INTRODUCTION
Chronic pain disorders are the leading cause of disability globally and in India.[1] Both depression and anxiety are associated with increased pain intensity, poor pain outcomes, worse prognosis, increased medical visits, and higher medical costs during chronic pain management.[2–5] The complex interplay of chronic pain with comorbid depression and anxiety has not been well studied globally and even less so in India. This paper reviews the literature on comorbid depressive and/or anxiety disorders with chronic pain conditions in the Indian population, to understand the current landscape of the management for these comorbidities and identify need gaps for future research.
METHODS
Search strategy
The scope of psychiatric comorbidities in this paper was limited to depressive and anxiety disorders as they are the leading contributors of disability due to psychiatric disorders accounting for 33.8% and 19.0% of disability-adjusted life-years, respectively in 2017.[6] A MEDLINE® database search through PubMed® was conducted on March 23, 2020, by an independent reviewer to identify relevant peer-reviewed scientific publications published from 2010 onward. The search string combined MeSH terms and keyword search terms related to chronic pain, depression and anxiety: ([“Pain”] OR [“Chronic Pain”] OR [“Neuralgia”] OR [“Diabetic Neuropathies”] OR Pain OR neuralgia OR neuropath*OR [Cancer Pain] OR [Cancer-Associated Pain] OR [Tumor-related Pain] OR [Oncology Pain] OR [Cancer-Related Pain] OR [Neoplasm-Associated Pain] OR [Neoplasm-Related Pain] OR [Cancer Pain]) AND ([“Depression”] OR [“Depressive Disorder”] OR [depression] OR “depressive disorder” OR depressive*OR [“Anxiety”] OR [“Anxiety Disorders”] OR anxiety) AND India*. The PubMed search results were limited to articles published in English language and with the availability of full texts. In addition, the archives of Indian Journal of Pain were searched using the terms “Pain,” “Depression,” “Anxiety,” and “Cancer Pain” for relevant articles published 2010 onward by the independent reviewer on March 25, 2020.
Eligibility criteria
The predefined eligibility criteria for articles included studies addressing chronic pain conditions (defined as persistent or recurrent pain lasting more than 3 months[7] or as specified in the study) as well as general pain (i.e., studies that did not specify pain location or duration); presence of comorbid depression and/or anxiety symptoms; and population sample comprised of Indian population. Articles reporting randomized controlled studies, systematic reviews, meta-analyses, literature reviews, observational studies, patient-reported outcomes, and treatment guidelines were included, whereas, case reports and conference proceedings were excluded. Acute pain was excluded as the scope of this study was limited to chronic pain conditions.
Data extraction and synthesis
The search output was exported into a Microsoft Excel document and deduplicated. In the first level screening, titles and abstracts of articles were independently screened by two reviewers for eligibility. In the second level screening, the full texts of articles were retrieved and screened for eligibility. Any disagreements regarding the eligibility of studies were resolved following discussion with the authors. Relevant, representative, and evidence-based data were extracted. Quality assessment of studies was not performed given the heterogeneity of study types. Given the broad scope of review, i.e., to analyze the landscape of chronic pain with comorbid depression and anxiety in the Indian population, the extracted data were summarized as a narrative review.
RESULTS
Overall, 866 articles were retrieved through structured search from PubMed, and 593 articles were retrieved through unstructured search; of these 84 articles met the inclusion criteria [Figure 1]. The population samples comprised of a wide variety of chronic pain etiologies, with cancer pain (25%) being the most commonly studied etiology. Both depression and anxiety were assessed with chronic pain in most of the articles (~60%). Between 2010 and 2019, there was an increasing trend observed in the number of articles published on chronic pain and comorbid depression/anxiety in the Indian population [Figure 2].
