Relationship between Nontraumatic Shoulder Disorders and Neuropathic Pain: Retrospective Observational Analyses of Clinical Features and Background Factors

Background Accurate identification of neuropathic pain is necessary for appropriate treatment; however, the relationship between nontraumatic shoulder disorders and neuropathic pain remains unknown. Therefore, this retrospective observational study aimed to investigate the relationship, features, background factors, and prevalence of neuropathic pain among patients with nontraumatic shoulder disorders. Methods We evaluated 198 patients who visited our outpatient clinic, which specializes in shoulder disorders, from April 2015 to March 2016. The patients' age, sex, affected side, diagnosis, and pain duration were recorded, and the results of physical examination, including passive range of motion, impingement sign, and muscular strength assessments, were analyzed. The presence of neuropathic pain was assessed using the painDETECT questionnaire. Participants were divided into two groups according to the presence of neuropathic pain. Pain intensity was assessed using a visual analog scale, and the patient's mental status was assessed using the short-form McGill Pain Questionnaire and Hospital Anxiety and Depression Scale. The scores were compared between the groups. Results Neuropathic pain was observed in 7.6% of patients. The visual analog scale score for pain, short-form McGill Pain Questionnaire score, and Hospital Anxiety and Depression Scale score were significantly associated with the presence of neuropathic pain in the univariate analysis. Patient background factors and physical function were not associated with the presence of neuropathic pain. The prevalence of neuropathic pain in patients with frozen shoulder was 33.3%, which was significantly higher than that in patients with other shoulder disorders. Conclusion The occurrence of neuropathic pain may aggravate pain in patients with nontraumatic shoulder disorders. Neuropathic pain was not a rare condition in patients with nontraumatic shoulder disorders, particularly in those with frozen shoulder. The coexistence of neuropathic pain cannot be determined from background factors or physical function. Accurate diagnosis of neuropathic pain is essential in patients with nontraumatic shoulder disorders.


Introduction
Neuropathic pain is defned as "pain caused by a lesion or disease of the somatosensory system" [1] and is associated with allodynia and hyperalgesia [2].Generally, nociceptive pain and neuropathic pain have diferent clinical presentations and require diferent treatment approaches [3].Often, neuropathic pain is unresponsive to traditional analgesics and is sometimes refractory to other pharmacotherapies [3][4][5].Terefore, accurate identifcation of neuropathic pain is necessary for appropriate treatment.However, neuropathic pain is underestimated in many cases, resulting in inadequate treatment [6].Chronic pain, including neuropathic pain, is underestimated worldwide, and it has been pointed out that correct pain assessment by specialists and scoring of pain intensity at each visit are needed [7].However, a previous survey of anesthesiologists reported a low interest concerning the use of pain scales in the treatment of chronic pain [8], suggesting that chronic pain, including neuropathic pain, is difcult to treat.Adequate pain care should be regarded as a right and be effectively guaranteed to patients with chronic pain [9].In this context, accurate evaluation and treatment of chronic pain and related neuropathic pain are desirable.
Phantom pain following limb amputation is a well-known example of neuropathic pain in patients with orthopedic disorders.Recently, neuropathic pain has been associated with nontraumatic orthopedic disorders, such as osteoarthritis of the knee or hip, lower back pain, and rheumatoid arthritis [10][11][12].In shoulder disorders, neuropathic pain is known to be associated with rotator cuf tears.Although several studies have reported the relationship between neuropathic pain and pain intensity in patients with rotator cuf tears [13,14], the relationship between neuropathic pain and other nontraumatic shoulder disorders, except for rotator cuf tears, was not clarifed.Moreover, the nature of pain in patients with neuropathic pain has not been elucidated.
Terefore, this study aimed to determine the relationship between neuropathic pain and pain in various nontraumatic shoulder disorders and to identify characteristics and background factors in patients with neuropathic pain in shoulder disorders.We hypothesized that neuropathic pain is negatively associated with pain in patients with rotator cuf tears and in those with various nontraumatic shoulder disorders.

Ethics. Te Institutional Ethical Review Board for
Medical Research involving human subjects approved this cross-sectional observational study (approval number: 14-74).Te research was performed in accordance with the tenets of the Declaration of Helsinki.All participants provided written informed consent after receiving an appropriate explanation of the study.

