Clinical manifestations

Presentation and course

	• Chronic pain manifests by several sensations such as stabbing and burning and is usually triggered by noxious stimuli or by lesions in the nervous system.
	• Neuropsychological testing of chronic pain patients has shown that mental processing speed mediates the relationship between pain and physical function.
	• Prognosis and complications are determined by the primary condition causing pain and condition of the patient.

Pain is described by the patient mostly in terms such as stabbing, burning, tearing, squeezing, etc. Acute pain is accompanied by a stress response consisting of increase in blood pressure, tachycardia, pupillary dilatation, and high plasma cortisol levels. This may be accompanied by local muscle contraction. Four broad categories of pain are generally recognized:

(1) Nociception. This is the detection of tissue damage by specialized transducers attached to A delta and C fibers. Aspirin and nonsteroidal anti-inflammatory drugs produce pain relief by restoring nociceptivity to its normal state.

(2) Pain perception. This is usually triggered by noxious stimuli or by lesions in the nervous system. Pain due to injury to the nervous system usually does not respond to opioids.

(3) Suffering. This is the result of pain and accompanying stress.

(4) Pain behaviors. These are the responses of an individual to pain, such as crying or refusal to work.

Other symptoms in patients with chronic pain. Patients with chronic pain frequently experience depression, sleep disturbances, fatigue, and decreased mental and physical functioning. About one half of patients with chronic pain suffer from depression. Depression may develop secondarily or independently of the chronic pain syndrome, or it may occur as the primary cause of chronic pain. Evidence suggests that depression and chronic pain share common biological pathways, namely, the serotonergic and norepinephrine systems.

Assessment of pain. Patients can quantify their pain at the time of examination by rating the intensity on a visual analog scale from none to severe, or on a box intensity scale from 0 (no pain) to 10 (the most severe pain). The most frequently used instrument to assess pain is McGill pain questionnaire. It consists of 3 parts:

(1) A descriptive scale of pain intensity with numbers for adjectives: 1 equals mild, 2 equals discomforting, 3 equals distressing, 4 equals horrible, 5 equals excruciating.

(2) A diagram of a human figure on which the patient can mark the location of pain.

(3) A pain rating index based on the patient's selection of adjectives from 20 categories of pain representing sensory, affective, and cognitive components of pain.

The McGill scale, a more time-consuming, but shorter version of the scale is also available. Quantification of pain does not measure the functional activities in everyday life. Self-report measures and diaries of activities enable an assessment of relevant behavior as well as social and mental function. Although pain descriptors in the McGill scale, which appear to be most useful in assessing physical disability-related pain, have been identified, caution should be exercised when doing diagnostic workups based solely on sensory and affective pain descriptions.

Quantitative sensory testing is used for the assessment and study of pain caused by injury or disease, peripheral neuropathies associated with diabetes, AIDS and toxic substances, as well as the evaluation of medications. Devices are available for the evaluation of both small and large-diameter nerve fibers of the peripheral nervous system. Although measurement of sensory impairment for clinical and research studies is useful, the results should not be used as sole criteria for clinical diagnosis.

Psychological assessment of pain. This is usually done by a clinical psychologist, and the essential components of this examination are:

• Behavioral analysis to identify factors perpetuating pain behavior in chronic pain patients.

• Psychomotor testing to evaluate psychological functioning. The limitation of most of the tests used is that they are originally designed to evaluate psychopathology in persons with significant mental dysfunctions. In pain patients, most of the symptomatology is reactive to their current condition. In addition to the McGill scale, Minnesota Multiphasic Personality Inventory is the most common method of assessing the personality of patients with chronic pain, particularly those who show significant psychiatric dysfunction.

Assessment of disability. The object of assessment is the patient as a whole and not just the pain. Usually, this assessment is for the patient's ability to work and is complicated by Workmen's Compensation, legal issues, disability retirement, financial status, etc. Considerable objectivity and careful judgment are required for such assessment. It involves assessing the psychogenic and organic components of the patient's condition as well as the functional capabilities. The limitation of assessing pain is that disease is only one factor contributing to pain. The experience of pain is influenced by psychological, genetic, social, and cultural factors. In the absence of objective findings, pain, suffering, and disability cannot be proven.

Trained physicians using standard testing procedure can assess the functional disability due to chronic pain with reasonable accuracy. Neuropsychological testing of chronic pain patients has shown that mental processing speed mediates the relationship between pain and physical function (38). This may be considered in the objective assessment of chronic pain and functional disability.

Pain in children. Various pediatric pain measurement tools are available for clinical use including self-report measures (for older children), behavioral measures, psychological instruments, and observer reports. Faces scales have become the most popular approach to eliciting children's self-reports of pain. One of these is Wong-Baker scale that includes drawings of a range of facial expression from smiling to crying. The Computer Face Scale, which records expression of relative amounts of pain or hurt and happiness, has advantages over other pain measurement tools for children as it provides time-stamped electronic recording and real time review (07).

Psychosocial and sex factors. Pain is common in patients with delayed recovery from mild traumatic brain injury. A study did not find sex differences in pain frequencies or severity following mild traumatic brain injury, but pain was significantly associated with sociodemographic, behavioral, and clinical variables, which explained 60% of the pain variation in males and 46% in females (30).

