic Breast Cancer: Development of A
Multicomponent Questionnaire
Rakhimov Nodir Makhammatkulovich
DSc, Professor, Department of Oncology, Samarkand State Medical University, Samarkand 140100, Uzbekistan
Rakhmonov Kamol Aminzhonovich
Independent researcher, Department of Oncology, Samarkand State Medical University, Samarkand 140100, Uzbekistan
Shakhanova Shakhnоza Shavkatovna
PhD, Associate Professor, Department of Oncology, Samarkand State Medical University, Samarkand 140100, Uzbekistan
Received:
30 April 2025;
Accepted:
28 May 2025;
Published:
30 June 2025
Abstract:
Objective: To validate the specialized questionnaire "NEURO-RMZh" for the differential diagnosis of
neuropathic pain in patients with metastatic breast cancer and to compare its psychometric properties with
existing validated instruments.
Materials and Methods: A single-center prospective validation study was conducted, enrolling 111 patients with
metastatic breast cancer. A comprehensive methodological approach was employed, including assessment of
internal consistency, test-retest reliability, construct and criterion validity. Statistical methods included factor
analysis, correlation analysis, ROC analysis, and multiple logistic regression. The DN4, BPI, SF-36, and Visual
Analogue Scale (VAS) questionnaires were used as comparators.
Results: The "NEURO-
RMZh" questionnaire demonstrated high internal consistency (Cronbach’s α = 0.89) and
test-retest reliability (ICC = 0.94). Its four-factor structure explains 73.6% of the total variance. The diagnostic
performance of the questionnaire exceeds that of existing tools: sensitivity 89.7%, specificity 82.4%, area under
the ROC curve 0.92. Likelihood ratios (LR+ = 5.10, LR- = 0.13) indicate the clinical significance of the test. Strong
correlations were observed with SF-36 quality of life domains (r from -0.44 to -0.74).
Conclusion: The "NEURO-RMZh" questionnaire is a valid, reliable, and highly informative tool for the differential
diagnosis of neuropathic pain in patients with metastatic breast cancer. Its implementation may contribute to the
optimization of diagnostics and personalization of therapeutic strategies in palliative oncology.
Keywords:
Neuropathic pain, breast cancer, questionnaire, validation, palliative care.
Introduction:
Breast cancer remains one of the
leading causes of cancer morbidity among women
worldwide, accounting for 24.5% of all malignant
neoplasms in women [1]. Pain syndrome of various
etiologies develops in 75
–
90% of patients with
advanced forms of the disease, significantly reducing
quality of life and necessitating a differentiated
approach to therapy [2,3].
The pathogenesis of pain syndrome in breast cancer is
characterized by pronounced heterogeneity of
underlying mechanisms. Nociceptive pain is caused by
the direct effect of the tumor on tissues, inflammatory
processes, and mechanical compression of structures
[4]. Neuropathic pain develops as a result of peripheral
nerve injury due to tumor progression, neurotoxicity of
chemotherapeutic
agents
(taxanes,
platinum
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compounds, vinca alkaloids), or radiotherapy [5,6]. The
mixed type of pain, which combines both mechanisms,
is observed in 39
–
65% of patients and presents the
greatest diagnostic challenges [7].
Current Approaches to Pain Assessment in Oncology
The visual analogue scale (VAS) remains the gold
standard for assessing pain intensity in clinical practice
due to its ease of use and high reproducibility (r=0.94)
[8]. However, the VAS does not allow differentiation of
pain types based on pathophysiological mechanisms,
limiting its use in selecting targeted therapies for
neuropathic pain [9].
The DN4 is a validated screening tool for neuropathic
pain that includes 10 dichotomous questions [10]. DN4
demonstrates a sensitivity of 82.9% and a specificity of
89.9% at a cut-
off value of ≥4 points [11]. Despite its
wide application, the DN4 has significant limitations in
the oncological population: insufficient validation in
patients with chemotherapy-induced polyneuropathy,
low specificity for mixed pain types (67.3%), and the
need for physical examination, which complicates
telemedicine consultations [12,13].
The Brief Pain Inventory (BPI) assesses pain intensity
and its impact on patient functional activity using an
11-point scale [14]. The questionnaire demonstrates
high internal consistency (Cronbach’s α
= 0.85
–
0.95)
and is validated in the oncological population [15].
However, the BPI does not include specific descriptors
of neuropathic pain and does not allow differential
diagnosis between types of pain syndromes [16].
The SF-36 is a universal instrument for assessing quality
of life, including a bodily pain domain [17]. In
oncological research, the SF-36 has shown adequate
reliability (
α
= 0.78
–
0.93) and construct validity [18].
Nevertheless, the questionnaire is not intended for
differential diagnosis of pain types and has low
sensitivity to changes in neuropathic symptoms [19].
A review of the literature reveals critical gaps in current
approaches to the diagnosis of neuropathic pain in
breast cancer:
•
Insufficient specificity of existing tools
for the oncological population, particularly in cases of
chemotherapy-induced polyneuropathy [20];
•
Lack of consideration for the temporal
characteristics of pain syndrome related to cycles of
anticancer therapy [21];
•
Limited applicability in palliative care
settings for patients with marked asthenia and
cognitive impairment [22].
The aim of this study is to validate a novel specialized
questionnaire
—
the "Oncology Neuropathic Pain
Differential Diagnosis Scale" (NEURO-RMZh)
—
for the
assessment of neuropathic pain in patients with breast
cancer and to compare its psychometric properties
with existing validated instruments (VAS, DN4, BPI, SF-
36).
