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Slide 1-

Goals of treatment in managing cancer-related pain
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Deciding on the Best Course of Treatment for the Patient Collaborative Care Patient as the ultimate manager of his/her illness Ayad AE et al. J Int Med Res 2011;39(4):1123-41; Saltman D et al. Med J Aust 2001;175(Suppl):S92-6.
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Pain Is Characterized by Changes in Pain Response to Painful Stimuli Pain intensity 10 8 6 4 2 0 Stimulus intensity Normal pain response Hyperalgesia (increased response to a stimulus that is normally painful) Allodynia (pain due to stimulus that does not normally provoke pain) Adapted from: Gottschalk A et al. Am Fam Physician 2001; 63(10):1979-84. Response after injury
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Non-Pharmacological Management of Cancer-Related Pain Non-pharmacological treatments can be used to improve Pain control Coping Adaptation Self-efficacy Non-pharmacological approaches include Cognitive behavioral therapy Mind-body approaches Portenoy RK. Lancet. 2011;377:2236-47.
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CBT for Cancer-Related Pain Focuses on1 Maintaining quality of life through improved self-efficacy Developing a sense of control over the illness and its consequences Learning self-regulation skills to improve emotional functioning Modifies thinking patterns2 (dichotomous thinking, catastrophization, overgeneralization) Dysfunctional cognitive patterns typically arise from limited information and do not entirely reflect reality2 Gives patients a reality-based alternative version/interpretation of events2 Elicits a more adaptive emotional response, improved coping2 CBT = cognitive behavioral therapy Porter LS et al. Pain. 2008;137(2):306-15; 2. McCracken LM, Turk DC. Spine (Phila Pa 1976). 2002;27:2564-73.
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Mind-Body Approaches to Cancer-Related Pain Usually an adjunct to pharmacological therapy Relaxation therapy Can transiently reduce pain intensity2 May be associated with relaxation-induced panic3 Imagery creates a positive cognitive and emotional state that can ameliorate pain through4 Recall of pleasant sights, smells, sounds, or tastes, Somatic sensations (touch, movements, positions) 1. Porter LS et al. Pain. 2008;137(2):306-15; 2. Anderson KO et al. Cancer. 2006;107:207-14; 3. Adler CM et al. Integrative Psychiatry. 1987 5:94-100 http://psycnet.apa.org/psycinfo/1988-30404-001; 4. Achterberg J. Imagery in Healing: Shamanism and Modern Medicine. Shambhala Publications; 2013.
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Non-pharmacological Interventions for Cancer-related Pain CBT = cognitive behavioral therapy Bennett MI, Closs SJ. Pain Clinical Updates 2010; 18:1-6. Non-pharmacological interventions are commonly used in clinical practice It is challenging to design studies to obtain reliable evidence of efficacy
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Psychological Therapies for Cancer-related Pain Individual and group counseling Biofeedback Relaxation techniques Self-hypnosis Visual imaging Learning or conditioning techniques Behavioral techniques Cognitive techniques Psychotherapy American Academy of Pain Medicine. Essential Tools for Treating the Patient in Pain. Available at: http://www.painmed.org/AnnualMeeting/2014-essential-tools/. Accessed 21 January, 2015; Kerns RD et al. Annu Rev Clin Psychol 2011;7:411-34.
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Non-Pharmacological Management of Cancer-related Pain Can improve Pain control Coping Adaptation Self-efficacy Approaches include Cognitive behavioral therapy Mind-body approaches 1. Portenoy RK. Lancet. 2011;377(9784):2236-47.
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NCCN Guideline: Non-pharmacological Treatment of Cancer Pain NCCN = National Comprehensive Cancer Network Benedetti C et al. Oncology (Williston Park, NY). 2000;14(11A):135-50.