Prognosis and complications

Prognosis and complications are determined by the primary condition causing pain and condition of the patient. For example, chronic pain that interferes with activities of daily life is associated with greater risk of falls in older adults (23).

Biological basis

	• Delta C and A fibers carry nociceptive impulses from the site of injury to the dorsal horn of the spinal cord, and from there the ascending pathways relay the information to thalamic, limbic, and cortical structures, which are involved in the memory of pain.
	• Nociceptive visceral afferent discharges in chronic pain can produce changes in the central nervous system.
	• Acute pain can rapidly evolve into chronic pain because neuronal expression of new genes may occur within less than half an hour after injury.
	• Several receptors are involved in chronic pain and some of them are targets for analgesic drugs.

Anatomic localization

Pain pathways. Mechanical, chemical, or thermal stimuli increase the discharge rate of nociceptive stimuli. Inflammatory mediators such as cytokines are released at the site of injury and bathe the sensitized nociceptors. Topical analgesics act at this site. Delta C and A fibers carry nociceptive impulses from the site of injury to the dorsal horn of the spinal cord. Ascending pathways then relay the information to thalamic, limbic, and cortical structures, which are involved in the memory of pain. Spinal nociceptive input is subject to modulatory influences from supraspinal sites.

A plethora of ascending pathways to the brain are available other than the classic routes (ie, spinothalamic tracts). Positron emission tomography and functional magnetic resonance imaging have revealed that various brain regions are activated during acute pain. These regions, however, are not suitable targets for pharmacotherapy of pain that is directed at the spinal and peripheral levels.

Electrical stimulation of supraspinal sites, eg, the thalamus, can produce pronounced analgesia. Midbrain periaqueductal gray matter is an effective site for stimulation to produce analgesia and is a component of the endogenous pain inhibitory system. In contrast, stimulation of the rostral ventral medulla can facilitate spinal nociceptive transmission. Hyperalgesic responses observed during acute opioid withdrawal involved activation of descending nociceptive facilitatory systems from the rostral ventral medulla. The spinal mediators of descending nociceptive inhibitory influences include serotonin, norepinephrine, and acetylcholine. This may be relevant to the action of antidepressants in relieving pain in the absence of depression. Some antidepressants may act on the descending tracts from the brain through norepinephrine and serotonin systems to modulate the signaling of pain in the spinal cord.

Pathophysiology

The consequences of tissue injury extend beyond the site of injury and include spinal as well as supraspinal changes in neuron excitability and neurochemical changes. The pathomechanism of pain has been studied to improve therapy of pain.

Epigenetic mechanisms. Epigenetic mechanisms such as histone modifications and DNA methylation have been linked to the development of chronic pain (06). This is the basis of development of new analgesic compounds that target specific epigenetic proteins.

Chronic pain-induced changes in the brain. Nociceptive visceral afferent discharges can also produce changes in the central nervous system. Visceral nociceptive information is transmitted by the dorsal columns. This explains why visceral pain is relieved after dorsal commissural myelotomy. Thalamic stimulation can evoke memories of visceral pain. Application of noxious stimuli to the viscera has shown activation of areas in the brain that have been mapped by positron emission tomography.

Functional neuroimaging is useful to understanding the neurobiology of pain and will be instrumental in helping the design of more rational treatments for chronic pain. Studies using functional MRI show that the prefrontal cortex, anterior cingulate cortex, posterior parietal cortex, thalamus, and caudate are engaged during evaluation of the spatial locations of noxious stimuli. Brain imaging studies have revealed new roles of cortical neuronal networks in chronic pain as well as molecular and synaptic mechanisms underlying relevant cortical plasticity. Neuroimaging can help in understanding cognitive influences on pain and has also been used for assessment of the effects of psychological manipulations on pain (49). PET imaging with the radiotracer C-diprenorphine in patients with arthritis pain has shown that within the arthritis group, as compared with healthy controls, greater opioid receptor availability was found in the striatum, including the caudate nucleus of patients reporting higher levels of recent chronic pain (03). Because the experience of pain in humans is modulated by endogenous opioids, this finding indicates that chronic pain may upregulate opioid receptor availability to dampen pain.

Chronic pain not only produces functional changes in the brain, but it can also alter the structure of the brain. Studies of neuropathic pain with spared nerve injury in the rat model show that basal, but not apical, dendrites of cortical neurons are longer with more branches than their counterparts in sham-operated animals, and their spine density is selectively increased (28). These results provide evidence that chronic neuropathic pain can lead to pain-associated morphological changes in the cortex at the single neuron level, such as rearrangement of the medial prefrontal cortex, which help to define the cellular basis for cognitive impairments associated with chronic pain. Some of the CNS changes return to a normal state with resolution of the pain (16).

Neurochemistry of pain. Substance P, a neurokinin, is an important mediator of spinal pain transmission and acts principally at neurokinin-1 receptor. However, neurokinin-1 receptor antagonists are only partially effective as analgesic agents. Other pain mediators are glutamate, calcitonin gene-related peptide, bradykinin, histamine, prostaglandins, and nitric oxide. Glutamate plays a major role in the development and maintenance of hyperalgesia, and glutamate receptor antagonists have been shown to be effective analgesic agents. Other pharmacological agents that impair the synthesis, release, and effect of molecules involved in spinal nociceptive integration include morphine and sodium or calcium channel blockers.