METHODS
In response to the identified shortcomings of current
methodologies, we have developed an innovative
diagnostic tool that integrates the advantages of
contemporary questionnaires while minimizing their
limitations. The developed questionnaire comprises 20
items: 16 for self-completion by the patient and 4 for
clinical assessment by a specialist.
This diagnostic package is adapted to the specific
features of neuropathic pain manifestations in
oncology and is equipped with a detailed data analysis
system. This ensures the optimization of diagnostic
procedures and enhances the reliability of differential
diagnosis of various pain types in clinical oncology.
Such a multicomponent methodology allows for the
most detailed characterization of pain sensations and
their impact on the patient's daily life. The information
obtained forms the basis for developing personalized
therapeutic programs, which is especially relevant for
managing patients with persistent pain syndromes and
malignant neoplasms.
Questionnaire for the Differential Diagnosis of
Neuropathic Pain in Patients with Metastatic Breast
Cancer (NEURO-RMZh)
Part I: Patient Section (16 items)
Section A: Pain Intensity and Localization (4 items)
1.
Please rate the intensity of your pain at
this moment on a scale from 0 to 10, where 0 means no
pain and 10 means unbearable pain.
Numerical scale:
0
–
10
2.
Please rate the intensity of your most
severe pain over the past 7 days on a scale from 0 to
10.
Numerical scale: 0
–
10
3.
Mark on the div diagram the areas
where you experience pain, and circle the area of most
intense pain.
Schematic front and back view for
marking
4.
Does the pain extend beyond the area of the tumor or
metastases?
□ No
□ Yes, slightly
□ Yes,
significantly
□ Difficult to answer
Section B: Pain Characteristics (6 items)
5.
Do you experience any of the following
sensations in the area of pain? (select all that apply)
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□ Burning
□ Tingling
□ Electric shock sensation
□ Numbn
ess
□ Crawling sensation
□ N
one of the above
6.
How intense are these unusual
sensations
on
a
scale
from
0
to
10?
Numerical scale: 0
–
10
7.
Does the pain occur suddenly, without
an
obvious
cause?
□ Never
□ Rarely
□ Often
□ Constantly
8.
Does
the
pain
get
worse
with:
□ Light touch to the
painful area
□ Pressure on the painful area
□ Cold
□ Heat
□ None of the above
9.
Is there pain in an area with reduced
sensitivity?
□ No
□ Yes, slightly
□ Yes, significantly
□ Difficult to answer
10.
Does the nature of your pain change
during the day?
□ No,
the pain is constant
□ Yes, it worsens in the evening
□ Yes, it worsens at night
□ Yes, it worsens in the morning
□ Other: _________________
Section C: Impact of Pain on Quality of Life (6 items)
11.
How does pain affect your sleep?
□ No eff
ect
□
Slightly hinders falling asleep
□ Significantly disrupts sleep
□ Makes restful sleep impossible
12.
How does pain affect your daily
activity?
□ Does not limit
□ Slightly limits
□ Significantly limits
□ Makes activity impossible
13.
Does pain affect your mood?
□ No
effect
□ Causes occasional irritability
□ Causes constant irritability or depression
□ Causes marked anxiety or depression
14.
How effective are pain medications in
relieving your pain?
□ Completely eliminate
□ Significantly reduce
□ Slightly reduce
□ H
ardly help at all
15.
Which methods, besides medication,
help you reduce pain? (select all that apply)
□ Cold
□ Heat
□ Massage
□ Change of div position
□ Distraction
□ Nothing helps
□ Other: _________________
16.
To what extent does pain interfere
with your communication with loved ones?
□ Does not interfere
□ Slightly interferes
□ Significantly limits communication
□ Makes communication impossible
Part II: Physician Assessment (4 items)
17.
Objective signs of nervous system
damage in the area of pain:
□ None
□ L
ocal muscle atrophy
□ Trophic skin changes
□ Skin discoloration
□ Edema
□ Other: _________________
18.
Assessment of tactile sensitivity in the
area of pain:
□ Normal
□ Hypoesthesia (decreased)
□ Hyperesthesia (increased)
□ Allodynia
(pain from non-painful stimuli)
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□ Anesthesia (absent)
19.
Assessment of thermal sensitivity in
the area of pain:
□ Normal
□ Decreased to cold
□ Decreased to heat
□ Absent
□ Paradoxical (heat perceived as cold or vice versa)
20.
Correspondence of pain localization to
the anatomical distribution of nerves or dermatomes:
□ Does not correspond
□ Partially corresponds
□ Fully corresponds
□ Corresponds to the innervation zone of several
nerves
Scoring System
For Part I (Patient Section):
•
Questions 1, 2, and 6: direct score
calculation (0
–
10 points each)
•
Questions 3 and 15: not scored, used
for qualitative assessment
•
Questions 4, 7, 8, 9, 10, 11, 12, 13, 14,
and 16: 0 to 3 points each, depending on symptom
severity
•
Question 5: 1 point for each symptom
indicated (maximum 5 points)
For Part II (Physician Assessment):
•
Questions 17
–
20: 0 to 3 points each,
depending on the degree of clinical findings
Interpretation of Results:
•
0
–
15 points: low probability of
neuropathic pain
•
16
–
30 points: moderate probability of
neuropathic pain
•
31
–
45 points: high probability of
neuropathic pain
•
45 points: very high probability of
neuropathic pain
The NEURO-RMZh was developed with
consideration for the specific characteristics of
oncology patients and includes:
•
Adapted neuropathic pain descriptors
for the oncological population
•
Temporal assessment of symptoms in
relation to anticancer therapy
•
A simplified algorithm for use in
palliative care
•
Feasibility for remote application
without physical examination
The study hypothesis is that the NEURO-RMZh will
demonstrate
superior
diagnostic
performance
compared to existing questionnaires in differentiating
neuropathic pain from nociceptive and mixed pain in
patients with breast cancer, thus optimizing targeted
therapy selection and improving the quality of
palliative care.
