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Despite enormous progress in the field of pain management over the recent years, pain continues to be a highly prevalent medical condition worldwide. In the developing countries, pain is often an undertreated and neglected aspect of treatment. Awareness issues and several misconceptions associated with the use of analgesics, fear of adverse events – particularly with opioids and surgical methods of analgesia – are major factors contributing to suboptimal treatment of pain. Untreated pain, as a consequence, is associated with disability, loss of income, unemployment and considerable mortality; besides contributing majorly to the economic burden on the society and the health care system in general. Available guidelines suggest that a strategic treatment approach may be helpful for physicians in managing pain in real-world settings. The aim of this manuscript is to propose treatment recommendations for the management of different types of pain, based on the available evidence. Evidence search was performed by using MEDLINE (by PubMed) and Cochrane databases. The types of articles included in this review were based on randomized control studies, case–control or cohort studies, prospective and retrospective studies, systematic reviews, meta-analyses, clinical practice guidelines and evidence-based consensus recommendations. Articles were reviewed by a multidisciplinary expert panel and recommendations were developed. A stepwise treatment algorithm-based approach based on a careful diagnosis and evaluation of the underlying disease, associated comorbidities and type/duration of pain is proposed to assist general practitioners, physicians and pain specialists in clinical decision making.
Pain, as defined by the International Association for the Study of Pain (IASP) is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”.1 Pain can be experienced as an acute, chronic or intermittent sensation, or as a combination of the three, and is reported to be the common reason for medical visits. However, since pain has always been regarded as a symptom, not a disease state,2 there has been an enormous gap between prevalence and treatment, and it remains largely undertreated.3,4 Acute pain, the most commonly experienced type of pain, may be a result of injuries, acute illnesses, surgeries or labor.5 The overall prevalence of acute pain in hospital and ambulatory settings is reported to range between 30% and 80%.6–8 In addition to discomfort, uncontrolled acute pain translates to chronic pain, which may lead to delayed healing, prolonged hospitalization and increased morbidity.9 Globally, approximately 20% of adults suffer from pain, of which, 10% report persistent pain.10 Contrary to acute pain, chronic pain is seldom considered an individual entity, the focus majorly being on symptom relief. Chronic pain is generally associated with chronic illnesses such as neuropathy, cancer or human immunodeficiency virus infection–acquired immune deficiency syndrome (HIV-AIDS), and it is difficult to predict the nature and severity of pain.11 Several studies report a significantly high prevalence of chronic pain with certain neuropathic characteristics (6%–10%), which is of higher severity and longer duration.12–14 Untreated chronic pain significantly affects the quality of life (QoL) of the patients,15 is associated with considerable mortality,16 and can be a major cause of absenteeism from work or reduced work performance as well as loss of productivity.17
In developed countries too, pain is a commonly reported medical problem and comes with immense personal costs and a huge societal health care burden;18,19 the cost of chronic pain in the US has been estimated at $560–$635 billion.19 It is, therefore, not surprising to note an uncharacteristically high prevalence of pain in a developing economy like India, which is already struggling with a growing disease burden and lack of quality health care resources.20 According to the Global Burden of Diseases (GBD) survey, low-back pain (LBP) and migraine were amongst the top five medical conditions resulting in years lived with disability in the Indian population in 2013.21 In India, around 100,000 patients with cancer or HIV-AIDS die every year due to inadequate pain treatment.22 A survey of chronic pain conducted across eight major cities in India highlighted a high point prevalence (13%) of chronic pain, with 30% of the patients without treatment and 56% reporting unsatisfactory treatment.23
Currently, there is a need to develop treatment recommendations based on available evidence to guide Indian physicians in the management of pain.
According to a survey by the World Health Organization (WHO), the incidence of chronic pain was demonstrated to range between 5% and 33% in 15 centers across Asia, Africa, Europe and the USA.10 India has a high burden of chronic diseases and injuries, which are the leading causes of disability and mortality and have pain as comorbidity.24,25 Globally, pain prevalence in the elderly population is high26 and is further expected to rise,27,28 owing to the presence of multiple comorbidities29 and barriers related to communication and cognition.30 With a considerable increase in life expectancy in the past decade, India has witnessed an unprecedented rise in the ailing population, who are struggling to get adequate treatment for pain.31,32 Furthermore, there are some additional challenges, such as lack of adequate health care facilities, poverty, inadequate health care expenditure and lack of awareness among health care practitioners and patients.33 Health care centers in India are often not well equipped to provide adequate treatment for pain, with physicians relying mostly on over-the-counter analgesics.34,35 This generalized approach seldom works in most complex pain disorders, which require a detailed diagnosis and thoughtful, planned management.36 Another concern stemming from lack of awareness is the use of irrational and inappropriate multidrug prescriptions in India. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the second most common components of prescriptions in India.37–39 Rampant polypharmacy, coupled with lack of awareness, has had a huge impact on analgesic efficacy and presents tolerability issues.40 Several misconceptions regarding use of analgesics and fear of adverse events associated with the use of opioids or surgical methods of analgesia result in suboptimal treatment of pain.41,42 These inadequacies might be overcome by the amalgamation of expert opinions and available evidence to form standardized treatment guidelines for pain therapy. Hence, an expert panel was convened to delve on these lacunae and frame an appropriate treatment paradigm for pain management. The objective of this publication is to summarize the evidence-based consensus recommendations of this expert panel for the pharmacological management of pain in India.
