Indian Journal of Pain

ORIGINAL ARTICLE
Year
: 2020  |  Volume : 34  |  Issue : 1  |  Page : 15--21

Biomarkers of chronic nonspecific pain syndrome: A cross-sectional hospital-based pilot study


Deepak Goel1, Shobit Garg2, Malini Srivastav3, Saloni Gupta4, Ashneet Kaur4,  
1 Department of Neurology, Swami Rama Himalayan University, Dehradun, Uttarakhand, India
2 Department of Psychiatry, S. G. R. R. University, Dehradun, Uttarakhand, India
3 Department of Psychology, Swami Ram Himalayan University, Dehradun, Uttarakhand, India
4 Department of Psychology, Max Super Specialty Hospital, Dehradun, Uttarakhand, India

Correspondence Address:
Dr. Deepak Goel
Department of Neurology, Swami Ram Himalayan University, Dehradun - 248 001, Uttarakhand
India

Abstract

Background: More than 50 million American have chronic pain and 41% of them have poor response to the treatment. One large survey on Chronic Pain “Pain in Europe” reported it as 12%–30% in the European countries and 19.3% in a study from west India. Objective: We aimed to look for bio-psycho-social biomarkers for chronic nonspecific pain. Methods: Patients of chronic non-specific pain syndrome (CNPS) defined as “patients presenting with multiple site pain or widespread body pain for more than three days per week for more than 3 months duration without any specific medical, neurological, orthopedic or rheumatologic cause”. All patients were subjected to clinical severity scale (visual analogue score), chronic pain related quality of life (QOL) score (ranges from 0 (Bed ridden stage) to 10 (normal functioning). Then patients were subjected for complete Hemogram, serum ferritin level, serum vitamin B12 level and Vitamin D level and psycho-social screening. Psycho-social assessment done by psychologists for psychometric analysis and tools for central sensitization inventory (CSI) to find out sensitization index, Pittsburg sleep quality index (PSQI) for sleep quality, Hospital anxiety and depression scale (HADS), and Somatic symptom scale – 8 (SSS – 8) to know somatization index. Results: Among 120 patients absolute deficiency of ferritin, vitamin B12 and Vitamin D was found in 51 (42.5%), 40 (33.3%) and 60 (50%) patients respectively. High sensitization index (CSI > 50) and high somatization index (SSS-8 of > 12) was found in 22 (17.5%) and 27 (23.3%) patients respectively. Patients with low ferritin had better outcome. Conclusion: This bio-psycho-social model for chronic pain will help the clinicians and patients for better understanding of the problem and better prediction for outcome.



How to cite this article:
Goel D, Garg S, Srivastav M, Gupta S, Kaur A. Biomarkers of chronic nonspecific pain syndrome: A cross-sectional hospital-based pilot study.Indian J Pain 2020;34:15-21


How to cite this URL:
Goel D, Garg S, Srivastav M, Gupta S, Kaur A. Biomarkers of chronic nonspecific pain syndrome: A cross-sectional hospital-based pilot study. Indian J Pain [serial online] 2020 [cited 2020 May 31 ];34:15-21
Available from: http://www.indianjpain.org/text.asp?2020/34/1/15/282549


Full Text

 Introduction



According to one estimate, more than 50 million Americans have chronic pain and 41% of them have poor response to the treatment.[1] Chronic pain is the most common cause of long-term disability and is associated with reduced physical, psychological, and social well-being. The prevalence of chronic pain in primary setting ranges from 5% to 33% and opioids are prescribed to treat pain in up to 90% of patients in the absence of definitive therapeutic options.[2] One large survey on chronic pain “Pain in Europe” reported it as 12%–30% in the European countries.[3] Few Asian countries such as Japan, Thailand, Singapore, and Myanmar reported the prevalence of chronic pain to be 17.5%, 19.9%, 8.7%, and 5.9%, respectively.[4] A recent community-based study from Western India showed the prevalence of chronic pain as 19.3%.[5] Thus, it is evident that chronic pain syndrome is a significantly prevalent and costly problem in world today.[1],[2]

