PREDICTORS FOR NEUROPATHIC PAIN - Chronic Pain after Non-traumatic, Non-compressive Myelopathy:

Introduction: Chronic pain is one of the most common and serious consequences of myelopathy. The aim of this study was to survey chronic pain experience in a neurology out-patient clinic and to determine potential predictors for neuropathic pain after non-traumatic, non-compressive(NTNC) myelopathy.

Methods: We analyzed54 patients with a history of NTNC myelopathy at the neurology out-patient clinic. All patients completed questionnaires on pain severity, descriptors and impact on quality of life (QOL) and underwent neurologic examination with bedside sensory testing. The Short Form McGill Pain Questionnaire (SF-MPQ) and the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) were used to assess pain.

Neuropathic pain was diagnosed by LANSS score of 12 or more. Health-related QOL was evaluated by the Short Form 36-item (SF-36) health survey, while Hospital Anxiety and Depression Scale (HADS) and Patient Global Impression of Change (PGIC) were utilized to evaluate emotion and response to treatment for pain, respectively.

Results: Out of 54 patients, 48 reported pain; of these, 41 (85.4%) reported the initiation of pain during the first 3 months of myelopathy onset. The median (min-max) pain duration and SF-MPQ score was 41 (3.4-166) months and 10 (1-34), respectively. Thirty five (72.9%) patients reported continuous pain throughout the day. The most common pain descriptions were exhausting, gnawing and heavy. In total, 16 (33.3%) patients experienced neuropathic pain. Mean age was statistically significantly lower in patients with neuropathic pain than in patients with non-neuropathic pain (39.1 ± 12.5 vs. 49.8 ±

9.3, P = 0.002). A binary logistic regression revealed that onset age under 40, non-idiopathic etiologysuch as neuromyelitis optica, multiple sclerosis were independent predictors of the occurrence of neuropathic pain. Both SF-MPQ and LANSS scores were significantly correlated with SF-36 scores, adjusted by age, sex, presence of diabetes mellitus, and current EDSS scores (r = –0.624, P< 0.0001 for SF-MPQ; r = -0.357, P = 0.017 for LANSS). Patients who showed clinical improvement (PGIC scores >2) with treatment were female, non-idiopathic etiology or lengthy lesion (> 3 vertebral segments).

But the presence of diabetes was related to a poor treatment response.

Conclusion: Chronic pain is one of annoying complications in patients with NTNC myelopathy and also affects their quality of life. Onset age and etiology of

myelopathyare important factors in the development of neuropathic pain in NTNC myelopathy. Pain relief research is expected to improve health-related QOL in these patients..

Key words: Chronic pain, Non-traumatic non-compressive myelopathy, Neuropathic pain, Predictors

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A. GENERAL CHARACTERISTICS OF SUBJECTS WITH NON-TRAUMATIC, NON-COMPRESSIVE MYELOPATHY ··· 6

B. PAIN PROFILES ··· 6

C. PAIR-WISE COMPARISONS BETWEEN NOCICEPTIVE AND NEUROPATHIC PAIN GROUPS ··· 7

LIST OF TABLES

Table 1. Clinical characteristics of patients ... 16

Table 2.Pain characteristics in myelopathy ... 17

Table 3.Pain descriptors used in patients with myelopathy ... 18

Table 4. Predictive factors for occurrence of neuropathic pain ... 19

Table 5. The Patients’ Global Impression of Change (PGIC) after treatment for pain ... 20

LIST OF FIGURES

Fig. 1. Korean version of Short Form McGill Pain Questionnaire... 21

Fig. 2. Korean version of Leeds Assessment of Neuropathic Symptoms and Signs pain scale ... 22

Fig. 3. Korean version of Short Form 36 Health Survey ... 23

Fig. 4. Korean version of Hospital Anxiety and Depression Scale ... 26

Fig. 5. Korean version of Patients’ Global Impression of Change scale ... 27

Fig. 6.Flowchart of patient recruitment and participation... 28

Fig. 7. Relationship between quality of life and total pain score and neuropathic pain score after adjusted by age, sex, DM, current EDSS score ... 29

Ⅰ. Introduction

Myelopathy refers to any neurologic deficit related to the spinal cord. Patients with myelopathy experience a loss in the ability to move, feel, and control bowel and bladder function. While loss of motor function is generally considered to be the most serious sequela of myelopathy, pain can have the greatest impact on the patient. Furthermore, pain can interfere with emotions and directly affect the patient’s ability to recover levels of activity.