Literature search of the current evidence was performed using the MEDLINE (by PubMed) and Cochrane databases. The articles included randomized control studies, case–control or cohort studies, prospective and retrospective studies, systematic reviews, meta-analyses, clinical practice guidelines and evidence-based consensus recommendations. Evidence grading was performed as per the following criteria used by the National Guidelines Clearinghouse:43
A multidisciplinary expert panel, composed of pain specialists, orthopedic surgeons, gastroenterologists, cardiologists, neurologists and nephrologists, with clinical and research expertise in the diagnosis and treatment of pain was convened, and recommendations were formulated based on expert opinions and available evidence. Based on the level of evidence, recommendations were graded as follows:
Recommendation statements were developed, circulated among panel members and modified based on their feedback until unified consensus was achieved.
Several methods of classification of pain have been developed to assist the physician in the appropriate diagnosis and treatment of pain in routine clinical practice. Pain can be classified into different types on the basis of duration or intensity, pathological mechanism and anatomic location (Table 1).
Nociceptive pain is elicited through A, δ and C nociceptive receptors present in peripheral tissues, which are activated by chemical, mechanical or thermal stimuli.44 These receptors play an important role in the regulation of natural defense mechanisms and elicit pain as a response to potential tissue damage. A number of chemical substances aggravate the nociceptive response to pain; the most common ones are bradykinin, histamine, serotonin and prostaglandins (cyclooxygenase [COX] 1 and 2).
Neuropathic pain primarily refers to pain initiated or caused by a primary lesion or damage to the central nervous system and includes disorders such as peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, causalgia and certain types of cancer pain.45,46 The pathways attributed to the generation of neuropathic pain involve abnormal excitability of afferent neurons, central sensitization following peripheral activation of neurons, loss of primary afferent response and activation of proinflammatory cytokines.47,48 Each of these factors may correspond to a particular mechanistic pathway, causing differences in the pattern and intensity of the somatosensory response.49,50
Acute pain is caused due to an existing disease or injury, usually lasting for hours, days or months or until the disease or injury is healed.55 This type of pain has a certain identifiable biological origin and is predictable in nature.56 Acute pain is a part of the normal biological defense against a potential threat or injury and is accompanied by protective reflexes.57 The sources of acute pain could be an acute illness (eg, appendicitis), perioperative (pain due to existing disease and surgical procedure), major trauma (vehicle accident), burns or due to childbirth.
Chronic pain persists even after the healing of the disease or injury and may be physically and emotionally distressing. Often, there is no single biological point of origin for this pain, resulting in a complex pathophysiology that necessitates the use of multiple therapeutic interventional strategies for alleviation.58 This type of pain may be a result of an existing chronic disorder (examples are cancer or noncancer pain such as HIV-AIDS, rheumatoid arthritis and LBP) or may have no known cause (idiopathic pain). Moreover, some secondary causes may include increased sensitivity to external stimuli (hyperalgesia) or pain due to innocuous stimuli (allodynia).59
Breakthrough pain is defined as transient flare-ups of severe and uncontrolled pain, in adequately controlled pain settings.60 These episodic exacerbations of pain are characteristically observed in patients with cancer and last usually from a few seconds to hours. Breakthrough pain may be idiopathic (without known cause), incidental and associated with a precipitating factor (eg, movement), or may be experienced in the interim between two doses.61
Pain is the most common symptom experienced by patients with cancer. The origin of cancer pain may be nociceptive (somatic or visceral) when there are changes in the underlying tissue pathology and neuropathic, when there is an involvement of neuronal damage. The severity of cancer pain increases as the disease progresses, with patients in the metastatic stage reporting the most severe pain.62 Cancer pain may be felt at the site of tumor or may be referred to a secondary region of the body.63 Breakthrough pain is another feature of cancer pain, which may be a consequence of repeated nociceptive sprouting or synaptic changes at the spinal dorsal horn (DH).64 Optimization of opioid therapy may be useful in preventing episodic exacerbations at the end of dose.65