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Pharmacologic therapy for cancer-related pain
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Overview of Treatment Principles in the Management of Cancer-related Pain Pain control is an essential part of oncologic management1 A multidisciplinary team may be needed1 Psychosocial support must be available1 Analgesics for cancer pain should be given2 By the mouth By the clock By the ladder For the individual With attention to detail 1. Benedetti C et al. Oncology (Williston Park, NY). 2000;14(11A):135-50; 2. World Health Organization. Cancer Pain Relief: With a Guide to Opioid Availability. World Health Organization; 1996.
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Overview of Treatment Principles for Cancer-related Pain: Breakthrough Pain Give medication for continuous pain on a regular schedule1 Give added doses for breakthrough pain Allow rescue doses of 10-20% of the 24 h oral dose every hour as needed1 Ongoing need for rescue doses may indicate a need to increase regularly scheduled dose Opioids used as rescue medications should have2 Rapid onset of analgesic effect Short duration analgesic effect 1. Benedetti C et al. Oncology (Williston Park, NY). 2000;14(11A):135-50; 2. Ripamonti CI et al. Ann Oncol. 2012;23(suppl 7):vii139-vii154.
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Management of Breakthrough Cancer Pain Offer short-acting drugs as needed during regular opioid treatment1,2 Immediate release opioid Opioid + non-opioid combination product Rapid-onset, transmucosal fentanyl formulation Rapid-onset, transmucosal fentanyl formulations2 Indicated for cancer-related breakthrough pain Allow rapid absorption through mucosa Address mismatch between time course of typical breakthrough pain and slower onset of an oral drug 1. Zeppetella G. Current opinion in supportive and palliative care. 2009;3(1):1-6. 2. Portenoy RK. Lancet. 2011;377:2236-47.
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Bone Pain in Cancer Bone metastases are a frequent complication of cancer Metastatic bone disease is one of the most common causes of cancer pain Some patients have pain in the bones and others have pain due to complications, such as neurological impairment secondary to nerve compression in spine or the base of skull Pain can be unrelated to tumor size TENS = transcutaneous electrical nerve stimulation Buga S, Sarria JE. Cancer Control. 2012;19:154-66; Bonneau A. Can Fam Physician. 2008;54:524-7. 15
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Management of Cancer Bone Pain Non-pharmacological Cutaneous stimulation, TENS, massage therapy, exercise Chiropractic or Osteopathic Manipulation techniques Psychotherapeutic Relaxation techniques, mindfulness-based stress reduction, hypnosis, psychotherapy Pharmacological Calcitonin, bisphosphonates, corticosteroids, cannabinoids, analgesics Radiotherapy and Radionuclides Hormonal Interventional TENS = transcutaneous electrical nerve stimulation Buga S, Sarria JE. Cancer Control. 2012;19:154-66; Bonneau A. Can Fam Physician. 2008;54:524-7.
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Radiotherapy for Bone Pain Relieves pain Prevents impending pathological fractures Promotes healing of pathological fractures Successful in pain relief in 60-70% of patients Takes up to 3 weeks for full effect Single fraction treatments have same response rate as multiple fractions Bonneau A. Can Fam Physician. 2008;54:524-7.
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Medications for Bone Pain: Mechanisms of Action 1. Gralow JR et al. J Natl Compr Canc Netw. 2009;7(Suppl 3):S1-S35; 2. Fleisch H. Endocrine Reviews. 1998;19:80-100; 3. Hanley DA et al. Int J Clin Pract. 2012;66:1139-46.
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Medications for Bone Pain: Adverse Effects 1. Edwards BJ et al. Lancet Oncol. 2008;9(12):1166-1172; 2. Stopeck AT et al. J Clin Oncol. 2010;28(35):5132-9; 3. Perazella MA. Kidney Int. 2008;74(11):1385393; 4. Tanvetyanon T, Stiff PJ. Ann Oncol. 2006;17(6):897-907; 5. Wilkinson GS, et al. J Clin Oncol. 2010;28(33):4898-905; 6. Leibbrandt A, Penninger JM. Ann N Y Acad Sci. 2008;1143:123-50.