The role of nitric oxide in pain varies greatly according to the site and to the cellular concentration, and studies show conflicting results. Nitric oxide also has a role in the analgesic effects of acetylsalicylic acid as well as in the facilitation of spinal opioid action; therefore, it may have an antinociceptive role at some sites and in some circumstances. Nitric oxide also interacts with various receptors.

Molecular basis of pain. This is illustrated by use of some of the receptors as targets for analgesic drugs:

Opioid receptors. The pain response can be modulated by opioid receptors located in the dorsal horn as well as in other areas throughout the spinal cord and brain. Most clinically used opioids bind to the Mu1 (µ1) opioid receptor.

Glutamate receptor antagonists. Activation of AMPA, kainate, and N-methyl-D-aspartate receptors is involved in the development of chronic pain and is the basis of development of analgesics. The analgesic effect of N-methyl-D-aspartate antagonists, however, is less pronounced than that of AMPA or kainate antagonists.

Capsaicin receptor (vanilloid receptor-1). Vanilloid receptor-1 contributes to the activation of pain pathways by noxious chemical or thermal stimuli. This receptor is a promising drug target for pain resulting from tissue damage. However, vanilloid receptor-1 does not contribute to nerve injury-induced hyperalgesia, and blocking of vanilloid receptor-1 is unlikely to relieve hypersensitivity to touch such as that associated with herpes zoster.

Studies of mice with deletions of gene products show differences in the neurochemistry of acute and persistent pain, leading to the conclusion that persistent pain is a disease of the nervous system and simply an extension of the acute pain.

Nitric oxide interaction with other receptors in pain. Stimulation of ionotropic NMDA receptors causes intraneuronal elevation of Ca2+, which stimulates nitric oxide synthase and the production of nitric oxide. Nitric oxide as a gaseous molecule diffuses out from the neuron and by action on guanylyl cyclase stimulates the formation of cyclical guanosine monophosphate (cGMP) in neighboring neurons. Depending on the expression of cGMP-controlled ion channels in target neurons, nitric oxide may have either an excitatory or an inhibitory effect on pain. Nitric oxide has been implicated in the development of hyperexcitability, resulting in hyperalgesia, by increasing nociceptive transmitters at their central terminals.

Nicotinic acetylcholine receptors. Alpha4beta2 subtypes of these receptors are specifically for neuropathic pain, and ligands that bind preferentially to these receptors effectively relieve pain and do not cause adverse effects.

Role of superoxide dismutase in pain. Superoxide dismutase, a free radical scavenger, is as an important mediator of pain associated with inflammation. At time of peak hyperalgesia, endogenous superoxide dismutase is nitrated and subsequently deactivated, losing its capacity to remove superoxide radicals. This is the rationale for development of superoxide dismutase mimetics as novel nonnarcotic therapeutics in the management of pain.

Increased susceptibility to pain in red-haired individuals. Persons with natural red hair have an increased sensitivity to opioid analgesics but require larger doses of nonopioid analgesics. An experimental study in mice with red hair showed that loss of melanocortin 1 receptor function in the red-haired mice caused the animals’ melanocytes to secrete lower levels of proopiomelanocortin, a molecule that is the source of different hormones including one that sensitizes to pain and one that blocks pain (40). The presence of these hormones maintains a balance between opioid receptors that inhibit pain and melanocortin 4 receptors that enhance perception of pain.

Acute to chronic pain. Acute pain can rapidly evolve into chronic pain, known as pain chronification, because neuronal expression of new genes may occur within less than half an hour after injury. Experimental nerve ligation in animals can produce behavioral and histological changes within a day. This indicates that if acute pain is not treated it may progress to chronic pain. Pain also produces long-term alterations in the nervous system. This alteration is termed plasticity and is manifested by change in sensitivity of nociceptors. This central neural plasticity results in persistent pain after correction of pathology, hyperalgesia, allodynia, and the spread of pain to areas other than those involved with the initial pathology.

Pain is viewed as an active process generated partly in the periphery and partly in the CNS by plasticity rather than just a passive transfer of pain information to the cortex. Genotypic and phenotypic changes associated with chronic pain perception, which are expressed at all levels of the nervous system, include the upregulation of genes, altered synaptic connections in the dorsal horn, and cell death of interneurons due to excitotoxicity. Transcriptomic studies have identified many differences in the peripheral immune system that appear to contribute to the transition from acute to chronic pain. In summary, several processes are involved in the evolution of acute pain into chronic pain:

	• Increase in the activity of pain neuromatrix and its expansion into other cortical areas.
	• Neuroplasticity
	• Neurochemical changes in the brain
	• Structural changes in the brain
	• Activation of astrocytes promotes chronic pain following acute pain via neuronal-glial interactions.
	• Upregulation of genes relevant to pain perception.

Plasticity and sensitivity to the inflammatory cascade can be modified. A potential approach to pharmacotherapy is reduction of the function of nociceptors by specific antagonists.