Broadly chronic noncancer pain includes (1) chronic neuropathic pain (neuropathies, neuralgia, complex regional pain syndromes, and central pain syndrome) and (2) chronic nociceptive pain.[6] Chronic neuropathic pain is a well-indentified entity by the clinicians but chronic nociceptive pain-related problems are not well defined. Various terminologies used for unexplained pain are chronic noncancer/nonmalignant pain,[1],[2] chronic nonspecific pain,[7] and chronic myofacial pain syndrome,[8] etc., Various explanatory phenotypes to describe pain beyond the expected time of tissue healing are central hypersensitization pain,[9] chronic fatigue syndrome (CFS),[10], and somatoform pain disorder.[11]

In clinical practice, most patients presenting with chronic pain are labeled under nonspecific etiology group, as no definitive medical diagnosis is possible in a large proportion. In one study of low back pain, 70% of patients were categorized under the heading of nonspecific back pain.[12] Another study showed that a large number of patients attending rheumatology clinics are found to have nonspecific musculoskeletal pain, and a multidimensional approach was recommended for the evaluation of these patients.[7]

The biopsychosocial (BPS) model replaces the earlier biomedical approach of chronic pain. The BPS model emphasizes the importance of taking into account the dynamics and complex interactions among physiological, psychological, and social factors all together that perpetuate and may worsen the clinical presentation. Each individual experiences and maintains pain uniquely based on BPS factors. An evaluation of such interaction needs to be examined to tailor-specific treatment and prevention of chronic pain. The BPS model gives the opportunity to customize treatment and prevention of chronic pain depending on individual comorbidities. The continuous development and advancement of this BPS model in the past decade provides an opportunity to enhance much-required knowledge and skill for complex pain management and developing the coping skills for prevention.[13]

Various nutritional deficiencies have also been linked with chronic pain syndromes in different studies. The most common nutritional deficiencies related to painful conditions are iron, Vitamin B12, folic acid, and Vitamin D deficiencies.[14] Deficiency of iron storage protein that is ferritin is the most specific molecule in patients of chronic pain conditions such as fibromyalgia and headache; still, it is not being commonly utilized in clinical practice in patients of chronic pain.

In the process of clinical evaluation of patients of chronic nonspecific pain according to the BPS model in our outpatient department, we observed that nutritional deficiencies and psychosocial factors were very common in patients presenting with chronic pain. Therefore, we planned a longitudinal observational study to observe frequency, patterns, and response to the treatment related to various biomarkers (biological and psychosocial) in patients of chronic nonspecific pain syndrome (CNPS). Through this study, we describe various biochemical and psychosocial biomarkers in the relation of CNPS.

 Methods



Patients of CNPS were selected from the neurology outpatient department. CNPS was defined as “patients presenting with regional pain, multiple site pain or widespread body pain for more than 3 days/week for more than 3 months duration without any specific medical, neurological, orthopedic or rheumatologic disorders.”[7] All patients who were enrolled had already been evaluated for common and known medical cause pain clinically as well as with investigations and came with pain of unknown origin.

After detail history and clinical examination of patients presenting with CNPS, each patient was subjected to clinical severity scale according to the visual analog score (VAS) and pain-related quality-of-life (QoL) score according to the American Chronic Pain Association QoL scale, which ranges from 0 (bedridden stage) to 10 (normal functioning). In the second step, all patients were subjected to screening for deficiencies of hemoglobin, serum ferritin level, serum Vitamin B12 level, and Vitamin 25 hydroxy D level. Absolute deficiency was defined as level of Vitamin B12 of <200 pg/ml, of 25 (OH) D <50 nmol/L, and ferritin level <10 ng/ml. A relative deficiency was defined when the value of Vitamin B12 was between 200 and 500 pg/ml, Vitamin D level was between 50 and 75 nmol/L, and ferritin was between 10 and 50 ng/ml.

Subsequently, all patients were assessed on psychosocial aspects such as adjustment disorder, conflicts, negative or overprotective family environment, physical/mental overburden, and on clinical assessment scale. Clinical assessment was conducted using central sensitization inventory (CSI) to find out neural sensitization index and Pittsburgh Sleep Quality Index (PSQI) to know sleep quality, anxiety, and depression score by Hospital Anxiety and Depression Scale (HADS) and Somatic Symptom Scale-8 to know somatization index. Normals with abnormal scores and their interpretations are described in [Table 1].{Table 1}

The factors responsible for pain were divided into two categories:

Major factors – Absolute deficiency of ferritin level (<10 ng/ml), Vitamin B12 or Vitamin D, and high levels of sensitization (>50 CSI score) or somatization index (>12 SSS-8 score)Minor factors – Relative deficiency of ferritin, Vitamin B12, Vitamin D, high anxiety and depression (>11 on HADS score), poor quality of sleep (>5 score on PSQI), and positive history of social reinforcement.