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Figure 1: Flow diagram for study article selection
Figure 2: Trend in the number of articles published on chronic pain and comorbid depression or anxiety in the Indian population between 2010 and 2019
Epidemiology of comorbid depression and anxiety in chronic pain conditions
The prevalence and correlation of comorbid depression and anxiety in chronic pain conditions among the Indian population in different settings are provided in Supplementary Table S1.[8–45] The prevalence of comorbid depression with chronic pain ranged from 31% to 88% observed in prospective studies in Indian pain clinics.[8,9] The severity of depression and anxiety were positively correlated with the intensity of chronic pain.[10] In an online survey, most psychiatrists (85%) registered with the Indian Psychiatry Society agreed that pain and depression were interrelated and around 40% of the psychiatrists perceived that up to 50% of patients with chronic pain in India experienced depression.[11]
Supplementary Table S1: Epidemiology of comorbid depression and anxiety in chronic pain conditions among the Indian population
Psychiatric comorbidities have been observed in numerous chronic pain conditions and patient subgroups in India. Pain is the most commonly presented symptom among patients with cancer admitted in hospitals, and its severity is strongly associated with increased anxiety and depression scores.[12] Pain is frequently identified and treated by oncologists, however, anxiety, depression, and tiredness that co-occur with pain remains underreported.[13] In a palliative care setting, chronic pain in two-thirds of patients was due to cancer etiology, and psychiatric illness was strongly associated with pain perception, impaired activity, and functional status in these patients.[14]
Several studies have further demonstrated evidence for the association of depression or anxiety with other chronic pain conditions including fibromyalgia, ankylosing spondylitis, temporomandibular disorders, chronic facial pain, myofascial pain syndrome, carpel tunnel syndrome, Guillain–Barre Syndrome, and epicrania fugax, a rare primary headache, in the Indian population.[15–20,27,28] People with amputations and phantom pain had a high prevalence of psychiatric disorders particularly major depressive disorder.[21,22] Chronic perinatal pain and pain symptoms occurring in menopausal and post-menopausal women was observed to be associated with depression.[23–26]
Notably, depression and anxiety were not observed as a comorbidity in all pain conditions. No difference in the prevalence of anxiety and depression was observed in patients with moderate-to-severe migraine compared with healthy people.[29] Conversely, severe anxiety and depression were significantly more prevalent in patients with new daily persistent headache than those with chronic low back pain (CLBP) or healthy people.[30] The contradictory results reported in the field of migraine may be due to variations in socioeconomic status and clinical conditions or study methodology.
Comorbid pain and psychological distress were also associated with certain occupations and industries in India. Cross-sectional studies of people employed in iron and textile industries found that 40%-68% of all workers experienced pain/discomfort and depression/anxiety, associated with long working hours (>48 h per week).[31,32] CLBP was highly prevalent among medical university students, who also had high levels of depression, anxiety, and monotonous work.[33]
Risk factor determinants of pain, depression, and anxiety
Although genetic factors have often been implicated as determinants of pain perception and response, depression and anxiety were similarly associated with pain due to Parkinson’s disease among Caucasian and Indian patients. Interestingly, patients of Caucasian ethnicity experienced more debilitating pain symptoms interfering with several dimensions of life than their Indian counterparts.[34] Given the bidirectional causality between pain and depression or anxiety, psychological factors also related to the onset of chronic pain.[46] Risk factors for depression in Indian chronic pain patients included female sex, pain intensity, and poor sleep quality.[8]
The evidence is conflicting on pain as a commonly observed symptom in psychiatric conditions among Indian patients. While a survey found that 44% of physicians agreed that chronic pain is present in most patients with masked depression, another study found that pain was a higher complaint among general patients than psychiatric inpatients with depression or anxiety.[35,36] Depression was highly prevalent among type 2 diabetes mellitus patients, with diabetic neuropathy and foot disease as risk factors for its development.[37,38]
Pain and psychiatric disorders are also risk factors of sedentary behavior, which in turn, may result in diabetes, stroke, and premature mortality. Analyses of the World Health Organization’s (WHO) Study on Global Ageing and Adult Health survey found that patients with depression and comorbid bodily pain were more likely to display sedentary behavior, and pain was a contributing factor to the association between anxiety and sedentary behavior.[39,40]
Effect of chronic pain and psychiatric disorders on quality of life
