Clinical manifestations

Presentation and course

Pain is described by the patient in various terms such as stabbing, burning, tearing, squeezing, throbbing, pounding, etc. Acute pain is accompanied by a stress response consisting of increase in blood pressure, tachycardia, and pupillary dilatation.

Physiological pain is an essential early warning device that signals the environmental presence of potentially harmful stimuli. An example is the pain experienced on pinprick. Hyperalgesia is a consistent feature of somatic and visceral tissue injury and is defined as a leftward shift of the stimulus-response function that relates to the magnitude of pain to the stimulus intensity. It occurs not only at the site of injury (primary hyperalgesia) but also in the area surrounding it (secondary hyperalgesia). Primary hyperalgesia that develops at the site of burn injuries is mediated by a sensitization of the nociceptors. Sensitization is defined as leftward shift of the stimulus-response function that relates magnitude of the neural response to stimulus intensity. Hyperalgesia is a response by the subject whereas sensitization is a response of the fibers conducting the sensation. A characteristic of sensitization is decreased threshold for response, which corresponds to decreased pain threshold.

Differentiating between acute and chronic pain. Acute pain is the normal predicted physiological response to an adverse chemical, thermal or mechanical stimulus, which may be associated with trauma or acute illness. The term “chronic pain” is used if the pain intractable, ie, it persists for 3 months or more. Clinical manifestations depend on the type of pain. Most of the pain problems seen in neurologic practice are chronic but these may have an acute onset or episodes of acute exacerbations. A clinically oriented practical classification of various types of pain is shown in Table 1.

Table 1. A Practical Classification of Pain

Prognosis and complications

Prognosis depends on the cause of pain and associated disease. Acute nociceptive pain due to tissue injury requires short term treatment with analgesics if the injury heals. Prognosis in chronic peripheral neuropathic pain depends on the cause and extent of nerve damage. Central neuropathic pain is difficult to manage.

Results of an experimental study suggest that peripheral inflammatory pain can increase blood-to-brain transport of low molecular weight drugs due to alterations in tight junctions and paracellular permeability at the blood-brain barrier, which may also be enhanced by activation of the sympathetic nervous system (22). This increases passage to the brain of some drugs, such as the analgesic codeine.

Biological basis

An overview of different types of pain is presented in this article. Pathophysiology of chronic pain, central neuropathic pain, cancer pain, migraine pain, and phantom pain are discussed in articles dealing specifically with these topics. Pathomechanism of nociceptive pain and visceral pain will be discussed briefly followed by a more detailed description of neuropathic pain.

Nociceptive pain. Acute nociceptive pain protects the injured or inflamed tissue by sending a warning signal to the brain and triggering a withdrawal response. Activation of nociceptive neurons (nociceptors) in the peripheral nervous system is also known to cause neurogenic inflammation and neuroinflammation by producing neuropeptides, such as substance P and chemokines. If not resolved in the acute stage, inflammatory pain can also become chronic.

Visceral pain. Although the distinction between visceral pain and somatic pain is not well defined, there are important differences in the mechanism, perception, and psychological processing of pain originating from the viscera and that originating from other tissues. Most solid viscera such as the liver are not sensitive to pain, and pain in a viscus is not necessarily associated with injury but may be due to distension or stretching.

Natural stimuli associated with visceral pain are ischemia, hollow organ distension, inflammation, muscle spasm, and traction. Mediators of visceral pain are bradykinin, lactic acid, hydroxyl radicals, prostaglandins, serotonin, tachykinins, and transmitters such as glutamate and substance P. Vagal and spinal afferents both contribute to the sensory component of the gut-brain axis. Current evidence suggests that they convey different elements of the complex sensory experience. Spinal afferents play a key role in the discriminatory dimension, whereas vagal input primarily affects the strong emotional and autonomic reactions to noxious visceral stimuli. Drugs and surgical and nonpharmacological treatments can target these pathways and provide therapeutic options for patients with chronic visceral pain syndromes.

