Physiological Changes in Persistent Pain

Excitatory Mechanisms

Pain may be roughly divided into two broad categories: physiologic and pathologic pain. Physiologic (acute, nociceptive) pain is an essential early warning sign that usually elicits reflex withdrawal and thereby promotes survival by protecting the organism from further injury. In contrast, pathologic (e.g., neuropathic) pain is an expression of the maladaptive operation of the nervous system; it is pain as a disease. Physiologic pain is mediated by a sensory system consisting of primary afferent neurons, spinal interneurons and ascending tracts, and several supraspinal areas. Trigeminal and dorsal root ganglia (DRG) give rise to high-threshold Aδ− and C-fibers innervating peripheral tissues (skin, muscles, joints, viscera). These specialized primary afferent neurons, also called nociceptors, transduce noxious stimuli into action potentials and conduct them to the dorsal horn of the spinal cord ( Fig. 51.1 ). When peripheral tissue is damaged, primary afferent neurons are sensitized or directly activated (or both) by a variety of thermal, mechanical, and/or chemical stimuli. Examples are protons, sympathetic amines, adenosine triphosphate (ATP), glutamate, neuropeptides (calcitonin gene-related peptide, substance P), nerve growth factor, prostanoids, bradykinin, proinflammatory cytokines, and chemokines. Many of these agents lead to opening (gating) of cation channels in the neuronal membrane. Such channels include the capsaicin-, proton-, and heat-sensitive transient receptor potential vanilloid 1 (TRPV1), or the ATP-gated purinergic P2X ₃ receptor. Gating produces an inward current of Na ⁺ and Ca ⁺⁺ ions into the peripheral nociceptor terminal. If this depolarizing current is sufficient to activate voltage-gated Na ⁺ channels (e.g., Na _v 1.8), they too will open, further depolarizing the membrane and initiating a burst of action potentials that are then conducted along the sensory axon to the dorsal horn of the spinal cord.

Nociceptive pathways. For details see text.

Adapted from Brack A, Stein C, Schaible HG. Periphere und zentrale Mechanismen des Entzündungsschmerzes. In: Straub RH, ed. Lehrbuch der klinischen Pathophysiologie komplexer chronischer Erkrankungen . vol. 1. Göttingen Vandenhoeck & Ruprecht; 2006:183–192.

Transmission of input from nociceptors to spinal neurons that project to the brain is mediated by direct monosynaptic contact or through multiple excitatory or inhibitory interneurons. The central terminals of nociceptors contain excitatory transmitters such as glutamate, substance P, and neurotrophic factors that activate postsynaptic N-methyl-D-aspartate (NMDA), neurokinin (NK ₁ ), and tyrosine kinase receptors, respectively. Repeated nociceptor stimulation can sensitize both peripheral and central neurons (activity-dependent plasticity). In spinal neurons such a progressive increase of output in response to persistent nociceptor excitation has been termed “wind-up.” Later, sensitization can be sustained by transcriptional changes in the expression of genes coding for various neuropeptides, transmitters, ion channels, receptors, and signaling molecules (transcription-dependent plasticity) in both nociceptors and spinal neurons. Important examples include the NMDA receptor, cyclooxygenase-2 (COX-2), Ca ⁺⁺ and Na ⁺ channels, cytokines and chemokines expressed by neurons and/or glial cells. In addition, physical rearrangement of neuronal circuits by apoptosis, nerve growth, and sprouting occurs in the peripheral and central nervous system. Both induction and maintenance of central sensitization are critically dependent on the peripheral drive by nociceptors, indicating that therapeutic interventions targeting such neurons may be particularly effective, even in chronic pain syndromes.

Inhibitory Mechanisms

Concurrent with the events just described, powerful endogenous mechanisms counteracting pain unfold. This was initially proposed in the “gate control theory of pain” in 1965 and has since been corroborated and expanded by experimental data. In 1990, a “peripheral gate” was discovered at the source of pain generation by demonstrating that immune cell-derived opioid peptides can block the excitation of nociceptors carrying opioid receptors within injured tissue ( Fig. 51.2 ). This represented the first example of many subsequently described neuro-immune interactions relevant to pain. Inflammation of peripheral tissue leads to increased expression, axonal transport, and enhanced G-protein coupling of opioid receptors in DRG neurons as well as enhanced permeability of the perineurium. These phenomena are dependent on sensory neuron electrical activity, production of proinflammatory cytokines, and the presence of nerve growth factor within the inflamed tissue. In parallel, opioid peptide-containing immune cells extravasate and accumulate in the inflamed tissue. These cells upregulate the gene expression of opioid precursors and the enzymatic machinery for their processing into functionally active peptides. In response to stress, catecholamines, corticotropin-releasing factor, cytokines, chemokines, or bacteria, leukocytes secrete opioids, which then activate peripheral opioid receptors and produce analgesia by inhibiting the excitability of nociceptors, the release of excitatory neuropeptides, or both (see Fig. 51.2 ). The clinical relevance of these mechanisms has been shown in studies demonstrating that patients with knee joint inflammation express opioid peptides in immune cells and opioid receptors on sensory nerve terminals within synovial tissue. After knee surgery, pain and analgesic consumption was enhanced by blocking the interaction between the endogenous opioids and their receptors with intraarticular naloxone, and was diminished by stimulating opioid secretion.

