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symposium article Annals of Oncology 18 (Supplement 9): ix37–ix42, 2007 doi:10.1093/annonc/mdm292 Pain control in cancer: recent findings and trends D. Schrijvers Department Hematology–Oncology, Ziekenhuisnetwerk Antwerpen-Middelheim, Antwerp, Belgium Pain is an important symptom in cancer patients. 30–40% of patients present this symptom at diagnosis, 40–70% during treatment and 70–90% during the palliative care phase. The prevalence of pain depends on tumour type and varies from 5% in patients with leukaemia to 52% in patients with lung cancer. The cause of pain may be the tumour itself (77–80%) [bone invasion, compression of the spinal cord or neural structures, pressure on hollow organs (visceral pain)]; anti-cancer treatment (15–25%) [e.g. surgery (amputation, thoracotomy, mastectomy) chemotherapy (neuropathy), radiation (plexopathy, myelopathy), radiotherapy-induced nerve tumours or paraneoplastic syndromes]; non-cancer-related pain (3–5%) or; the origin may be unknown. Since the 1980s, the guidelines of pain treatment according to the World Health Organization (WHO) state that analgesics should be readily accessible, should be given ‘‘by the clock’’ on a regular basis; ‘‘by the ladder’’ according to the intensity of pain while the analgesic potency is sequentially escalated if pain intensifies; ‘‘by the mouth’’; and adapted to the individual patient. Appropriate medication for breakthrough pain should be given; additional medication for prevention and treatment of side effects should be provided; and careful and regular monitoring is essential. This approach enables pain control in 80% of cancer patients. Paracetamol and non-steroidal anti-inflammatory drugs (NSAID) are the standard drugs of the first step of the WHO pain ladder. Paracetamol is the simplest and safest analgesic; its mechanism of action is not fully understood; it has a central effect and is effective in (chemotherapy-induced) neuropathy. NSAIDs form a very diverse group of medication. Their principle mechanism of action is the reduction of prostaglandin synthesis. Their indication is malignant bone pain. They have a ceiling analgesic effect and an opioid dose-sparing effect. Weak opioids constitute the second step of the WHO pain ladder. Codeine is the standard weak opioid and can be used in combination with paracetamol. Tramadol has a weak opioid activity but influences also the noradrenaline and serotonin re-uptake. Buprenorphine has no ceiling effect for analgesia although it has a ceiling for side effects. It gives no restrictions for future opioid use and has an additive effect when co-administered with morphine. Strong opioids are classified at the highest step of the analgesic ladder. Morphine is still the standard drug. Other drugs are hydromorphone (5· more potent than morphine); ª 2007 European Society for Medical Oncology fentanyl (100· morphine; high lipid solubility); oxycodone (interfering with the j-opioid receptor); and methadone [racemic mix of an N-methyl-D-aspartate (NMDA)-antagonist and a l-receptor agonist with a half-life from up to 190 h and a steady state after 6–12 h]. It is possible to rotate among these strong opioids in case of side effects or insufficient activity [1]. Adjuvant or co-analgesic drugs are administered together with analgesic drugs for specific indications (Table 1) to improve pain control, and decrease opioid dosing and side effects [1]. pathophysiology of pain Pain is classified as nociceptive pain, linked to activation of pain receptors, and neuropathic pain, due to damage of nerve tissue [2]. It was thought to be a stable system with no changes in the structural nerve network. New insights show that pain perception is a dynamic system, and that structural changes in the neural network may contribute to pain perception [2]. nociceptive pain The nociceptive pathway is activated by specific receptors (Table 2) via stimulation of specialized free nerve endings in the skin, muscle and visceral tissues by chemical, mechanical and/or thermal stimuli. This signal is transmitted by primary nociceptive afferents: type I and II A-delta fibres, that are small (1–5 lm in diameter) myelinated, rapidly conducting (5–30 m/s) neurons correlated with the initial sensation of sharp, localized and subjectively punctuate