Chronic pain due to nonmalignant causes is referred to as chronic noncancer pain (CNCP). Unlike cancer pain, CNCP may present no identifiable underlying pathology, may show increased heterogeneity and may be more challenging to treat.66 CNCP may be classified further as neuropathic pain (peripheral and central), inflammatory pain (infectious, arthritic and postoperative pain), muscle pain (myofascial pain syndrome) and mechanical pain (LBP, neck-and-shoulder pain). Various practice guidelines advocate the use of opioids as first-, second- or third-line therapy in CNCP, following failure of nonopioid analgesics.67,68
For this purpose, anatomic location refers to a region or site where the actual pain may be localized, rather than the location of the body system where the pain originated.69 As per the IASP, pain is anatomically classified, regardless of origin, as localized to head, face and mouth pain; cervical pain; upper shoulder and upper limb pain; thoracic pain; abdominal pain; LBP, lumbar spine and coccyx pain; lower limb pain; pelvic pain; as well as anal, perineal and genital pain.70 Although this categorization helps in differential diagnosis, it cannot be used as a basis for therapeutic management.71
Somatic pain is a sharp, well-localized pain emanating from the skin due to superficial damage and activation of peripheral nociceptors on the skin or mucous membranes.72 Alternatively, the pain may be deep and central in origin, originating from muscles, tendons or joints. Examples are LBP, neck pain, musculoskeletal pain and pain due to burns, injuries or wounds.73
Visceral pain is deep, poorly localized pain resulting from pressure or damage to internal organs; it may be accompanied by low blood pressure, nausea or sweating as a response to stimulation of nerve endings that are at the site of pain and that relay signals to the CNS. Examples of visceral pain are gall/kidney stones, gastric ulcers or intestinal spasms.74,75
Pain that is felt at a site away from the site of injury is called referred pain. The origin of referred pain may be somatic (involving muscles or joints) or visceral (involving visceral organs).76 Several mechanistic theories have been suggested to be involved in the cause of referred pain. Referred visceral pain may be attributed to the hyperexcitability of adjacent spinal neurons in response to nociceptive stimuli or a possible activation of the peripheral reflex arc via the efferent pathway.77 Examples of referred pain are myocardial pain and anginal pain.
Although several methods of classification are available for the categorization of pain, there is a lack of accurate and consistent terminology for the coding of chronic pain in compliance with the ICD system used by the WHO. Responding to this, the IASP developed a system of classification of chronic pain based on the ICD criteria, which takes into consideration the etiology, location and pathophysiology of pain for better categorization of the disease. Categorization is based on multiple parenting, wherein each diagnosis falls under one primary category/parent but corresponds to more-than-one secondary categories.78 According to this classification, chronic pain may be categorized as primary pain, cancer pain, posttraumatic or postsurgical pain, neuropathic pain, headache and orofacial pain, and musculoskeletal and visceral pain.
Regardless of its categorization, pain cannot be distinctly attributed to any isolated pathological event. Pain experience is a complex process that involves the activation of multiple neuronal signaling pathways within the peripheral nervous system (PNS) and central nervous system (CNS).73,79,80 The subjective experience of pain may be summarized as a four-stage process - transduction, transmission, modulation and perception.81 In stage 1 (transduction), nociceptive stimuli of tissue-damaging potential (including mechanical, chemical and thermal stimuli) are converted by the sensory cells into action potentials. Stage 2 (transmission) involves the conduction of these action potentials along afferent neurons to the DH of the spinal cord. In stage 3 (modulation), coding of nociceptive information occurs at the level of spinal DH. Modulation at the DH can be excitatory or inhibitory, thereby increasing or decreasing the resulting pain. Stage 4 involves generation of autonomic, affective, cognitive and behavioral responses to the painful stimulus, leading to pain perception.
Peripheral sensitization is characterized by abnormal sensitivity of afferent nociceptors to noxious stimuli. Nociceptors on the skin and deeper tissues sometimes become extremely sensitive to intense noxious stimuli in the presence of inflammation. This further lowers the threshold of nociceptor activation to normally innocuous or less-painful stimuli, accompanied by an increase in the degree or magnitude of response. Additionally, extreme sensitization may lead to the activation of sleeping or silent nociceptors, which upon excitation amplify the pain response manifold. Drugs acting at the peripheral nociceptor level are NSAIDs, opioids, cannabinoids and transient-receptor potential vanilloid (TRPV1) receptor antagonists.