Sex differences in transition from acute to chronic pain. Although men and women perceive pain in the same way, transition from acute to chronic pain is different. Studies of the translatome (mRNA fragments that are translated into peptides) of the mouse dorsal root ganglion show striking sex differences in an enzyme called prostaglandin-H2 D-isomerase (PTDGS), which synthesizes the well-known pain mediator prostaglandin D2. In these studies, PTDGS and prostaglandin D2 levels are much higher in female mice (33). Another study has shown that male mice injected with PTDGS inhibitors exhibited a robust, dose-dependent pain response whereas female mice showed no significant effect, suggesting that baseline prostaglandin D2 levels are protective against pain (43).

Epidemiology

• Estimates of prevalence of chronic pain in the general population range from 10% to 30%.

The prevalence of chronic pain in the general population cannot be determined precisely because of the variations in definition of various pain syndromes, but various estimates range from 10% to 30%. According to a conservative estimate, 100 million Americans live with chronic pain (Institute of Medicine U.S. Committee on Advancing Pain Research, Care, and Education 2011). Chronic pain affects approximately 20% of the European population (45). Women are more likely than men to suffer from chronic pain, particularly during menopause (11). One study has shown that the prevalence of chronic pain in severely injured patients 3 years after the accident is considerably high (44%) and that psychological factors such as anxiety and depression following the accident predispose to the development of chronic pain (20).

Differential diagnosis

Confusing conditions

Localized pain in any part of the body can be a manifestation of neurologic as well as nonneurologic disorders (ie, rheumatoid arthritis, cancer, and systemic infections). Disorders of the nervous system may present with pain in other organs.

Abdominal pain. Pain arising from abdominal viscera has distinct clinical features as it is not elicited from all viscera and is not always linked to visceral injury. Visceral pain is poorly localized and may be referred to other locations, or it may be a manifestation of neurologic disease. Motor and autonomic reflexes may accompany visceral pain.

Neurologic disorders such as migraine can manifest as abdominal pain or abdominal migraine. Chronic lower abdominal or pelvic pain can be due to lesions of the lumbosacral spine, such as tumors or intervertebral disc herniation. In women with these lesions, pain may initially be attributed to endometriosis, uterine fibroids, or pelvic inflammatory disease before the neurologic symptoms appear.

Posttraumatic and postsurgical pain. Acute pain following recent trauma and surgery is controlled with use of analgesic medications. This type of pain is usually self-limiting and ceases with recovery from surgery and healing of injured tissues. Chronic pain can result from trauma or surgery involving neural structures, and a careful history of trauma or surgery may provide a clue to this etiology.

Cancer pain. Cancer pain is associated with malignancies of various parts of the body and is experienced by about one third of all cancer patients and 70% to 90% of those with advanced disease. Cancer pain has 3 out of the 4 pain constructs: (1) nociception, (2) pain, and (3) suffering. Although there may be a psychological element in pain, an organic lesion can be identified as a potential explanation of pain in nearly every case. Various pathomechanisms are involved and assessment includes identification of the pathophysiology in an individual patient as a guide to management. As many as three quarters of the pain syndromes in these patients are due to direct effects of cancer; others are related to the therapies for cancer. Cancer-related pain syndromes may be due to involvement of musculoskeletal tissues, viscera, or neuropathic syndromes associated with involvement of the nervous system.

Musculoskeletal pain. Differential diagnosis is challenging because a wide range of disorders can cause musculoskeletal pain. The patient history along with the duration and pattern of pain distribution and evidence of other organ system involvement are the most important clues to diagnosis. Distinctions should be made between articular and nonarticular pain and between inflammatory and noninflammatory conditions.

In myofascial pain syndrome, pain is referred from trigger points within myofascial structures, either local or distant from the pain. The pain may be acute or chronic, vary in intensity from mild to severe, and usually occurs in a single muscle but may spread to involve adjacent muscles. Altered sensation including numbness, tingling, and other paresthesias may occur near the trigger point. The diagnosis of myofascial pain is clinical, based on a combination of myofascial trigger points, taught bands, and recognition of perpetuating factors.

Neuropathic pain. Neuropathic pain is chronic pain initiated or caused by a primary lesion or dysfunction in the nervous system at any level. Neuropathic pain is distinct from nociceptive pain, which occurs when nociceptors are excited by an appropriate stimulus but with no neural damage. Differential diagnosis involves localization of the level and differentiation between peripheral and central neuropathic pain.

Phantom limb pain. Phantom limb pain is usually associated with limb amputation and the experience of unpleasant sensations. Usually, the diagnosis is obvious, but it should be distinguished from psychogenic phantom limb pain, stump pain, and lesions of the brachial plexus or spinal nerve roots that may occur in previously pain-free amputees and produce pain that may be localized to the territory of a nerve. Typically, the pain is neuralgic in character. Lesions of the central nervous system should also be ruled out.

Headache. Headache has characteristic features that distinguish it from other painful conditions, but it can be assessed within the general framework of assessment of pain. A distinction should be made between primary and secondary headache disorders. Primary headache disorders account for most cases and include conditions such as migraine, cluster type headaches, and tension headache. It may be nociceptive or neurogenic if the cause is within the intracranial structures. Secondary headache is associated with other disorders in which headache is a symptom and is nociceptive pain.

Chronic facial pain. With the exception of trigeminal neuralgia, chronic facial pain can be a diagnostic problem because a number of conditions can cause it. These include sinusitis, dental disorders, earache, temporomandibular pain and dysfunction syndrome, atypical facial pain, and glossodynia. Differential diagnosis may be difficult because the disorders may resemble one another, and adequate laboratory diagnostic methods are not available for all the conditions.