pain or C-fibres, that constitute the majority of cutaneous nociceptive innervation and are small (0.25–1.5 lm in diameter), unmyelinated afferents with slower conductance (0.5–2 m/s) and larger receptive fields than A-delta fibres giving rise to a poorly-localized burning, gnawing sensation. The primary afferent sensory neurons enter the spinal cord and synapse with neurons in the dorsal horn in the superficial layers of laminae: the A-delta neurons synapse in laminae I, II and V, and the C fibres in laminae I and II. A variety of neurotransmitters are released by the primary afferent sensory neurons: substance P, calcitonin gene-related peptide (CGRP), and excitatory amino acids (EAAs) such as aspartate and glutamate. Glutamate is the principal excitatory transmitter at the synapse and binds initially to the alpha-amino-3hydroxy-5-methyl-isoxazole-4 propionic acid (AMPA) symposium article introduction symposium article Table 1. Adjuvant drugs used in pain control Medication Antidepressants Amitriptyline Anticonvulsants Carbamazepine Gabapentin Neuroleptics Haloperidol Benzodiazepines Diazepam Midazolam Anti-histaminics Diphenhydramine Psychostimulants Methylphenidate Indication Annals of Oncology Table 2. Specific receptors, stimuli and effect(s) Daily oral dosing schedule Neuropathic pain 10–25 mg q 8 h Neuropathic pain Neuropathic pain 200 mg q 12 h 300 mg q 24–8 h Nausea, delirium, pychosis, agitation 2–5 mg q 8 h Anxiety, muscle spasm myoclonus Invasive procedures 2–10 mg q 6–8 h 0.3–0.5 mg/kg (SC) Pruritus, nausea 25–50 mg q 4–6 h Somnolence 5–15 mg q 8–12 h Receptor Stimuli Effect TRPV1 H+ Na+, Ca2+ channel activation Na+, Ca2+ channel activation TRPV2 ASIC CMR1 Prostanoid receptor Aspecific activation Serotonin (5-HT) receptor Noxious heat (>45C) Capsaicin Noxious heat (>53C) Protons Noxious cold (8–25C) Menthol progostaglandin E2 Mechanical distortion Serotonin kg, kilogram; mg, milligram; q, every; h, hours; SC, subcutaneously receptor. This induces a ligand-gated Na+ current to produce rapid depolarization. Sustained Na+ flux activates the NMDA receptor to develop a high affinity for glutamate. Activation of AMPA, NMDA and other receptors alters the sensitivity of these receptors and affects their shuttling to active zones on the neural membrane. Prolonged activation of newly synthesized glutamate receptors can affect genomic elements to produce durable change in the neuronal microstructure leading to plasticity and long-term potentiation of nociceptive circuits and long-term depression of pain modulating circuitry [2]. The second-order neurons are classified as wide dynamic range (WDR) and nociceptive specific (NS) neurons that spatially and temporally transform the afferent input. A small percentage of the axons from these neurons ascend ipsilateral in the spinal cord, but most project contralateral to form the spinothalamic tract(s) (STT) and ascend in the anterolateral quadrant. WDR and NS fibre activity contribute to the spatial and temporal qualities of pain. NS neurons can remain sensitized following repetitive noxious input and WDR neurons exhibit prolonged after-responses (e.g. ‘wind-up’) generated from the extent and frequency of primary nociceptive afferent input, thus intensifying and continuing nociceptive transmission and sensation(s). The anterolateral spinal pathway fibres terminate in specific regions of the thalamus, from which neuronal relays are sent to other central nervous system centres and the somatosensory cortex. These higher centres are responsible for the perception of pain and the emotional components that accompany it. The activation of supraspinal structures is mediated by EAAs [2]. Response to a painful stimulus is regulated by interactions between multiple regions within the brain via different neurochemical pathways. There is evidence to support interaction between dopaminergic and adrenergic pathways and opioid signalling pathways in the central nervous system. Catechol-O-methyltransferase (COMT) is one of the enzymes that metabolizes catecholamines and is an important ix38 | Schrijvers AMPA receptor Glutamate NMDA receptor Glutamate Polyglutamate mGlu receptor Glutamate Na+, Ca2+ channel activation Na+ channel activation Na+, K+, Ca2+ channel activation Metabotropic activation protein kinases Na+, K+, Ca2+ channel activation