Endogenous antinociceptive mechanisms within peripheral injured tissue.

Opioid peptide–containing circulating leukocytes extravasate upon activation of adhesion molecules and chemotaxis by chemokines. Subsequently, these leukocytes are stimulated by stress or releasing agents to secrete opioid peptides. For example, corticotropin-releasing factor (CRF) , interleukin-1β (IL–1) , and noradrenaline ( NA , released from postganglionic sympathetic neurons) can elicit opioid release by activating their respective CRF receptors (CRFR) , IL-1 receptors (IL-1R) , and adrenergic receptors (AR) on leukocytes. Exogenous opioids (EO) or endogenous opioid peptides ( OP , green triangles) bind to opioid receptors (OR) that are synthesized in dorsal root ganglia and transported along intraaxonal microtubules to peripheral (and central) terminals of sensory neurons. The subsequent inhibition of ion channels (e.g., TRPV1, Ca ⁺⁺ ) (see Fig. 64.3 and text) and of substance P (sP) release results in antinociceptive effects.

Adapted from Stein C, Machelska H. Modulation of peripheral sensory neurons by the immune system: implications for pain therapy. Pharmacol Rev . 2011;63:860–881.

In the spinal cord, inhibition is mediated by the release of opioids, γ-aminobutyric acid (GABA), or glycine from interneurons, which activate presynaptic opioid- or GABA-receptors (or both) on central nociceptor terminals to reduce excitatory transmitter release. In addition, the opening of postsynaptic K ⁺ or Cl ⁻ channels by opioids or GABA, respectively, evokes hyperpolarizing inhibitory potentials in dorsal horn neurons. During ongoing nociceptive stimulation spinal interneurons upregulate gene expression and the production of opioid peptides. Powerful descending inhibitory pathways from the brainstem also become active by operating mostly through noradrenergic, serotonergic, and opioid systems. Key regions are the periaqueductal grey and the rostral ventromedial medulla, which then projects along the dorsolateral funiculus to the dorsal horn. The integration of signals from excitatory and inhibitory neurotransmitters with cognitive, emotional, and environmental factors (see later) eventually results in the central perception of pain. When the intricate balance between biologic, psychological, and social factors becomes disturbed, chronic pain can develop.

Clinical Definitions, Prevalence, and Classification of Chronic Pain

Interdisciplinary Management of Chronic Pain

The anesthesiologist John J. Bonica was the first to appreciate the need for a multidisciplinary approach to chronic pain. His early experiences in and after World War II convinced Bonica that complex pain problems could be more effectively treated when different disciplines contribute their specialized knowledge and skills to the common goal of making a correct diagnosis and developing the most effective therapeutic strategy. The first multidisciplinary facility was put into practice at the Tacoma General Hospital, followed by the University of Washington in 1960. From 1970 through 1990, the number of pain management facilities continued to increase in North America and Europe, mostly directed by anesthesiologists. Such comprehensive pain centers should have personnel and facilities to evaluate and treat the biomedical, psychosocial, and occupational aspects of chronic pain and to educate and teach medical students, residents, and fellows. Guidelines for characteristics of pain treatment facilities have been published by the IASP. Interdisciplinary and multimodal management results in increased physical and psychosocial function, reduced health care use, and vocational rehabilitation. Such programs offer the most efficacious and cost-effective, evidence-based treatment of chronic nonmalignant pain. Treatment without an interdisciplinary approach is inadequate and may lead to misdiagnoses. For example, overlooking psychological processes in a presumed discogenic back pain, or overlooking a somatic etiology in a presumed “psychogenic” pain disorder may lead to the wrong conclusions. Moreover, conventional monomodal approaches such as pharmacotherapy alone only perpetuate the expensive, futile, and endless search for medical solutions. . A prominent example is the recent “opioid epidemic” with inadequate opioid medication as a monomodal therapy of chronic noncancer pain, which has significantly delayed appropriate diagnostic and therapeutic management. The “current opioid misuse measure” questionnaire may be a useful tool to detect inadequate opioid medication.

The core team usually comprises a pain management physician (often an anesthesiologist with subspecialty training but could also be a physical medicine and rehabilitation physician or psychiatrist with appropriate training), a psychologist, a physical therapist, and an occupational therapist. Depending on the local circumstances, administrators, social workers, pain nurses, and/ or pharmacists can also be involved. The initial screening of the patient by members of the core team determines what other specialists will be needed for a complete assessment. After this evaluation, the patient is presented to the entire core team and a comprehensive treatment plan is developed. This plan is tailored to the patient’s needs, abilities, and expectations, with a focus on achieving measurable treatment goals established with the patient. For some patients, education and medical management may suffice, whereas for others, an intensive full-day outpatient or inpatient rehabilitation program over several weeks may be needed. Early stratification of the management according to the patient’s prognosis (low, medium, or high risk for persistent disability because of pain) results in significantly higher clinical and cost effectiveness. To foster patient compliance, an open discussion of treatment goals with regard to the patient’s expectations is essential. Many patients expect the complete resolution of pain and the return to full function, a goal that may not be achievable. More realistic options are some reduction of pain, improvement of physical function, and/or return to work. Mood, sleep, active coping skills, and social functioning may also be improved. Thus, rehabilitation rather than cure is the most appropriate therapeutic option.