Chronic pain is a frequent problem for patients with myelopathy. Approximately 60 to 80% ofsuch patients report pain and almost a third rate their pain as severe(Siddall et al., 1999; Siddall et al., 2003; Wollaars et al., 2007).

The new International Spinal Cord Injury Pain (ISCIP) classification divides spinal cord injury (SCI) pain into nociceptive, neuropathic, and other pain(Bryce et al., 2012).

According to previous studies, nociceptive pain is the most common type associated with myelopathy (Siddall et al., 1999). However, approximately 30 to 40% of the pain manifests as neuropathic pain(Bonica, 1991; Siddall et al., 1997; Finnerup et al., 2001).

Neuropathic pain is caused by a lesion or disease of the somatosensory nervous system(Jensen et al., 2011) and is a result of nervous system dysfunction without peripheral nociceptive stimulation(Widerstrom-Noga and Turk, 2003). Neuropathic pain syndrome is associated with highlyheterogeneous clinical conditions(Yucel et al., 2004;

Calmels et al., 2009). In myelopathy, neuropathic pain is related to the damage of nerve root and spinal cord; it tends to be chronic and responds poorly to treatment, resulting in various complications such as joint contractures, muscle atrophy, pressure sores, and cardiovascular problems(Wu et al., 2013).Therefore, it is important to diagnose neuropathic pain accurately and rapidly; however, little is known about the predictive factors of neuropathic pain in myelopathy.

Mostprevious studies ofmyelopathy pain have been limited to traumatic and compressive causes. Numerous patients with non-traumatic, non-compressive (NTNC)myelopathy, such as acute transverse myelitis (ATM), neuomyelitisoptica (NMO), multiple sclerosis (MS) or infective myelopathy experience painfor a long

period after disease onset. Whilst pain continues to be a significant problem in these patients, it has been relatively understudied. Other studies have described the prevalence, characteristics,and risk factors of pain in patients with NTNC myelopathy. One study found that neuropathic pain is relatively rare in acute transverse myelitis, although below-level neuropathic pain can be a chronic debilitating factor(Laffey et al., 1999).A few recent studies reported frequent pain and pain related quality of life impairment in patients with demyelinating myelopathy including NMO and MS (Solaro et al., 2004;

Kanamori et al., 2011). However, these studies were limited to a specific disease and did notcomprehensively evaluate pain characteristics, severity, and treatment response.

The objective of this study was to surveychronic pain experience and to determine potential predictors for neuropathic after NTNC myelopathy. In addition, it aimed to investigate the influence of pain on daily life and emotion.

3 myelopathy at least 6 months of pain duration after onset of myelopathy, 2)aged over 18 years,3) an abnormal intra-cord signal demonstrated by spinal MRI. Patients with dementia and those who experienced pain from other diseases were excluded. Patients were examined and interviewed by an experienced neurologist at their regular visit to the out-patient clinic. All patientscompleted questionnaires for pain and quality of life. For analysis of predictors for neuropathic pain, patients were dived by the LANSS score 12;

non-neuropathic pain group and neuropathic pain group. We also divided patients according to PGIC score 2; poor response to pain treatment group and good response to pain treatment group. The study was approved by the Institutional Review Board of the AjouUniverity Hospital and all patients provided informed consent prior to participation.

B. Myelopathy characteristics

The etiology of myelopathy was classified as idiopathic, demyelinating diseases (NMO, MS), infection, or other causes. The diagnosis of NMO was made based on the 2006 Wingerchuk criteria(Wingerchuk et al., 2006),while MS was diagnosed according to the 2010 McDonald criteria(Hawkes and Giovannoni, 2010). The level of myelopathy was categorized as cervical, thoracic, lumbar, or multi-level lesion. Results from cerebrospinal fluid and electrophysiological tests, in addition to a number of laboratory tests for differentiating cause of myelopathy were also reviewed.

C. Pain assessment

The Short Form McGill Pain Questionnaire (SF-MPQ, Figure 1) was used to evaluate the type of pain and its severity. Neuropathic pain was diagnosed if patients scored 12 or more on the Leeds Assessment of Neuropathic Symptoms and Signs(LANSS, Figure 2).