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Overview of Medication Classes for Cancer-related Pain
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Nociceptive afferent fiber Descending modulation Ascending input Spinal cord Transduction Transmission Brain Perception How Opioids Affect Pain Modify perception, modulate transmission and affect transduction by: Altering limbic system activity; modify sensory and affective pain aspects Activating descending pathways that modulate transmission in spinal cord Affecting transduction of pain stimuli to nerve impulses Reisine T, Pasternak G. In: Hardman JG et al (eds). Goodman and Gilman’s: The Pharmacological Basics of Therapeutics. 9th ed. McGraw-Hill; New York, NY: 1996; Scholz J, Woolf CJ. Nat Neurosci 2002; 5(Suppl):1062-7; Trescot AM et al. Pain Physician 2008; 11(2 Suppl):S133-53.
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Opioids and Pain Management Gourlay GK. Support Care Cancer 2005; 13(3):153-9; Reisine T et al. In: Hardman JG et al (eds). Goodman and Gilman’s: The Pharmacological Basics of Therapeutics. 9th ed. McGraw-Hill; New York, NY: 1996.; Trescot AM et al. Pain Physician 2008; 11(2 Suppl):S133-53. Gourlay GK. Supp Care Cancer. 2005;13:153-9.
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Opioid stimulation of mu-receptors on “ON” cells Reduced “ON” cell activity Reduced facilitation of pain transmission at dorsal horn Less pain Opioid stimulation of mu-receptors on GABA-ergic interneurons innervating “OFF” cells Reduced GABA-ergic interneuron activity Reduced inhibition of “OFF” cells Increased “OFF” cell inhibition of pain transmission at dorsal horn Less pain GABA = γ-aminobutyric acid Fields HL et al. In: McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006. Opioids Modulate Control of “ON” and “OFF” Cells (-)
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Opioids Can Induce Hyperalgesia Primary hyperalgesia Sensitization of primary neurons  decrease threshold to noxious stimuli within site of injury May include response to innocuous stimuli Increase pain from suprathreshold stimuli Spontaneous pain Secondary hyperalgesia Sensitization of primary neurons in surrounding uninjured areas May involve peripheral and central sensitization Dolan S, Nolan AM. Neuroreport 1999; 10(3):449-52; Raja SN et al. In: Wall PB, Melzack R (eds). Textbook of Pain. 4th ed. Churchhill Livingstone; London, UK: 1999; Woolf CJ. Drugs 1994; 47(Suppl 5):1-9.
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Opioids Can Induce Allodynia Pain evoked by innocuous stimuli Central sensitization  pain produced by A fibers Possibly mediated by spinal NMDA receptors NMDA = N-methyl-D-aspartate Dolan S, Nolan AM. Neuroreport 1999;10:449-52; Raja SN et al. In: Wall PB, Melzack R (eds). Textbook of Pain. 4th ed. Churchhill Livingstone; London, UK: 1999; Woolf CJ. Drugs 1994; 47(Suppl 5):1-9.
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Adverse Effects of Opioids CNS = central nervous system Moreland LW, St Clair EW. Rheum Dis Clin North Am 1999; 25(1):153-91; Yaksh TL, Wallace MS. In: Brunton L et al (eds). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. (online version). McGraw-Hill; New York, NY: 2010.