Opioids

Opioids act on heptahelical G-protein-coupled receptors. Three types of opioid receptors (μ, δ, κ) have been cloned. Several subtypes (e.g., μ ₁ , μ ₂ , δ ₁ , δ ₂ ), possibly resulting from gene polymorphisms, splice variants, or alternative processing have been proposed. Opioid receptors are localized and can be activated along all levels of the neuraxis including peripheral and central processes of primary sensory neurons (nociceptors), spinal cord (interneurons, projection neurons), brainstem, midbrain, and cortex. All opioid receptors couple to G-proteins (mainly G _i /G _o ) and subsequently inhibit adenylyl cyclase, decrease the conductance of voltage-gated Ca ⁺⁺ channels, or open rectifying K ⁺ channels, or any combination of these actions ( Fig. 51.3 a ). These effects ultimately result in decreased neuronal activity. The prevention of Ca ⁺⁺ influx inhibits the release of excitatory (pronociceptive) neurotransmitters. A prominent example is the suppression of substance P release from primary sensory neurons, both within the spinal cord and from their peripheral terminals within injured tissue. At the postsynaptic membrane, opioids produce hyperpolarization by opening K ⁺ channels, thereby preventing excitation or propagation of action potentials in second-order projection neurons. In addition, opioids inhibit sensory neuron-specific tetrodotoxin-resistant Na ⁺ channels, TRPV1 channels, and excitatory postsynaptic currents evoked by glutamate receptors (e.g., NMDA) in the spinal cord. The result is decreased transmission of nociceptive stimuli at all levels of the neuraxis and profoundly reduced perception of pain. Endogenous opioid receptor ligands are derived from the precursors proopiomelanocortin (encoding β-endorphin), proenkephalin (encoding Met-enkephalin and Leu-enkephalin), and prodynorphin (encoding dynorphins). These peptides contain the common Tyr-Gly-Gly-Phe-Met/Leu sequence at their amino terminals, known as the opioid motif. β-Endorphin and the enkephalins are potent antinociceptive agents acting at μ− and δ−receptors. Dynorphins can elicit both pro- and antinociceptive effects via NMDA receptors and κ−opioid receptors, respectively. A fourth group of tetrapeptides (endomorphins) with yet unknown precursors do not contain the pan-opioid motif but bind to μ−receptors with high selectivity. Opioid peptides and receptors are expressed throughout the central and peripheral nervous system, in neuroendocrine tissues, and in immune cells. Extracellular opioid peptides are susceptible to rapid enzymatic inactivation by aminopeptidase N and neutral endopeptidase. Both peptidases are expressed in the central nervous system, peripheral nerves, and leukocytes and, among opioids, enkephalins are considered their preferred substrates. Preventing the extracellular degradation of endogenous opioid peptides by peptidase inhibitors, both in central and peripheral compartments, has been shown to produce potent analgesic effects in many animal models and in some small human trials.

Opioid receptor signaling and recycling. Upper panel: Opioid ligands induce a conformational change at the receptor which allows coupling of G proteins to the receptor. The heterotrimeric G-protein dissociates into active G _α and G _βγ subunits (a) which can inhibit adenylyl cyclase and reduce cAMP (b), decrease the conductance of voltage-gated Ca ⁺⁺ channels, or open rectifying K ⁺ channels (c). In addition, the phospholipase C/phosphokinase C pathways can be activated (d) to modulate Ca ⁺⁺ channel activity in the plasma membrane (e). Lower panel: Opioid receptor desensitization and trafficking is activated by G protein-coupled receptor kinases (GRK) . After arrestin binding, the receptor is in a desensitized state at the plasma membrane (a). Arrestin-bound receptors can then be internalized via a clathrin-dependent pathway, and either be recycled to the cell surface (b) or degraded in lysosomes (c).

Adapted from Zöllner C, Stein C. Opioids. Handb Exp Pharmacol . 2007;(177):31–63.

The commonly available opioid drugs (morphine, codeine, methadone, fentanyl and its derivatives) are μ−agonists. Naloxone is a nonselective antagonist at all three receptors. Partial agonists must occupy a greater fraction of the available pool of functional receptors than full agonists to induce a response of equivalent magnitude. Mixed agonist/antagonists (buprenorphine, butorphanol, nalbuphine, pentazocine) may act as agonists at low doses and as antagonists (at the same or a different receptor type) at higher doses. Such compounds typically exhibit ceiling effects for analgesia and they may elicit an acute withdrawal syndrome when administered together with a pure agonist. All three receptors (μ, δ, κ) mediate analgesia but differing side effects. μ-Receptors mediate respiratory depression, sedation, reward/euphoria, nausea, urinary retention, biliary spasm, and constipation. κ-Receptors mediate dysphoric, aversive, sedative, and diuretic effects. δ-Receptors mediate reward/euphoria, respiratory depression, convulsions, and constipation. Immunosuppressive effects of opioids were frequently proposed in experimental studies but have not been verified in clinical outcome trials.

