Difficult Pain Syndromes: Bone Pain, Visceral Pain, Neuropathic Pain

Marco Pappagallo

Lauren Shaiova

Eugene Perlov

Helena Knotkova

Nociception is what occurs physiologically in our bodies during the activation and sensitization of tissue nociceptors, also known as A-delta and C nerve fibers. Pain corresponds to our awareness of nociception and has been defined as “an unpleasant sensory and emotional experience associated with tissue damage or described in terms of such damage” (1).

In the clinical setting, pain may occur as a response to a noxious event in the tissue, for example, tissue inflammation due to a burn injury, or as a response to an abnormal pathologic process occurring within the nervous system pain pathways. In the first case, the pain signal presumably originates from “healthy” tissue nociceptors activated or sensitized by the local release of algogenic substances (e.g., protons, prostaglandins, bradykinin, adenosine, cytokines, etc.). This type of pain is called nociceptive. In the second case, the pain signal is generated ectopically by abnormal peripheral nerve fibers involved in pain transmission and/or by abnormal pain circuits in the central nervous system (CNS); this type of pain has been called neuropathic. However, the separation between nociceptive and neuropathic pain states is often blurred. Indeed, as discussed in the subsequent text, neuropathic pain may arise from inflammation (i.e., inflammatory neuropathic pain) (2). Inflammatory and neuropathic mechanisms may be present at the same time or at different times in patients who have been diagnosed with cancer pain syndromes of bone or visceral origin. In fact, cancer pain, whether arising from viscera, bone, or any other somatic structure, is more often than commonly thought the result of a mixture of pain mechanisms. When cancer pain becomes a clinical challenge to treatment, it has been labeled as a difficult pain syndrome.

Difficult Pain Syndromes: Peripheral and Central Mechanisms

The pain signal is transmitted from the peripheral nociceptors, through the dorsal horn of the spinal cord and the thalamus, up to the cortex. In the periphery, nociceptors can be activated by chemical products of tissue damage and inflammation, which include prostanoids, serotonin, bradykinin, cytokines, adenosine, adenosine-5′-triphosphate (ATP), histamine, protons, free radicals, and growth factors. These agents can activate afferent fibers or sensitize them to a range of mechanical, thermal, and chemical stimuli. Notably, a proportion of the afferent fibers that are normally unresponsive to noxious stimuli (“silent” or “sleeping” nociceptors) can be “awakened” by inflammatory chemicals and be stimulated to contribute to pain and hyperalgesia. The products of tissue damage and inflammation interact with receptors located on the A-delta fibers and C fibers to initiate membrane excitability and intracellular transcriptional changes.

Most neuropathic pain conditions develop after partial injuries to the peripheral nervous system (PNS). For example, as observed in animal models of partial nerve injury, both injured and uninjured primary sensory neurons acquire the ability to express genes de novo and, therefore, change their phenotype (phenotypic shift). Nerve endings develop sensitivity to a number of factors, such as prostanoids and cytokines [e.g., tumor necrosis factor-α (TNF-α)] (3, 4, 5, 6). One example is the upregulation or induction of catecholamine receptors in undamaged nociceptors; in this condition, nociceptors are activated by noradrenaline, and the resulting neuropathic pain has been called sympathetically maintained pain (SMP) (7, 8). Reversal of the phenotypic shift is associated with the reduction of neuropathic pain (9).

Recent findings suggest that during cancer (and other pathologic inflammatory conditions), a number of diffusible factors might be involved in causing a “neuropathic spin” in the cancer-related pain state. Tissue-related growth factors [e.g., nerve growth factor (NGF)] in combination with specific proinflammatory cytokines (e.g., TNF-α, interleukin-1β (10)) might sensitize nociceptors and generate ectopic and spontaneous activity in tissue nociceptors. In these instances, pain caused by cancer could be classified more properly as inflammatory neuropathic pain. There is considerable hope that the identification of the diffusible factors causing altered gene expression in the dorsal root ganglia (DRG) sensory neurons will direct research to discover more effective treatments. Early and aggressive pain interventions and the use of specific therapies that disengage gene expression might be sufficient to uncouple the phenotypic shift and reverse a difficult pain syndrome into an easy-to-treat condition.