Participants.
Patients who visited our outpatient clinic, which specializes in shoulder disorders, from April 2015 to March 2016 were retrospectively evaluated.Te inclusion criterion was as follows: presence of nontraumatic shoulder disorders, such as degenerative rotator cuf tear or osteoarthritis.Te exclusion criteria were as follows: history of previous trauma, previous surgery, or any other treatment to the afected shoulder; cervical spine disorders or neuromuscular disease; bilateral cases; and refusal to participate.Te study population comprised 118 male and 80 female individuals (average age: 62.7 years; standard deviation (SD): 11.9 years; range: 26-85 years).Te mean duration of pain was 8.3 months (SD: 15.4 months; range: 0.03-132.0months).Based on the International Association for the Study of Pain defnition of chronic pain (pain lasting >3 months), 80 patients had acute pain and 118 had chronic pain.Physical examination of participants was conducted to evaluate the passive range of motion (ROM), muscular strength, and impingement signs.Te upper extremity ROM was evaluated in four positions (ROM in fexion, abduction, external rotation, and internal rotation), with the patient in the sitting position.Te internal rotation ROM was assessed based on the highest spinal segment that patients could reach with their thumb.Te spinal segment was converted to a numerical value, as described previously [15].Muscular strength was assessed during abduction and external rotation.In particular, muscular strength during abduction was assessed with the patient's arm at 90 °of abduction and the palm down, whereas muscular strength during external rotation was assessed with the arm at the side, with 90 °of elbow fexion, and a neutral position in pronation/supination. Te peak isometric muscular strength was assessed using a digital myodynamometer (Micro FET, Hoggan Health Industries Inc., West Jordan, UT, USA) positioned at the distal end of the arm.Te impingement sign was assessed in the Neer and Hawkins positions [16,17]; it was considered positive when impingement sign positivity was observed in at least one of these positions.

Radiographic Evaluation.
Plain radiographs of both shoulders were obtained in anterior-posterior, scapular-Y view, and axial directions.Magnetic resonance imaging (MRI) or ultrasound examination was performed when deemed necessary by the treating physician to evaluate soft tissue status.Computed tomography was performed when it was necessary to evaluate bone morphology.

Shoulder Disorder Diagnosis.
Diagnosis was guided by a combination of physical examination and imaging fndings.A rotator cuf tear was identifed when a rotator cuf footprint avulsion was visible on MRI or ultrasound.Subacromial impingement syndrome was diagnosed when patients had a positive subacromial impingement sign [16,17] without rotator cuf avulsion.A frozen shoulder was diagnosed when there was (1) history of pain and stifness for >1 month, (2) passive ROM limitation <100 °of fexion and <10 °of external rotation and internal rotation (ffth lumbar vertebra or below), and (3) normal radiographic appearance [18].Osteoarthritis was diagnosed if the patient had an osteoarthritic change with the Samilson-Prieto classifcation ≥1 on plain anterior-posterior radiography [19,20].Calcifc tendinitis was diagnosed if the patient had calcifcation in the subacromial space on plain anterior-posterior radiography [21].

Neuropathic Pain Diagnosis.
Neuropathic pain is usually diagnosed based on responses to a self-reported questionnaire regarding pain, such as painDETECT [22], which has been used worldwide for neuropathic pain diagnosis in various clinical settings [23].In this study, the Japanese version of painDETECT was adopted for diagnosis of neuropathic pain.Te validity and reliability of this version 2 Anesthesiology Research and Practice have been demonstrated previously [24], and it is widely used in Japan [25,26].Te study patients completed the questionnaire during their frst hospital visit.Using pain-DETECT, neuropathic pain is defned as a total score of ≥19 points [22]; this threshold was used to evaluate neuropathic pain prevalence in patients with shoulder disorders.
2.7.Pain Severity Assessment.Pain severity was assessed using a 100 mm visual analog scale (VAS) during the patients' frst hospital visit.Patients were asked about their pain intensity over the preceding 3 days, including the day of the frst visit.
Pain at rest, pain on motion, and pain during the night were assessed separately.Using the questions in the painDETECT, pain at the frst visit as well as the most severe pain and average pain experienced in the past 4 weeks before the frst visit were also investigated using a numerical rating scale.