Neuropathic pain. This form of pain is distinct from nociceptive pain and has been defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. Because it is difficult to distinguish neuropathic dysfunction from physiologic neuroplasticity, a more precise definition was offered by a group of neurologists and pain experts as "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system" (38). This definition is compatible with the terminology of neurologic disorders and the authors proposed a grading system of possible, probable, and definite neuropathic pain, which requires confirmatory evidence from a neurologic examination. This grading system is proposed for clinical and research purposes.

The involvement of the nervous system in pain can be at various levels: nerves, nerve roots, and central pain pathways in the spinal cord and the brain. Truncal neuropathy, an important cause of chest or abdominal pain, is usually unilateral and may be described as “burning” or a “deep ache” (14). The zone of hyperalgesia, which is dermatomal in distribution, does not cross the midline. The most common cause is diabetes.

Central pain is a term used to describe pain initiated or caused by a primary lesion or dysfunction in the CNS and can be included under the broad term of neuropathic pain. Neuropathic pain is a form of chronic pain, which is persistently generated and serves no beneficial function for the affected individual. A classification of neuropathic pain is shown in Table 2.

Table 2. Classification of Neuropathic Pain

Neuropathic pain remains a prevalent and persistent clinical problem because of our incomplete understanding of its pathogenesis. It is a very complex disease, involving several molecular pathways, excitatory as well as inhibitory, which show altered gene expression, caused by neuronal damage. Currently available drugs are usually not acting on the various mechanisms underlying the generation and propagation of neuropathic pain. Neuropathic pain is a major neurologic disorder rather than just a pain problem due to peripheral nerve injury. Some of the mechanisms of chronic pain apply to neuropathic pain but some specific mechanisms are:

Role of intact nerve fibers in neuropathic pain. Chronic neuropathic pain originates from intact nerve fibers rather than those damaged from injury or disease. Further research is needed to establish how this mechanism may contribute to ongoing pain associated with a wide variety of conditions such nerve injury and herpes zoster (shingles) that result in cumulative neuroinflammation, which is a proinflammatory cytokine-mediated process involving neural-immune interactions that activate immune cells, glial cells, and neurons and can lead to neuropathic pain. This pathomechanism indicates that anticytokine agents, cytokine receptor antibodies, and cytokine-signaling inhibitors may be useful for treating neuropathic pain.

Spinal inhibitory malfunction. Two amino acids, gamma amino butyric acid and glycine, mediate fast inhibitory neurotransmission in different CNS areas and serve key roles in the spinal sensory processing by limiting the excitability of spinal terminals of primary sensory nerve fibers. Malfunction of spinal inhibitory malfunction in dorsal root sensory circuits can lead to neuropathic pain (42).

Cytokines as mediators of neuropathic pain. Cytokine-mediated neuroinflammation controls the pathogenesis of neuropathic pain. Tumor necrosis factor-alfa orchestrates the subsequent neuropathologic changes in the injured nerve, eventually recruiting immune cells (primarily macrophages) from the circulation to participate in the nerve degeneration process. Blocking the upregulation of tumor necrosis factor-alfa can interfere with the rate and magnitude of Wallerian degeneration, influencing the magnitude and duration of the associated pain state.

Chemokines as mediators of neuropathic pain. Chemokines and their receptors have been demonstrated in the neural and nonneural elements of pain pathways. Under these circumstances, chemokines have been shown to modulate the electrical activity of neurons by multiple regulatory pathways including increases in neurotransmitter release through Ca-dependent mechanisms and transactivation of transient receptor channels. Because upregulation of chemokines and their receptors may be one of the mechanisms that directly or indirectly contribute to the development and maintenance of chronic neuropathic pain, these molecules may represent novel targets for therapeutic intervention (41).

Chemotherapy-induced neuropathic pain. Chemotherapy-induced neuropathic pain can be caused by certain chemotherapy drugs, including taxanes, vinca alkaloids, and platinum-derived compounds. The onset of chemotherapy-induced neuropathic pain is generally early in treatment, between the first and third cycle, with the peak in severity occurring approximately 3 months into therapy. There may be neurobiological differences between cancer patients who develop chemotherapy-induced pain and patients who experience little or no pain. Research in this area could lead to new treatments to prevent pain by extending the therapeutic value of current chemotherapies as well as by helping the development of new chemotherapies with less severe pain-related side effects.