Table 2.1 Development of Pathologic Pain: Relevant Peripheral Nervous System Factors

Target—peripheral nervous system mechanisms	Target—activation and cellular effect	Target—clinical importance for	Notes	References
TRPV-1, 2, 3,4 channels	TRPV channels activated by noxious heat, low pH, and capsaicin A subpopulation of primary nociceptive neurons coexpresses TRPV-1 with the ANKTM-1 channels; the ANKTM channels are activated by noxious cold stimulation Nociceptive sensory nerve fibers activation and release of neuropeptides occur	Inflammatory neuropathic pain	Activation of TRPV-1 nociceptive neurons leads to the release of neuropeptides, including SP; on endothelial cells, SP binds to the neurokinin-1 receptor and promotes the extravasation of plasma into the interstitial tissue; SP can activate osteoclasts and mast cells; mast cells are known to produce, store, and release NGF (see subsequent text) and proinflammatory cytokines	(11, 12)
α-2-Δ subunit of N- and P/Q-type voltage-gated calcium channels	Neuronal membrane voltage changes and nerve fiber activation occur Intracellular calcium influx occurs Nociceptive sensory nerve fiber activation and release of neuropeptides occur	Inflammatory neuropathic pain	The gabapentinoids, gabapentin and pregabalin, likely produce their analgesic effect by modulating the activity of the neuronal N- and P/Q-type voltage-gated calcium channels Gabapentinoids bind with high affinity to the α-2-Δ subunit of voltage-gated calcium channels and produce a decrease in intracellular calcium influx Ziconotide, a peptide analgesic derived from the venom of the predatory marine snail Conus magellaris, is a neuron-specific (N-type) calcium channel blocker that has recently been approved for intrathecal use	(13, 14, 15)
Voltage-gated sodium channels, for example, TTX-R Na (v) 1.8 and TTX-S Na (v) 1.7	Neuronal membrane voltage changes Intracellular sodium influx occurs Nociceptive sensory nerve fiber activation and release of neuropeptides occur	Inflammatory neuropathic pain	Chronic inflammation results in an upregulation in the expression of both TTX-S and TTX-R sodium channels Primary nociceptive sensory neurons express multiple voltage-gated sodium channels, of which the TTX-R channel Na (v) 1.8 has been suggested to play a major role in inflammatory pain Observations also suggest that the TTX-S channel Na (v) 1.7 may play a role in pathologic pain; for example, recent studies have shown that the neuropathic pain disorder, known as familial erythromelalgia, is a channelopathy caused by mutations in the gene encoding the TTX-S Na (v) 1.7 sodium channel; familial erythromelalgia is an autosomal dominant disease characterized by severe burning pain in distal extremities; the pain is typically relieved by cold temperature or ice pack application to the painful extremities; warm environments and physical exercise aggravate the pain	(16, 17, 18)
Proton-gated or ASIC 1, 3 channels	Activated by low pH and by noxious mechanical stimuli Nociceptive sensory nerve fiber activation and release of neuropeptides occur	Bone pain Mechanical pain	ASICs are amiloride-sensitive channels; the acidic environment created by the osteoclasts during bone resorption activates ASICs; ASICs also appear to play a role in the transduction of mechanical painful stimuli and in the genesis of bone pain	(19)
TrkA	Activated by NGF The TrkA–NGF complex is internalized and retrogradely transported to the dorsal root ganglia sensory neuron cell body, where it initiates gene transcription that gives rise to the upregulation of receptors and ion channels (e.g., ASICs), and release of neuropeptides involved in pain transmission	Bone pain Inflammatory neuropathic pain	The sensory innervation of cortical and trabecular bone, as well as bone marrow, is extensive and primarily consists of TrkA-expressing fibers New evidence indicates that NGF plays an important role in cancer bone pain; antibodies directed against NGF are effective against bone pain in animal models of cancer-induced bone pain	(9, 20, 21, 22)
Purine receptors (P2X3, P2X2/3)	Activated by ATP Nociceptive sensory nerve fiber activation and release of neuropeptides occur	Inflammatory pain Mechanical pain	P2X3 receptors are localized on peripheral sensory afferents; their activation causes nociception and contributes to hyperalgesia and mechanical allodynia ATP may also activate the adenosine receptors (see text)	(23, 24, 25, 26, 27)
PAR-2	Activated by mast cell–derived tryptase and other proteinases	Inflammatory neuropathic pain	PAR-2 receptors were recently discovered They are present in primary sensory neurons and are involved in mechanisms of hyperalgesia	(28)
Cannabinoid receptors (CB1, CB2)	Activated by endocannabinoids	Inflammatory neuropathic pain	CB1 receptors are primarily located in the central nervous system and CB2 receptors in the peripheral tissues Recent studies suggest a potential role of cannabinoids not only as anti-inflammatory and antihyperalgesic agents but also in the potentiation of opioid analgesia	(19)
Bradykinin receptors (B1, B2)	Activated by bradykinin Inflammatory pain	Nociceptive sensory neurons express the bradykinin receptors B1 and B2; expression of B1 receptors is induced by tissue injury, and B1 contributes significantly to inflammatory hyperalgesia	(29)
TRPV, transient receptor potential vanilloid; SP, substance P; ANKTM, ankyrin-like protein with transmembrane domains; NGF, nerve growth factor; TTX-R, tetrodotoxin-resistant; TTX-S, tetrodotoxin-sensitive; ASIC, acid-sensing ion channel; TrkA, tyrosine kinase A; ATP, adenosine-5′-triphosphate; PAR-2, proteinase-activated receptor-2.