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What Are NSAIDs (nsNSAIDs/Coxibs)? Analgesic effect via inhibition of prostaglandin production Broad class incorporating many different medications: Coxib = COX-2-specific inhibitor; nsNSAID = non-specific non-steroidal anti-inflammatory drug Brune K. In: Kopf A et al (eds). Guide to Pain Management in Low-Resource Settings. International Association for the Study of Pain; Seattle, WA: 2010. Examples of Coxibs: Celecoxib Etoricoxib Parecoxib Examples of nsNSAIDs: Diclofenac Ibuprofen Naproxen NSAID = Non-Steroidal Anti-Inflammatory Drug
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How Do nsNSAIDs/Coxibs Work? Coxib = COX-2-specific inhibitor; NSAID = non-steroidal anti-inflammatory drug; nsNSAID = non-specific non-steroidal anti-inflammatory drug Gastrosource. Non-steroidal Anti-inflammatory Drug (NSAID)-Associated Upper Gastrointestinal Side-Effects. Available at: http://www.gastrosource.com/11674565?itemId=11674565. Accessed: December 4, 2010; Vane JR, Botting RM. Inflamm Res 1995;44:1-10. COX-1 (constitutive) COX-2 (induced by inflammatory stimuli) Prostaglandins Gastrointestinal cytoprotection, platelet activity Prostaglandins Inflammation, pain, fever nsNSAIDs Coxibs Pain relief BLOCK BLOCK BLOCK Arachidonic acid
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COX-2 Is Expressed in the CNS PGs in the CNS are important in central sensitization and hyperalgesia1 Peripheral inflammation  central induction of COX-2 Occurs even with complete sensory nerve block3 Humoral signal (IL-6?) may play a role in signal transduction across blood-brain barrier3 IL-1beta plays an important role centrally3 Elevation of PGs in CSF lead to hyperalgesia3 Inhibition of IL-1beta synthesis or receptors reduce CSF levels of COX-2, PGs and hyperalgesia3 Central inhibition of COX-2 has similar effects3,4 CNS = central nervous system; CSF = cerebrospinal fluid; IL = interleukin; {G = prostaglandin 1. Taiwo YO, Levine JD. Brain Res 1986;373(1-2):81-4; 2. Ghilardi JR et al. J Neurosci 2004;24:2727-32; 3. Samad TA et al. Nature 2001;410(6827):471-5; 4. Smith CJ et al. Proc Natl Acad Sci US 1998;95(22):13313-8.
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COX-2 Results in Sensitization to Pain Peripheral Sensitization COX-2 is expressed following tissue injury PGs produced increase nociceptor sensitivity to pain Central Sensitization Peripheral inflammation induction of COX-2 in CNS Occurs even with complete sensory nerve block, possibly due to a humoral signal PGs produced by COX-2 in CNS further sensitization to pain Result: hyperalgesia and allodynia CNS = central nervous system; PG = prostaglandin Ahmadi S et al. Nat Neurosci 2002;5:34-40; Baba H et al. J Neurosci 2001;21:1750-6; Samad TA et al. Nature 2001;410:471-5; Woolf CJ, Salter MW. Science 2000;288:1765-9.
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COX-2 Is Involved in Central Sensitization Central induction of COX-2 increased PG production PGE2 stimulation of EP receptors in dorsal horn will: Activate PKC phosphorylation and further enhancement of NMDA channel opening Directly activate certain dorsal horn neurons by opening EP2 receptor-linked ion channels Reduce inhibitory transmission of glycinergic inter-neurons Increase depolarization and excitability of dorsal horn neurons EP = E-prostanoid; NMDA = N-methyl-D-aspartate; PG = prostaglandin; PGE2 = prostaglandin E2; PKC = protein kinase C Ahmadi S et al. Nat Neurosci 2002;5:34-40; Baba H et al. J Neurosci 2001;21:1750-6; Samad TA et al. Nature 2001;410:471-5; Woolf CJ, Salter MW. Science 2000;288:1765-9.
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COX-2 Inhibition Minimizes Sensitization Signal for COX-2 induction likely to persist with peripheral inflammation To minimize sensitization, COX-2 should be inhibited both centrally and in the periphery as early as possible Continue until peripheral inflammation resolved Samad TA et al. Nature 2001;410:471-5; Woolf CJ, Salter MW. Science 2000;288:1765-9. Ideal COX-2 inhibitor should be able to act peripherally as well as centrally and should readily cross the blood-brain barrier
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Adverse Effects of NSAIDs/Coxibs All NSAIDs Gastroenteropathy (e.g., gastritis, bleeding, ulceration, perforation) Cardiovascular thrombotic events Renovascular effects Decreased renal blood flow Fluid retention/edema Hypertension Hypersensitivity Cox-1-mediated NSAIDs (nsNSAIDs) Decreased platelet aggregation Coxib = COX-2-specific inhibitor; NSAID = non-steroidal anti-inflammatory drug; NSAID = non-specific non-steroidal anti-inflammatory drug Clemett D, Goa KL. Drugs 2000;59:957-80; Grosser T et al. In: Brunton L et al (eds.). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. (online version). McGraw-Hill; New York, NY: 2010.