Role of free radicals in generation of neuropathic pain. Free radicals or reactive oxygen species are produced in biological systems and are involved in the pathogenesis of various diseases. Animal experimental studies have shown evidence of generation of free radicals in peripheral neuropathic pain and reduction of signs of hyperalgesia and allodynia by administration of free radical scavengers.

Genetic basis of pain. It is now increasingly recognized that genetics plays an important role in the development of complex chronic painful conditions. Approximately 60% of the risk of developing chronic backache or neck pain is attributed to genetic factors.

Primary erythermalgia is a rare autosomal dominant inherited disorder characterized by recurrent attacks of red, warm, and painful burning extremities. The gene involved in primary erythermalgia, SCN9A, encodes for a voltage-dependent sodium channel alpha subunit (NaV1.7). NaV1.7 is found in dorsal root ganglions and in nociceptive peripheral neurons. This mutation disturbs the passage of sodium ions through the channels with generation of electrical nerve impulses, including those that produce abnormal pain. Mutations also lower the threshold for activation, causing neurons to become hyperexcitable, and produce rapid bursts of nerve impulses in response to normally nonpainful stimuli. The brain, in turn, interprets such nerve impulses as signaling a painful stimulus. A relatively more common single-nucleotide polymorphism within SCN9A called 3312G>T, which occurs in 5% of the population, has been shown to determine sensitivity to postoperative pain and the amount of opioid medication needed to control it. Another single-nucleotide polymorphism in the SCN9A gene causes greater sensitivity for those with pain caused by osteoarthritis, lumbar disc removal surgery, and phantom pain.

A study has analyzed 410 pain-related genes and identified functional areas that are important for analgesic drug development (23). The authors concluded that future drug development strategies should focus on substances modulating intracellular signal transduction, ion transport, and anatomical structure development – processes involved in the genetic-based absence of pain.

Role of autonomic nervous system in pain. Both sympathetic and parasympathetic nervous systems are involved in regulating pain states and their activity is disturbed in states of chronic pain. Disruption in autonomic balance can be measured through the assessment of heart rate variability, ie, the variability of the interval between consecutive heart beats. Pooled results from the meta-analyses of studies on this topic indicate a consistent, moderate-to-large effect of decreased high-frequency heart rate variability in chronic pain, implicating a decrease in parasympathetic activation (37). Activity in nociceptors induces an increase in sympathetic discharge but the reverse is not true under normal circumstances; sympathetic activity does not affect the discharge of nociceptive neurons. In some painful conditions, however, pain is dependent on the activity of the nervous system and is referred to as sympathetically maintained pain.

Ion channels and pain. The importance of ion channels in the generation and transmission of signals in the nervous system is well recognized and aberrant activity in these channels underlies or initiates many painful conditions. Of all the ion channels involved in pain, sodium channels are most relevant. They are the target for anticonvulsant drugs used for treatment of pain. The acid-sensing ion channels (ASICs) can induce action potential triggering on sensory neurons after a moderate extracellular pH decrease and they participate in the hypersensitization of the nociceptive system in inflammatory pain. Among various types of ASICs, ASIC3 and ASIC1 have been implicated in transmission of pain from the musculoskeletal system. Inhibition of the expression of ASICs is the mechanism of action of nonsteroidal antiinflammatory drugs.

Currently, research is focused on targeting ion channels involved in pain transduction, axonal conduction, and neurotransmitter release to provide targets for discovery of new analgesics. Knowledge of function of voltage‐gated ion channels, such as Na+ channels and K+ channels involved in neuronal excitability and Ca2+ channels responsible for transmitter release, has advanced through measurement of protein up‐regulation during pain states, knowledge of channel dysfunction in pain syndromes associated with human genetics, and development of transgenic knock‐down and knock‐in technology to support in vitro and in vivo models of pain (35).

The originally described congenital insensitivity to pain, now known as channelopathy-associated insensitivity to pain and hereditary sensory and autonomic neuropathy, is the result of specific mutations or deletions within single genes required for transmitting pain signals.