Peripheral Mechanisms of Pathologic Pain

In the PNS, several elements of the cellular “machinery” thought to be relevant to the development of pathologic pain have been identified as potential targets for analgesic drugs. These PNS targets are summarized in Table 2.1.

Central Mechanisms of Pathologic Pain

In the CNS, in particular within the spinal cord, a variety of neurobiologic events can occur during the course of ongoing peripheral tissue damage and inflammation (Fig. 2.1)) (30). Spinal cord CNS factors known to be relevant to the development of pathologic pain are listed in Table 2.2.

Neuropathic Pain

Clinical Findings and Diagnosis

The clinical interview of a patient with cancer pain should focus on questions about onset, duration, progression, and nature of complaints suggestive of neurologic deficits (e.g., persistent numbness in a body area, or limb weakness, such as tripping episodes, the progressive inability to open jars, etc.), as well as complaints suggestive of sensory dysfunction (e.g., touch-evoked pain, intermittent abnormal sensations, spontaneous burning, and shooting pains). Notably, patients may report only sensory symptoms and have no neurologic deficits.

Figure 2.1. Central mechanisms of pathologic pain. NK-1, neurokinin-1; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; NMDA, N-methyl-D-aspartate; EAA, excitatory amino acid; ATP, adenosine-5′-triphosphate; cNOS, constitutive nitric oxide synthase; NO, nitric oxide; PTN, pain-transmitting neuron; PGs, prostaglandins; IL, interleukin; TNF, tumor necrosis factor; ROS, reactive oxygen species. (Modified and adapted from

Watkins LR, Milligan ED, Maier SF. Glial activation: a driving force for pathologic pain. Trends Neurosci 2001;24(8):450–455

Patients with neuropathic pain may present with some or all of the following abnormal sensory symptoms and signs:

Paresthesias Spontaneous, intermittent, painless, abnormal sensations
Dysesthesias Spontaneous or evoked unpleasant sensations, such as annoying sensations elicited by cold stimuli or pinprick testing
Allodynia Pain elicited by nonnoxious stimuli (i.e., clothing, air movement, tactile stimuli) when applied to the symptomatic cutaneous area; allodynia may be mechanical (static, e.g., induced by application of a light pressure, or dynamic, e.g., induced by moving a soft brush) or thermal (e.g., induced by a nonpainful cold or warm stimulus)
Hyperalgesia An exaggerated pain response to a mildly noxious (mechanical or thermal) stimulus applied to the symptomatic area
Hyperpathia A delayed and explosive pain response to a stimulus applied to the symptomatic area

Allodynia, hyperalgesia, and hyperpathia represent positive abnormal findings, as opposed to the negative findings of the neurologic sensory examination, that is, hypesthesia and anesthesia. Heat hyperalgesia and deep mechanical allodynia (i.e., tenderness on soft tissue palpation) are findings commonly present at the cutaneous epicenter of an inflammatory pain generator, also known as the zone of primary hyperalgesia. These findings are indicative of PNS sensitization and are related to a local inflammatory state. On the other hand, the skin surrounding the site of inflammation, also known as the zone of secondary hyperalgesia, may present the finding of mechanical allodynia, which can be elicited, for example, by stroking the area with a soft brush. Secondary hyperalgesia is indicative of CNS sensitization. Patients affected by SMP typically complain of cold allodynia/hyperalgesia. This is assessed by providing a cold stimulus, such as placing a cold metallic tuning fork, to the painful region for a few seconds.