The association of depression and/or anxiety with pain impacts the quality of life (QOL) of patients [Supplementary Table S2].[47–53] Patients with higher pain, depression, and anxiety scores had lower QOL and meaning in life scores.[47–49] Besides depression and generalized anxiety disorder, pain conditions were also associated with panic disorder and poor QOL.[50,51] QOL also varied according to the population sub-group. Well-being of patients with advanced cancer was lower in India compared with the US patients.[52] Pain severity was a predictor of most QOL outcomes.[52]
Supplementary Table S2: Impact of chronic pain and common comorbid psychiatric disorders on quality of life assessed in the Indian population
Screening and assessment tools
Evaluating patient history is an important step in diagnosing chronic pain and it aids clinicians in proper pain management. Numerous unidimensional instruments such as the Numerical Rating Scale (NRS) and Visual Analog Scale (VAS), and multidimensional instruments such as McGill Pain Questionnaire (MPQ) and Brief Pain Inventory (BPI) are used to assess pain intensity. Due to the high prevalence of comorbid psychiatric conditions in chronic pain conditions, patient history assessment must evaluate the mental status through questionnaires such as Patient Health Questionnaire-9 (PHQ-9), Beck Depression Inventory (BDI), Hamilton Depression Scale, Hospital Anxiety and Depression Scale, and Pain Catastrophizing Scale (PCS).[54] Several studies have validated chronic pain screening and assessment tools for the Indian population [Supplementary Table S3].[54–61]
Supplementary Table S3: Chronic pain screening tools including depression and anxiety assessment evaluated in the Indian population
The American College of Rheumatology (ACR) 2016 criteria for fibromyalgia was validated as a diagnostic tool for use in tertiary settings in India.[55] Diagnosis by the ACR 2016 criteria had higher anxiety and depression scores than the ACR 1990 criteria suggesting that the two criteria identified different patient subsets with fibromyalgia; therefore, both criteria were recommended for diagnosis in referral settings.[55] Several international pain assessment instruments have been translated to local languages and validated for Indian populations, including the PCS, the University of Washington QOL Questionnaire, and the EuroQol five-dimensions (EQ-5D) questionnaire.[56–58]
In cancer, assessments of psychological well-being and QOL along with personalized symptom goals are important to manage symptoms properly.[59] Psychological assessments in a cancer pain clinic observed that physical aspects of distress were appropriately recorded; however, psychosocial aspects were severely underreported.[60] Of the 14 pain assessment tools assessed, the Distress Inventory for Cancer-2 and the American Pain Society Patient Outcome Questionnaire were recommended for the evaluation of both functional and nonfunctional pain symptoms.[60]
Treatment modalities
Supplementary Table S4 presents an overview of pain management treatment modalities studied in the Indian context and their effect on depression or anxiety scores.[62–88] Antidepressants such as selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs) have demonstrated efficacy in the treatment of several painful conditions.[63] In an international randomized controlled study of juvenile fibromyalgia including Indian patients, although treatment with the SNRI duloxetine did not improve the mean 24-h pain severity scores, a 30%-50% reduction in pain severity was observed compared with placebo.[64] In patients with central poststroke pain, pregabalin or lamotrigine treatment was equally effective in improving pain, depression, and anxiety.[65] Lamotrigine, however, was associated with withdrawal in 10% of the patients due to adverse effects.[65] In patients with type 2 diabetes, minocycline treatment had greater improvement in peripheral and autonomic neuropathy accompanied with significant improvements in VAS and BDI scores compared with placebo.[66] The antipsychotic levosulpiride in combination with trigger point injections was associated with greater reductions in pain and depression for the treatment of myofascial pain syndrome compared with only trigger point injections.[67,79]
Supplementary Table S4: Treatment strategies for chronic pain and comorbid depression and/or anxiety in the Indian population
Various nonpharmacological interventions for pain management demonstrated improvements in pain and associated depression or anxiety in Indian populations. Transcranial magnetic stimulation, spinal manipulation, use of lumbar belt, and surgical treatment improved pain, anxiety/depression scores, and QOL in several chronic pain conditions.[69–72] Music therapy, hypnotherapy, and cannabis powder were found to reduce cancer-associated pain, with cannabis also reducing anxiety and depression.[73–75] Cognitive behavioral therapy, largely used in managing psychological disorders, was effective in reducing headache severity and anxiety in adolescents with both these conditions and also in managing CLBP and fibromyalgia.[63,76]