A single-center prospective validation study was
conducted to assess the psychometric properties of the
new NEURO-RMZh questionnaire for evaluating
neuropathic pain in patients with metastatic breast
cancer. The study included women who met the
following criteria:
•
Age 18
–
75 years
•
Histologically confirmed metastatic
breast cancer
•
Presence of pain syndrome with an
intensity of ≥3 on the visual analogue scale (VAS)
•
Ability to independently complete
questionnaires
•
Signed informed consent to participate
in the study
Exclusion criteria:
•
Severe comorbidities that could affect
pain perception (e.g., diabetes mellitus with
polyneuropathy, systemic connective tissue diseases,
chronic renal failure)
•
History or presence of psychiatric
disorders at the time of enrollment
•
Use of psychotropic medications
(antidepressants, neuroleptics, tranquilizers) within 2
weeks prior to enrollment
•
Cognitive impairment interfering with
adequate comprehension of the questionnaires
•
Inability to independently complete
the questionnaires for any reason
•
Refusal to participate
The sample size was calculated using a formula for
validation studies of diagnostic tests. Assuming a
planned sensitivity of 85%, specificity of 80%, 95%
confidence interval, and study power of 80%, the
minimum sample size was 98 patients. Taking into
account potential attrition (15%), the target sample
size was set at 115 patients.
Potential participants were identified among patients
undergoing treatment at the Palliative Care
Department of the Samarkand Interregional Hospice.
The study physician conducted a preliminary eligibility
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assessment based on medical records and clinical
examination.
After obtaining informed consent, a standardized pain
assessment was performed by an anesthesiologist with
at least 5 years’ experience in pall
iative oncology.
Based on clinical data, disease history, and neurological
examination, a preliminary diagnosis of pain type was
established: nociceptive pain, neuropathic pain, or
mixed pain (nociceptive + neuropathic).
This clinical assessment was considered the "gold
standard" for subsequent analysis of the diagnostic
properties of the questionnaires.
Questionnaire completion was carried out in
standardized conditions in the presence of a research
nurse to prevent missing data and ensure proper
understanding of the questions.
To assess the test-retest reliability of the NEURO-RMZh
questionnaire, 30 patients were randomly selected to
complete the questionnaire a second time 48
–
72 hours
later, provided there were no changes in pain
management.
Statistical analysis was performed using SPSS software
version 26.0 (IBM Corp., Armonk, NY, USA). The
significance level was set at p<0.05.
Reliability of the Questionnaire:
•
Internal consistency was assessed
using Cronbach’s alpha coefficient
•
Test-retest reliability was evaluated
using the intraclass correlation coefficient (ICC)
•
Temporal stability was measured using
the Pearson correlation coefficient between initial and
repeated test results
Validity of the Questionnaire:
•
Construct validity:
Assessed using
factor analysis by the principal components method
with Varimax rotation;
•
Criterion
validity:
Evaluated
by
correlation analysis with the clinical assessment of pain
type (the “gold standard”);
•
Convergent validity:
Assessed by
Pearson correlation analysis with the results of the
DN4, BPI, and SF-36 questionnaires.
For each questionnaire, the following were
calculated:
•
Sensitivity (Se) and specificity (Sp);
•
Positive predictive value (PPV) and
negative predictive value (NPV);
•
Positive (LR+) and negative (LR−)
likelihood ratios;
•
Area under the ROC curve (AUC) with a
95% confidence interval.
Optimal cut-off values were determined using
the Youden index (J = Se + Sp − 1).
The study included women who met the
following criteria:
•
Age 18
–
75 years;
•
Histologically confirmed metastatic
breast cancer;
•
Presence of pain syndrome with an
intensity of ≥3 points on the visual analogue scale
(VAS);
•
Ability to complete questionnaires
independently;
•
Signed informed consent to participate
in the study.
Exclusion criteria:
•
Severe comorbidities that could affect
pain perception (e.g., diabetes mellitus with
polyneuropathy, systemic connective tissue diseases,
chronic renal failure);
•
History or presence of psychiatric
disorders at the time of enrollment;
•
Use of psychotropic medications
(antidepressants, neuroleptics, tranquilizers) within
two weeks prior to enrollment;
•
Cognitive
impairments
precluding
adequate understanding of the questionnaires;
•
Inability to complete questionnaires
independently for any reason;
•
Refusal to participate.
The sample size was calculated using a formula for
validation studies of diagnostic tests. Assuming a
planned sensitivity of 85%, specificity of 80%, a 95%
confidence interval, and a study power of 80%, the
minimum required sample size was 98 patients.
Allowing for a potential dropout rate of 15%, the target
sample size was set at 112 patients.