Chronic pain in traumatic brain injury. The role of structural brain damage in brain trauma and chronic pain is difficult to establish, but psychological disorders, including posttraumatic stress disorder, posttraumatic headaches, posttraumatic central pain, as well as depression and anxiety, are commonly reported comorbidities, even after mild traumatic brain injury. Genetic, biochemical, and imaging studies indicate the role of dopaminergic, neurotrophic factors and apolipoprotein in chronic pain following brain injury (22).

Backache and neck pain. Pain in these regions may be due to a wide range of causes including trauma, intervertebral disc disease, myofascial pain, arthritis of the spine, spinal cord tumors, and psychogenic pain. Psychological and socioeconomic factors can complicate the diagnosis and assessment of backache.

Limb pain. Pain in extremities may be due to intervertebral disc disease, peripheral neuropathies, complex regional pain syndromes, or CNS lesions. Limb pain needs to be differentiated from pain associated with peripheral vascular disease.

Pain in dementia. Although pain is a frequently encountered problem in persons with dementia, the exact prevalence of pain in dementia subtypes, eg, Alzheimer disease, vascular dementia, frontotemporal dementia, and dementia with Lewy bodies, is unknown. A cross-sectional, longitudinal observational study will determine the prevalence of different types of pain in various dementia subtypes as well as assess the relationships between pain and cognitive symptoms (46). The study will also evaluate the effect of feedback to the attending physician on the presence of pain, based on examination by investigators with backgrounds in neuropsychology and geriatric medicine.

Psychogenic pain. A psychogenic component appears to be an inherent characteristic of chronic pain, and it may be dominant in some patients, particularly those without any objective evidence of disease. The examiner should balance the somatogenic and psychogenic contributions to pain. A correlation should be made between the subjective symptoms and objective signs. Observation of spontaneous activities of the patient is important. The neurologist examining the patient should make observations about the patient's psychological condition even though an assessment may be done by a clinical psychologist or a psychiatrist.

Chronic unexplained pain. Central sensitization accounts for chronic “unexplained” pain in several disorders including whiplash injury, temporomandibular joint disorders, chronic low-back pain, osteoarthritis, fibromyalgia, chronic fatigue syndrome, and chronic tension-type headache (34).

Itching. Itching is an unpleasant sensation related to pain. Specialized subpopulations of unmyelinated chemonociceptors and dedicated spinal neurons, which are responsible for the itch sensation, have been identified. Under physiological conditions, painful stimuli such as activation of conventional mechano-heat-sensitive (“polymodal”) nociceptors (scratching) inhibit the itch sensation via central mechanisms. Conversely, centrally acting pain-inhibiting opioids enhance itch by disinhibition. These traditional concepts concerning mechanisms of sensitization to itch or pain are now being revised. Pain and itch may occur together and share the same pathways for transmission eg, in the spinal cord. Thus, analgesic therapeutic concepts can be validated in chronic itch conditions, and sensitization in easily accessible pruritic skin may help to validate concepts of nociception in humans. Peripheral (pruritoceptive) should be differentiated from central (neurogenic or neuropathic) itch.

Diagnostic workup

Key tests and procedures

	• Blood biochemistry
	• Biomarkers
	• Electrophysiological studies
	• Brain imaging
	• Cognitive assessment

Special diagnostic procedures. These are required for a patient with chronic pain when the nature of the underlying cause is not clear. Use of electrophysiological studies and brain imaging should be done according to neurologic lesions suspected or considered important for exclusion. Functional MRI may be useful for the investigation of chronic unexplained pain because it provides insight into some of the underlying mechanisms. Patients with chronic pain have frequent complaints of impaired cognitive functioning. Cognitive assessment should be a part of workup of such patients.

Biomarkers. Pain itself is a biomarker of many diseases, but there is lack of validated biomarkers of chronic pain syndromes. There is a need for objective data for assessment of pain as a symptom. Mechanistic biomarkers not only improve an understanding and ability to accurately diagnose pain disorders, but also facilitate the development of disease modifying analgesics and guide the personalized management of chronic pain.

Abnormal biochemistry findings are common in patients with chronic pain. A study reported that 77% of patients with chronic pain exhibited at least one abnormal biomarker result; the most common being elevated quinolinic acid, which was observed in 29% of patients (12).

There is an overlap between diagnostic procedures and biomarkers. Currently functional MRI is the only reliable biomarker of pain. Activation of brain areas involved in pain can be visualized in response to painful stimuli and action of analgesics can be assessed.

Management

	• Nonsteroidal antiinflammatory drugs are commonly used for treatment of chronic pain and opioids are used for more severe pain.
	• Alternative drugs for chronic pain include antidepressants and anticonvulsants.
	• Analgesic drugs can be delivered to the central nervous by drug delivery methods such as intrathecal and epidural.
	• Noninvasive approaches include transcutaneous electrical nerve stimulation.
	• Neurosurgical approaches to intractable pain include several methods, most importantly deep brain and spinal cord stimulation.
	• Cell and gene therapies are still experimental but have a potential for clinical application.
	• The ideal management of a chronic pain patient is by a multidisciplinary approach and should be personalized.