Several studies extol the benefits of yoga therapy as an adjunct to the conventional pain therapies. Yoga reduced pain and psychological disorder symptoms in patients with CLBP and with knee osteoarthritis compared with physical therapy.[77–81] Yoga in combination with conventional therapy improved pain, anxiety, and stress in Guillain-Barré syndrome, myofascial pain syndrome, and cancer to varying degrees.[82–84] The use of other complementary and alternative treatments such as meditation and mindfulness also improved pain and psychological distress in numerous chronic pain conditions, including painful diabetic neuropathy pain, fibromyalgia, rheumatoid arthritis, migraine, and myofascial pain syndrome.[85,86]
In India, palliative care is mostly limited to patients with cancer as the field is still in the early stages of development.[87,88] Palliative care is not equipped to handle patients with special needs and often issues related to psychosocial and spiritual needs of patient subgroups such as adolescents remain unmet.[41]
Treatment guidelines
A consensus on pharmacological pain management in India recommended thorough evaluation of patient history, use of appropriate pain assessment tools (unidimensional: E.g., NRS and VAS; multidimensional: E.g., BPI and MPQ; disease-specific: Leeds Assessment of Neuropathic Symptoms and Signs and Neuropathic Pain Scale; elderly patients: Abbey’s Pain Scale) and systematic screening of underlying comorbidity including psychiatric comorbidities (depression, anxiety, psychological disorders) prior to starting treatment.[89] Treatment goals for chronic pain management included decreasing pain symptoms, reducing emotional distress, as well as increasing the coping ability and psychosocial well-being of patients. The multimodal treatment recommended for chronic pain included a combination of paracetamol, non-steroidal anti-inflammatory drugs, selective cyclooxygenase-2 inhibitors, analgesics, opioids, TCAs, corticosteroids, muscle relaxants, sedatives, and anxiolytics.[89] The recommended treatment for various neuropathic conditions included TCAs, antiseizure medications, and opioids.[89] In the case of suspected depression comorbidity, antidepressants may be included in the treatment plan.[89]
The Indian Society for Study of Pain recently issued Cancer Pain Special Interest Group guidelines for the assessment of cancer pain in adults. The guidelines recommended comprehensive pain assessment using scales such as the MPQ and the BPI Short Form and also screening for psychological distress using the PHQ-9.[61] Appropriately educating patients about the pharmacological and nonpharmacological methods of pain management was also recommended.[61] For patients with cancer experiencing comorbid pain and psychological distress, the guidelines recommended psychological intervention including psychoeducation and physical and complementary therapy as an adjunct treatment.[61,90] In ambulatory palliative care setting, the guidelines recommended following the WHO 3-step analgesic ladder for managing cancer pain.[91]
DISCUSSION
The prevalence of chronic pain among the general Indian population is estimated at 13%–30%.[92–94] Chronic pain adversely impacts the QOL such as the ability to sleep, exercise, walk, do household chores and attend social activities. The economic impact of chronic pain is a consequence of healthcare expenditure and lost employment and productivity.[93] Psychiatric illnesses such as depression and anxiety often coexist with chronic pain, with mean global prevalence rates of 13%–56% for comorbid major depression in patients with chronic pain.[95] From a neurobiological perspective, pain and depression are closely linked, whereby chronic pain may lead to depression.[96] The underlying mechanisms governing the interactions between pain and depression are not clearly defined, though some common factors such morphological changes in the brain, monoamine deficiency, brain-derived neurotrophic factor reduction in the hippocampus have been identified.[97] Similarly, anxiety disorders occur at rates similar to depression in individuals with chronic pain; the adjusted odds ratio for any anxiety disorder among people with chronic pain conditions was similar to that for any mood disorder (2.13 vs. 2.00).[3]
This review observed a high prevalence of comorbid depression and anxiety with chronic pain in the Indian population, which highlights a serious healthcare concern as the inadequate management of these interlinked conditions predict poor prognoses and outcomes. Depression and anxiety comorbidities are observed in numerous chronic pain conditions and population subgroups in the Indian setting. A recent study in primary care attendees in the Indian state of Kerala estimated chronic pain prevalence in those experiencing depression at 66% versus an overall prevalence of 27%.[98] Similar to global trends, Indian women are at a greater risk of developing chronic pain conditions than men.[99,100] Chromosomal or hormonal differences may contribute to this sex-based difference in pain prevalence.[100] Given the sex and gender differences in pain and analgesia, the International Association for the Study of Pain Sex, Gender, and Pain Special Interest Group outlined best practices for pain research with respect to sex and gender.[101]