Tolerance describes the phenomenon that the magnitude of a given drug effect decreases with repeated administration of the same dose, or that increasing doses are needed to produce the same effect. Tolerance is not synonymous with dependence. Physical dependence is defined as a state of adaptation that is manifested by a withdrawal syndrome elicited by abrupt cessation, rapid dose reduction, and/or administration of an antagonist. All opioids produce clinically relevant physical dependence, even when administered only for a relatively short period of time. All opioid effects (e.g., analgesia, nausea, respiratory depression, sedation, constipation) can be subject to tolerance development, albeit to different degrees. For example, tolerance to respiratory depression, sedation, and nausea often develops faster than to constipation or miosis. Incomplete cross-tolerance between opioids or genetic differences may explain clinical observations that switching drugs (“opioid rotation”) is occasionally useful in patients with inadequate pain relief or intolerable side effects. Opioid-induced adaptations occur at multiple levels in the nervous and other organ systems, beginning with direct modulation of opioid receptor signaling and extending to complex neuronal networks including learned behavior. Proposed mechanisms involved in pharmacodynamic tolerance include opioid receptor-G-protein uncoupling, decreased receptor internalization/recycling, and increased sensitivity of the NMDA receptor (see Fig. 51.3 b ). In addition, pharmacokinetic (e.g., altered distribution or metabolism of the opioid) and learned tolerance (e.g., compensatory skills developed during mild intoxication) as well as increased nociceptive stimulation by tumor growth, inflammation, or neuroma formation are possible reasons for increased dose requirements. There is a lack of carefully controlled studies that unequivocally demonstrate pharmacodynamic tolerance to opioid analgesia (i.e., reduction of clinical pain) in patients.

There is an ongoing debate whether opioids may paradoxically induce hyperalgesia. However, many studies have, in fact, shown withdrawal-induced hyperalgesia, a well-known phenomenon following the abrupt cessation of opioids. At high doses, occasionally encountered in extreme cancer pain, singular cases of allodynia have been observed and attributed to neuroexcitatory effects of opioid metabolites. There is no conclusive evidence that hyperalgesia occurs during the perioperative or chronic administration of regular opioid doses in patients.

Opioids are effective in the periphery (e.g., topical or intraarticular administration, particularly in inflamed tissue), at the neuraxis (intrathecal, epidural, or intracerebroventricular administration), and systemically (intravenous, oral, subcutaneous, sublingual, or transdermal administration). The clinical choice of a particular compound or its formulation is based on pharmacokinetic considerations (route of administration, desired onset or duration, lipophilicity) and on side effects associated with the respective route of drug delivery. Dosages are dependent on patient characteristics, type of pain, and route of administration. Systemically and spinally administered opioids can produce similar side effects, depending on dosage and rostral/systemic redistribution. For intrathecal application lipophilic drugs are preferred because they are trapped in the spinal cord and less likely to migrate to the brain within the cerebrospinal fluid. Adverse side effects can be minimized by careful dose titration and close patient monitoring, or can be treated by co-medication (antiemetics, laxatives) or opioid receptor antagonists (e.g., naloxone). No significant side effects have been reported for the peripheral (e.g., topical) application of small, systemically inactive doses of opioids.

Opioids are considered the most effective analgesics for severe acute (e.g., postoperative) and cancer-related chronic pain. However, the long-term use of opioids in chronic noncancer (e.g., neuropathic, musculoskeletal, abdominal) pain is highly controversial. Randomized controlled trials (RCTs) have only been conducted for a maximum period of 3 months. In meta-analyses, the reduction of pain scores was clinically insignificant and epidemiological data suggest that quality of life or functional capacity are not improved. A recent meta-analysis of RCTs of patients with chronic noncancer pain, evidence from high-quality studies showed that opioid use was associated with statistically significant but small improvements in pain and physical functioning, and increased risk of vomiting compared with placebo. [CR] In this meta-analysis comparisons of opioids with nonopioid alternatives suggested that the benefit for pain and functioning may be similar, although the evidence was from studies of only low to moderate quality. Adverse side effects (nausea, sedation, constipation, dizziness, etc.) and lack of analgesic efficacy led to the dropout of high numbers of subjects, both in RCTs and in uncontrolled observational studies beyond 3 months. Psychosocial outcome variables were rarely investigated and showed only modest improvement. Thus, consistent with the multifactorial nature of chronic pain, opioids alone probably cannot produce an analgesic response. Clearly, the entire patient must be evaluated, not just the pain. The target of intervention is not only the source of nociception (if at all identifiable) but suffering, dysfunction, psychosocial factors, and dependence on the healthcare system. In addition, addiction has been reported in high numbers of patients treated with opioids for chronic pain, and overdoses, death rates, and abuse of prescription opioids have become a public health problem. Thus, the use of opioids as a sole treatment modality in chronic nonmalignant pain is strongly discouraged.