Clinical and research tools to assess and measure the intensity and quality of neuropathic pain include the Brief Pain Inventory (BPI) and the Neuropathic Pain Scale (NPS) (41). The BPI is a well-validated instrument that consists of 15 items asking the patient about average pain, worst pain in the past week, whether the patient has received relief from pain treatment, and whether the pain has interfered with daily activities (42). The NPS is a self-report scale for measuring neuropathic pain. It consists of 12 distinct questions, which ask about intensity and quality of the patient’s pain. In validation studies, it has been found to have a good predictive power in discriminating between major subgroups of patients with neuropathic pain (42).

Table 2.3 (43) lists the most common neuropathic pain syndromes that have been reported in association with cancer. Neuropathy may result from one or more cancer-related mechanisms (44), for example, compression, mechanical traction, inflammation, or infiltration of nerve trunks or plexi caused by the progression of the primary cancer or by metastatic disease affecting bone or soft tissues. Head and neck cancer and skull-based tumors can cause painful cranial neuropathies by direct nerve compression. Salivary gland cancers may cause painful facial neuropathies. Breast or lung cancer can infiltrate the brachial plexus and cause painful plexitis. Pelvic or retroperitoneal cancer may invade the lumbosacral plexus. If the meninges are affected (meningeal carcinomatosis), the involvement of adjacent roots, spinal nerves, and plexi can occur. Metastatic disease or lymphoma can cause meningeal carcinomatosis and affect multiple spinal roots. Peripheral neuropathies with pain and dysesthesia may also be observed in the presence of lymphomas. Acute inflammatory demyelinating polyneuropathy of the Guillain-Barré syndrome type may occur with lymphomas, particularly Hodgkin’s disease.

Antineoplastic therapeutic agents such as cis-platinum, taxoids, and vincristine may cause painful neuropathies. Postradiation plexopathies may arise when >60 Gy (6000 rad)

of irradiation are given to the patient. Surgical resection of cancers may result in traumatic injuries to peripheral nerves, with the development of painful neuromas. For example, postthoracotomy pain can be caused by injury to the intercostal nerves, and postmastectomy pain may arise through injury to the intercostobrachial nerve.

Table 2.2 Development of Pathologic Pain: Relevant Central Nervous System Factors

Target—central nervous system mechanisms	Target—activation and cellular effect	Target—clinical importance for	Notes	References
NMDA receptors	NK-1 receptors are activated by SP and NMDA and AMPA receptors by EAAs	Inflammatory neuropathic pain	SP and EAAs can induce central sensitization. NMDA receptors seem to play a relevant role in pain modulation; these receptors are normally inoperative because of the Mg²⁺-blocking effect; however, in the traditional model of pathologic pain, the intense and/or prolonged “bombardment” of SP and EAAs causes the removal of the Mg²⁺ block from the NMDA receptor and the sensitization of the dorsal horn PTNs
AMPA receptors	Within the dorsal horn, on incoming nociceptive activity, the small fiber afferents release neuropeptides (SP, as well calcitonin gene–related peptide, cholecystokinin, neurokinin A) and EAAs (glutamate and aspartate)		The resulting influx of Ca²⁺ causes a series of intracellular changes, including the activation of cNOS, which, in turn, converts L-arginine into NO
NK-1 receptors	SP and EAAs cause transient depolarization of the dorsal horn (PTN); EAAs act on several PTN receptors, including NMDA, AMPA, kainate, and the metabotropic receptors			(9, 19, 31, 32)
Microglia Fractalkines Microglia-derived p38 MAP kinase NO, PGs, ATP, and ROS	Increasing evidence suggests that as a consequence of inflammation and/or trauma to peripheral nerves, dorsal horn PTN hyperexcitability is dramatically amplified as a result of spinal cord microglia activation It is still unclear what activates the microglia in the spinal cord; however, neuron-to-glia signals exist and include specific substances called fractalkines, proteins in the chemokine family, which are expressed on the extracellular surface of spinal neurons and spinal sensory afferents; in specific pathologic states or conditions, fractalkines detach from neurons and bind to activate nearby microglia, the only spinal cells that express fractalkine receptors Several lines of evidence indicate an emerging role of the microglia-derived p38 MAP kinase in the development of pathologic pain; in microglia, p38 MAP kinase promotes the synthesis and release of proinflammatory cytokines, including interleukin TNF-α, IL-1β, and IL-6 Microglia activation also leads to an increase in the spinal expression of cyclo-oxygenase and NOS and in the production of PGs and NO, as well EAAs, ATP, and ROS	Inflammatory neuropathic pain	Microglia are called the macrophages of the central nervous system; when they become activated, in addition to hypertrophy, there is hyperplasia. The tetracycline antibiotic minocycline can specifically inhibit microglial activation. Minocycline prevents the development of hypersensitivity in animal models of neuropathic pain when given before nerve injury; however, minocycline becomes ineffective when administered after the injury Other immunosuppressive or immunomodulatory agents (intrathecal methotrexate and intraperitoneal propentofylline) were tested with the aim of suppressing microglia-derived proinflammatory cytokines It is also known that in vitro TNF activates the phosphorylation of p38 MAP kinase (the active form of the kinase); in animal models of neuropathic pain, the TNF antagonist etanercept was found to decrease the hypersensitive pain state in the animal model only when given as a preventive treatment 2 days before the nerve injury; notably, systemic etanercept was shown to affect only the dorsal root ganglia capsaicin-sensitive neuronal p38 MAP kinase and not the spinal microglia p38 MAP kinase	(6, 33, 34, 35, 36, 37, 38, 39, 40)
NMDA, N-methyl-D-aspartate; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; NK-1, neurokinin; SP, substance P; EAAs, excitatory amino acids; PTN, pain-transmitting neuron; MAP, mitogen-activated protein; cNOS, constitutive nitric oxide synthase; NO, nitric oxide; PGs, prostaglandins; ATP, adenosine-5′-triphosphate; ROS, reactive oxygen species; TNF, tumor necrosis factor; IL, interleukin.