Afferent pain signals from the peripheral nociceptors to the spinal neurons may sometimes activate low-threshold mechanoceptors at the DH, thus amplifying the central neuronal response to noxious stimuli.82 This phenomenon of altered sensitivity of neuronal cells at the level of the second-order neuron is known as central sensitization. Central sensitization is implicated in the transition of acute pain to chronic degenerative pain. As observed with peripheral sensitization, primary hyperalgesia is the first manifestation of altered threshold at the central neuronal level.82 Under pathological conditions, receptors that are normally associated with sensory response to stimuli such as touch may acquire the ability to produce pain, resulting in secondary hyperalgesia, an important aspect of central sensitization.64 Unlike peripheral nociception, a number of neurochemical drivers are involved in the modulation of pain perception at the central level, resulting in a complex interplay of events that underlie the pathology of many chronic and neuropathic pain conditions (Figure 1).80,83
Drugs that modulate the pathways leading to central sensitization act by increasing the level of biogenic amines and reducing the spontaneous ectopic discharges. These include serotonin–norepinephrine reuptake inhibitors (SNRIs, such as duloxetine, paroxetine, venlafaxine), anticonvulsants (gabapentin and pregabalin) and tricyclic antidepressants (TCAs, such as amitriptyline, imipramine and desipramine).84–86
Wind-up is the temporal summation of excitatory impulses following repeated firing of spinal dorsal neurons due to C-fiber discharges.64 The process of wind-up begins with the release of excitatory neurotransmitter glutamate, which binds to the N-methyl-d-aspartate receptor (NMDA)/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor.87 Activation of these receptors, together with release of substance P from the C-fibers, initiates the depolarization of the cell membrane and triggers the intracellular release of Ca2+. Repetitive sensitization of NMDA receptors further contributes to hyperexcitability of the membrane, which aggravates the resulting response to pain, resembling an unending loop.80,88 Antagonism of NMDA receptor by drugs such as ketamine prevents the generation of excitatory response and provides therapeutic benefit in chronic neuropathic pain.89
Apart from central sensitization, inflammation induces significant changes in the neuroplastic structure of the brain and spinal cord. Altered neuroplasticity is a characteristic feature of neuropathic pain and is often a consequence of tissue damage or injury.90 The positive feedback-mediated structural repair following an injury or nerve damage may also contribute to selective degeneration and alteration of function, often progressing to the neuropathic state.91 Modulation of peripheral nociceptor function may result in painful neuropathies, characterized by heightened sensitivity to noxious or normal stimuli and a pricking, tingling or burning pain. On the contrary, central nerve damage triggered by infection, metabolic disorders or mechanical insult may result in loss of pain sensation such as in diabetic neuropathy.90
All events in the DH do not facilitate nociception. Spinal interneurons release amino acids (eg, γ-aminobutyric acid [GABA]) and neuropeptides (endogenous opioids) that bind to receptors on primary afferent and DH neurons and inhibit nociceptive transmission by presynaptic and postsynaptic mechanisms.
Descending transmission pathways are responsible for abolishing the ascending signals traveling up the central nervous system so that the pain perception is reduced,64 via release of endorphins and monoamines.92 Opioids like morphine act by modulation of both ascending and descending pain pathways (Figure 2).93
Acute and chronic pain cannot be segregated into two distinct types; chronic pain is rather an extension of acute pain, resulting from poorly managed acute pain.94 The metamorphosis of acute to chronic pain is believed to proceed through one of the following processes: central sensitization, modulation or modification of nociceptors, and altered neuroplasticity.95,96 Under normal circumstances, as a healing process begins, the noxious stimuli reduce and pain diminishes. However, in cases of persistent pain, peripheral and central sensitization most frequently transcends to hyperalgesia (increased response to less-painful stimuli) and allodynia (pain response to normally nonpainful stimuli). Altered spinal neuroplasticity as a result of glial cells modifying the neuronal cytoarchitecture is another important aspect of chronic pain and may be a consequence of repetitive nociceptive firing in the central neurons (reversible) or nerve damage due to neuropathy (irreversible).97 Studies have reported substantial loss of gray matter in the brain and changes in the structure, sensitivity and activity of neurons as well as internal rewiring in certain chronic pain conditions.91,98,99 These changes may be clinically manifested in the form of fibromyalgia or complex regional pain syndrome.98 There is also a significant decline in neurotransmitter receptors and their function, which may explain the lack of efficacy with central opioid agonists in neuropathic pain.91 While management of acute pain symptoms might seem to be the most rational approach from a clinician’s perspective, it is essential to evaluate the risk factors associated with pain chronification.100 Increased pain intensity, loss of functionality and affected psychosocial ability are a few predictive factors for development of chronic pain.101,102 Studies have shown that assessment of functional and psychosocial outcomes is a highly favorable measure in predicting the risk of chronic pain.103,104
Pain is the most prevalent, yet frequently undertreated, medical condition globally.105,106 Untreated or inadequately treated pain is the major cause of depression and eventually leads to loss of productivity and functionality, as well as poor health-related QoL, of patients.107,108 There are several impediments that contribute to the undertreatment of pain in India, which include lack of awareness, regulatory restrictions on opioid use, physician attitudes, overuse of NSAIDs and insufficient resources for managing pain in primary care settings.42,109–111 It is essential to minimize these barriers to ensure optimal treatment of pain.