Patient's Mental Status Assessment.
Patients' distress was assessed on the frst visit using the Japanese version of the short-form McGill Pain Questionnaire (SF-MPQ) [27].Te SF-MPQ pain scale comprises 15 questions related to patients' distress due to pain and was originally written in English.Te Japanese version of the SF-MPQ has been proven to be reliable, valid, and equivalent to the original questionnaire [28].Patients rate each question on a 4-point intensity scale as follows: 0 � none, 1 � mild, 2 � moderate, and 3 � severe.Te questions are divided into two components to assess the intensity of pain and the afected mental status separately.In this study, both the total score and the scores of each component were evaluated.
Te patients' mental status was evaluated during the frst hospital visit using the Hospital Anxiety and Depression Scale (HADS) [29], which has been widely used for diagnosing depression and anxiety [30].In this study, both HADS-depression (HADS-D) and HADS-anxiety (HADS-A) were used [29,31].
2.9.Neuropathic Pain Prevalence.Te prevalence of neuropathic pain was studied for the entire study population and for patients with each shoulder disorder.First, this prevalence was evaluated in all participants, and then, it was computed and compared for each nontraumatic shoulder disorder.

Statistical Analysis.
Te participants were divided into two groups according to the presence or absence of neuropathic pain: groups with and without neuropathic pain.Patient demographics and all scale scores were compared between these two groups.Continuous variables were compared using the t-test or Mann-Whitney U test.Categorical variables were compared using the chi-squared test or Fisher's exact test.
As the outpatient data were retrospectively analyzed, no prior power analysis was performed for recruitment.Instead, efect sizes and confdence intervals for t-tests between the two groups were described to statistically examine the impact of neuropathic pain on pain in patients with nontraumatic shoulder disorders.Furthermore, to determine whether there were any diferences in the prevalence of neuropathic pain among patients with fve nontraumatic shoulder disorders, the prevalence for each disorder was compared using Fisher's exact test adjusted with Bonferroni's method.
All statistical analyses were conducted using SPSS version 26 (IBM Japan, Tokyo, Japan).Results are considered statistically signifcant at P values <0.05.

Results
A total of 296 patients visited our outpatient clinic during the study period.Of these, 213 had nontraumatic shoulder disorders.Fifteen patients were excluded from the study, as they met the exclusion criteria, had missing data, or did not agree to participate.In total, 93.0% of patients who attended our clinic during the study period with nontraumatic shoulder disorders were included (Figure 1).

Demographics and Features of Patients with Neuropathic
Pain.All patients completed all questionnaires regarding demographic characteristics and clinical background, as well as physical examination tests.Neuropathic pain was observed in 7.6% of subjects (n � 15).No diferences in background factors were noted between patients with and without neuropathic pain (Table 1).Table 2 presents the details of participants' diagnoses.
Pain at rest, pain on motion, and pain during the night were signifcantly more severe in patients with neuropathic pain.Te efect sizes and 95% confdence intervals of the diferences between the two groups in mean pain intensity at rest, on motion, and during the night are shown in Table 3. Te most severe pain in the past 4 weeks before the frst visit was not diferent between the two groups.In contrast, the average pain during the past 4 weeks was signifcantly more severe in patients with neuropathic pain.Te analysis of the SF-MPQ results revealed that patients with neuropathic pain had higher total, sensation, and emotion scores (Table 1).Tere was a statistically signifcant diference in the total HADS scores between the two groups (Table 1).Patients with neuropathic pain had a higher HADS-D score than those without neuropathic pain; however, there were no statistically signifcant diferences in the HADS-A scores between the two groups.Physical examinations did not reveal any signifcant diferences between these two groups (Table 1).

Neuropathic Pain Prevalence in Diferent Shoulder
Disorders.Te prevalence of neuropathic pain was shown to be unevenly distributed according to Fisher's exact test.Tis prevalence was signifcantly higher in patients with frozen shoulder than in patients with other shoulder disorders after Bonferroni's adjustment (Table 4).