Na+ channel activation NK-1 receptor sensitization NO production Na+, Ca2+ channel activation Activation protein kinase C Sensitization of trk-B Na+, Ca2+ channel activation Activation protein kinase C Sensitization of trk-B Na+, Ca2+ channel activation Activation protein kinase C Sensitization of trk-B TRPV1, vanilloid receptor-1; TRPV2, vanilloid receptor-like protein; ASIC, acid-sensitive ion channel; CMR1, cold and menthol receptor-1; AMPA, 2amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; NMDA, N-methylD-aspartate; mGlu, G-protein-coupled glutamate; NK, neurokinine; NO, nitrogen oxide; trkB, tyrosine kinase B. modulator of neurotransmitters in the brain. Polymorphic variation in the COMT gene has been shown to affect lopioid neurotransmitter responses to a pain stressor and to influence inter-individual variation in pain sensitivity [3]. neuropathic pain Neuropathic pain arises following nerve injury or dysfunction. After nerve damage, an altered expression of ion channels results in neurons becoming hyperexcitable and generating ectopic activity, which is thought to lead to the genesis of spontaneous and paroxysmal pain. Peripheral nerve injury causes changes in gene transcription and activation of various kinases and proteins, including increased NMDA receptor activity. It also elicits hypertrophy Volume 18 | Supplement 9 | July 2007 symposium article Annals of Oncology and activation of glial cells, including microglia within the grey matter of the spinal cord. Following activation, microglia release various pronociceptive cytokines (interleukin-1, tumour necrosis factor alpha, neurotrophins), which exacerbates nociceptive transmission and contributes to the sensitization and maintenance of neuropathic pain [4]. Neuropathic pain may be caused by peripheral mechanisms such as regeneration after nerve injury or demyelination of nerves. These processes may cause increased neuronal excitability and are linked to an increased expression of sodium channels. Central mechanisms involve the spinal sensitization with heightened sensitivity of spinal neurons, reduced activation thresholds and enhanced responsiveness to synaptic inputs. It is mediated by the NMDA receptor [4]. The sympathetic nervous system is also important in neuropathic pain since sympathectomy induces pain relief. Sympathetically maintained pain may be due to sprouting of sympathetic neurons into dorsal root ganglia of injured sensory neurons and post-injury sprouting of sympathetic fibres into the dermis [4]. Several efferent pathways and ligands or drugs that modulate pain have been described (Table 3). These include the corticospinal tracts, which start in the motor cortex and synapse in laminae III–IV; hypothalamic efferents, which arise in the hypothalamus and synapse in the mid-brain, pons, medulla and lamina I; and extensive efferent fibres from the periaqueductal gray matter in the mid-brain and the nucleus raphe magnus in the medulla to the dorsal horn [2]. These pathways modulate nociceptive transmission in the periphery, in the spinal cord by altering neurotransmitter release, or supraspinally by activation of inhibitory pathways. Several neurotransmitters are involved in inhibition of pain transmission: norepinephrine, serotonin and opiate-like substances (endorphins) are present in the brainstem inhibitory pathways that modulate pain in the spinal cord; gamma-amino butyric acid (GABA) and glycine in the dorsal horn; somatostatin in the dorsal root ganglion and in afferent terminals of the dorsal horn of the spinal cord; and galanin present in primary afferent nociceptive fibres and is thought to be an inhibitory peptide [2]. are all pain modulating receptors the same Several opioid (l1 and 2; d and j) and cannabinoid receptors (CR1 and CR2) have been identified that are activated by endogenous ligands and are implicated in pain modulation. l1 and 2 opioid receptors are influenced by b-endorphin 1 and 2; d receptors by enkephalin; and j receptors by dynorphin while the cannabinoid receptors are influenced by endogenous anandamide and 2-arachidonoylglycerol. Opioid receptors are widely distributed in the gastrointestinal and pulmonary tract and influence other systems (e.g. immune system) but in pain control opioid receptors localized in the terminal regions of primary afferent neurons, in