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*7-10 days Coxib = COX-2-specific inhibitor; CV = cardiovascular; nsNSAID = non-specific non-steroidal anti-inflammatory drug Schjerning Olsen AM et al. Circulation 2011;123:2226-35. Risk of Death/Myocardial Infarction within First 7 Days of nsNSAID/Coxib Treatment in Patients with Previous Death/Myocardial Infarction CV Risk of nsNSAIDs/Coxibs in Acute Pain*
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3.8 Gastrointestinal Risk of nsNSAIDs/Coxibs Pooled Relative Risks and 95% CIs of Upper Gastrointestinal Complications CI = confidence interval; Coxib = COX-2 inhibitor; NSAID = non-steroidal anti-inflammatory drug; nsNSAID = non-specific non-steroidal anti-inflammatory drug Castellsague J et al. Drug Saf 2012;35:1127-46. 100 10 1 0.1 Pooled Relative Risk (Log Scale) 1.4 1.5 1.8 2.3 2.9 3.3 3.5 3.9 4.1 4.1 4.1 4.4 7.4 11.5 18.5 Aceclofenac Celecoxib Ibuprofen Rofecoxib Sulindac Diclofenac Meloxicam Nimesulide Ketoprofen Tenoxicam Naproxen Indomethacin Diflunisal Piroxicam Ketorolac Azapropazone NSAID
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Risk Factors for Gastrointestinal Complications Associated with nsNSAIDs/Coxibs Odds ratio/relative risk for ulcer complications ASA = acetylsalicylic acid; coxib = COX-2-specific inhibitor; GI = gastrointestinal; NSAID = non-steroidal anti-inflammatory drug; nsNSAID = non-specific non-steroidal anti-inflammatory drug; SSRI = selective serotonin reuptake inhibitor 1. Garcia Rodriguez LA, Jick H. Lancet 1994;343:769-72; 2. Gabriel SE et al. Ann Intern Med 1991;115:787-96; 3. Bardou M. Barkun AN. Joint Bone Spine 2010;77:6-12; 4. Garcia Rodríguez LA, Hernández-Díaz S. Arthritis Res 2001;3:98-101. 1 1 1 1 1 2 3 3 3 4
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0 4 8 12 During week 1 (53 cases, 22 controls) After week 1 until discontinuation (353 cases, 268 controls) First week after discontinuation (52 cases, 59 controls) *7-10 days CI = confidence interval; coxib = COX-2-specific inhibitor; GI = gastrointestinal; nsNSAID = non-specific non-steroidal anti-inflammatory drug Lewis SC et al. Br J Clin Pharmacol 2002;54:320-6. Odds Ratio for GI Bleeding 5.6 (95% CI 4.6-7.0) 11.7 (95% CI 6.5-21.0) 3.2 (95% CI 2.1-5.1) GI Risk of nsNSAIDs/Coxibs in Acute Pain*
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p = NS Platelet Function Analyzer 100 Closure Time (seconds) 550 mg 400 mg 200 mg ASA = acetyl salicylic acid; coxib = COX-2-inhibitor; NSAID = non-steroidal anti-inflammatory drug; nsNSAID = non-specific non-steroidal anti-inflammatory drug Gladding PA et al. Am J Cardiol 2008;101:1060-3. p <0.0001 p = 0.001 p = 0.04 Effects of nsNSAIDs/Coxibs + ASA on Platelet Function n=24 healthy subjects
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Guidelines for ASA + NSAID Use Individuals taking low-dose ASA (75–162 mg/day) for vascular protection should avoid the concomitant use of nsNSAIDs If a patient taking low-dose ASA for vascular protection requires an anti-inflammatory drug, coxibs are preferred to nsNSAIDs ASA = acetyl salicylic acid; coxib = COX-2-inhibitor; NSAID = non-steroidal anti-inflammatory drug; nsNSAID = non-specific non-steroidal anti-inflammatory drug Bell AD et al. Can J Cardiol 2011;123(20 Suppl A):S1-59. Both coxibs and nsNSAIDs increase cardiovascular risk and should be avoided if possible in patients at risk of ischemic vascular events