In the wake of increased understanding of the pathophysiology of pain, various receptors have been identified as potential targets for drug therapy over the years. In the early 1970s, Vane et al112 proposed the involvement of prostaglandin inhibition as the mechanism of action of aspirin-like drugs. These findings paved the path for development of NSAIDs, targeting the COX-1 enzyme system involved in the synthesis of prostaglandins, thereby reducing both pain and associated inflammation. The earliest known marketed NSAIDs were ibuprofen and aspirin, which were followed up by similar compounds, with varying efficacies.113 Acetaminophen, the safest analgesic till date was developed in 1946, after two synthetic antipyretics, acetanilide and phenacetin, were developed and had significant associated toxicities.114 In the search for a more effective and safer analgesic, research was focused on the development of the selective COX-2 inhibitors celecoxib and rofecoxib.115 However, there were severe concerns of cardiac toxicities observed with these agents, limiting their use.
Morphine and codeine were the earliest natural opioid analgesics to be developed and used in clinical practice. Further research led to the development of synthetic opioids such as fentanyl and pethidine, with increased efficacy and long-term activity. However, in the light of associated risk of overuse, addiction and misuse of these analgesics, it was recommended to follow a risk-management and monitoring program during opioid therapy. Tramadol, an opioid analgesic different from conventional opioids, was developed in 1977 and has since been routinely used in moderate-to-severe pain, owing to its high safety and efficacy.
Further scientific investigation into pain pathology has led to the development of anti-nerve growth factor (anti-NGF)- and anti-TRPV1-based therapies. However, these agents are still under clinical development, and there is a lack of conclusive evidence supporting their efficacy and safety in routine clinical practice.116,117 Deeper insights into the central pain pathways have uncovered some overlapping pathological factors implicated in pain, depression and other psychological disorders.118 Antidepressant-induced increase in the neurotransmitters serotonin and norepinephrine has been thought to alleviate pain, the postulation being reinforced by the remarkable efficacy shown by antidepressants in chronic pain, particularly of neuropathic origin.119 Similarly, the efficacy of the anticonvulsants pregabalin, gabapentin and carbamazepine was demonstrated in several clinical studies.120 As a guidance to physicians treating chronic cancer pain, the WHO established an evidence-based three-step analgesic ladder that provides a stepwise approach for deciding treatment according to the intensity of pain.121 This ladder has been widely adopted for use in noncancer pain settings.122 However, the three-step ladder is not considered applicable anymore and has been modified to suit different clinical settings, due to the practical delays in administering pain relief for patients with severe pain and also due to concerns over the efficacy of low-dose opioids used in step two.
Evidence from several studies has highlighted the importance of nonpharmacological interventions for pain relief.123 Exercises such as stretching and strengthening, relaxation, postural stabilization and yoga; therapeutic heat and cold packs; ergonomic adaptations; modification of daily activities; chiropractic treatment; massage or traction are some of the nonpharmacological approaches that are routinely used with pharmacological therapy.124–129
An individual’s perception of pain may be greatly influenced by the emotional and behavioral responses and is strongly correlated to his/her culture, personal history and genetic makeup.130–133 For instance, presence of different haplotypes of the catecholamine-O-methyltransferase gene has been linked to variability in pain perception in humans.134 Thus, treatment for pain must be tailored for each individual and should focus on interruption of reinforcement of the pain behavior and modulation of the pain response. Important factors for consideration for treatment recommendation include individual’s response to prior appropriate treatment management, compliance and drug abuse/dependence behavior.56 The biopsychosocial model of pain encompasses the biological, psychological and social aspects of pain and has been increasingly used in a variety of chronic pain settings.135,136 Since the experience of pain is heterogenic in nature; a “one size fits all” approach would not be the most ideal way to manage pain. In short, an individualized approach to treatment based on the genetic, cultural, social and behavioral aspects of the patient may help in the optimal management of pain across different clinical settings.56,137
Combination therapies may consist of combination of two or more drugs administered separately or as fixed-dose combinations (FDCs) of two or more active ingredients in a single-dosage form.138 Use of FDCs of analgesics represents a multimodal approach that is based on the integration of various mechanisms to result in pain relief.139 FDCs have been hugely preferred to treat a variety of disorders owing to their safety and efficacy. Additionally, use of FDCs may improve patient adherence to therapy and reduce the cost associated with multiple medications.140 However, not all FDCs are rational, and the majority of them may present no evidence of improved efficacy or tolerability.141,142 In India, FDCs have been used generously, notwithstanding the complete lack of efficacy with some combinations.143 The Central Drugs Standard Control Organization (CDSCO) has taken cognizance of the increased use of irrational drug combinations by physicians in India and has recently banned more than 300 FDCs from the market.144 From a physician’s perspective, the rationale for use of FDCs must identify clear association between FDC use and increased efficacy or reduced adverse events. Furthermore, from a regulatory perspective, the components of an FDC must possess complementary pharmacokinetic profiles and should not have supra-additive toxicity.