Outcome assessment

Patients were managed according to findings of nutritional status and pain modification therapy. Pharmacotherapy for the pain modification was given in the form of antiepileptics (gabapentin and pregabaline), tricyclic antidepressant, selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors or muscle relaxant (baclofen or tolpersone), and flupirtine (a nonopioid analgesic) as described in the literature.[15] Nutritional supplementation was given according to the serum levels of ferritin and Vitamin B12 or Vitamin D. When ferritin level was very low (<10 ng/ml), single intravenous injection of ferric carboxymaltose 500 mg was infused over 1 h; otherwise, patients were advised for oral iron supplementation till it reaches more than 50 ng/ml. Follow-up of these patients was done after 3 months of management and feedback was taken for VAS, QoL, and overall subjective improvement in patient's language in the form of full recovery (no pain), partial recovery (>50% reduction), or no recovery (almost same).

 Results



All consecutive patients of CNPS were collected from the neurology OPD over a period of 3 months (April–June 2019) and followed up a minimum for 3 months (July to September 2019). Longitudinal assessment and follow-up data were collected from the neurology and clinical psychology department, then analysis was done in October 2019 when all patients had minimum 3-month follow-up. Those patients who were lost to follow-up were not included in the analysis.

In 3 months' time, a total of 129 patients were assessed and 9 lost to follow-up. The analysis of 120 patients with a minimum 3 month follow-up is described in the results.

Details of patient parameters are given in [Table 2]. In this study, 91.7% were female and 72.5% were 40 years or less. About 62.5% had an illness of more than 1 year and 35.8% had diffuse body pain.{Table 2}

Measurement of serum ferritin, Vitamin B12, and Vitamin D level was estimated in all patients to look for nutritional deficiencies. The findings of vitamin estimation are given in [Table 3]. Nearly 75% of the patients had low levels of ferritin and 42.5% had absolute deficiency of ferritin (less than 10). Among those patients who had very low ferritin level (51 patients), 35 (68.6%) had normal hemoglobin. Absolute low levels of Vitamin D (<50 nmol/l) and Vitamin B12 were found in 50% and 33.3% patients, respectively.{Table 3}

Psychosocial assessment was done in all patients at the entry point to see contributory factors for persistent and worsening of pain symptoms. The details of these psychosocial factors are described in [Table 4]. One-third of the patients were found to have positive social conflicts/adjustment problems/negative reinforcements or overprotection at home. High CSI in 21% and high somatization index in 28% was associated with patents of chronic nonspecific pain. More than half (57.5%) had poor sleep quality along with chronic pain, 26.7% had associated anxiety, and 29.2% had an association of depression.{Table 4}

Outcome

Significant improvement (P = 0.0001) was noted both in VAS and QoL score at 3-month follow-up for chronic pain [Table 5]. About 60.8% of the patients gave a good response rate on subjective feedback after 3 months of treatment [Table 6]. We have finally divided our patients of CNPS into four categories based on major or minor contributing factors of pain [Table 7] and [Table 8].{Table 5}{Table 6}{Table 7}{Table 8}

Minor factors

A total of 38 (31.7%) patients had no major contributory factors responsible for pain and had only minor factors in different combinations. Among 38 patients who had none of the major biomarker had a good outcome in 28 (73.7%) who had reported complete remission of symptoms after 3 months.

Major factors

A total of 51 (42.5%) patients had very low ferritin; among them, 42 patients had normal or insignificant sensitization/somatization index. A total of 22 (18.3%) patients had high sensitization index (>50 score on CSI) and 27 (22.5%) had high somatization index (>12 score on SSS-8). A total of 9 patients (7.5%) had both high sensitization and somatization. Out of 51 patients with very low ferritin, 39/51 (76.5%) reported full remission of symptoms after 3 months, while among 31 patients with normal or insufficient ferritin and high sensitization/somatization, only 6 (19.4%) reported complete remission of symptoms after 3 months. The patients with an absolute deficiency of ferritin had significantly higher rates of a good outcome at 3 months as compared with patients having a normal or relative deficiency of ferritin (P = 0.002), while patients with a high level of somatization (P = 0.00005) or sensitization index (P = 0.00001) had significantly lower rate of treatment response at 3 months when compared with low to medium somatization and sensitization index [Table 9] and [Table 10].{Table 9}{Table 10}