Nonsteroidal Antiinflammatory Drugs and Antipyretic Analgesics

NSAIDs and antipyretic analgesics (e.g., acetaminophen, phenazones) inhibit COX, the enzymes that catalyze the transformation of arachidonic acid (a ubiquitous cell component generated from phospholipids) to prostaglandins and thromboxanes. Two isoforms, COX-1 and COX-2, are constitutively expressed in peripheral tissues and in the central nervous system. In response to injury and inflammatory mediators (e.g., cytokines, growth factors) both isoforms can be upregulated, resulting in increased concentrations of prostanoids. In the periphery, prostanoids (mainly PGE ₂ ) sensitize nociceptors by phosphorylation of ion channels (e.g., Na ⁺ , TRPV1) via EP receptor activation. As a result, nociceptors become more responsive to noxious mechanical (e.g., pressure, hollow organ distension), chemical (e.g., acidosis, bradykinin, neurotrophic factors), or thermal stimuli. In the spinal cord PGE ₂ blocks glycinergic neuronal inhibition, enhances excitatory amino acid release, and depolarizes ascending neurons. These mechanisms facilitate the generation of impulses within nociceptors and their transmission through the spinal cord to higher brain areas. By blocking COX, prostanoid formation diminishes. Subsequently, nociceptors become less responsive to noxious stimuli and spinal neurotransmission is attenuated.

Less severe pain states (e.g., early arthritis, headache) are commonly treated with nonselective NSAIDs (e.g., aspirin, ibuprofen, indomethacin, diclofenac) or antipyretic analgesics (e.g., acetaminophen), mostly used orally. Some drugs are available for parenteral, rectal, or topical application. Over-the-counter availability and self-medication have led to frequent abuse and toxicity. Adverse side effects are attributed to COX-1-induced blockade of thromboxane production and impairment of platelet function (gastrointestinal and other bleeding disorders), decrease of tissue-protective prostanoids (gastrointestinal ulcers, perforation), decrease of renal vasodilatory prostanoids (nephrotoxicity), and to formation of highly reactive metabolites (acetaminophen hepatotoxicity). The development of selective COX-2 inhibitors was driven by the assumption that COX-2 expression is selectively induced in inflamed tissue and that the constitutive tissue-protective COX-1 would be spared. It has now become clear that COX-2 expression is constitutive in many tissues (e.g., gastrointestinal epithelium, vascular endothelium, spinal cord) and COX-2 inhibition may exacerbate inflammation, impair ulcer healing, and decrease formation of vasoprotective prostacyclin. COX inhibitors confer an increased risk of thrombosis, myocardial infarction, renal impairment, hypertension, stroke, and liver toxicity, and can cause rare anaphylactic reactions.

NSAIDs and antipyretic analgesics play a controversial role in chronic pain. For example, their uncontrolled use may result in medication overuse headache. In chronic degenerative musculoskeletal pain, their use is disputed and they are not indicated in neuropathic pain.

Serotonergic Drugs

Serotonin (5-hydroxytryptamine; 5-HT) is a monoamine neurotransmitter found in the sympathetic nervous system, in the gastrointestinal tract, and in platelets. It acts on 5-HT receptors expressed at all levels of the neuraxis and on blood vessels. Within the dorsal horn of the spinal cord serotoninergic neurons contribute to endogenous pain inhibition. With the exception of 5-HT ₃ (a ligand-gated ion channel), 5-HT receptors are G-protein coupled receptors. 5-HT _1B/1D agonists (triptans) have been studied extensively and are effective against neurovascular (migraine, cluster) headaches. Migraine is thought to be related to the release of neuropeptides (e.g., calcitonin gene-related peptide) from trigeminal sensory neurons innervating meningeal and intracranial blood vessels. This leads to vasodilation, an inflammatory reaction, and subsequent pain. Triptans inhibit neurogenic inflammation via 5-HT _1D receptors on trigeminal afferents, with possible additional sites of action on thalamic neurons and in the periaqueductal grey. The activation of vascular 5-HT _1B receptors constricts meningeal (and coronary) vessels. The latter effects have stimulated a search for alternative approaches such as targeting calcitonin-gene-related-peptide or highly selective 5HT _1F agonists. Triptans can be applied orally, subcutaneously, or transnasally and have been used in the treatment of migraine. All triptans narrow coronary arteries via 5-HT _1B receptors at clinical doses and should not be administered to patients with risk factors or coronary, cerebrovascular, or peripheral vascular disease. Many compounds have the potential for significant drug-drug interactions.