The LANSS scale, first invented by Bennett(Bennett, 2001), is a useful tool which helps distinguish neuropathic pain from nociceptive pain. The validation and reliability of the Korean versions of the SF-MPQ and LANSS have been confirmed previously(Yun et al., 2012).

Patients were interviewed about the location, patterns, and characteristics of their pain.

The length of time between onset of disease to pain occurrence, and the total pain duration were also recorded. When neuropathic pain was present, it was classified as either above-level, at-level, or below-level neuropathic pain(Siddall et al., 1997).

D. Assessment of functional and emotional status

Patient functional status was assessed using the Short Form-36 (SF-36, Figure 3)(Han et al., 2004). This is a general health status measure, containing eight domains: physical functioning, physical role limitation, mental health, bodily pain, general health, vitality, social functioning, and emotional role limitation. The eight domains are aggregated into two summary scales, generating a physical component score and a mental component score. The validity and reliability of the Korean version of the SF-36 has been confirmed previously(Han et al., 2004). Depression and anxiety were assessed using the Hospital Anxiety and Depression Scale (HADS, Figure 4), a14-items questionnaire, in which high scores indicate poor emotional wellbeing(Zigmond and Snaith, 1983). The validation and reliability for the Korean version has also been confirmed(Oh et al., 1999).

E. Pain response to treatment

The Patients’ Global Impression of Change (PGIC, Figure 5) was used to measure the

response of pain to treatment(Farrar et al., 2001).It comprises a seven-point scale in which patients rate any change in their overall pain status since the initiation of treatment; clinical improvement was defined as a PGIC score more than 2. The Korean version of questionnaire(Moon et al., 2010) was completed by all patients.

F. Statistical analysis

The results for the overall patient group and sub-groups were presented as absolute numbers and percentages. The χ²-test and Fisher’s exact test were used to analyze the association between categorical variables. For continuous variables with normal distribution and non-normal distribution, the t-test and Mann-Whitney U test were used, respectively. Binary logistic regression analyses were performed to adjust for various factors such as age, sex, and etiology laboratory test result. The relationship between variables was examined by Spearson’s correlation coefficient. All statistical analyses were performed by the Statistical Package for Social Sciences 11.0 software. P<0.05 was considered statistically significant.

Ⅲ. Results

Of the 58 patients interviewed, four patients were subsequently excluded due todementia (n = 2) and refusal to study consent (n = 2). The results of 48 patients who reported pain and 6 patients who did not have pain were analyzed (Figure 6).

A. General characteristics ofpatients with NTNC myelopathy

Demographics and clinical characteristics of patients with pain are summarized in Table 1. In pain(+) group, the mean (±standard deviation [SD])patient age was 46.2±11.5 years;

27 patients (56.3%) were men. Eighteen (37.5%) patients had recurrent myelopathy and six (12.5%) patients had diabetes mellitus (DM). Median (range) initial and current Expanded Disability Status Scale (EDSS) scores were 3.0(0-9) and 2.2 (0-7.5), respectively. The majority of cases had idiopathic etiology (n=36, 75%), and the most common level of lesion was in the thoracic cord (n=23, 47.9%). In six patients who did not have pain, the mean (±SD) age was 36.5±21.7 years; 4 patients were men. Median (range) initial and current EDSS score were 3.5 (2-8) and 3 (0-9). Current EDSS score of three patients were 0, while another 3 patients showed the score over 6. Unlike the pain (+) group, the most common etiology in the pain (-) group was NMO (n=3, 50%) without statistical significance due to low number of patients. Thoracic cord was also the most common level(n= 4, 66.7%) in pain (-) group.

B. Pain profiles

In total, 41 (85.4%) patients stated that pain initiated during the first 3 months of myelopathy onset. Median (range)pain duration was 52 (3.5-162) months and the median (range) SF-MPQ score was 12 (1-34). Thirty five (72.9%) patients reported continuous pain throughout the day. The most common words used by patients to describe their pain wereexhausting, gnawing and heavyin order.

Non-neuropathic pain (LANSS score < 12) was present in 32 (66%) patients and was more common than neuropathic pain (33%). In all cases of neuropathic pain, below-level neuropathic pain was the most frequently reported (in 93.7% of patients), followed by at-level neuropathic pain(37.5%); only one patient reported above-at-level neuropathic pain (data not shown).