The US Food and Drug Administration (USFDA) draft guidance for industry mandates the fulfillment of some necessary conditions prior to the approval of analgesic FDCs. Thus, an FDC awaiting FDA approval must demonstrate strong evidence of efficacy over the available single-agent therapy in well-controlled single- or multiple-dose clinical studies. Moreover, each component of the FDC must contribute to the overall efficacy and safety of the product, in order to justify its use over single-agent therapies.145 A similar guidance document has been developed by the CDSCO to guide the development of FDCs in India.146 A list of approved analgesic FDCs in India is provided by the CDSCO.147
Adequate treatment according to national and international treatment guidelines can result in sufficient pain relief in majority of the patients. However, barriers to the use of analgesics can result in undertreatment of pain. Other than institutional barriers such as government regulations regarding opioid prescription and irregularities in the treatment of patients with pain, physician and patient barriers hinder effective management of pain.
Physician’s knowledge and understanding regarding patients’ pain, principles of treating pain, analgesics ladder and knowledge about the efficacy of different routes of opioid administration are very important for pain management.148–152 Another factor affecting inadequate assessment of pain by physicians included concerns regarding side effects or tolerance to opioids.43,153–155 In cancer patients, inadequate pain assessment was considered a major barrier (20%–80%) in pain assessment.42,148,149 The physicians either do not use an appropriate method to measure the pain intensity or fail to appropriately classify the pain. Misconceptions regarding the regulations governing opioid use also exist.156
Concerns regarding addiction to or physical dependence on, as well as side effects of opioids prevent physicians from prescribing opioids according to standardized guidelines.68,127,157–159 According to the guidelines by the WHO, strong opioids should be the first choice of treatment for moderate-to-severe pain and the use of these opioids must be continuously personalized based on patients’ response in terms of pain relief. In a study by Tournebize et al,160 more than 50% of surveyed physicians reported insufficient adherence to treatment guidelines for chronic pain. Studies have also shown that physicians hesitate to administer adequate doses of opioids because of the fear of the potential development of tolerance by the patient.42,161,162 Most often, physicians do not consider assessment of pain as a priority and, as a result, do not give pain relief its due importance. Furthermore, a patient’s self-report of pain, considered the best indication of pain, is viewed with skepticism.
Cognitive barrier results from patients’ lack of understanding about the different options of pain management, along with attitudes and beliefs that not only affect patients’ pain communication and adherence to analgesic regimen but also have a negative impact on the outcomes of pain management.163
Many patients lack the knowledge of the principles involved in effective pain management and have concerns about taking pain medication (mostly concerns about addiction and side effects of pain medication). A few researchers believe that there is a relationship between better knowledge and less pain intensity or between more negative beliefs and more intensive pain.164–169 However, this association was either partially confirmed or not confirmed by other researchers.170,171
Patients beliefs and attitudes that hinder pain management include the following: fear of addiction, that originates from a misunderstanding of the relationship between psychological addiction, physical dependence and tolerance; concerns about analgesic use (side effects); concerns about pain communication due to age, language, cultural traditions or other illness (communication issues between patients, nurses and doctors [sensory barrier]; willingness to tolerate pain to be a good patient and to not trouble the family); not adapting adequately to the possibility of controlling pain in general (stigma of using pain medication, stoicism about dealing with pain, assuming that pain is a part of the disease and suffering, concerns regarding the capability of the caregiver to understand their needs, hesitation to question authority); and inadequate adherence to pain medication (sensory barrier).42,155,166,169,172–175 Financial barriers could also result in reduced adherence to treatment.
Several myths about pain and its treatment exist in our society, which ultimately prevent the patient from receiving adequate care. According to the American Chronic Pain Association, some of the commonly accepted beliefs revolve around the perception (pain is an emotional and not a physical disorder) and treatment of pain (analgesic therapies may not be effective or may lead to addiction).176 In addition, undertreatment of pain in the elderly and children may be primarily due to the assumption that pain cannot be felt by newborns and babies but is an acceptable and natural part of the aging process and therefore may not warrant medical attention.177 It is essential to disprove these myths by promoting awareness among patients, physicians and the society in general.
Presence of comorbid medical conditions may not only influence the response to analgesics but may present difficulties in diagnosis as well. The most commonly associated psychological comorbidities in pain are depression and anxiety.178–180 These may be preexisting or may result from the pain itself, often aggravated in untreated or undertreated chronic pain.181 Presence of depression is known to have considerable impact on outcomes of pain treatment, signifying the two-way relationship between pain and depression. A systematic review of studies correlating the effect of depression on pain showed increased severity, intensity and duration of pain in depressed patients.124 Functional assessment using valid tools may indicate the presence of underlying symptoms, necessitating the use of antidepressant therapy, which can in turn effectively help control pain.126,182 Until recently, the outcome of pain therapies was evaluated on the basis of reduction in pain intensity and improvement in sensory/motor ability, seldom delving into the psychological or cognitive aspects that frequently led to mismanaged pain. Clinical investigations over the years have resulted in the use of cognitive behavioral therapy in pain treatment programs, with remarkable efficacy in the acute and chronic pain settings.183,184
The recommendations are based on graded evidence as explained previously. The grades are mentioned in parenthesis next to each recommendation.