Antiepileptic Drugs

Antiepileptics are used in neuropathic pain resulting from lesions to the peripheral (e.g., diabetes, herpes) or central (e.g., stroke) nervous system and for migraine prophylaxis. Neuropathic syndromes have been attributed to ectopic activity in sensitized nociceptors from regenerating nerve sprouts, recruitment of previously “silent” nociceptors, or spontaneous neuronal activity (or any combination of these processes). These events may result in sensitization of primary afferents and subsequent sensitization of second- and third-order ascending neurons. Among the best studied mechanisms are the increased expression and trafficking of ion channels (e.g., Na ⁺ , Ca ⁺⁺ , TRP) and increased activity at glutamate (NMDA) receptor sites. The mechanisms of action of antiepileptics include neuronal membrane stabilization by blockage of pathologically active voltage-sensitive Na ⁺ channels (e.g., carbamazepine, lamotrigine, topiramate), blockage of voltage-dependent Ca ⁺⁺ channels (gabapentin, pregabalin), inhibition of presynaptic release of excitatory neurotransmitters (gabapentin, lamotrigine), and enhancing the activity of GABA receptors (topiramate). The most common adverse effects are impaired mental (somnolence, dizziness, cognitive impairment, fatigue) and motor (ataxia) function, which limit clinical use, particularly in elderly patients. Other serious side effects have been reported, including hepatotoxicity, thrombocytopenia, dermatologic and hematologic reactions. Specific indications include trigeminal neuralgia for sodium- and diabetic neuropathy for calcium-channel blockers.

Antidepressants

Antidepressants are used in the treatment of neuropathic pain and headache. They are divided into nonselective noradrenaline/5-HT reuptake inhibitors (amitriptyline, imipramine, clomipramine, duloxetine, venlafaxine), preferential noradrenaline reuptake inhibitors (desipramine), and selective 5-HT reuptake inhibitors (citalopram, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminergic pain inhibition in the spinal cord and brain. Tricyclic antidepressants also have NMDA receptor antagonist, endogenous opioid enhancing, Na ⁺ channel blocking, and K ⁺ channel opening effects, which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to arrhythmias. In patients with ischemic heart disease, there may be increased risk of sudden arrhythmia, and in patients with recent myocardial infarction, arrhythmia, or cardiac decompensation tricyclics should not be used at all. Tricyclics also block histamine, cholinergic, and adrenergic receptor sites. Adverse events of antidepressants include sedation, nausea, dry mouth, constipation, dizziness, sleep disturbance, and blurred vision.

Topical Analgesics

The topical application of various analgesics is an area of considerable interest because many chronic pain syndromes depend on the peripheral activation of primary afferent neurons. The localized administration can potentially optimize drug concentrations at the site of pain generation, while avoiding high plasma levels, systemic side effects, drug interactions, and the need to titrate doses into a therapeutic range. Studies have demonstrated effectiveness for topical NSAIDs, tricyclic antidepressants, capsaicin, local anesthetics, and opioids.

Topical NSAIDs are typical over-the-counter medications, widely advertised and used for acute and chronic pain. A large number of formulations (cream, gel, ointment) are commercially available. Meta-analyses concluded that topical NSAIDs have limited efficacy in chronic musculoskeletal pain. Topically applied capsaicin interacts with nociceptive neurons via the TRPV1 receptor. It causes an initial activation of these neurons with release of substance P. This is perceived as a burning or itching sensation with a flare response and occurs in a high number of patients. After repeated application desensitization occurs, probably due to depleting sensory neurons of substance P. Another potential mechanism is a direct toxic effect on small-diameter sensory nerve fibers. Topical capsaicin was shown to provide pain relief in postherpetic neuralgia, postmastectomy syndrome, osteoarthritis, and a variety of neuropathic syndromes.

Topical formulations of local anesthetics block Na ⁺ channels in primary afferent neurons. Blockade of Na ⁺ channels reduces impulse generation both in normal and in damaged sensory neurons. Such neurons exhibit spontaneous and ectopic firing, possibly contributing to certain conditions of chronic neuropathic pain. Under these conditions the altered expression, distribution, and function of ion channels along axons is associated with increased sensitivity to local anesthetics. Thus, pain relief may be achieved with local anesthetic concentrations lower than those that totally block impulse conduction. Some studies using lidocaine patches and gels showed reduction of allodynia in postherpetic neuralgia and other types of neuropathic pain.

Topically applied or locally injected opioids produce analgesia by activating opioid receptors on primary afferent neurons. This leads to inhibition of Ca ⁺⁺ , Na ⁺ , and TRPV1 currents, which are activated by inflammatory agents. Subsequently the excitability of nociceptors, the propagation of action potentials, and the release of proinflammatory neuropeptides (substance P) from sensory nerve endings are inhibited. All of these mechanisms result in analgesia or antiinflammatory effects (or both). Other mechanisms accounting for the particular efficacy of peripheral opioids in pain associated with inflammation include upregulation and accelerated centrifugal transport of opioid receptors in sensory neurons, enhanced G-protein coupling of peripheral opioid receptors, and disruption of the perineural barrier facilitating access of opioid agonists to their receptors. Consistently, the perineural application of opioids along uninjured nerves (e.g., axillary plexus) does not reliably produce analgesic effects. In addition, the production and secretion of endogenous opioid peptides from immune cells within injured tissue appears to produce additive/synergistic interactions rather than tolerance at peripheral opioid receptors. Peripheral opioid administration is regularly used and well documented in the case of perioperative intraarticular morphine. Intraarticular morphine also produces analgesia in chronic rheumatoid and osteoarthritis where its effect was shown to be similarly potent to standard intraarticular steroids and long lasting, possibly due to morphine’s antiinflammatory activity. In numerous small studies, locally applied opioids (e.g., in gels) have shown analgesic efficacy in the treatment of skin ulcers, cystitis, cancer-related oral mucositis, corneal abrasion, and bone injury. No significant adverse effects have been reported.