C. Pair-wise comparisons between non-neuropathic and neuropathic pain groups

Mean (±SD) age was statistically significantly lower in patients with neuropathic pain than in patients with non-neuropathic pain (39.1 ± 12.5 vs. 49.8 ± 9.3, P = 0.002).

However, overall median pain score (assessed by SF-MPQ) was statistically significantly higher in patients with neuropathic pain (8 vs 17.5, P = 0.004). There were no statistically significant differences in the other variables including gender, DM, etiology of myelopathy, CSF study, pain duration, total SF-36 score, and HADS score between the two pain groups (Table 2).

Similar to the all types of pain, the most common descriptions for neuropathic pain were gnawing, exhausting and heavy. However, in the presence of neuropathic pain, shooting, stabbing, and aching were used statistically significantly more than for overall pain (Table 3).

D. Predictors for neuropathic pain

A binary logistic regression was performed to evaluate the predictive factors for the development of neuropathic pain in NTNC myelopathy. The following factors were entered into the model: (1) age of myelopathy onset > 40 year old, (2) gender, (3) etiology, idiopathic or non-idiopathic, (4) initial EDSS score. The results showed that onset age under 40, non-idiopathic etiology were independent predictors of the occurrence of neuropathic pain (Table 4) The Nagelkerke R²value was 0.383, suggesting a strong association between neuropathic pain and the independent variables in the regression analysis.

8 E. Effect of pain on quality of life

Both the SF-MPQ and LANSS scores showed significant correlation with SF-36 scores adjusted by age, sex, presence of DM, and current EDSS scores (r = -0.624, P< 0.0001 for SF-MPQ; r = -0.357, P = 0.017 for LANSS). However, SF-MPQ scores, which indicated total pain, showed a higher correlation with SF-36 scores than the LANSS scores (Figure 7).

F. Pain response to treatment

Patients were divided into two groups based on their PGIC score; those with no improvement or worsening pain (score ≤ 2) and those with improvement of pain after treatment (score > 2). Patients showing clinical improvementwith treatment were female (n=16, 55.2%), non-idiopathic etiology (n=11, 37.9%) or long lesion (n=18, 62.1%). But the presence of diabetes was related to poor pain treatment response (Table 5).

Ⅳ. Discussion

In this study, almost all patients with NTNC myelopathy reported chronic pain and one third of the pain had neuropathic features. Patients with neuropathic pain were younger and had higher SF-MPQ scores than those with non-neuropathic pain. Being aged under 40 and having non-idiopathic etiology were independent predictive factors for the development of neuropathic pain. Patients responded well to pain treatment tended to be ofthe female gender, have non-idiopathic etiology, and have a lesion length longer than 3 vertebral segments. In contrast,the presence of diabetes was related to poor response to pain treatment.

It is common for patients with myelopathy to develop serious and often life-threatening complications after the acute phase has passed. Chronic pain, a common secondary complication following SCI, has a wide reported range of prevalence, ranging from 11 to 94%(Defrin et al., 2001). Recent studies have shown that more than 80% of patients with SCIexperience pain (Siddall et al., 2003)and a third of them rated the pain as severe(Cruz-Almeida et al., 2005).Several studies of non-traumatic myelopathy have reported a 20 to 60% prevalence of chronic pain (New et al., 2002; Pidcock et al., 2007;

Werhagen et al., 2007).Pain after idiopathic myelitis is generally considered rare (Laffey et al., 1999);however, one study found that 75% of patients with ATM had acute pain;

chronic pain developed in 54% of patients(Pidcock et al., 2007).Furthermore, recent studies have reported frequent pain and pain related quality of life impairment in patients with demyelinating myelopathy including NMO and MS(Solaro et al., 2004; Kanamori et al., 2011; Qian et al., 2012).In the present study, 88.9% of NTNC myelopathy patients interviewed reported pain. Patients without pain were classified as either of two groups;

EDSS score 0 or severely disabled status (EDSS ≥ 6.5) with no sensory function at all.

There were no significant differences in epidemiological or clinical data between patients with pain and without pain.