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Canadian Consensus on Prescribing NSAIDs *In high-risk patients, a coxib and an nsNSAID + PPI show similar reductions of rebleeding rates, but these reductions may be incomplete †Most patients on ASA + naproxen would need an added PPI, but naproxen alone may be appropriate for some patients at very low gastrointestinal risk ASA = acetylsalicylic acid; coxib = COX-2-specific inhibitor; NSAID = non-steroidal anti-inflammatory drug; nsNSAID = non-specific NSAID; PPI = proton pump inhibitor Rostom A et al. Aliment Pharmacol Ther 2009;29:481-96. Patient requires NSAID Low gastrointestinal risk High cardiovascular risk (on ASA) Low cardiovascular risk Avoid NSAID if possible Cannot avoid NSAID Coxib alone or nsNSAID + PPI* Naproxen + PPI† nsNSAID Primary concern = very high cardiovascular risk: naproxen + PPI Primary concern = very high gastrointestinal risk: coxib + PPI Low gastrointestinal risk High cardiovascular risk (on ASA) Low cardiovascular risk
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Guidelines for nsNSAIDs/Coxibs Use Based on Gastrointestinal Risk and ASA Use ASA = acetylsalicylic acid; coxib = COX-2-specific inhibitor; nsNSAID = non-selective non-steroidal anti-inflammatory drug; PPI = proton pump inhibitor Tannenbaum H et al. J Rheumatol 2006;33:140-57.
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Note: gabapentin and pregabalin are α2δ ligands Bauer CS et al. J Neurosci 2009;29:4076-88. Role of a2d-Linked Calcium Channels in Neuropathic Pain
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2 Ligands Bind to 2 Subunit of Voltage-Gated Calcium Channels Note: gabapentin and pregabalin are α2δ ligands Arikkath J, Campbell KP. Curr Opin Neurobio 2003;13:298-307; Catterall WA. J Bioenerg Biomembr 1996;28:219-30; Gee NS et al. Biol Chem 1996;271:5768-76..
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2 Ligands Reduce Calcium Influx in Depolarized Human Neocortex Synaptosomes * * * * *p <0.05 vs. vehicle Vehicle Concentration (μM) 100 1,000 50 60 70 80 90 100 110 Ca2+ Fluorescence (% of control) 10 Fink K et al. Neuropharmacology 2002;42:229-36.
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2 Ligands Modulate Calcium Channel Trafficking Hendrich et al. 2008 Bauer et al., 2009 10 mg/kg 2 ligand Vehicle **p <0.001 ***p <0.01 ** *** % Increase in α2δ-1 100 80 60 40 20 0 L4 L5 L6 2 ligands reduce trafficking of voltage-gated calcium channel complexes to cell surface in vitro 2 ligands prevent nerve-injury induced up-regulation of a2d in the dorsal horny BCH = 2-(−)-endoamino-bicycloheptene-2-carboxylic acid; ER = endoplasmic reticulum; GBP = gabapentin Bauer CS et al. Neurosci 2009;29:4076-88; Hendrich J et al. Proc Natl Acad Sci U S A 2008;105:3628-33. Region
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Adverse Effects of a2d Ligands α2δ ligands include gabapentin and pregabalin CNS = central nervous system Attal N, Finnerup NB. Pain Clinical Updates 2010;18:1-8.