Since comorbidities may influence pain perception and affect the treatment outcomes, it is necessary to carry out screening of the patient for possible physical illnesses (liver impairments, gastrointestinal diseases, renal impairments, physical dependence to opioids and so on) and psychiatric comorbidities (depression, anxiety, psychological disorders) prior to initiating treatment (Figure 3).
Prior to starting treatment, it is essential to decide the treatment goals so as to prevent undertreatment. It is important to consider the ethical implications of the associated treatment. The following questions may help: how severe is the pain? Is the pain associated with disability or loss of function? What are the existing comorbidities? Is psychosocial function impaired? Is opioid therapy required?
According to Cohen and Jangro,196 treatment goals need to be broader, achieving a little more than pain reduction (must include QoL and the functional impact of pain treatment), and must be realistic, in order to ensure optimal therapy with minimal side effects.
A detailed diagnosis of neuropathic pain involves, in addition to pain assessment tools (using neuropathic pain scales) and QST, evaluation of neurological function using functional neuroimaging, neurophysiology studies, skin biopsy techniques and other laboratory testing methods.197 Additional laboratory investigations include microneurography studies, laser-evoked potentials, electrophysiology studies and nociceptive reflexes.189
In order to understand the nature of pain and to determine the treatment course, it is essential to distinguish the physical causes of pain in addition to assessing the mental and environmental factors.
The choice of analgesic prescribed is based on the type of pain, duration of pain and comorbidities. A few years ago, NSAIDs, acetaminophen and opioids were prescribed in the treatment of all types of pain. This methodology is now considered ineffective, and with an increase in the awareness regarding different classifications of pain, mechanism-specific treatment is recommended.
Studies have shown that a number of comorbidities influence the treatment outcomes of analgesic therapy. It is widely known that several chronic pain conditions are accompanied by psychosocial comorbidities such as anxiety and depression, which may amplify the pain perception, physical function, adaptation and treatment response.198,199 Systematic screening of patients for any associated psychiatric comorbidity may support the physician in deciding the treatment plan. In the case of suspected depression, antidepressants may be added to the therapeutic regimen to control the clinical symptoms.200 While psychiatric comorbidities significantly affect the emotional response to pain, any coexisting physical comorbidities may affect the efficacy and tolerability of the analgesic. For example, decreased liver function may significantly affect the metabolism of NSAIDs and opioids, leading to increased levels in blood and associated toxicity. Preliminary screening by performing liver function tests and assessment of the Child–Pugh score may be important in determining liver failure.201 Similar considerations are necessitated in suspected gastrointestinal or renal comorbidities.202,203
A person’s experience of pain generally manifests itself in emotional and behavioral responses and is strongly correlated to the culture, personal history and perceptions of the individual.130 Thus, treatment for pain must be tailored for each individual patient and should focus on interruption of reinforcement of the pain behavior and modulation of the pain response. Important factors to be considered for treatment recommendation include individual’s response to prior appropriate treatment management, compliance and drug abuse/dependence behavior.56 An understanding of cultural-based attitudes about pain is critical in the management of pain.
Undertreatment of pain in special populations, such as the elderly, children or patients with renal/hepatic impairment, results from inadequate pain assessment and efficacy issues. Pain treatment in these populations must be performed following careful consideration of adverse events and the pharmacokinetic profile of the analgesic.
Studies report that the prevalence of pain is higher in the elderly population, with high proportion of patients with disability and poor QoL.62,217 The most commonly occurring pain conditions in the elderly are rheumatoid or osteoarthritis, cancer and diabetic neuropathy.218 In addition, elderly patients with chronic pain present several clinical comorbidities, which may influence the outcome of pain therapy. These may include gastrointestinal/renal/hepatic dysfunction, depression, anxiety and cognitive impairment, among others.219,220 Due to the limited evidence from clinical studies on the geriatric population with pain,221 the health care practitioner needs to evaluate the possible risk factors that may impede effective analgesia. NSAIDs should be avoided in such patients due to the potential for gastrointestinal bleeding and renal toxicity. Opioids such as morphine, codeine, fentanyl or oxycodone may cause constipation or respiratory depression and should be used with caution, preferably in low doses and along with laxatives.222 Paracetamol is the analgesic of choice for the geriatric population with pain.