 Discussion



Evaluation and management including psychoeducation of chronic non-specific pain is continuing to be a challenge for treating physicians and patients. Poor response rates perpetuate psychological dogma and queries in these probands. These queries regarding etiology are poorly answered and labeled as psychosomatic at best of the times leading to increased dissatisfaction among the patients. BPS model was discussed for many years to answer these questions, and in the current study, this model was translated in clinical practice for those patients who were suffering from “real pain” without specific etiology or medical diagnosis.

Patterns of the nonspecific pain vary in a clinical presentation, so we had divided them into three groups: diffuse body pain/multiple site pain (4 or more sites), hemi-body pain (right or left half body), and local-regional pain syndrome (1–3 sites). Many patients presenting with whole-body pain and multiple site pain can have overlapping criteria of fibromyalgia syndrome (FMS), somatic symptoms disorder, or CFS; therefore, central sensitization index and somatization index were included in the current study. QoL of these patients depends on various factors such as severity of pain, quality of sleep, and associated anxiety or depression; therefore, pain severity scale (VAS), sleep quality scale (PSQI), and HADS were included in the assessment.

This current study had shown the following prominent outcomes: (1) very low level of ferritin (<10 ng/ml) with high sensitization index (>50 CSI score) and high somatization index (>12 score on SSS-8) were good diagnostic and prognostic biomarkers of chronic nonspecific pain; (2) patient with ferritin below 10 ng/ml is a predictor of better response to treatment at 3 months; and (3) high sensitization/somatization index is a predictor of poor response to treatment at 3 months.

Ferritin level was very low (<10 ng/ml) in 51% of the patients of chronic pain which had a good correlation with pain response and more than 70% had a good outcome of pain-free status after correction of ferritin level at more than 50 ng/ml.

Ferritin was discovered in 1937 by the French scientist, and in 1972, serum level estimation in human was done successfully. Later, it was demonstrated that ferritin is high in iron overload and lower levels detected in iron deficiency.[16] Gradually, the serum level of ferritin was proved to be a useful marker of inflammation, infection, and malignancy along with iron storage biomarkers.[16] After so many years of this knowledge, fundamental aspects of biology such as tissue of origin, secretary pathway, receptor interaction, and cellular effects of serum ferritin were still unclear. Wang et al. in 2010 has described the fundamentals of the biology of ferritin and also commented on the clinical use of ferritin estimation.[16] Extracellular ferritin is found useful as an iron delivery system, as signaling molecule for inflammation, in immunity cascade, and in angiogenesis.[16] Low level of ferritin and normal hemoglobin had been linked with many neurological disorders such as restless leg syndrome, fibromyalgia, headache, and syncope.[17],[18],[19],[20] Other clinical indications described for ferritin estimation are chronic kidney disease, inflammatory, cancer, and iron overload conditions.[16]

Ferritin is essential for a number of enzymes involved in neurotransmitter synthesis including tryptophan hydroxylase (serotonin) and tyrosine hydroxylase (norepinephrine and dopamine).[21] Therefore, iron deficiency anemia can present with multiple mood and behavioral signs that are similar to depressed individuals. Iron supplementation therapy can resolve many of the symptoms of depression in patients with iron deficiency anemia before any improvement in red blood cell counts or red blood cell indices is achieved. This may result from the recovery of neurotransmitters and enzyme levels dependent on iron and unrelated to hemoglobin concentration.[22] In the current series, half of the patients were found to have very low serum ferritin level and most of them (69%) had a normal hemoglobin level. Patients with chronic pain having ferritin deficiency had characteristic features of worsening of pain while in bed due to associated restless leg syndrome. CFS diagnostic criteria include symptoms of fatigue for last at least 6 months with at least 4 of the following physical symptoms: (1) post exertion malaise, (2) nonrefreshing sleep, (3) chronic muscle and joint pain, (4) impaired memory or concentration, (5) flu-like symptoms, and (6) headache.[23] Many of these symptoms are also found in severe iron deficiency and low ferritin.