Management of pain depends on the type of pain: acute, chronic, and special types (ie, neuropathic pain). Treatment of chronic pain in specific locations such as headache and backache require somewhat different approaches, which are described in articles dealing with these problems. It is generally recommended that acute pain should be treated by use of appropriate and effective measures including opioid analgesics. Inadequate treatment of acute pain facilitates the development of chronic pain, which is difficult to manage. Most of the patients who try to find relief from chronic pain by over-the-counter preparations are dissatisfied and would like to have special and more effective treatments for pain. Chronic unexplained pain due to central sensitization can be treated with various analgesic agents or nonpharmacological methods, such as neurofeedback training or virtual reality, which changes the activity of the body's pain modulation system.

The ideal management of a chronic pain patient is by a multidisciplinary approach, including disciplines such as internal medicine, neurology, anesthesia, nursing, psychology, pharmacy, rehabilitation medicine, physical therapy, etc. The limitation of this approach is that access to such a wide range of specialists is available only at large medical centers and special pain clinics restricting access to a limited number of the patients. Even within the team approach, an overlap of services exists, and careful coordination and communication between the team members is essential. Although an ideal multimodal approach has not been defined, a comparative study of various methods for the management of perioperative pain in joint disorders showed the advantages of the combined use of physical therapy, psychosocial support, and pharmacotherapy with nonsteroidal antiinflammatory drugs for reducing the use of opioids, shortening the length of hospital stay, and lowering the cost of care (27).

Pharmacological approaches. The most commonly used medications for acute pain are nonsteroidal antiinflammatory drugs and opioid analgesics. One of the characteristics of neuropathic pain is poor or incomplete relief with opioids. Drugs such as antidepressants and anticonvulsants are used for chronic pain, particularly neuropathic pain.

Nonsteroidal antiinflammatory drugs. Nonsteroidal antiinflammatory drugs are the drugs of choice in the treatment of acute and chronic pain and may reduce pain by several mechanisms. These drugs inhibit the synthesis of prostaglandins and thromboxane by inhibiting the enzyme cyclo-oxygenase 1 or cyclo-oxygenase 2. Other proposed mechanisms of action include a direct action at an excitatory or inhibitory amino acid site and a central mechanism of action.

Inhibition of cyclo-oxygenase 1 is associated with side effects such as gastrointestinal irritation, and this complication is reduced considerably by use of cyclo-oxygenase 2 inhibitors that are shown to be effective in rheumatoid arthritis. The role of cyclo-oxygenase 2 agents as analgesics, however, remains to be proven.

Opioid analgesics. Opioid analgesics are the most powerful analgesics. The pharmacology is different when used for treatment of pain from that of use in normal subjects, where it can lead to addiction. Careful use, titrated against pain, is safe in patients with severe pain. Besides morphine, common opioids are meperidine, methadone, hydromorphone, oxycodone, fentanyl, and buprenorphine. A controlled-release formulation of the opioid oxymorphone has been approved, but its efficacy in relief of pain does not differ significantly from oxycodone at equipotent doses. Oral morphine is available and can be used for chronic pain. For long-term outpatient management, controlled-release oxycodone hydrochloride, methadone, or sustained-release morphine is recommended. Other routes of administration are being developed for various opioids. There are some patients for whom opioids are the best treatment for chronic pain, but the challenge is to identify these conditions. For many others who are unlikely to benefit from opioids there may be more effective approaches that need to be investigated further. There is a considerable concern in the United States about the misuse of opioids, addiction, and rise of mortality rate. The 12-point guideline on opioid prescribing by Centers for Disease Control emphasizes both patient care and safety (09). An important recommendation is that nonopioid therapy is preferred for chronic pain outside the context of active cancer treatment, palliative care, or end-of-life care. According to this guide, opioids should be added to other treatments for chronic pain only when their expected benefits for both pain and function are likely to outweigh the substantial risks inherent in this class of medication.

Opioids are well-accepted treatment for cancer pain, but this pain cannot always be relieved by opioids. Opioid-insensitive pain is defined as pain that does not respond to progressively increasing doses of opioids. The most common is neuropathic pain associated with cancer.

Nonopioid alternatives to the management of chronic pain under investigation include antinerve growth factor therapies, calcium and sodium ion channel blockers, angiotensin II receptor antagonists, and toxin-based local anesthetics.

Antidepressants. Chronic pain patients who are depressed require aggressive, full-dose treatment with antidepressants. Classic tricyclic antidepressants as well as selective serotonin reuptake inhibitors may be effective in pain even in the absence of clinical depression. The analgesic effect of antidepressants differs from their effect on depression. Amitriptyline is effective as an analgesic in a dose range of 25 mg daily to 150 mg daily, which is much lower than the usual dose for depression of 15 mg daily to 300 mg daily.