the dorsal horn of the spinal cord, the medulla and in the central nervous system (e.g. caudate Volume 18 | Supplement 9 | July 2007 Table 3. Endogenous ligands and receptors in pain modulation Ligand System Receptor Dynorphin Enkephalin j-opioid receptor l- and d-opioid receptor Endorphin Orphanin GABA Glycine Anandamide 5-hydroxytryptamine Intraspinal Intraspinal Midbrain Midbrain Midbrain Intraspinal Intraspinal Intraspinal Bulbospinal Nor-epinephrine Bulbospinal l-opioid receptor d-opioid receptor GABA receptors Glycine receptors CB1 receptors 5-hydroxytryptamine 1b receptor 5-hydroxytryptamine 3 receptor alpha2 receptors putamen, nucleus accumbens, claustrum, medial habenula, dorsal endopiriform nucleus, basolateral nucleus of the amygdala, hypothalamus, thalamus and ventral tegmental area) are of importance [3]. The majority of the l-receptors in the spinal cord are found presynaptically on the afferent nociceptive terminals. Opioids that are l and/or d agonists cause a reduced release of neurotransmitters (substance P, glutamate) from C-fibres. Opioids also inhibit the release of CGRP. Activated opioid receptors block the release of neurotransmitters by inhibiting adenylyl cyclase resulting in a fall of intracellular cyclic adenosine monophosphate (cAMP). The predominance of presynaptic opioid receptors on C fibres, as opposed to A-fibre terminals, accounts for the selective effect of spinal opioids on noxious evoked activity. The deeper layers of the spinal cord contain relatively fewer opioid receptors; those present are believed to be situated on nociceptive circuitry such that they have selective inhibitory effects. When stimulated, these postsynaptic opioid receptors hyperpolarize the membrane of dorsal horn neurons, thereby reducing activity in nociceptive pathways. Cannabinoid receptors influencing transmission and modulation of pain signals are localized in the dorsal horn of the spinal cord, the rostral ventromedial medulla and the periaqueductal gray [5]. Activation of the different opioid receptors not only results in pain control but induces different side effects (Table 4) and these are dependent on the receptors that are influenced by the agonist: l-opioid receptor agonists give rise to respiratory depression, constipation, development of tolerance and physical dependence, and addiction; d receptor activation causes autonomic and neuro-endocrine system dysfunction and mood changes; and j-opioid receptor agonists may cause respiratory depression. Cannabinoid receptors are influenced by cannabinoids (e.g. delta-9-tetrahydrocannabinol of benzopyranoperidine, benzopyranoperidine, cannabidiol, levonantradol). At analgesic doses they may produce side effects such as mental disturbances, ataxia, dizziness, numbness, disorientation, doi:10.1093/annonc/mdm292 | ix39 symposium article Annals of Oncology Table 4. Effects of different opioid receptors Activity Supraspinal analgesia Spinal analgesia Respiratory depression Cardiovascular depression Hypothermia Diuresis Anti-diuresis Nausea and vomiting Constipation Gastroparesis Euphoria Dysphoria Tolerance/dependency Convulsions/stress/shock Table 5. Receptor and pharmacokinetics characteristics of different opioids Receptor l1 l2 j d x x x x (x) x x x x x x x x (x) (x) x (x) (x) x Opioid receptor activation l j d Morphine Oxycodone Fentanyl Methadone Hydromorphone Buprenorphine Tramadol A(1+2) A A(1) A A a a a A a Receptor affinity Solubility Low L High + a + + A a I H + + + + + + A: High affinity; a: moderate affinity. x x X (x) x (x): May be associated with this receptor activation. disconnected thoughts, slurred speech, muscle twitching, impaired memory, dry mouth, and blurred vision and sedation [6]. The opioid receptors are G-protein-coupled receptors (GPCR) and their activation by opioids including morphine, oxycodone, hydromorphone, methadone or fentanyl results in inhibition of neuronal transmission of painful stimuli. GPCR signalling is regulated by receptor desensitization, endocytosis and down regulation and the intracellular protein ß-arrestin-2 is involved at multiple sites in this process. The rates of l-opioid receptor internalization and desensitization differ according to the ligand and polymorphic variation of ß-arrestin-2. The pain controlling effect of opioids is also influenced by changes