Pain in children may be mostly due to injuries, burns, inflammation and chronic illnesses such as cancer, HIV/AIDS or postoperative status. The WHO guidelines on management of chronic pain in children emphasize the importance of pain assessment in children.223 Since self-reports of pain severity cannot be obtained in infants or small children, pain assessment entirely depends upon the clinician’s reports. Symptoms of crying, agitation, irritation or facial expression may be indicative of pain in infants. For children >4 years of age, Faces Pain Scale may be used for pain assessment.224,225 Pharmacological therapy of pain in children should take into account the age, pain intensity, underlying disease or comorbidities as well as the functional ability. The first-line therapy generally includes safer analgesics such as paracetamol, followed by ibuprofen.223 The second-line therapy may include other NSAIDs. Strong opioids should only be used in moderate-to-severe pain.226 The most preferred route of medication administration should be oral, either as tablets or as syrups.134
During pregnancy, women may experience LBP, joint pain, as well as abdominal and pelvic pain, among other conditions. Analgesic treatment during pregnancy and lactation may be difficult considering certain medications can potentially harm the fetus or may pass through breast milk and affect a nursing infant. Administration of NSAIDs in the first trimester has been linked to premature ductal closure and should be avoided.227 Aspirin may be used in the first trimester but should be avoided near term, as it may delay labor and cause hemostatic abnormalities.228 Paracetamol and opioids are relatively safer analgesics to use in pregnant women. In the case of lactating women, paracetamol and NSAIDs may be safe to use, while opioids should be avoided due to the risk of toxicity and dependence.229
A majority of analgesics are excreted by the renal route, and it is important to assess kidney function prior to administering analgesics for chronic pain. Since impaired renal function may lead to accumulation of drugs, there are chances of toxicity in such patients. Clinicians should conduct adequate assessment of kidney function by estimating serum creatinine values and the estimated glomerular filtration rate (eGFR).203 An eGFR of <60 mL/min/1.73m2 may warrant dose adjustment.230 NSAIDs, such as indomethacin, naproxen, diclofenac and ibuprofen, have been shown to decrease the GFR and increase the possibility of edema due to prostaglandin-mediated inhibition of renin.231 Therefore, NSAIDs are best avoided in patients with renal impairment. Alternatives to NSAIDs are paracetamol and opioids such as codeine, tramadol or buprenorphine;232 morphine and codeine are undialyzable and should be avoided in patients who are undergoing hemodialysis.231 For moderate-to-severe pain, fentanyl can be safely administered to patients with renal dysfunction or those who require dialysis (although caution needs to be exercised in such patients as fentanyl is poorly dialyzable).232,233
Deciding analgesic therapy for patients with hepatic impairment can be a challenge, since most analgesics undergo hepatic metabolism. Cirrhosis is the most prevalent manifestation of liver disease, and it may be caused due to excessive alcohol intake, hepatitis infection or drug-induced toxicity. Since liver is the main site of metabolism for paracetamol, NSAIDs and opioids such as morphine, its dysfunction may lead to increased blood levels of these drugs, particularly those that are primarily metabolized by cytochrome P450 (CYP) enzymes.234 On the contrary, changes in CYP enzymes may result in decreased efficacy of codeine and tramadol, which undergo biotransformation to active metabolites.235 Thus, a thorough understanding of the pharmacokinetic profile of analgesics may help in deciding the appropriate pharmacotherapy for patients with liver dysfunction.236 For instance, although paracetamol undergoes metabolic conversion to a hepatotoxic metabolite N-acetyl-p-benzoquinone imine,237 clinically significant toxicity is observed only at large doses, and small doses of this drug may appear to be safe in such patients.238 Dose adjustment should be considered while administering NSAIDs and opioids to patients with hepatic impairment.
Disease-specific treatment recommendations are presented in the Supplementary materials section.
We wish to acknowledge the efforts of other members of the Pain Working Group who contributed significantly to the development of this manuscript, namely, SS Sukumar, Hammad Usmani, Rajeev Rao, Ananth Hazare, PR Krishnan, Poorna Chandra and Umesh Gupta. Padmini Deshpande (Siro Clinpharm Pvt Ltd) provided writing assistance, and Dr Sangita Patil (SIRO Clinpharm Pvt Ltd) provided additional editorial support for the development of this manuscript. This study was funded by Johnson & Johnson Pvt Ltd, Mumbai, Maharashtra, India.
All authors contributed towards drafting and critically revising the review and agree to be accountable for all aspects of the work. All authors met International Committee of Medical Journal Editors criteria and all those who fulfilled those criteria are listed as authors. All authors provided direction and comments on the manuscript, made the final decision about where to publish as well as approved the submission of the manuscript to the journal.
Prashant Narang and Jaishid Ahdal are employees and/or shareholders of Johnson & Johnson Private Limited, Mumbai, Maharashtra, India. Gur Prasad Dureja, Rajagopalan N Iyer, and Gautam Das report no conflicts of interest in this work.