Antidepressants may be used for patients who fail to respond to other medications or who are intolerant of their side effects. A secondary role of antidepressants in treating chronic pain is their use in addition to conventional analgesics. This can be particularly effective in patients with cancer who have pain in multiple locations of mixed type. Improved sleep is an additional advantage in these patients. Various pain syndromes treated with antidepressants are as follows:

• Neuropathic pain • Postherpetic neuralgia • Diabetic neuropathy • Tension headache • Temporomandibular joint dysfunction • Atypical facial pain • Rheumatic pain • Fibromyalgia • Pain associated with cancer • Central poststroke pain

Anticonvulsants. Antiepileptic drugs have been used widely for the relief of acute as well as chronic pain. No clinical trial has compared different anticonvulsants for the treatment of chronic pain. No evidence supports the notion that anticonvulsants work in acute pain. The use of carbamazepine for trigeminal neuralgia and valproic acid for prophylaxis of migraine has been supported by clinical evidence.

Tramadol. Tramadol is effective for mild to moderate acute and chronic pain. The mechanism of action is not well understood in animal models, but it has been shown to bind to the Mu (µ) opioid receptor and is an inhibitor of serotonin and norepinephrine reuptake. These actions are like those of antidepressants.

Placebo. A review of controlled and open clinical studies has shown that placebo effects are evidence-based, clinically relevant, and potentially ethical tools for relieving chronic pain (21).

Behavioral approaches. Behavioral methods used for treating chronic pain include relaxation techniques, autogenic training, meditation, hypnotic techniques, biofeedback, and cognitive-behavioral therapy. Behavioral approaches can lead to reduction in pain and are best used as part of a multidisciplinary approach.

Physical activity. In the past, rest and inactivity were recommended for a variety of chronic pain conditions, but physical activity and exercise programs are now increasingly offered in various healthcare systems. According to an overview of Cochrane reviews of adults with chronic pain, the quality of the evidence examining physical activity and exercise for chronic pain is low, but available evidence suggests that they may improve physical function, reduce pain severity, and have few adverse events (10).

Electroconvulsive therapy. Several publications have reported the use of electroconvulsive therapy in chronic pain patients. Repeated electroconvulsive therapy improved chronic regional pain with depression caused by failed back syndrome in a patient where depression was the first symptom to resolve (42). Electroconvulsive therapy has also been used for the treatment of phantom limb pain.

Transcutaneous electrical nerve stimulation. This has been used in medical practice since the 1970s. The mechanism of action in relieving pain is not known, but several theories flourish, including a placebo response, local blockage of receptors in peripheral nerves, and activation of the inhibitory system at the level of the dorsal horns of the spinal cord. Both uncontrolled and controlled studies have shown its utility in acute musculoskeletal injury, postoperative pain, pain of peripheral vascular origin, and chronic pain due to various causes.

Noninvasive brain stimulation/transcranial magnetic stimulation. A systematic review of randomized clinical trials did not find evidence that low-frequency repetitive transcranial magnetic stimulation applied to the dorsolateral prefrontal cortex and cranial electrotherapy stimulation are effective for reducing pain intensity in chronic pain (35).

Nerve blocks. Nerve blocks are often performed by anesthetists for the control of a wide variety of chronic painful conditions. The substances administered include local anesthetics, steroids, or neurodestructive agents. Trigger point injections are used for myofascial pain syndrome.

Implantation of drug delivery devices. Various drug delivery methods have been used to deliver analgesic drugs to the central nervous system. These are used mainly for intrathecal and epidural drug delivery. Some drug delivery devices are implanted in the CNS. These are used for cancer as well as noncancer chronic pain. These invasive methods are used only after failure of noninvasive methods of drug administration.

Neurosurgical methods of pain relief. These have been used for intractable posttraumatic pain, cancer pain, neuropathic pain, and phantom limb pain. Procedures include neurolysis, neurectomy, spinothalamic tractotomy, spinal cord stimulation, and thalamic stimulation. Deep brain stimulation of the anterior cingulate cortex can relieve chronic neuropathic pain refractory to pharmacotherapy and restore quality of life (01). Motor cortex stimulation is an additional therapeutic option for patients with refractory chronic trigeminal neuropathic pain, and significant long-term pain suppression can be achieved (39).

Spinal cord stimulation involves insertion of an epidural electrode connected to a subcutaneous implanted pulse generator. The electrode generates an electrical field at the dorsal columns of the spinal cord that inhibits pain pathways. Randomized controlled trials have demonstrated efficacy of spinal cord stimulation in chronic pain conditions such as failed back surgery syndrome and complex regional pain syndrome (36). A systematic review of the literature has shown that spinal cord stimulation is effective for facilitating the return to work of patients with specific chronic pain syndromes (29). This minimally invasive technique is suitable for management of chronic pain in children.

The rapidly advancing knowledge about microglia and their involvement in pain suggests that the era of pain therapeutics targeting both neural cells and glial cells that optimize the response from both targets is just beginning (13). Three-month results from a randomized controlled trial showed statistically significant and superior back pain relief with differential target multiplexed compared to conventional spinal cord stimulation (NCT03606187).

Neuromodulation. Advances in neuromodulation techniques are improving the management of chronic pain. New targets such as the dorsal root ganglion, high-frequency and patterned stimulation methods like burst stimulation, and neural sensing will increase the efficacy of neuromodulation, whereas select biomarkers may guide the use of neuromodulation as well as objective evaluation of outcomes (08).

Photobiostimulation is a noninvasive form of light therapy that utilizes nonionizing forms of light sources including lasers and broadband light in the visible and infrared spectrum. Photobiostimulation can be combined with neuromodulation for pain control and is useful for the management of chronic back pain as well as myofascial pain associated with temporomandibular joint dysfunction (32).