Other Analgesics and Adjuvants

Local anesthetics have been used orally, intravenously, in trigger-point injections, and in regional anesthetic techniques for selected chronic pain syndromes (see later under “Interventional Methods Used in Chronic Pain” and other chapters on “local anesthetics”). Their systemic application exhibited mixed success in various neuropathies. Metaanalyses indicate that local anesthetics produce moderate analgesic effects of questionable clinical significance in neuropathic pain. Severe side effects including arrhythmias, dizziness, nausea, and fatigue limit the systemic application of local anesthetics.

α ₂ -Adrenergic receptors are G-protein coupled and, similar to opioids, α _2- agonists (clonidine) lead to opening of K ⁺ channels, inhibition of presynaptic Ca ⁺⁺ channels, and inhibition of adenylyl cyclase. Thus, like opioids, α ₂ -agonists reduce neurotransmitter release and decrease postsynaptic transmission, resulting in an overall inhibitory effect. Clonidine may exert analgesic effects in some neuropathic pain syndromes. However, its systemic use is limited by sedation, hypotension, and bradycardia.

Cannabinoids have been studied extensively and are currently in the focus of public interest. Animal and in vitro models have shown that derivatives of tetrahydrocannabinol produce antinociceptive effects and that cannabinoid receptors and their endogenous ligands are expressed in pain-processing areas of the brain, spinal cord, and periphery. Peripheral cannabinoid receptors likely play a prominent role in pain inhibition. Meta-analyses of human studies concluded that the analgesic effects of cannabinoids are modest, not superior to those of other analgesics, and of questionable clinical significance. Psychotropic side effects, sedation, dizziness, cognitive impairment, nausea, dry mouth, and motor deficits are limiting factors in clinical practice.

Drugs reducing muscle spasm (e.g., benzodiazepines, baclofen) are often used in musculoskeletal pain but the available evidence does not indicate lasting beneficial effects while drowsiness and dizziness are frequently encountered. Baclofen activates GABA-B receptors presynaptically and postsynaptically, leading to a decrease in excitatory and an increase in inhibitory neurotransmission. In some reports it was found to exhibit analgesic effects in trigeminal neuralgia and central neuropathic pain. The most common side effects are drowsiness, dizziness, and gastrointestinal distress. Botulinum toxin inhibits acetylcholine release at the neuromuscular junction and may alleviate muscle spasticity. The use of botulinum toxin injections has produced inconsistent results in headaches and was not effective in myofascial trigger points, orofacial, or neck pain. Side effects include pain and erythema at the injection site and unintended paralysis of adjacent muscles.

The synthetic peptide ziconotide blocks N-type voltage-sensitive Ca ⁺⁺ channels and thereby inhibits release of excitatory neurotransmitters from central terminals of primary afferent neurons in the spinal cord. It has been approved for intrathecal application but produces substantial side effects (dizziness, confusion, abnormal gait, memory impairment, nystagmus, hallucinations, vertigo, delirium, apnea, hypotension) and, thus, is suitable for only a small subset of patients with otherwise intractable pain. Under the assumption of antiinflammatory activity, steroid injections are frequently used epidurally or perineurally, albeit without convincing evidence for effectiveness (see the later section, “Therapeutic Nerve Blocks”).

Antiemetics are used to treat nausea, a frequent side effect of analgesics (particularly opioids) and a frequent complaint in cancer patients. Recommendations for the treatment of postoperative nausea and vomiting cannot readily be extrapolated to the chronic pain patient. For example, in cancer patients, etiologies other than opioids have to be considered, such as radiotherapy and chemotherapy, uremia, hypercalcemia, bowel obstruction, and increased intracranial pressure. In addition, pain itself, as well as anxiety, can cause nausea. Management guidelines for the treatment of nausea and vomiting are available and the selection of antiemetics should be mechanism-based. The medullary chemoreceptor trigger zone, gastrointestinal stimulation or failure, vestibular and cortical mechanisms, as well as alterations of taste and smell, may contribute to nausea and vomiting, particularly in cancer patients. Most recommendations for the choice of antiemetic medication include gastrointestinal prokinetics (metoclopramide), phenothiazines (e.g., levomepromazine), dopamine receptor antagonists (e.g., haloperidol), serotonin antagonists (e.g., ondansetron), and antihistamines (e.g., cyclizine). In addition, the use of dexamethasone (unknown mechanism), anticholinergics (e.g., scopolamine), and neurokinin-1 receptor antagonists has been reported. Combinations of antiemetics with different modes of action can be used. Many of these drugs cause undesirable side effects by themselves (e.g., sedation, drowsiness, confusion, extrapyramidal symptoms). The efficacy of cannabinoids and benzodiazepines is considered comparatively low and they are not recommended as first-line treatment.