in l-opioid receptor densities by allelic variants with 30–50% inter-individual differences in l-opioid receptor densities; and polymorphism in the human l-opioid receptor gene altering the binding affinities to different opioids [7]. Cannabinoid receptors are also GPCRs that are acting via cAMP levels and ion channels but may also be intrinsically active and possibly coupled to more than one type of G protein. These findings show that the pain conducting system is modulated by different receptors and that different drugs may act differently in individual patients at the receptor level due to differences in genetic variability. are all opioids the same Several different opioids are used in pain control. However, it should be noted that not all opioids have the same pharmacodynamic (e.g. potency in receptor activation and binding, number and morphology of target receptors, variation in downstream events after receptor–ligand binding) and pharmacokinetic characteristics (e.g. drug absorption, distribution, metabolism, elimination) (Table 5). This may explain the inter-individual variability in opioid analgesic response and side effects among different opioids [7]. ix40 | Schrijvers Drug There is no single common metabolic pathway for the metabolism of opioids: after administration opioids are metabolized by the liver but this may be by different enzymatic systems: codeine and oxycodone are primarily metabolized by the cytochrome P450 (CYP)2D6 enzyme; morphine and hydromorphone by the uridine-diphosphoglucuronosyltransferase (UGT) system and fentanyl and methadone by the CYP3A4 enzyme [7]. Genetic variation in enzymatic systems may influence the effect of opioids: Codeine metabolisation to its active metabolite morphine is influenced by genetic variation in CYP2D6 and 7% of Caucasians have inactivating mutations or complete deletion of this gene. Morphine is metabolized by UGT2B7 to morphine-3glucuronide and morphine-6-glucuronide, and genetic polymorphism may lead to differences in pharmacokinetics. However, polymorphism in genes controlling the metabolism of morphine is not sufficient to explain inter-individual variability in morphine response. Oxycodone, fentanyl, tramadol and methadone are metabolized by CYP enzymes CYP3A4, CYP3A5 and CYP2D6. Multiple single nucleotide polymorphisms have been described in the CYP3A4 gene and some of them affect drug metabolism; CYP3A5 may show high or low activity due to polymorphic variation resulting in a non-functional protein (5–15% of Caucasians); and CYP2D6 may influence response to tramadol dependent on poor or rapid metabolisation [7]. These findings indicate that there are important interindividual differences in the activity of different opioids and this shows the rationale of opioid rotation in pain control [8]. does opioid-resistant pain exist Opioid-resistant pain is defined as pain that is completely unresponsive to large doses of opioids and that is not related to side effects. It is estimated that 20% of cancer patients do not respond to the traditional treatment approach with opioids. The diagnosis of opioid-resistant pain can be made if morphine sulfate has been administered in a dosage of at least 100 mg/h Volume 18 | Supplement 9 | July 2007 symposium article Annals of Oncology (or equivalent intravenous dosing of another opiate); if there is no pain relief, as evidenced by persistently high pain ratings and the pain persists even after the dose of medication is doubled and the route of administration is changed (e.g. from intravenous to epidural); and if another opioid has been tried unsuccessfully [9]. Several pathophysiological mechanisms have been formulated such as down regulation of the number of lreceptors, which may be observed in peripheral nerve damage and long-term use of opioids; cholecystokinin production which influences the control of opioid sensitivity and is present in certain cancer syndromes; de-activation of opioid-receptors by G protein-activated inwardly rectifying K(+) channels (GIRK) receptor activation leading to the inhibition of the l-receptor or opioid-induced hyperalgesia (OIH). OIH develops due to an imbalance of initial opioid-induced analgesia and subsequent OIH. OIH may be turned ‘off ’ by NMDA antagonists such as dextromethorphan, ketamine or methadone; nitric oxide synthase