Table 2.3 Classification of Neuropathic Cancer Pain Syndromes

Syndromes related to cancer	Clinical examples
Cranial nerve neuralgias	Base of skull or leptomeningeal metastases, head and neck cancers
Mononeuropathy and other neuralgias	Rib metastases with intercostal nerve injury
Radiculopathy	Epidural mass, leptomeningeal metastases
Cervical plexopathy	Head and neck cancer with local extension, cervical lymph node metastases
Brachial plexopathy	Lymph node metastases from breast cancer or lymphoma, direct extension of Pancoast tumor
Lumbosacral plexopathy	Extension of colorectal cancer, cervical cancer, sarcoma, or lymphoma; breast cancer metastases
Paraneoplastic peripheral neuropathy	Small cell lung cancer, antineuronal nuclear antibodies type 1
Central pain	Spinal cord compression
Cachexia	Compression or entrapment neuropathies
Sequela to therapeutic interventions	Clinical examples
Hyperalgesia	Extremely high doses of opioids
Postsurgical	Postmastectomy, neck dissection, postthoracotomy
Phantom pain	Postamputation, postmastectomy
Radiation therapy	Myelopathy, plexopathy, neuropathy
Chemotherapy	Neuropathy from cis-platinum, taxoids, vincristine
Parenteral corticosteroids	Perineal burning sensation
Intrathecal methotrexate	Acute meningitic syndrome
Adapted from Martin LA, Hagen NA. Neuropathic pain in cancer patients: mechanisms, syndromes, and clinical controversies. J Pain Symptom Manage 1997;14:99–117.

Compression or entrapment neuropathies occur in the presence of cachexia; for example, patients with cancer who have lost substantial fat and muscle body weight are prone to develop peroneal neuropathies.

Paraneoplastic autoimmune syndromes due to antineuronal antibodies may present as painful neuropathies. Patients who complain of burning dysesthesias in their feet, hands, and face (in the setting of diagnosed or undiagnosed carcinoma) may have antineuronal nuclear antibodies type 1 (ANNA-1), also known as anti-Hu. Most patients who present with sensory neuronopathy and small cell carcinoma of the lung have significantly elevated titers of anti-Hu. All patients with burning dysesthesias of face, hands, and legs and positive titers for anti-Hu should undergo a computed tomography (CT) or magnetic resonance imaging (MRI) of the chest. In fact, small cell carcinoma of the lung may remain undetected by plain chest x-ray. In any case, anti-Hu positivity should prompt a careful search for malignancy, especially for a small cell carcinoma of the lung. Painful dysesthesias develop first in one limb and then progress to involve other limbs, face, scalp, and trunk over weeks or months. In these patients, deep tendon reflexes are reduced or absent and muscle strength is preserved. Patients may be disabled in their ambulation because of the sensory ataxia that is often associated with the painful symptoms.