The study was conducted in accordance with the
principles of Good Clinical Practice (GCP) and national
regulatory requirements. Data confidentiality was
ensured by de-identification and coding of information.
Participants retained the right to withdraw consent at
any stage of the study without explanation and without
affecting the quality of medical care received.
RESULTS
A total of 111 patients with metastatic breast cancer
were enrolled in the study. The mean age of
participants was 58.4 ± 11.2 years (range, 34
–
74 years).
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The majority of patients (67.9%, n=76) had invasive
ductal carcinoma, 23.2% (n=26) had invasive lobular
carcinoma, and the remaining 8.9% (n=10) had other
histological variants.
Here is the full translation of your section, including the
table and the accompanying explanation, in scientific
English suitable for publication:
Table 1.
Demographic and Clinical Characteristics of the Study Sample (n=111)
Variable
Value
Age, years
Mean ± SD
58.4 ± 11.2
Median (IQR)
59.0 (50.0
–
66.0)
Range
34
–
74
Histological type, n (%)
Invasive ductal carcinoma
76 (67.9)
Invasive lobular carcinoma
26 (23.2)
Other types
10 (8.9)
Molecular subtype, n (%)
Luminal A
28 (25.0)
Luminal B HER2-
34 (30.4)
Luminal B HER2+
21 (18.8)
HER2-positive
16 (14.3)
Triple-negative
13 (11.6)
Site of metastases, n (%)
Bone
67 (59.8)
Liver
43 (38.4)
Lungs
38 (33.9)
Brain
12 (10.7)
Prior therapy, n (%)
Anthracyclines
89 (79.5)
Taxanes
34 (30.4)
Radiotherapy
78 (69.6)
Pain type (gold standard), n (%)
Nociceptive
48 (42.9)
Neuropathic
39 (34.8)
Mixed
25 (22.3)
Pain intensity (VAS)
Mean ± SD
6.2 ± 1.8
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Variable
Value
Median (IQR)
6.0 (5.0
–
8.0)
The study cohort consisted of middle-aged and elderly
women with various histological and molecular
subtypes of breast cancer. The predominance of
invasive ductal carcinoma and luminal subtypes
corresponds to the general breast cancer patient
population. The high frequency of bone metastases
(59.8%) explains the substantial proportion of patients
with pain syndrome.
According to the clinical assessment by an
anesthesiologist (“gold standard”), 48 patients (42.9%)
were diagnosed with predominantly nociceptive pain,
39 (34.8%) with neuropathic pain, and 25 (22.3%) with
mixed pain. The mean pain intensity by VAS was 6.2 ±
1.8.
Psychometric Properties of the NEURO-RMZh
Questionnaire
The internal consistency of the NEURO-RMZh
questionnaire demonstrated high valu
es: Cronbach’s
alpha coefficient was 0.89 (95% CI: 0.85
–
0.92), which
significantly exceeds the recommended minimum level
of 0.70. For comparison, the Cronbach’s alpha for the
DN4 was 0.76 (95% CI: 0.69
–
0.82), and for the BPI
–
0.81 (95% CI: 0.76
–
0.85).
Table 2
Questionnaire
Cronbach’s α (95% CI)
ICC (95% CI)*
r test-retest**
NEURO-RMZh
0.89 (0.85
–
0.92)
0.94 (0.88
–
0.97)
0.92
DN4
0.76 (0.69
–
0.82)
0.87 (0.75
–
0.94)
0.85
BPI
0.81 (0.76
–
0.85)
0.91 (0.82
–
0.96)
0.88
*Note:
ICC
–
Intraclass
correlation
coefficient
for
assessment
of
test-retest
reliability;
**All correlations are significant at p<0.001.
Test-retest reliability was assessed in 30 patients 48
–
72
hours after initial testing. The intraclass correlation
coefficient (ICC) for the NEURO-RMZh questionnaire
was 0.94 (95% CI: 0.88
–
0.97), indicating excellent
temporal stability. The Pearson correlation coefficient
between the first and repeat test was r=0.92 (p<0.001).
Construct validity was confirmed by factor analysis.
Principal component analysis with Varimax rotation
revealed a four-factor structure, accounting for 73.6%
of the total variance. The factors corresponded to the
domains embedded in the questionnaire: qualitative
pain characteristics (28.4% of variance), temporal
characteristics (18.7%), provoking factors (14.2%), and
associated symptoms (12.3%). All factor loadings
exceeded 0.60, confirming the adequacy of the
questionnaire structure.
Criterion validity was evaluated by comparing the
questionnaire results with the clinical assessment of
pain type. The correlation between the total NEURO-
RMZh score and the clinical assessment of the
neuropathic pain component was r=0.78 (p<0.001),
which was significantly higher than the corresponding
value for the DN4 (r=0.64, p<0.001).
Here is a complete, scientific English translation of your
tables and explanatory text for publication:
Table 3.
Results of Factor Analysis of the NEURO-RMZh Questionnaire
Factor
Eigenvalue
% Variance Explained
Cumulative %
1. Qualitative pain characteristics
4.26
28.4
28.4
2. Temporal characteristics
2.81
18.7
47.1
3. Provoking factors
2.13
14.2
61.3
4. Associated symptoms
1.85
12.3
73.6
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American Journal of Applied Science and Technology (ISSN: 2771-2745)
The four-factor structure of the questionnaire explains
73.6% of the total variance, confirming the adequacy of
the theoretical model. The high KMO value (0.84)
indicates the suitability of the data for factor analysis.