inhibitors; calcium channel antagonists; orphanin (nociceptin) receptor modulators; neurokinin antagonists; dynorphin modulators; or ultra-low dose opioid antagonists. Other drugs [e.g. anticonvulsants (e.g. phenytoin, carbamazepine, barbiturates, gabapentin); antidepressants (tricyclic antidepressant agents, selective serotonin-reuptake inhibitors), antihistamines (e.g. diphenhydramine, hydroxyzine), steroids (e.g. dexamethasone, prednisone), non-steroidal anti-inflammatory agents (e.g. acetaminophen, ibuprofen); and psychotropic neuroleptic agents (e.g. haloperidol)] may be tried to control this opioid-resistant pain [9]. s Interventional treatment: n Neurolytic blocks Pain treatment should be decided on these factors, but the rationale for pain treatment should be based on the pathophysiological mechanisms. This means that an in-depth anamnesis and clinical examination are necessary to differentiate between the different pain types. Differentiation between nociceptive and neuropathic pain may be by the use of a neuropathic pain questionnaire (e.g. DN4) (Figure 1) [3, 10]. Based on anamnesis and clinical examination a treatment algorithm may be followed (Figure 2). There have been other schedules. Most of them have to be validated in clinical settings. conclusion The use of the pain medication according to the WHO pain ladder controls around 80% of cancer pain. However, with the increased knowledge of the pathophysiology of pain and the introduction of new drugs or the fine-tuning of older medications pain treatment will become hopefully more effective in all cancer patients. The new drugs and schedules should however been tested in clinical settings in order to prove their value. new pain treatment approaches Several factors have to be taken into account when dealing with cancer pain: Patient characteristics such as performance status, age, organ function (liver, kidney function), previous experiences with certain medication and co-medication. Tumour involvement as cause of pain that may direct to antitumour treatments (surgery, radiotherapy, anti-cancer drugs). Pain characteristics: s Pathophysiological mechanisms: n Nociceptive (superficial or deep somatic, visceral) or neuropathic pain n Opioid-resistant pain s Temporal relationship based on which pain is classified as acute, chronic, or incident pain. Treatment characteristics: s Drug treatment: n Analgesics n Adjuvant drugs Volume 18 | Supplement 9 | July 2007 Figure 1. Neuropathic pain (DN4) questionnaire. doi:10.1093/annonc/mdm292 | ix41 symposium article Annals of Oncology Pain characteristics Nociceptive Neuropathic Mixed Visceral Peripheral Deep Anti-depressants + Opioids Adjuvant analgesics Spasmolytics Local anesthetics Anti-depressants Anti-convulsants + opioids Somatic Superficial Deep Paracetamol NSAID Opioids Anti-depressants Anticonvulsants Opioids Adjuvant analgesics Anti-convulsants Opioids Opioids Figure 2. Pain treatment according to pain characteristics. references 1. World Health Organization. Cancer Pain Relief with a Guide to Opioid Availability. Geneva: World Health Organization 1996. 2. Giordano J. The Neurobiology of Nociceptive and Anti-nociceptive Systems. Pain Physician 2005; 8: 277–290. 3. Zadina JE, Martin-Schild S, Gerall AA et al. Endomorphins: novel endogenous mu-opiate receptor agonists in regions of high mu-opiate receptor density. Ann NY Acad Sci 1999; 897: 136–144. 4. Gilron I, Watson CP, Cahill CM et al. Neuropathic pain: a practical guide for the clinician. CMAJ 2006; 175: 265–275. 5. Hohmann A, Suplita R. Endocannabinoid mechanisms of pain modulation. AAPS J 2006; 8: E693–708. ix42 | Schrijvers 6. Campbell FA, Tramer MR, Carroll D et al. Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. BMJ 2001; 323: 13–16. 7. Klepstad P, Dale O, Borchgrevink PC et al. Genetic variation—important for the clinical effect of opioids? Tidsskr Nor Laegeforen 2005; 6: 2655–2658. 8. Rossa J, Rileya J, Quigleyc C et al. Clinical pharmacology and pharmacotherapy of opioid switching in cancer patients. Oncologist 2006; 11: 765–773. 9. McCormick W, Schreiner R. Diagnosis and treatment of opiate-resistant pain in advanced AIDS West. J Med 2001; 175: 408–411. 10. Bouhassira D, Attal N, Alchaar H et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain 2005; 114: 29–36. Volume 18 | Supplement 9 | July 2007