Discussion
In this study, we examined the relationship, features, background factors, and prevalence of neuropathic pain in patients with nontraumatic shoulder disorders.important fndings were that 7.6% of patients with shoulder disorders were afected by neuropathic pain and that neuropathic pain was negatively associated with pain in patients with rotator cuf tears and in those with various nontraumatic shoulder disorders, as hypothesized.Te VAS scores for pain at rest, on motion, and during the night and the SF-MPQ and HADS scores were signifcantly associated with neuropathic pain.Tere were no diferences in background factors or in the results of physical examination between patients with and without neuropathic pain.Te prevalence of neuropathic pain in patients with frozen shoulder was signifcantly higher than that in patients with other shoulder disorders.

Neuropathic Pain in Orthopedic
Disorders.Phantom limb pain after amputation is a typical example of neuropathic pain in patients with orthopedic disorders, and the pathology may include both peripheral nerve injury caused by surgery and disorders of the central nervous system [32].Conversely, some nontraumatic orthopedic disorders, which are not necessarily associated with direct nerve injury, such as osteoarthritis of the knee and hip, lower back pain, and rheumatoid arthritis, are known to be associated with neuropathic pain [10,12,[33][34][35].Karasugi et al. reported the characteristics of neuropathic pain using the painDETECT questionnaire in patients with rotator cuf tears and identifed that the VAS score for pain in the previous 4 weeks was a factor in discriminating neuropathic pain [13].Ko et al. investigated the characteristics of neuropathic pain in patients undergoing rotator cuf repair and reported that the VAS score for pain in the previous 4 weeks and tear size were factors in discriminating neuropathic pain [14].However, we found no signifcant diference in the severity of pain in the previous 4 weeks between the groups with and without neuropathic pain among patients with rotator cuf tear in the present study.Tis diference may be attributed to the diference in population between the studies.In contrast, as these previous studies only evaluated the data of patients with rotator cuf tear, the relationship between neuropathic pain and shoulder disorders excluding rotator cuf tears has not been elucidated.Moreover, although they reported the intensity of pain in patients with neuropathic pain, the nature of the pain was not examined adequately.In the present study, neuropathic pain was diagnosed using painDETECT in both the overall population and in patients with each type of shoulder disorder, and the nature of pain was investigated in detail, which are the strengths of our study.Te coexistence of neuropathic pain was negatively associated with pain severity in patients with general shoulder disorders, suggesting that neuropathic pain medications may be useful in the treatment of general shoulder disorders in some cases and that further research is warranted.

Background Factors. Patients' background factors
were not associated with the presence of neuropathic pain, which is consistent with the fndings of previous reports that patients' background factors were not correlated with a neuropathic pain component in patients with orthopedic disorders [10,13,14,33,36].Terefore, neuropathic pain may afect patients with orthopedic diseases regardless of background factors, indicating the importance for physicians to recognize the difculty in predicting the coexistence of neuropathic pain based on patients' background factors alone.

Pain Duration.
Pain duration was not correlated with the presence of neuropathic pain.Te temporal change in pain signaling is known to contribute to the development of chronic neuropathic pain [4,6].In general population surveys, pain duration was correlated with a neuropathic component [37,38].However, pain location in these surveys    [10,36,39].Furthermore, as the coexistence of neuropathic pain amplifes the intensity of pain during the night, neuropathic pain could be one of the reasons for pain during the night in patients with shoulder disorders.Further investigation is needed to clarify the correlation between neuropathic aberrations and pain during the night in patients with shoulder disorders.

Mental Status.
Te SF-MPQ scores were higher in patients with neuropathic pain than in those without neuropathic pain.Te SF-MPQ consists of two components that assess both the intensity of pain and an altered mental status.In this study, scores for both the components were higher in patients with neuropathic pain than in those without neuropathic pain.Tese results may suggest that the coexistence of neuropathic pain aggravates not only the intensity of pain but also the patient's mental health status.Furthermore, the total HADS score and HADS-D score were higher in patients with neuropathic pain than in those without neuropathic pain.Previous studies have described a correlation between neuropathic pain and a depressive state [40][41][42]; our results were consistent with the fndings of these studies.Tus, in the neuropathic pain treatment, it is also important to consider the patient's mental status.