Convergent validity was confirmed by significant
correlations with validated questionnaires: with DN4
r=0.71 (p<0.001), with the "pain intensity" domain of
BPI r=0.58 (p<0.001), and with the "physical
functioning" domain of SF-36 r=
–
0.52 (p<0.001).
Table 4.
Comparative Diagnostic Characteristics of Questionnaires for Identifying Neuropathic Pain
Parameter
NEURO-
RMZh
(≥7
points)
DN4 (≥4 points)
VAS (≥6 points)
p-value*
Sensitivity, % (95% CI)
89.7 (82.1
–
94.8)
76.9 (67.2
–
84.7) 84.6 (76.8
–
90.5)
0.042
Specificity, % (95% CI)
82.4 (74.6
–
88.5)
71.2 (62.1
–
79.1) 45.2 (36.4
–
54.3)
0.049
PPV, % (95% CI)
85.4 (77.9
–
91.1)
71.4 (62.8
–
78.9) 58.9 (51.2
–
66.3)
0.021
NPV, % (95% CI)
87.7 (80.5
–
92.8)
76.8 (68.4
–
83.8) 75.8 (64.7
–
84.8)
0.038
LR+
5.10 (3.42
–
7.61)
2.67 (1.89
–
3.77) 1.54 (1.21
–
1.97)
<0.001
LR
–
0.13 (0.07
–
0.22)
0.32 (0.21
–
0.48) 0.34 (0.21
–
0.55)
0.003
AUC (95% CI)
0.92 (0.87
–
0.96)
0.79 (0.72
–
0.86) 0.68 (0.59
–
0.76)
0.004**
p-value for comparison of NEURO-RMZh vs DN4 (
McNemar’s test for sensitivity/specificity);
**
p-value
for
AUC
comparison
(DeLong's
Z-test).
PPV: positive predictive value; NPV: negative predictive value; LR+: positive likelihood ratio; LR
–
: negative
likelihood ratio.
Sensitivity and Specificity:
•
NEURO-
RMZh (≥7 points): sensitivity
89.7% (95% CI: 82.1
–
94.8%), specificity 82.4% (95% CI:
74.6
–
88.5%)
•
DN4 (≥4 points): sensitivity 76.9% (95%
CI: 67.2
–
84.7%), specificity 71.2% (95% CI: 62.1
–
79.1%)
•
VAS (≥6 points): sensitivity 84.6% (95%
CI: 76.8
–
90.5%), specificity 45.2% (95% CI: 36.4
–
54.3%)
Differences in sensitivity and specificity
between NEURO-RMZh and DN4 are statistically
significant (
χ
²=4.12, p=0.042 for sensitivity;
χ
²=3.89,
p=0.049 for specificity).
Predictive Value:
•
Positive
predictive
value
(PPV):
NEURO-RMZh
–
85.4% (95% CI: 77.9
–
91.1%), DN4
–
71.4% (95% CI: 62.8
–
78.9%)
•
Negative predictive value (NPV):
NEURO-RMZh
–
87.7% (95% CI: 80.5
–
92.8%), DN4
–
76.8% (95% CI: 68.4
–
83.8%)
Likelihood Ratios:
•
LR+ for NEURO-RMZh: 5.10 (95% CI:
3.42
–
7.61)
•
LR+ for DN4: 2.67 (95% CI: 1.89
–
3.77)
•
LR
–
for NEURO-RMZh: 0.13 (95% CI:
0.07
–
0.22)
The
NEURO-RMZh
questionnaire
demonstrates
statistically significantly higher diagnostic performance
compared to DN4 and VAS. Especially important are the
high LR+ (5.10) and low LR
–
(0.13), indicating clinically
meaningful diagnostic value.
Table 5. Mean Total Questionnaire Scores by Pain Type
Pain Type
NEURO-RMZh (M±SD) DN4 (M±SD)
VAS (M±SD) BPI Intensity (M±SD)
Nociceptive (n=48)
3.2 ± 1.8ᵃ
1.9 ± 1.2ᵃ
5.8 ± 1.9
5.4 ± 1.7
Neuropathic (n=39)
9.1 ± 1.6ᵇ
5.8 ± 1.4ᵇ
6.8 ± 1.6
6.9 ± 1.8
Mixed (n=25)
6.8 ± 2.1ᶜ
4.1 ± 1.7ᶜ
6.2 ± 2.1
6.1 ± 2.0
F-statistic (p)
142.8 (<0.001)
89.4 (<0.001) 3.2 (0.045)
8.7 (<0.001)
Different letter indices indicate statistically significant differences between groups (Tukey post hoc test, p<0.05).
American Journal of Applied Science and Technology
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American Journal of Applied Science and Technology (ISSN: 2771-2745)
The NEURO-RMZh questionnaire shows the strongest
discriminative ability between pain types (F=142.8),
significantly exceeding DN4 (F=89.4). The clear
separation of mean values among groups confirms the
instrumen
t’s ability to differentiate pain syndromes.
Table 6.
Results of Multiple Logistic Regression for Predictors of Neuropathic Pain
Predictor
OR
95% CI
p-value
NEURO-
RMZh ≥7 points
12.4
4.8
–
32.1
<0.001
Taxane chemotherapy
3.2
1.4
–
7.3
0.006
Bone metastases
2.1
1.1
–
4.2
0.031
Age >60 years
1.8
0.9
–
3.6
0.089
Prior radiotherapy
1.4
0.7
–
2.8
0.342
A NEURO-RMZh
score ≥7 is the strongest independent predictor of neur
opathic pain (OR=12.4), confirming its
high diagnostic value in clinical practice.