Laxatives are indicated when bowel movements are less than three per week, and are associated with difficulty or discomfort. Risk factors for constipation include opioid medication, older age, advanced cancer, hypokalemia, immobilization, as well as therapy with tricyclics, phenothiazines, anticonvulsants, diuretics, and iron supplements. Opioid-related constipation is mediated through intestinal and (partially) through central μ-receptors. It is the most commonly occurring side effect of opioid medication in cancer patients and frequently does not exhibit tolerance. Ample fluid intake, fiber-rich nutrition, and mobilization are nonpharmacologic approaches to prophylaxis, but recommendations are mostly derived from anecdotal evidence. Laxatives include bulk forming, osmotic, and hyperosmolar agents; substances for colonic lavage; prokinetic drugs; and opioid antagonists. Recommendations usually include lactulose, senna, or polyethylene glycol as a first choice. However, lactulose should be avoided in patients with impaired fluid intake, such as the elderly and those with advanced cancer. If insufficient, the drugs of first choice may be combined with paraffin or anthraglycosides (bisacodyl). Rectal sorbitol or contrast medium are the choices for the next more intensified step. Prokinetic drugs, such as metoclopramide, are sometimes added for refractory constipation. A possible alternative in opioid-related constipation are opioid antagonists. To avoid central effects reducing analgesia or producing withdrawal, oral naloxone and the peripherally restricted antagonists methylnaltrexone and alvimopan were developed. Their use in clinical practice is limited by relatively low response rates, adverse effects, and high costs.

Development of Novel Analgesics

Areas of intense research and examples emerging as potential drug targets include calcitonin-gene-related-peptide, Na ⁺ channels expressed in peripheral nociceptive neurons (Na _v 1.8, Na _v 1.7), voltage-gated Ca ⁺⁺ channels (e.g., Ca _v 2.2), antibodies against nerve growth factor, the capsaicin receptor TRPV1, and the P2X receptors. Increasing attention is paid to augmentation of endogenous opioid and cannabinoid mechanisms, to (biased) opioid receptor signaling, and to the activation of peripheral opioid receptors to avoid central side effects. However, failures in clinical phases of analgesic drug development are common and have been attributed to inappropriate animal models or nociceptive tests, species differences, publication bias, lack of mechanistic understanding, shortcomings in experimental design, randomization, blinding, and statistical analysis.

Diagnostic Nerve Blocks

Neural blockade is thought to be a useful tool to better understand the mechanisms underlying pain in an individual patient and to provide a prognosis for planned neuroablative procedures (particularly in cancer pain). Differential blockade aims to selectively block either single peripheral nerves to identify an anatomical pain source, or to selectively block only one type of nerve fiber (autonomic vs. somatic). However, the clinical usefulness of these procedures could not be confirmed. In particular, the validity of diagnostic nerve blocks is limited by the complexity of factors determining pain perception (see above section, “Biopsychosocial Concept of Pain” and “Interdisciplinary Management of Chronic Pain”). Furthermore, the assumption that local anesthetics can selectively produce conduction block of only one fiber type in a nerve is probably false. Nevertheless, experienced and observant clinicians have found that such procedures may occasionally provide information that is helpful in guiding subsequent therapy, although systematic reviews had methodological limitations.

Therapeutic Nerve Blocks

Continuous Catheter Techniques

Continuous drug delivery to the intrathecal or epidural space can be accomplished via programmable implanted pumps, implanted accessible reservoir systems, and tunneled exteriorized catheters. The principal benefit appears to be the reduction of systemic side effects. As with nerve blocks, the evidence of effectiveness of these approaches is stronger for cancer pain than for chronic nonmalignant pain.

Stimulation Techniques

Stimulation techniques frequently used in pain management include acupuncture, spinal cord (or dorsal column) stimulation (SCS), and transcutaneous electrical nerve stimulation (TENS). Acupuncture has been popular among patients for a long time and lately also within the medical community. Systematic reviews of sham-controlled studies in migraine prophylaxis and arthritic pain showed that using traditional Chinese concepts of meridians and specified classic points are as effective as the selection of acupuncture points at random. There is inconclusive evidence that acupuncture may be of benefit in osteoarthritis and chronic low back pain. SCS has gained new interest with the introduction of the high-frequency technique, but its superiority still has to be demonstrated. So far SCS has not been validated by adequately powered and blinded RCTs in chronic pain. Unblinded studies suggest that selected patients with complex regional pain syndrome or back pain, especially with failed back surgery syndrome, might benefit from SCS, but controlled trials are needed.