TRP ion channels in pain. TRP (transient receptor potential) ion channels, a large superfamily of related cation channels, function as dedicated biological sensors that are essential in processes such as vision, taste, tactile sensation and hearing. There are six different TRPs (TRPV1, TRPV2, TRPV3, TRPV4, TRPM8, and TRPA1), which are expressed in pain sensing neurons and primary afferent nociceptors. The TRP family contains a novel group of nonselective cation channels that are distinct from classic voltage-gated ion channels. TRPs respond to a variety of stimuli, including changes to specific ligands, temperature, acid, salt concentration, and second messenger signaling. As such, TRPs act as multimodal signal integrators, representing approximately 20% of all ion channels found in the body. Various TRP channels are associated with different types of neuropathic pain. Several TRP ion channels--particularly TRPV1, TRPA1, TRPV4, and TRPM8--are clearly expressed in the trigeminal sensory system and have critical functions in the transduction and pathogenesis of orofacial pain (24). TRP channel modulators are in development for the treatment of neuropathic pain.

Glial activation and neuropathic pain. Interactions between central glial cells and neurons in the pain circuitry are critical contributors to the pathogenesis of chronic pain. The inflammasome in activated microglia drives maturation and release of key pro-inflammatory cytokines, which drive pain through neuronal- and glial regulations (05). There is a potential for developing pain therapeutics targeting glial cell mediators.

Neuropathic pain following damage to peripheral nerve cells is associated with neuronal plasticity in peripheral and central sensory afferents and the spinal cord. Peripheral nerve injury has been associated with an increase in spinal glial. Activation of spinal cord glia, including both microglia and astrocytes, occurs in a temporal pattern that is consistent with retrograde transport of TNF-alpha. Using specific glial inhibitors, it has been shown that microglial activation is superseded by astrocyte activation. This astrocyte activation dominates the central neuroinflammation environment and the further development of the neuropathic pain state. It is feasible to target glia to interrupt the cascade of neuroinflammatory events that produce neuropathic pain.

Immune cell-derived opioids and neuropathic pain. Neuronal damage can involve inflammation and it is generally assumed that immune cells act predominately as generators of neuropathic pain. However, a study has demonstrated that leukocytes containing opioids are essential regulators of pain in a mouse model of neuropathy (20). Selective targeting of opioid-containing immune cells promotes endogenous pain control and offers opportunities for management of neuropathic pain.

Spinal leptin and neuropathic pain. Leptin, an adipocytokine produced mainly by nonneuronal tissue, has been implicated in the regulation of neuronal functions. The role of leptin has been examined in neuropathic pain using a rat model of chronic constriction injury of the sciatic nerve injury (21). Spinal administration of a leptin antagonist prevented and reversed neuropathic pain behaviors in rats. These findings reveal a critical role for spinal leptin in the pathogenesis of neuropathic pain and suggest a novel form of nonneuronal and neuronal interaction in the mechanisms of neuropathic pain.

Psychogenic pain. There is a psychological component in chronic pain and it may be dominant in some patients, particularly those without any objective evidence of disease. The term psychogenic may be misleading as it may indicate that the patient complains of pain in the absence of a physical disease. Psychologic and neurologic mechanisms of pain interact. The affective dimension of pain is made up of feelings of unpleasantness and emotions associated with future implications termed secondary affect. Spinal afferent pain pathways to limbic structures and medial thalamic nuclei provide direct input to brain areas involved in affect. Another input is from the somatosensory cortex via the corticolimbic pathways. The latter integrates nociceptive input with contextual information and memory to provide cognition mediation of pain affect.

Chronic unexplained pain. In some cases, the cause of chronic pain remains unexplained. Central sensitization accounts for chronic “unexplained” pain in a wide variety of disorders, including chronic whiplash-associated disorders, temporomandibular disorders, chronic low back pain, osteoarthritis, fibromyalgia, chronic fatigue syndrome, and chronic tension-type headache, among others (29). This forms the basis for recommendation of desensitization of the central nervous system by pharmacological as well as nonpharmacological approaches.