Therapeutic Interventions for Neuropathic Pain

Management of severe neuropathic pain can be a challenge, and a combination of therapies employing agents from a variety of pharmacologic classes and pain procedures represent the contemporary standard approach (Table 2.4). Treatment includes a wide range of modalities, ranging from opioid and nonopioid analgesics to implantable devices and surgery.

Antiepileptic Drugs

Antiepileptic drugs (AEDs) are becoming the most promising agents for the management of neuropathic pain. The gabapentinoid anticonvulsants gabapentin and pregabalin have both established efficacy in treating neuropathic pain. In May 2002, gabapentin gained U.S. Food and Drug Administration (FDA) approval for the treatment of postherpetic neuralgia (PHN), a state characterized by allodynia and burning pain. However, gabapentin is also known to be effective in treating neuropathic pain from diabetic neuropathy, a state predominantly characterized by spontaneous burning pain (45, 46, 47). In December 2004, the gabapentin analog pregabalin gained FDA approval for the treatment of PHN and painful diabetic neuropathy. Gabapentinoids act on neither γ-aminobutyric acid (GABA) receptors nor sodium channels. Recent evidence suggests that gabapentin and pregabalin may modulate the cellular calcium influx into nociceptive neurons by binding to voltage-gated calcium channels, in particular to the α-2-Δ subunit of the channel (48). Trigeminal neuralgia
(a neuropathic condition characterized by brief excruciating lancinating pains) responds extremely well to carbamazepine, while another AED, lamotrigine, has shown some efficacy in treating carbamazepine-resistant trigeminal neuralgia (49). Topiramate has been anecdotally used in the treatment of complex regional pain syndrome (CRPS) type 1 (50). Several new AEDs (e.g., levetiracetam, zonisamide, oxcarbazepine, and tiagabine) have become available for medical use, and some of these, along with topiramate, may have analgesic effect in primary headache and perhaps in neuropathic pain (51, 52). Interestingly, in a recent randomized, double-blind, active placebo-controlled, crossover trial, patients with neuropathic pain received lorazepam (active placebo), controlled-release morphine, gabapentin, and a combination of gabapentin and morphine, each treatment given orally for 5 weeks. The study indicated that the best analgesia was obtained from the gabapentin–morphine combination, with each medication given at a lower dose when given as a combination than when given as a single agent (53).

Table 2.4 Analgesic Algorithm For Neuropathic Pain—Steps of Intervention

Pharmacologic Interventions^a

Moderate to severe pain/functional impairment, with a pain score of >4 on the Brief Pain Inventory:

Opioid/opioid rotation + gabapentinoids (e.g., gabapentin, pregabalin) + topical therapy for cutaneous allodynia/hyperalgesia^b c
± Antidepressants (e.g., tricyclic antidepressants, duloxetine, venlafaxine), nongabapentinoid antiepileptic drugs (for intermittent lancinating pain due to cranial neuralgias, consider carbamazepine or oxcarbazepine and/or lamotrigine ± baclofen)
± Anti-inflammatory drugs (corticosteroids for acute inflammatory neuropathic pain)
± Mexiletine, N-methyl-D-aspartate antagonists

Procedure steps

Severe pain/functional impairment, treatment not amenable to conventional drug delivery routes:

Implantable intrathecal pump or tunneled intraspinal catheter system for neuroaxial analgesia (opioids ± bupivacaine, clonidine, or ziconotide)
Neurostimulatory procedure by implantable device (spinal cord or motor cortex stimulation)
Neuroablative procedure (e.g., dorsal root entry zone lesion, midline myelotomy)

^aOn a compassionate basis, according to the patient’s clinical condition and pain mechanism, the physician may want to consider an empiric trial of one or more of the emergent topical, oral, or parenteral/intrathecal therapies, as discussed in the text.
^bIn case of sympathetically maintained pain, consider topical clonidine and sympatholytic interventions.
^cIf clinically feasible, trials of topical therapies, for example, lidocaine 5% patch, may be considered for a variety of neuropathic pain states and features.