Other deficiencies of Vitamin B12 and Vitamin D were seen as minor contributory factors for persistent pain. One study also looked for Vitamin B12 deficiency in patients of chronic nonspecific pain and sensory symptoms, in which 34% (70 patients [51 female]) had absolute deficiency and 66% had relative deficiency of Vitamin B12 and vague body pain was found in 82% of the patients often unilateral in distribution.[24] In our study, 33.3% had absolute deficiency and 50% had relative deficiency of Vitamin B12 with the same criteria. Interrelationship of chronic pain and Vitamin D deficiency was looked by Prakash et al., in this study of 71 patients, 52 (73%) had low serum level of Vitamin D.[25] Mechanisms of chronic pain in Vitamin B12 and Vitamin D deficiency are many folds, such as the role of Vitamin B12 in neural tissue maturation and the role of Vitamin D in musculoskeletal dysfunction, mood disorders, and inflammation.[26] In our series, absolute and relative deficiency of Vitamin D level was found in 50% and 22.5% of the patients, respectively.

Phenomenon of central hypersensitivity is a major pathophysiological process in widespread pain disorders beyond anatomical boundaries such as FMS and other pain disorders.[9] We have used CSI to find sensitization index in patients with persistent chronic pain, and about 17.5% had a very high sensitization index leading to persistent or worsening pain. We found that in case of high sensitization, environmental factors contribute to a major way for the worsening of pain. Other than pharmacotherapy, various nonpharmacological techniques had been described for the management of hypersensitization.[27] Unexplained medical symptoms and persistent or worsening of pain by medical diseases come under the category of somatoform pain disorders.[28] Somatization index was judged by SSS-8 in our study, and 23% of the patients found to have a very high somatization index. In our study, those patients who had high sensitization and somatization index had a poor response to medical treatment. The poor response can be due to a lack of specific psychotherapeutic techniques such as biofeedback or cognitive behavior therapy (CBT) along with standard medical treatment. Niculescu et al. studied psychiatry probands and did propose two forms of high pain states: psychotic subtype (increased perception of pain is centrally) and anxious subtype (more peripheral pain reactivity). These subtypes could be phenotypically similar to the high central sensitization and somatization index found in our probands, respectively.[29] Similar biomarkers based studies are conducted in other chronic conditions such as chronic pancreatitis too.[30]

 Conclusion



The above-mentioned way of BPS-based evaluation of chronic pain patients is easy to apply and helpful for the patient's counseling. The parameters such as serum ferritin level with a calculation of somatization/sensitization index can help to make wiser decisions for individual-based treatment. This model will also help the clinicians and patients for better understanding of the problem and better prediction for the outcome. The combination of various abnormalities found in nutritional and psychosomatic parameters in a given patient is helpful for “personalized” medical treatment and prevention plan.