Neuropathic Pain Prevalence.
Previous studies on orthopedic disorders have reported that the prevalence of neuropathic pain is approximately 12%-15% in patients with low back pain [10,33] and 23% in patients with osteoarthritis of the knee or hip [11].In this study, neuropathic pain was observed in 7.6% of the study population, with the highest prevalence observed in patients with frozen shoulder (33.3%), followed by patients with osteoarthritis (16.7%), calcifc tendinitis (16.7%), rotator cuf tear (5.0%), and impingement syndrome (4.8%).Tese results indicate that, similar to that in patients with other orthopedic diseases, neuropathic pain is a common condition among patients with nontraumatic shoulder disorders, highlighting the importance of correctly diagnosing and adequately treating neuropathic pain in patients with shoulder disorders.

Diferences in Neuropathic Pain between Rotator Cuf Tear and Frozen
Shoulder.Te symptoms of early stage rotator cuf tear and frozen shoulder are similar.Terefore, it is often difcult to diagnose these conditions based on physical fndings alone without MRI results.In this study, when comparing the diferent shoulder disorders, the prevalence of neuropathic pain in patients with frozen shoulder was more than six times higher than that in patients with rotator cuf tear.Neuropathic aberrations detected by painDETECT can be used as supporting evidence to diferentiate between rotator cuf tear and frozen shoulder.

4.5.
Limitations.Tis study has some limitations.First, we only used a self-descriptive questionnaire to diagnose neuropathic pain.Future studies should objectively evaluate neuropathic pain, e.g., by confrming the presence of sensory abnormalities consistent with innervation.Second, patients' health behaviors, such as smoking and alcohol consumption, as well as the presence or absence of underlying diseases, such as hypertension and diabetes, were not investigated.Tus, the potential infuence of these factors on neuropathic pain in patients with shoulder disorders was not clarifed.Tird, a multivariate analysis could not be performed owing to the small number of neuropathic pain-positive patients.Fourth, this study was performed at a single institution; therefore, larger multi-institutional studies are needed.
Nevertheless, this study revealed that neuropathic pain in patients with nontraumatic shoulder disorders is not a rare condition.Tis fnding may help ensure better pain control in these patients.

Conclusions
We assessed the impact, features, and prevalence of neuropathic pain in 198 patients with nontraumatic shoulder disorders.Neuropathic pain was observed in 7.6% of participants.Te occurrence of neuropathic pain may aggravate pain in patients with shoulder disorders.However, the coexistence of neuropathic pain could not be detected from the patients' background or physical examination fndings alone.Neuropathic pain in patients with shoulder disorders was not a rare condition, particularly in patients with frozen shoulder.Clinicians should ensure that neuropathic pain is accurately diagnosed in patients with shoulder disorders.
Te following patient characteristics were recorded: age, sex, afected side, and duration of pain.

Table 1 :
Te most Anesthesiology Research and PracticeFigure 1: Flow diagram of patients included in the study based on the presence or absence of neuropathic pain.Overall, 93% of patients who attended our clinic during the study period with nontraumatic shoulder disorders were included in our study.Neuropathic pain was observed in 7.6% of the participants.Patient demographics and diferences between patients with (+) and without (−) neuropathic pain.
Values are presented as means ± standard deviations; P values represent the results of statistical comparisons between the groups with and without neuropathic pain.Te VAS scores for pain, SF-MPQ score, and HADS score were signifcantly associated with the presence of neuropathic pain.Patient background factors and physical function were not associated with the presence of neuropathic pain.Nep, neuropathic pain; VAS, visual analog scale; SF-MPQ, short-form McGill pain questionnaire; HADS, Hospital Anxiety and Depression Scale; HADS-D, HADS-depression; HADS-A, HADS-anxiety; ROM, range of motion.Te P value is bolded to emphasize that the diference is statistically signifcant (P value <0.05).

Table 2 :
Categorization of shoulder disorders.

Table 3 :
Te efect sizes and 95% confdence intervals of the diferences in mean pain intensity at rest, on motion, and during the night between the two groups.Te 95% confdence interval for the diference in mean pain intensity between the two groups does not include 0, indicating that pain intensity was higher in patients with neuropathic pain than in patients without neuropathic pain.VAS, visual analog scale; d, Cohen's d (efect size); CI, confdence interval.

Table 4 :
Prevalence of neuropathic pain in patients with shoulder disorders.