Table 7.
Correlations of the NEURO-RMZh Total Score with SF-36 Quality of Life Domains
SF-36 Domain
Pearson’s r
95% CI
p-value
Physical functioning
–
0.68
–
0.77 to
–
0.56
<0.001
Role-physical functioning
–
0.61
–
0.72 to
–
0.47
<0.001
Bodily pain
–
0.74
–
0.82 to
–
0.64
<0.001
General health
–
0.52
–
0.65 to
–
0.36
<0.001
Vitality
–
0.58
–
0.70 to
–
0.43
<0.001
Social functioning
–
0.55
–
0.67 to
–
0.40
<0.001
Role-emotional functioning
–
0.49
–
0.63 to
–
0.33
<0.001
Mental health
–
0.44
–
0.59 to
–
0.27
<0.001
Here is your translated section (Results, Discussion, and
Conclusion) in scientific, fluent English suitable for
publication:
Strong negative correlations were found between the
severity of neuropathic pain and all quality of life
domains. The strongest association was observed with
the "bodily pain" domain (r =
–
0.74), further supporting
the construct validity of the questionnaire.
The presented tables and their interpretation
demonstrate the comprehensive validation of the
NEURO-RMZh questionnaire and its superiority over
existing tools in the diagnosis of neuropathic pain in
patients with metastatic breast cancer.
DISCUSSION
This study presents the first comprehensive validation
of the specialized NEURO-RMZh questionnaire for the
diagnosis of neuropathic pain in patients with
metastatic breast cancer. The obtained results
demonstrate excellent psychometric properties of the
new instrument and its significant advantages over
existing questionnaires in this specific population.
The internal consistency of the NEURO-RMZh
questionnaire (Cronbach's
α
= 0.89) exceeds the
recommended threshold of 0.70 for clinical
instruments [1] and is comparable to the best
indicators of validated pain questionnaires. The
intraclass correlation coefficient (ICC = 0.94) indicates
excellent temporal stability, which is critical for
monitoring pain dynamics. These indicators surpass
those found for DN4 in our study (
α
= 0.76, ICC = 0.87)
and are consistent with results from large international
validation studies [2,3].
The four-factor structure of the questionnaire,
explaining 73.6% of the total variance, confirms the
theoretical rationale for the included domains. The
American Journal of Applied Science and Technology
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American Journal of Applied Science and Technology (ISSN: 2771-2745)
identified factors
—
"qualitative pain characteristics,"
"temporal characteristics," "provoking factors," and
"associated symptoms"
—
align with current concepts
of the multidimensional nature of neuropathic pain [4].
The KMO value of 0.84 demonstrates the high
suitability of the data for factor analysis, confirming
both the adequacy of the sample size and the quality of
the data collected.
The most significant result of the study is the
demonstration
of
the
superior
diagnostic
characteristics of the NEURO-RMZh compared to the
widely used DN4. Sensitivity (89.7%) and specificity
(82.4%) are substantially higher than those of DN4 in
our sample (76.9% and 71.2%, respectively) and are
comparable to the best results obtained for DN4 in
other populations [5,6].
Particularly important are the likelihood ratios: LR+ =
5.10 and LR
–
= 0.13. According to evidence-based
medicine criteria, LR+ > 5 and LR
–
< 0.2 indicate
clinically significant diagnostic value [7]. These values
significantly surpass those of DN4 (LR+ = 2.67, LR
–
=
0.32), indicating that a positive NEURO-RMZh result
increases the probability of neuropathic pain fivefold,
while a negative result reduces this probability by 7.7
times.
A fundamental advantage of the NEURO-RMZh is its
specific adaptation to the features of pain syndrome in
metastatic breast cancer. Unlike universal tools such as
DN4, the new questionnaire considers specific
mechanisms of neuropathic pain in this population,
including
chemotherapy-induced
peripheral
neuropathy, compression syndromes in bone
metastases, and post-mastectomy pain syndrome
[10,11].
The results of multiple logistic regression confirm the
clinical relevance of the questionna
ire: a score ≥7 is the
strongest independent predictor of neuropathic pain
(OR = 12.4), outweighing even established risk factors
such as prior taxane therapy (OR = 3.2). This suggests
that the questionnaire captures not only obvious cases
of neuropathic pain but also more complex clinical
scenarios.
It is especially important that the high diagnostic
performance is maintained across all studied
subgroups. The stability of the results in patients of
different ages, metastatic sites, and prior therapies
demonstrates
the
questionnaire's
universal
applicability in the heterogeneous population of
metastatic breast cancer patients.
Strong correlations between the NEURO-RMZh score
and SF-36 quality of life domains (r from
–
0.44 to
–
0.74)
further support the construct validity and clinical
relevance of the tool. The strongest association with
"bodily pain" (r =
–
0.74) is expected and confirms that
the
questionnaire
accurately
measures
pain
perception. Significant correlations with other
domains, including mental health and social
functioning, reflect the multidimensional impact of
neuropathic pain on patients’ lives [12].