Differential diagnosis

Confusing conditions

Localized pain in any part of the body can be a manifestation of neurologic as well as non-neurologic 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 three of the four 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 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 without 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 headache, and tension-type headache. It may be nociceptive or neurogenic if the cause is within the intracranial structures. Secondary headache is associated with other disorders in which it is a symptom.

Chronic facial pain. Except trigeminal neuralgia, chronic facial pain can be a diagnostic problem because several 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 appear like one another, and adequate laboratory diagnostic methods are not available for all the conditions.

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.

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.

Diagnostic workup

A thorough general physical examination, with a special emphasis on the nervous system, is required for a patient with pain when the nature of the underlying cause is not clear. Pain may be the warning signal and the first manifestation of a disease and an attempt should be made to rule out underlying disease. Attention is paid to the region involved in pain as well the organ with the suspected pathology. Use of special diagnostic procedures such as imaging studies should be done according to lesions suspected. In patients with known underlying disease such as cancer, the purpose of examination is to determine the pathomechanism of pain, which is helpful in planning the management. Assessment is difficult in patients with pain who have no demonstrable underlying pathology.

Patients can quantify their pain at the time of examination by rating the intensity on a visual analogue 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 the McGill Pain Questionnaire, which consists of three parts:

The McGill scale is time-consuming but a 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.

Quantitative sensory testing is the use of precisely measured and repeatable sensory stimuli to determine the absolute threshold of sensation within specific somatosensory modalities. Several devices have been used for the evaluation of both small- and large-diameter nerve fibers of the peripheral nervous system. Clinical applications include the assessment and study of pain caused by injury or disease and peripheral neuropathies associated with various diseases.

The preferred, frequently used approach uses laser stimulators to deliver radiant-heat pulses that selectively excite the free nerve endings in the superficial skin layers (03).

Artificial intelligence and machine learning have been used to develop a mobile device for measuring pain, emotions, and associated bodily feelings in patients with chronic pain in their daily life conditions (09).

PET and fMRI have been used in clinical neuropharmacology to visualize the brain function and action of drugs on the brain in vivo. These noninvasive methods can be applied for facilitating new drug development as well as for the longitudinal assessment of pain therapies in clinical trials. Involvement of the brain in complex regional pain syndrome has been shown on fMRI (34). Functional brain imaging studies in persons with chronic pain syndromes often show abnormalities in cortical and subcortical brain regions, often referred to as the "pain matrix” (13). Some of these CNS changes return to a normal state with resolution of pain.

Management

Details are given in management of specific types of pain and painful diseases in other articles. Management of chronic pain is multidisciplinary.

A list of drugs used for the management of pain is shown in Table 3 and nonpharmacological approaches are listed in Table 4. Biological therapies are listed in Table 5, and neurosurgical procedures for pain are listed in Table 6.

Table 3. Drugs Used for the Treatment of Pain

Narcotics. Among pharmacotherapies, the major concern is the use of narcotics. Pain intensity does not reflect the entirety of the pain experience and often is not a measure of the suffering induced by pain. Therefore, overdependence on the assessment of pain with the use of various scales can lead to unnecessary opioid use. For the management of acute pain, the use of multiple approaches that do not include opioids and the establishment of acute pain services for postoperative pain management can reduce opioid-related adverse effects and dependence (07).

Medical cannabis. Use of medical cannabis for pain has remained controversial despite clinical trials. However, a prospective study provides evidence for the effects of medical cannabis on chronic pain and related symptoms, with mild-to-modest long-term improvement (01).

Table 4. Nonpharmacological Approaches to Management of Pain

Table 5. Biological Therapies for Pain

Table 6. Neurosurgical Procedures for Pain

Social touch approach. Handholding during pain reduces the intensity of pain. An EEG study has shown that interpersonal touch during pain increases the brain-to-brain coupling network that correlates with the magnitude of the analgesia and the empathic accuracy of the observer (10).