A 6-month prospective study on chronic pain patients requiring prescription analgesics showed that a nonprescription electromagnetic neuromodulation device that uses pulsed shortwave therapy provided clinically significant pain relief in 97% of subjects that enabled reduction of analgesic use (41).

Cell therapy. Cell therapy can be considered a sophisticated method of prolonged in vivo analgesic delivery (18). Examples of use of cells for improving drug delivery in pain include encapsulated cells and engineered stem cells that release analgesic molecules.

Gene therapy. Gene therapy provides targeted approaches for delivery of antinociceptive molecules or interruption of pain pathways without subjecting the patient to systemic toxicity of drugs. Some of these approaches are aimed at correcting the underlying pathology of the diseases (19). Directed gene transfer enables selective interruption of nociceptive neurotransmission or plastic changes in the nervous system that underlie the development and persistence of chronic pain (24).

The dorsal horn of the spinal cord is an attractive site for interventions designed to treat chronic pain. One approach is the use of viral vector-mediated gene transfer to achieve focal production and release of short-lived analgesic peptides, eg, topical application of recombinant herpes simplex virus encoding human preproenkephalin. This experimental approach may be a viable means of treating localized cutaneous burning pain and hyperalgesia. Herpes simplex-mediated gene transfer to sensory neurons provides an effective means to achieve local biosynthesis of endomorphin peptides for the treatment of chronic pain (52). The first human trial of gene therapy for chronic pain is an ongoing phase I study of a nonreplicating herpes simplex virus-based vector engineered to express preproenkephalin in patients with intractable pain from cancer (53).

Alternative or complimentary therapies for pain. Acupuncture is used widely for relief of pain. A systematic review of randomized controlled trials has shown significant differences between true and sham acupuncture, indicating that acupuncture is more than a placebo and is effective for the treatment of chronic pain (48). Various herbals have been in continuous use for several centuries. Aroma therapy has been used as part of an integrated, multidisciplinary approach to pain management. This therapy is thought to enhance the parasympathetic response through the effects of touch and smell by encouraging relaxation. Marijuana has been used for the treatment of chronic pain. A systematic review of studies of chronic neuropathic pain suggests that cannabinoids may provide effective analgesia in conditions that are refractory to other treatments (02). A systematic review of randomized, double-blind, placebo-controlled trials of medical cannabis, plant-derived and synthetic cannabis-based medicines, concluded that potential benefits of cannabis-based medicine in chronic neuropathic pain might be offset by their potential harm (31).

Personalized management of pain. There is now considerable evidence demonstrating differences in analgesic response to various pharmacotherapies, although the source of this variability largely remains to be explained. This difference, however, is being considered in clinical trials of analgesics. A prospective genome-wide association study has identified single-nucleotide polymorphisms associated with the development of chronic postoperative pain indicating the role of genetic risk factors (47). Genetic factors are also important contributors to individual differences in pain sensitivity; for instance, polymorphisms in genes coding for catechol-O-methyltransferase activity and opioid receptors can determine variability among the pain responses of individuals. Codeine analgesia is mostly due to its metabolism to morphine by the cytochrome P450 enzyme CYP2D6, which shows significant genetic variation in activity. Patients with a mutation in the gene coding for CYP2D6 will show little or no analgesic effect from codeine because it requires a properly functioning CYP2D6 to metabolize it to the active metabolite morphine. Recognition of interindividual difference is the basis of personalized management of pain.

A study has shown that it is possible to use fMRI to assess pain elicited by noxious heat in healthy persons by identification of a pattern of fMRI activity – a neurologic signature (50). Further studies are needed to assess whether the signature predicts clinical pain and to use it as a guide for the development of personalized analgesics. Another example of a personalized approach to chronic pain is the treatment of inherited erythromelalgia due to gain-of-function mutation in the SCN9A gene encoding sodium channel Nav1.7, which is expressed in the peripheral nervous system, leading to aberrant sensory neuronal activity and severe pain. A clinical study has shown that it is possible to predict drug responses to Nav 1.7 channel blockers in individual patients by using induced pluripotential stem cell (iPSC)-derived neurons from the patient’s blood as a tool to test drug response (04). One of the patients in a clinical trial whose iPSC-derived neurons did not respond to the treatment also failed to get pain relief from the drug. Given the importance of peripherally expressed Na channels in many pain conditions, this personalized approach has potential use for a wide range of pain and sensory conditions.

Management of chronic pain in Parkinson disease. Treatment strategies vary according to whether the pain is nociceptive or neuropathic. Nociceptive pain is related to rigidity, akinesia, or dystonia. Various measures used for the management of pain in Parkinson disease include duloxetine, rotigotine, and stimulation or lesioning of subthalamic or pallidum nuclei. Repetitive transcranial magnetic stimulation, apomorphine, and botulinum toxin may be effective for relieving painful off-period dystonia (37).

Management of noncancer chronic pain in the elderly. This is a common problem in the elderly and is not adequately assessed and managed because of the concern for adverse effects. The wide choice of analgesics available combined with alternative methods should enable safe protocols for pain relief in the elderly. Adjuvant drugs such as antidepressants or anticonvulsants can be effective in the treatment neuropathic pain associated with diabetic neuropathy.