Numerous studies have found that pain typically occurs within the first 6 months of myelopathy(Ravenscroft et al., 2000; Norrbrink Budh et al., 2003b; Henwood and Ellis, 2004), though in some studies it has been reported within the first year (Stormer et al.,

1997).The present results show that 80% of pain began within the first 3 months of disease onset; earlier than that reported in the previous myelopathy pain studies(Miguel and Kraychete, 2009).This difference is assumed to be due to the inclusion of non-traumatic, non-compressive causes of myelopathy inthe present study. At the onset of NTNC myelopathy, many patients complain of sensory symptoms, in contrast to traumatic myelopathy where motor symptoms are most frequently reported.According to previous studies, almost all patients with myelopathy pain report continuous pain, which is usually intensified in the evening(Demirel et al., 1998; Celik et al., 2012).Similarly, 35 (72.9%) patients in the present studyalso reported continuous pain. The various descriptions of pain have included pricking, tingling, and tiring(Stormer et al., 1997;

Finnerup et al., 2001; Celik et al., 2012). In contrast, the most frequently used pain descriptions in our data included exhausting, gnawing and heavy. This difference may be due to variations in patient populations between studies, or cultural differences in pain perception.

Nociceptive pain is the most common type of myelopathy pain both in the acute and chronic phase(Siddall et al., 2003).It can be identified by location (above- or at-lesion level in patients with complete spinal cord damage) and by pain features (aching, dull, worse with activities)(Siddall et al., 1997).Shoulder pain due to acute phase trauma or overuse, muscle weakness, and spasticity, in the chronic phase is common(Akbar et al., 2011). Pain related to spasms, muscle contractures, and pain in the back and wrist are also examples of nociceptive pain(Finnerup, 2013).Nociceptive pain is less severe than the other types andusually presents early on following the onset of disease or trauma(Siddall et al., 2003).In NTNC myelopathy, unlike traumatic SCI, there is no injury or compression to the structures surrounding the spinal cord.Therefore, neuropathic pain could be considered more common than nociceptive pain in NTNC myelopathy. However, the present study revealed that 32 (67%) patients had non-neuropathic pain (LANSS score <12). We speculate that this result had several causes, Firstly, we only evaluated pain in the chronic phase. After the acute stage of myelopathy, nociceptive pain due to weakness, overuse, and spasticityincreases naturally. Secondly, patients with NTNC myelopathy are older than those with traumatic SCI(Burney et al.,

1993; New et al., 2002). Even if we excluded patients who experienced pain from other diseases, the elderly would have more pain-causing problems such as arthritis or muscle cramps. These factors could affect the majority of our patients having NTNC myelopathy with non-neuropathic pain.

There are two types of neuropathic pain in myelopathy: myelopathy-related neuropathic pain and other neuropathic pain. Myelopathy-related neuropathic pain is further classified as either at-level or below-level neuropathic pain. Other neuropathic pain describes pain which is not a direct consequence of myelopathy (e.g. post-thoracostomy pain, and pain due to carpal tunnel syndrome fromwheelchair use), which may occur above-, at-, or below- lesion level(Finnerup, 2013).

The mechanisms of myelopathy-related neuropathic pain are multiple and not yet fully understood. At-level neuropathic paincould result from a lesion in the nerve roots or spinal cord, whilebelow-level neuropathic pain is considered as central pain due to spinal cord lesions, suggesting a different underlying cause.At-level neuropathic paincan be initiated early following damage and it therefore appears to share some of the characteristics of nociceptive pain. However, at-level neuropathic pain is more likely to be described as severe, and persists despite treatment. Below-level neuropathic paingenerally occurs later than nociceptive or at-level neuropathic pain and is also described as severe and excruciating. Neuroplasticity is an important component of the spontaneous recovery from a myelopathy; however, it can generate negative consequences such as spasticity, autonomic dysreflexia, and neuropathic pain(Brown and Weaver, 2012).Increasing evidence has indicated that neuroplasticity may limit the effects of experimental myelopathy therapy due to undesired results such as neuropathic pain(Brown and Weaver, 2012).Central sensitization is considered to be the main cellular change responsible for central neuropathic pain and manifests as a decrease in pain thresholds, increased response to synaptic input, and expansion of receptor fields(Woolf, 2011). Additionally, an imbalance between descending inhibitory activity and facilitation,

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