Chronic pain conditions, specifically CLBP and musculoskeletal pain were more prevalent in industrial workers than the general population.[102–104] The working conditions of these populations predispose them to pain conditions as well as concurrent psychological distress. Therefore, it is important to educate patients about work-related conditions to improve the management of their symptoms.[31,32] Economic status is identified as a risk factor for both CLBP and depression.[105–108] Therefore, clinicians and policy makers must consider these unequal disparities while treating patients with chronic pain and formulate comprehensive chronic pain management policies.[106]
Several cultural, genetic, and biosocial factors contribute to variations in pain causation, manifestation, and reporting; hence, Western studies on the prevalence of chronic pain and comorbid psychiatric illnesses cannot be extrapolated to Asian populations.[34,52,109,110] India has a huge burden of chronic pain, with an estimated 180–200 million people living with chronic pain.[94] Compared with other Asian countries, chronic pain prevalence is higher among adult Indian population.[94] The shared mechanisms between pain, depression, and anxiety highlight the need to manage these conditions concurrently in comorbid populations to optimize diagnosis and treatment.[111]
Chronic pain had a higher prevalence in developing countries (41.1% vs. 37.3%) compared with developed countries, despite being similarly associated with depression-anxiety spectrum disorders in both developing and developed countries.[112] Reliable data on chronic pain is limited in developing countries such as India and is a contributing factor toward under-treatment of pain. In addition, barriers related to low levels of pain education among healthcare professionals and poor access to pain management facilities and medication, particularly strong opioids, prevent the delivery of adequate pain relief in developing countries.[113] Access to morphine is a crucial component to manage cancer and deliver quality palliative care. In the past two decades, six developed countries accounted for 79% of global morphine consumption while developing countries only accounted for 6%, highlighting the disparate status of pain treatment.[114] In 2007, the Indian government-produced < 10% of the morphine needed in the country for treating cancer patients in pain.[113] Undertreatment of chronic pain conditions has serious public health implications including high rates of disability, direct and indirect economic losses to health systems, families, and individuals, and an overall impact on the QOL of population. Building a current evidence base identifying risk factors and challenges in pain management allows the development of appropriate healthcare strategies to reduce the disease burden. Health systems in India need to consider developing stepped care and collaborative care models for pain management in primary care and specialized pain clinics in tertiary care.[98]
Pain management is a newly established specialty in India. The Medical Council of India has deemed pain clinic as an essential service in all teaching hospitals.[115] Currently, pain clinics are managed as independent outpatient facilities by pain physicians, as part of larger private/public institutes, or in anesthesiology departments of hospitals. Pain clinics are proficient in the assessment and management of pain, conducting interventional procedures, prescribing pain medications, and managing the psycho-socio-somatic aspect of pain.[116]
The barriers toward effective pain management in India can be categorized as related to patients, physicians, or healthcare systems. When seeking pain treatment, most Indians do not seek help from qualified physicians in the first instance, instead preferring the use of local topical treatments, followed by over-the-counter analgesics, then managing pain through relaxation techniques, and if still unresolved, take leave from work.[36] Cancer pain is accepted as an inevitable consequence of the condition and patients frequently avoid analgesics;[117] opioid use is perceived as a sign of imminent death for these patients.[118] Social stigma associated with opioid addiction discourages patients from seeking optimal pain management with opioids, instead preferring to bear the pain.[119] Many patients without access to pain medications remain untreated or undertreated and are likely to develop depression.
Psychiatrists diagnosing depression in patients with chronic pain are subjected to social stigma and nonacceptance of the psychiatric diagnosis by the patients. Other challenges include the lack of awareness among physicians, lack of diagnostic tools, comorbid conditions, and nonadherence to treatment.[11] In addition, primary care physicians’ lack of knowledge on the association between depression and chronic pain and appropriate use of opioids often leads to delayed referrals and improper pain management.[95,120] Effective communication between healthcare professionals and patients following a patient-centered care approach can help overcome these barriers.[121] Undergraduate medical curriculum is also in urgent need of updating pain and psychiatry education programs.[122,123] Affordability of pain treatment is a critical issue in India, with most pain relief drugs available only in private health facilities and not covered under health insurance.[124] Availability and access to drugs and carers are also obstacles in the rehabilitation of pain conditions, particularly cancer care.