Noninvasive brain stimulation. Techniques used for relief of chronic pain include repetitive transcranial magnetic stimulation (rTMS), cranial electrotherapy stimulation (CES), transcranial direct current stimulation (tDCS), transcranial random noise stimulation (tRNS), and reduced impedance noninvasive cortical electrostimulation (RINCE). A Cochrane review of randomized and quasi-randomized studies of these methods found very low-quality evidence that single doses of high-frequency rTMS of the motor cortex and tDCS may have short-term effects on chronic pain and found no evidence that low-frequency rTMS, rTMS applied to the dorsolateral prefrontal cortex, and CES are effective for reducing intensity of chronic pain (30).

Occipital nerve stimulation. Occipital nerve stimulation is a promising therapy for medically refractory occipital neuralgia because it is reversible with minimal side effects and has shown continued efficacy with long-term follow-up. Based on the data derived from this systematic literature review, a level III recommendation is made for the use of occipital nerve stimulation as a treatment option for patients with medically refractory occipital neuralgia (36).

Biological therapies. These are mainly cell and gene therapies. Cell therapy can be considered a sophisticated method of analgesic delivery, and cells can function as biological pumps for the release of neuroactive compounds (16). Data from various studies appear promising for the use of stem cells as a novel therapeutic strategy for discogenic pain, neuropathic pain, and osteoarthritis, but additional clinical studies will be needed to validate the benefit of the technology for clinical use (02).

Several promising gene therapy approaches, as well as antisense and RNA interference-based approaches, have been identified (15). These provide targeted approaches to 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, eg, by treating degenerative joint diseases causing pain. Management of neuropathic pain is a challenge, and several ongoing studies are addressing it.

Spinal cord stimulation. In a prospective cohort study, 64% of patients who were using opioids prior to spinal cord stimulation reduced or eliminated opioid use at 1 year postoperatively (08). Patients who eliminated opioid use or never used opioids had superior clinical outcomes to those who continued use.

Personalized management of pain. There is a trend toward the development of personalized pain therapy in the postgenomic era (18). Genetic factors have been implicated in pain thresholds or predisposition to neuropathic pain. Polymorphisms of some genes and changes in protein expression may be associated with some chronic painful conditions. Correlation of polymorphisms and gene expression profile obtained by microarrays with neurologic features may be helpful in developing novel therapeutic intervention and tailoring the therapeutics to the specific pain syndrome.

Gene expression biomarkers for personalizing pain management. Blood gene expression biomarkers are predictive of pain, particularly if they are personalized by gender and diagnosis. In a study, MFAP3 had the most robust empirical evidence from discovery and validation steps and was a strong predictor for pain in the independent cohorts of females and males with posttraumatic stress disorder (28). Other biomarkers with the best functional evidence for involvement in pain were GNG7, CNTN1, LY9, CCDC144B, and GBP1. Some of these biomarkers are targets of existing analgesics. Moreover, the biomarker gene expression signatures were used for bioinformatic drug repurposing analyses, yielding leads for possible new drug candidates such as SC-560 (a NSAID) and amoxapine (an antidepressant), as well as natural compounds such as pyridoxine (vitamin B6), cyanocobalamin (vitamin B12), and apigenin (a plant flavonoid). A blood test has been developed to measure pain and enable physicians to improve precision in diagnosis and prescriptions, enabling personalized management of pain.

Nitric oxide-based strategies for personalized management of pain. The nitric oxide system plays a key role in the development and chronicity of peripheral pain. Genetic studies have shown that single nucleotide variants of nitric oxide synthase genes -- NOS1, NOS2, and NOS3 -- encoding neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS) may be associated with acute and chronic peripheral pain. Nitric oxide synthase inhibitors are used to modulate the effect of analgesic drugs. Studies of nitric oxide synthase gene variants are important for the development of new personalized pharmacotherapy strategies (32).