Limitations in our study are that it is single-center data, small number of patients, and a short duration of follow-up. We do not know those who showed good response might have relapse of symptoms in a long follow-up. Another limitation was we have not subjected psychotherapeutic techniques such as biofeedback or CBT in patients with high sensitization/somatization index. Therefore, a long follow-up multicentric study with a large cohort of patients is required to confirm the findings of the current study. Longer duration of follow-up and inclusion of CBT/Biofeedback will tell us the response/relapse rates in a better way.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Jackman RP, Purvis JM. Chronic non-malignant pain in primary care. Am Fam Physician 2008;78:1155-62.
2Nicholson B, Passik SD. Management of chronic noncancer pain in the primary care setting. South Med J 2007;100:1028-36.
3Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D. Survey of chronic pain in Europe: Prevalence, impact on daily life, and treatment. Eur J Pain 2006;10:287-333.
4Sakakibara T, Wang Z, Paholpak P, Kosuwon W, Oo M, Kasai Y. A comparison of chronic pain prevalence in Japan, Thailand, and Myanmar. Pain Physician 2013;16:603-8.
5Saxena AK, Jain PN, Bhatnagar S. Prevalence of chronic pain among adults in India. Indian J Palliat Care 2018;24:472-7.
6Nicholson B. Differential diagnosis: Nociceptive and neuropathic pain. Am J Manag Care 2006;12:S256-62.
7O'Sullivan P, Beales D, Jensen L, Murray K, Myers T. Characteristics of chronic non-specific musculoskeletal pain in children and adolescents attending a rheumatology outpatients clinic: A cross-sectional study. Pediatr Rheumatol Online J 2011;9:3.
8Gerwin RD. A review of myofascial pain and fibromyalgia–factors that promote their persistence. Acupunct Med 2005;23:121-34.
9Kindler LL, Bennett RM, Jones KD. Central sensitivity syndromes: Mounting pathophysiologic evidence to link fibromyalgia with other common chronic pain disorders. Pain Manag Nurs 2011;12:15-24.
10Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: A comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med 1994;121:953-9.
11Lahmann C, Henningsen P, Noll-Hussong M. Somatoform pain disorder-overview. Psychiatr Danub 2010;22:453-8.
12Last AR, Hulbert K. Chronic low back pain: Evaluation and management. Am Fam Physician 2009;79:1067-74.
13Bevers K, Watts L, Kishino ND, Gatchel RJ. The biopsychosocial model of the assessment, prevention, and treatment of chronic pain. US Neurol 2016;12:98-104.
14Acar A, Evliyaoglu O, Uzar E, Yucel Y, Cevik MU, Guzel I, et al. Serum Vitamin B12, folic acid, and ferritin levels in patients with migraine. Turk Norol Derg 2011;17:90-5.
15Sullivan MD, Robinson JP. Antidepressant and anticonvulsant medication for chronic pain. Phys Med Rehabil Clin N Am 2006;17:381-400, vi-vii.
16Wang W, Knovich MA, Coffman LG, Torti FM, Torti SV. Serum ferritin: Past, present and future. Biochim Biophys Acta 2010;1800:760-9.
17Ortancil O, Sanli A, Eryuksel R, Basaran A, Ankarali H. Association between serum ferritin level and fibromyalgia syndrome. Eur J Clin Nutr 2010;64:308-12.
18Akdag Uzun Z, Kurt S, Karaer Unaldi H. The relationship with restless legs syndrome, fibromyalgia, and depressive symptoms in migraine patients. Neurol Sci 2018;39:1409-14.
19Aamodt AH, Borch-Iohnsen B, Hagen K, Stovner LJ, Asberg A, Zwart JA. Headache prevalence related to haemoglobin and ferritin. The HUNT Study. Cephalalgia 2004;24:758-62.
20Soppi ET. Iron deficiency without anemia-A clinical challenge. Clin Case Rep 2018;6:1082-6.
21Beard JL, Connor JR, Jones BC. Iron in the brain. Nutr Rev 1993;51:157-70.
22Kathlen ML, Escott-Stump S. Krauses Food Nutrition and Diet Therapy. 10th ed. Philadelphia, PA: Chapman and Hall; 2004.
23Yancey JR, Thomas SM. Chronic fatigue syndrome: Diagnosis and treatment. Am Fam Physians 2012;86:741-46.
24Ummer K, Noone M. Prevalence of B12 deficiency in patients presenting with non-specific pain and other sensory symptoms: A clinical observational study. Neurology 2015;84: Supp 14:P3.307.
25Prakash S, Kumar M, Belani P, Susvirkar A, Ahuja S. Interrelationships between chronic tension-type headache, musculoskeletal pain, and vitamin D deficiency: Is osteomalacia responsible for both headache and musculoskeletal pain? Ann Indian Acad Neurol 2013;16:650-8.
26Fazelian S, Amani R, Paknahad Z, Kheiri S, Khajehali L. Effect of Vitamin D supplement on mood status and inflammation in Vitamin D deficient type 2 diabetic women with anxiety: A randomized clinical trial. Int J Prev Med 2019;10:17.
27Nijs J, Meeus M, Van Oosterwijck J, Roussel N, De Kooning M, Ickmans K, et al. Treatment of central sensitization in patients with 'unexplained' chronic pain: What options do we have? Expert Opin Pharmacother 2011;12:1087-98.
28Oyama O, Paltoo C, Greengold J. Somatoform disorders. Am Fam Physician 2007;76:1333-8.
29Niculescu AB, Le-Niculescu H, Levey DF, Roseberry K, Soe KC, Rogers J, et al. Towards precision medicine for pain: Diagnostic biomarkers and repurposed drugs. Mol Psychiatry 2019;24:501-22.
30Greer JB, Greer P, Sandhu BS, Alkaade S, Wilcox CM, Anderson MA, et al. Nutrition and Inflammatory Biomarkers in Chronic Pancreatitis Patients. Nutr Clin Pract 2019;34:387-99.