Palliative care was introduced in India in the mid-80s; however, it still remains in infancy and is largely limited to cancer pain management.[125] Majority of Indian patients with cancer were not treated according to the WHO recommendations for pain management and inadequate pain management was correlated to hospital settings and patient groups.[126] Therefore, outpatient home-based palliative care may be utilized to treat patients with chronic conditions.[125] Palliative care must move toward a patient-oriented approach, with improved communication between medical personnel and patients to set personalized treatment goals and improve pain management.[59,125]
There are limited data available on the evidence-based treatment of chronic pain and comorbid depression or anxiety for Indian populations. Antidepressants are recommended to manage symptoms in case of comorbid depression with chronic pain.[89] Recent guidelines recommended antidepressants like TCAs including amitriptyline and SNRIs including venlafaxine and duloxetine along with anticonvulsants gabapentinoids including gabapentin and pregabalin as first-line treatments for neuropathic pain.[127,128] Antidepressants such as TCAs and SNRIs increase the levels of serotonin and norepinephrine neurotransmitters, which are involved in both pain and major depression pathways.[129] The effects of these antidepressants on alleviating pain in patients with comorbid depression are independent of their effect on depression.[129] SNRI antidepressants also demonstrated decreased functional connectivity in a thalamo-cortico-periaqueductal network associated with pain; this decrease was correlated with improvements in depressive symptom severity and pain symptoms.[130]
Psychological treatments such as cognitive behavior therapy, biofeedback therapy, mindfulness-based stress reduction, acceptance and commitment therapy, and Jacobson’s progressive muscle relaxation technique reduced pain and psychiatric distress in multiple pain conditions to varying degrees.[131,132] Compared with pharmacological treatments alone, a multidisciplinary approach adopting a biopsychosocial model of care provides a more comprehensive treatment for managing cancer pain conditions.[90] Yoga as an adjunct to conventional therapy demonstrated benefits in managing pain conditions; however, Indian yoga trials were significantly more likely to have positive outcomes compared with yoga trials elsewhere. Therefore, results of yoga trials performed in India must be cautiously evaluated before incorporating into pain practice.[133] Complexities of chronic pain require the collaboration of multidisciplinary experts, including pain specialists, psychiatrists, physical/occupational therapists, psychologists/social workers, and pharmacists, and registered nurses. The aim of this review is to impress upon the pain physicians that psychological comorbidities must be addressed alongside analgesics and/or nerve blocks to obtain satisfactory outcomes. Psychiatric comorbidities must be an important consideration in the evaluation and treatment planning for chronic pain.
Strengths and limitations
This review article provides an updated evidence base for chronic pain and comorbid depression and/or anxiety in the Indian population, as there are scarce recent reviews on this topic from an Indian perspective. A strength of the review is the systematic search to locate evidence on this topic supplemented with an unstructured search of local studies. This allowed coverage of maximum available data on comorbid pain and psychological disorders. Timeframe of the review was considered adequate as only one eligible article was retrieved from 2010, therefore, very minimal published data was expected prior to that period. A limitation of the review is the lack of quality appraisal step due to the heterogeneity of included study types. Another limitation was the inclusion of articles addressing chronic pain, defined as lasting more than 3 months,[7] as well as articles using any other specified definitions of chronic pain. This selection of articles was made to ensure a comprehensive review of the landscape of chronic pain with comorbid depression/anxiety in India.
CONCLUSION
The published literature on chronic pain with comorbid depression and/or anxiety emphasized the high burden of these interlinked comorbidities in India and highlighted challenges in the effective management of these conditions concurrently. Addressing barriers pertaining to patients, physicians, and the healthcare system is essential to improve both pain and depression/anxiety outcomes. Future initiatives are needed to support research to inform evidence-based treatment of chronic pain and comorbid psychiatric conditions and to promote a multidisciplinary approach for managing chronic pain in the Indian setting.
Financial support and sponsorship
Medical writing support for the development of this manuscript was funded by Pfizer Upjohn.
Conflicts of interest
There are no conflicts of interest.
Acknowledgments
The authors would like to thank Kaveri Sidhu and Aditi Karmarkar, from Pfizer Upjohn for providing medical writing support funded by Pfizer Upjohn.
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