Pharmacogenetics/pharmacogenomics of pain. Advances in pharmacogenomics/pharmacogenetics, particularly those relevant to the action of analgesics, will facilitate personalized management of pain. Genes related to the opioid receptors, ATP-binding cassette subfamily B, catechol-O-methyltransferase (COMT), cytochrome 2D6, interleukin-1 receptor antagonist, and the melanocortin-1 receptor show promise in helping to predict the gene phenotype (06). Catecholamines are involved in the modulation of pain and are partly metabolized by the COMT enzyme. Genetic variability in the COMT gene may, therefore, contribute to differences in pain sensitivity and response to analgesics. Genetic variation in the COMT gene can influence the efficacy of morphine and can explain differences in morphine requirements in individual cancer patients with pain. Brain imaging studies have been conducted to develop an fMRI-based measure for predicting pain intensity at the level of the individual person (39).

Genetic polymorphisms linked with musculoskeletal pain are found in genes contributing to serotonergic and adrenergic pathways. The study of the biological mechanisms by which these biomarkers contribute to the perception of pain in these patients will enable the development of better diagnostic methods and more effective drugs to facilitate personalized management of pain.

Although most of these studies have focused on the pharmacogenetics of opioids, owing to their prominent status as analgesics, the number of pharmacotherapies evincing genetically based variability is rapidly expanding. In addition, analogous studies have been undertaken in humans, as clinical trials have begun to prospectively evaluate of interindividual differences in analgesic drug response. Presentation of the spectrum of individual responses and associated prediction intervals in clinical trials can convey clinically meaningful information regarding the impact of a pain treatment on health-related quality of life. Individual responder analyses in clinical trials can improve detection of analgesic activity across patient groups and within subgroups and identify molecular-genetic mechanisms that contribute to individual variation.

Special considerations

Pediatrics

Pediatric chronic pain is widespread, underrecognized, and undertreated. Not only do children experience severe pain and are no more at risk for addiction than adults, but they are also at greater risk for psychological disturbances that have immediate and long-term developmental impact. Randomized clinical trials may not be the best approach to evaluate treatment in low-frequency pediatric chronic and complex pain conditions. A nationally representative study, documenting rates of codeine prescription to children in the United States in the emergency department setting, found that although there has been a decline in codeine prescription over the past 10 years, many children are still being prescribed codeine yearly (19). Codeine prescriptions are being given to children not just for pain but even for those with cough or upper respiratory problems despite professional recommendations warning about this practice. Some concerns with the use of codeine are that genetic variations in some individuals may interfere with drug metabolism resulting in dangerous side-effects including excessive sleepiness. Another genetic variation makes the drug ineffective for pain relief in as many as a third of patients. Codeine for children's pain should be given only if anticipated benefits outweigh the risks. Ibuprofen may be considered as an alternative.

Geriatrics

Pain is more likely to occur in elderly individuals than in younger persons. Chronic pain that is severe enough to interfere with daily activities is associated with greater risk of falls in older adults. More than half of nursing home residents have substantial cognitive impairment or dementia. Patients with Alzheimer disease may have impairment in language, which limits their ability to communicate about their pain. There is a need for an understanding of pain recognition in this population. A standardized pain assessment using validated instruments for pain should be part of the care and treatment of geriatric patients suffering from dementia, and measurement for age as well as dementia should be integrated into daily clinical practice (31).

Pregnancy

Analgesics are commonly used during pregnancy, but caution should be exercised, and only those with no adverse effects on the fetus should be selected. Measures to overcome pain in labor are frequently requested by women. There are various methods, either nonpharmacological such as emotional support, psychological conditioning, yoga, and hypnosis, or anesthetic procedures such as epidural block. Intramuscular analgesics such as tramadol, an opioid, have been used but are not as effective as epidural anesthesia and may have adverse side effects. Detailed management of pain during pregnancy is described in a report by Australian & New Zealand College of Anaesthetists and Faculty of Pain Medicine (33).

Anesthesia

Anesthetic agents are used for pain relief, and anesthetists manage intraoperative and postoperative pain. Anesthetists are also important members of multidisciplinary pain management teams. Interactions of analgesics with anesthetics in patients requiring surgery is usually not an issue, as analgesic medications are discontinued prior to surgery.

Future directions

Some of the points discussed at the National Academies workshop on the role of nonpharmacological approaches in multidisciplinary pain management include the following (27):