Opioids

Opioids are currently the most potent and effective analgesics used to treat acute and chronic pain, and, as such, they have been prescribed to patients suffering from intractable pain. Morphine, a μ agonist, represents the mainstay for the treatment of moderate to severe nociceptive cancer pain (54). Long considered to be ineffective for neuropathic pain, opioids have demonstrated efficacy in several recent clinical trials (55, 56, 57, 58, 59, 60). A double-blind, placebo-controlled, crossover trial (57) in which 76 patients with PHN received opioids (e.g., controlled-release morphine or methadone), tricyclic antidepressants (TCAs) (e.g., amitriptyline or nortriptyline), and placebo found that both opioids and TCAs provided significantly better pain relief than placebo. Among patients completing the study, most preferred opioids (50%) to TCAs (30%; p = .02). The results indicate that opioids are as effective as TCAs in the treatment of PHN.

The analgesic action of the pure opioid agonists (e.g., morphine, methadone, fentanyl, oxycodone, hydromorphone, etc.) is well known and utilized clinically. Among all the analgesic medications currently available, the most powerful and effective drugs are still the agents acting on the μ-, κ-, and Δ-opioid receptors. Opioid receptors are located not only in the CNS (primarily in the dorsal horn) but also peripherally on the nociceptors. Opioids may have a relevant peripheral analgesic effect during painful inflammatory states (61).

The pure opioid agonists are the mainstay for the treatment of severe disabling pain. The treatment of chronic pain may rely on the use of long-acting agents (i.e., methadone, levorphanol) or controlled-release preparations of morphine, fentanyl, and oxycodone. Among the pure opioid agonists, methadone has peculiar properties. It has an intrinsic N-methyl-D-aspartate (NMDA) receptor antagonistic effect, which may add adjuvant analgesic effect in case of neuropathic pain (see subsequent text). Interestingly, recent animal studies suggest that the addition of an extremely low dose of an opioid receptor antagonist (e.g., naltrexone) to morphine in a ratio of 1:1000 may enhance the analgesic efficacy of the opioid agonists (62). Tramadol is an analgesic agent with a weak μ-opioid agonistic effect. Its potency is comparable to that of a codeine–acetaminophen preparation. Notably, in controlled trials, tramadol has shown efficacy in the treatment of neuropathic pain (62, 63, 64).

Clinicians should be careful during opioid titration because the requirement for neuropathic pain may be high. The opioid dose should be increased until analgesia is achieved or till side effects become intolerable. Common side effects are constipation, sedation, pruritus, and nausea/vomiting. Rarely, frank confusion may develop. Except for constipation, tolerance occurs for most of the opioid-related side effects (e.g., nausea, vomiting, respiratory depression, and drowsiness). The most feared complication of respiratory depression is rare, especially in patients who are somewhat tolerant to opioids. Unlike anti-inflammatory drugs, opioid agonists have no true “ceiling dose” for analgesia and do not cause direct organ damage. Side effects can often be managed with additional pharmacotherapy, and the clinician may choose to treat the side effects and continue the opioid dose, or “rotate” to another opioid. When converting to another opioid, it is wise to refer to an opioid conversion table or a similar reference and reduce the dose by 50% to avoid incomplete cross-tolerance. Opioid titration and opioid rotation are essential concepts in the management of neuropathic pain. To determine adequate opioid responsiveness, a careful titration of the opioid dose is necessary. However, the development of tolerance to opioid side effects, degree of analgesia, and the development of analgesic tolerance are extremely variable among patients with pain receiving these medications. If severe pain persists or side effects become intolerable during the initial drug trial, trials of different opioids (i.e., opioid rotation) are recommended. Studies indicate that patients on a stable opioid regimen do not report significant impairment in their driving ability, attention, mood, and general cognitive functioning (65).

Antidepressants

Antidepressants also play an important role in the treatment of chronic pain. TCAs, such as amitriptyline, nortriptyline, and desipramine (66), have established efficacy in the treatment of neuropathic pain. They have been used successfully for painful diabetic neuropathy and PHN and provide pain relief in nondepressed patients affected by neuropathic pain. Notably, TCAs such as amitriptyline, doxepin, and imipramine have been found to have potent local anesthetic properties. Amitriptyline appears to be more potent than bupivacaine as a sodium channel blocker (67). TCAs frequently have poorly tolerated adverse effects, including cardiotoxicity, confusion, urinary retention, orthostatic hypotension, nightmares, weight gain, drowsiness, dry mouth, and constipation.

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