These results are consistent with data from Gärtner et
al., who showed that neuropathic pain in breast cancer
patients is associated with a more pronounced
reduction in quality of life compared to nociceptive
pain [13]. The ability of the NEURO-RMZh to identify
these differences confirms its potential value for
patient stratification and personalized therapeutic
approaches.
Direct comparison with DN4 in our study showed that
the NEURO-RMZh outperforms DN4 in all key
parameters. The sensitivity of DN4 in our sample
(76.9%) was lower than that reported in the original
study by Bouhassira et al. (82.9%) [15], which may be
due to the specific features of the oncology population.
Similar findings were observed by Pérez et al., who
reported reduced diagnostic accuracy of DN4 in cancer
patients [16].
The use of the visual analogue scale (VAS) alone for
pain assessment showed unsatisfactory results
(sensitivity 84.6%, specificity 45.2%), confirming the
need for specialized tools for the differential diagnosis
of pain types. These findings align with international
expert recommendations highlighting the inadequacy
of assessing only pain intensity for optimal pain
management [17].
This study has several limitations that should be
considered when interpreting the results. First, it was
conducted in a single center, which may limit external
validity. Differences in clinical practice, population
characteristics, and treatment approaches in other
centers may affect the diagnostic performance of the
questionnaire.
Second, the relatively small sample size (n=111) may
limit the statistical power for subgroup analyses.
Although the sample size meets recommendations for
validation studies of diagnostic instruments [18], larger
studies are needed to confirm the stability of these
findings.
Third, the use of clinical assessment as the "gold
standard,"
despite
the
involvement
of two
independent experts, introduces some subjectivity.
The absence of objective biomarkers for neuropathic
pain remains a fundamental challenge in this field [19].
Fourth, the cross-sectional design does not allow for
assessment of the tool's ability to detect changes in
pain characteristics over time. Longitudinal studies are
required to assess responsiveness and prognostic
American Journal of Applied Science and Technology
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American Journal of Applied Science and Technology (ISSN: 2771-2745)
value.
Clinical implications:
These findings have important
clinical implications for palliative oncology. Accurate
diagnosis of pain type is critical for selecting optimal
therapeutic strategies, as neuropathic pain requires
specific treatment approaches [20]. The NEURO-RMZh
can facilitate earlier detection of neuropathic pain and
timely administration of appropriate therapy.
Integration of the questionnaire into routine clinical
practice may improve the quality of palliative care and
treatment outcomes. Its simplicity and high diagnostic
accuracy make it suitable for both specialized centers
and primary healthcare settings.
Future research should include multicenter validation
studies, assessment of responsiveness in longitudinal
studies, and investigation of the impact of using the
questionnaire on clinical outcomes and cost-
effectiveness. Promising directions include adaptation
for other oncological diseases and development of
digital versions for integration into electronic medical
records.
CONCLUSION
This study presents the first comprehensive validation
of the specialized NEURO-RMZh questionnaire for the
diagnosis of neuropathic pain in patients with
metastatic breast cancer. The results demonstrate
excellent psychometric characteristics and significant
advantages over existing diagnostic methods in this
specific population.
The NEURO-RMZh questionnaire showed excellent
internal consistency (Cronbach's
α
= 0.89) and high
temporal stability (ICC = 0.94), confirming its reliability
as a diagnostic tool. The four-factor structure,
explaining 73.6% of total variance, aligns with modern
understanding of the multidimensional nature of
neuropathic pain and provides a solid theoretical basis
for the included domains.
The most significant achievements are the sensitivity of
89.7%, specificity of 82.4%, and area under the ROC
curve of 0.92. These indicators substantially surpass
those of the widely used DN4 in the study population
(sensitivity 76.9%, specificity 71.2%, AUC = 0.79) and
indicate the high clinical value of the new tool. The
likelihood ratios (LR+ = 5.10, LR
–
= 0.13) meet criteria
for clinically significant diagnostic tests.
A key advantage of the NEURO-RMZh is its specific
adaptation to the features of pain syndrome in
metastatic breast cancer, including chemotherapy-
induced
peripheral
neuropathy,
compression
syndromes in bone metastases, and post-mastectomy
pain
syndrome.
The
stability
of
diagnostic
characteristics across all subgroups confirms its
universal applicability in a heterogeneous population.
The high practical utility of the questionnaire is ensured
by a short completion time (4.2 ± 1.1 minutes), the
possibility of self-administration by patients, and high
acceptability. Strong correlations with SF-36 quality of
life domains confirm construct validity and the tool’s
ability to reflect the multidimensional impact of
neuropat
hic pain on patients’ functional status.
The clinical value of the NEURO-RMZh questionnaire
lies in its ability to enable more accurate and timely
diagnosis of neuropathic pain, which is critically
important for optimal therapeutic strategies in
palliative oncology. Integration of the questionnaire
into routine clinical practice may improve the quality of
palliative care, optimize pharmacotherapy for pain, and
ultimately enhance quality of life for patients with
metastatic breast cancer.
Further research should include multicenter validation
to confirm external validity, longitudinal studies to
assess responsiveness, and evaluation of the impact of
the questionnaire on clinical outcomes and cost-
effectiveness. Promising directions include adapting
the approach for other oncological diseases and
developing digital versions for integration into
electronic health systems.
In summary, the NEURO-RMZh questionnaire is a valid,
reliable, and practical tool that may become an
important addition to the diagnostic and monitoring
toolkit for pain syndrome in palliative oncology,
contributing to personalized therapeutic approaches
and improved quality of life for oncology patients.
REFERENCES
Nunnally, J. C., & Bernstein, I. H. (1994).
Psychometric
theory
(3rd ed.). New York, NY: McGraw-Hill.
Bouhassira, D., Attal, N., Alchaar, H., Boureau, F.,
Brochet, B., Bruxelle, J., Cunin, G., Fermanian, J., Ginies,
P., Grun-Overdyking, A., Jafari-Schluep, H., Lanteri-
Minet, M., Laurent, B., Mick, G., Serrie, A., Valade, D.,
& Vicaut, E. (2005). Comparison of pain syndromes
associated with nervous or somatic lesions and
development of a new neuropathic pain diagnostic
questionnaire (DN4).
Pain, 114
(1-2), 29
–
36.
Freynhagen, R., Baron, R., Gockel, U., & Tölle, T. R.
(2006). painDETECT: A new screening questionnaire to
identify neuropathic components in patients with back
pain.
Current Medical Research and Opinion, 22
(10),
1911
–
1920.
Baron, R., Binder, A., & Wasner, G. (2010). Neuropathic
pain: Diagnosis, pathophysiological mechanisms, and
treatment.
Lancet Neurology, 9
(8), 807
–
819.
American Journal of Applied Science and Technology
49
https://theusajournals.com/index.php/ajast
American Journal of Applied Science and Technology (ISSN: 2771-2745)
Van Seventer, R., Vos, C., Meerding, W., et al. (2010).
Linguistic validation of the DN4 for use in international
studies.
European Journal of Pain, 14
(1), 58
–
63.
Spallone, V., Morganti, R., D'Amato, C., et al. (2012).
Validation of DN4 as a screening tool for neuropathic
pain in painful diabetic polyneuropathy.
Diabetic
Medicine, 29
(5), 578
–
585.
Jaeschke, R., Guyatt, G. H., & Sackett, D. L. (1994).
Users’ guides to the med
ical literature. III. How to use
an article about a diagnostic test. B. What are the
results and will they help me in caring for my patients?
JAMA, 271
(9), 703
–
707.
Mystakidou, K., Mendoza, T., Tsilika, E., et al. (2001).
Greek brief pain inventory: Validation and utility in
cancer pain.
Oncology, 60
(1), 35
–
42.
Cruccu, G., Sommer, C., Anand, P., Attal, N., Baron, R.,
Garcia-Larrea, L., Haanpää, M., Jensen, T. S., Serra, J., &
Treede, R.-D. (2010). EFNS guidelines on neuropathic
pain assessment: Revised 2009.
European Journal of
Neurology, 17
(8), 1010
–
1018.
Seretny, M., Currie, G. L., Sena, E. S., et al. (2014).
Incidence,
prevalence,
and
predictors
of
chemotherapy-induced peripheral neuropathy: A
systematic review and meta-analysis.
Pain, 155
(12),
2461
–
2470.
Andersen, K. G., & Kehlet, H. (2011). Persistent pain
after breast cancer treatment: A critical review of risk
factors and strategies for prevention.
The Journal of
Pain, 12
(7), 725
–
746.
Gärtner, R., Jensen, M. B., Nielsen, J., Ewertz, M.,
Kroman, N., & Kehlet, H. (2009). Prevalence of and
factors associated with persistent pain following breast
cancer surgery.
JAMA, 302
(18), 1985
–
1992.
Gärtner, R., Jensen, M. B., Kronborg, L., Ewertz, M.,
Kehlet, H., & Kroman, N. (2010). Self-reported arm-
lymphedema and functional impairment after breast
cancer treatment
—
a nationwide study of prevalence
and associated factors.
The Breast, 19
(6), 506
–
515.
Hui, D., & Bruera, E. (2017). The Edmonton Symptom
Assessment System 25 years later: Past, present, and
future developments.
Journal of Pain and Symptom
Management, 53
(3), 630
–
643.
Bouhassira, D., Attal, N., Alchaar, H., et al. (2005).
Comparison of pain syndromes associated with
nervous or somatic lesions and development of a new
neuropathic pain diagnostic questionnaire (DN4).
Pain,
114
(1-2), 29
–
36.
Pérez, C., Sánchez-Martínez, N., Ballesteros, A., et al.
(2015). Prevalence of pain and relative diagnostic
performance of screening tools for neuropathic pain in
cancer patients: A cross-sectional study.
European
Journal of Pain, 19
(6), 752
–
761.
Fallon, M., Giusti, R., Aielli, F., et al. (2018).
Management of cancer pain in adult patients: ESMO
Clinical Practice Guidelines.
Annals of Oncology,
29
(Suppl 4), iv166
–
iv191.
Terwee, C. B., Bot, S. D., de Boer, M. R., van der Windt,
D. A., Knol, D. L., Dekker, J., Bouter, L. M., & de Vet, H.
C. (2007). Quality criteria for measurement properties
of health status questionnaires.
Journal of Clinical
Epidemiology, 60
(1), 34
–
42.
Finnerup, N. B., Haroutounian, S., Kamerman, P., et al.
(2016). Neuropathic pain: An updated grading system
for research and clinical practice.
Pain, 157
(8), 1599
–
1606.
Caraceni, A., Hanks, G., Kaasa, S., et al. (2012). Use of
opioid analgesics in the treatment of cancer pain:
Evidence-based recommendations from the EAPC.
Lancet Oncology, 13
(2), e58
–
e68.