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Antidepressants for Cancer Pain Antidepressants Can be used to treat pain in opioid-treated populations with advanced medical illness Predominantly used for neuropathic pain May also be considered for other types of chronic pain Verdu B et al. Drugs. 2008;68:2611-32; Collins Sl et al. J Pain Symptom Manage. 2000;20:449-58; Saarto T et al. Cochrane Database Syst Rev. 2007;:CD005454.
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How Antidepressants Modulate Pain Nerve lesion Spinal cord Nociceptive afferent fiber Verdu B et al. Drugs 2008; 68(18):2611-2632. Descending modulation Ascending input Ectopic discharge Transmission Perception Glial cell activation Inhibiting reuptake of serotonin and norepinephrine enhances descending modulation Brain
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Suggested Mechanisms of Analgesic Action of Antidepressants GABA = γ-aminobutyric acid; NDMA = N-methyl-D-aspartate; PGE = prostaglandin E; SNRI = serotonin-norepinephrine reuptake inhibitor; TCA = tricyclic antidepressant; TNF = tumor necrosis factor Verdu B et al. Drugs 2008;68:2611-32.
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Adverse Effects of Antidepressants CNS = central nervous system; TCA = tricyclic antidepressant; SNRI = serotonin-norepinephrine reuptake inhibitor Attal N, Finnerup NB. Pain Clinical Updates 2010;18:1-8.
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Acetaminophen Action at molecular level is unclear Potential mechanisms: Inhibition of COX enzymes (COX-2 and/or COX-3) Interaction with opioid pathway Activation of serotoninergic bulbospinal pathway Involvement of nitric oxide pathway Increase in cannabinoid-vanilloid tone COX = cyclooxygenase Mattia A, Coluzzi F. Minerva Anestesiol 2009;75:644-53.
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Invasive Modalities for Cancer Pain Management May provide pain relief to patients who do not respond adequately to traditional analgesic therapies Use of neurolytic substances has found a niche in treating pain related to abdominal and pelvic cancers Simple percutaneous injections of alcohol or phenol can provide relief in pancreatic, colon, or gynecologic cancer Percutaneous catheters for infusion of spinal analgesics can provide relief anywhere in the body Internal or external infusion pumps can be managed at home Sloan PA. J Support Oncol. 2004;2:491-500, 503.
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Invasive Modalities for Cancer Pain Management Sloan PA. J Support Oncol. 2004;2:491-500, 503. Neurolytic blocks Spinal analgesics Regional local anesthetic infusions Other techniques Spinal cord stimulation Vertebroplasty Lumbar epidural steroid Intracerebroventricular opioids Human chromaffin cell transplants
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Invasive Therapies for Cancer-related Pain: Neurolytic Therapies Neurolytic techniques produce analgesia by destroying Afferent neural pathways or Sympathetic structures involved in pain transmission Achieving neural destruction Surgery Cold (cryotherapy) Heat (radiofrequency thermal coagulation) Injection of a material that damages the nerve Rowe DS. Pain Clin. 1995;8:107-15. Neurolytic techniques may produce deafferentiation pain
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Invasive Therapies for Cancer-related Pain: Injection Therapies Soft tissue or joint injection of a dilute local anesthetic Can reduce focal musculoskeletal pain Should not be used in the presence of clinically significant coagulopathy or leukopenia Sist T et al. J Pain Symptom Manage. 1999;18:95-102.
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Invasive Therapies for Cancer-related Pain: Neurolytic Therapies Implanted catheters can be used for Prolonged perineural or neuraxial infusion of analgesics Electrical stimulation of peripheral nerves or spinal cord Both procedures avoid or limit side effects associated with systemic pharmacotherapy Disadvantages Cost Risk of infection Mechanical failure Landau B, Levy RM. Annu Rev Med. 1993;44:279-87; Smith TJ et al. J Clin Oncol. 2002;20:4040-9.
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Co-Analgesics and Cancer Pain Drugs with a primary indication other than pain that have analgesic properties in some painful conditions Usually combined with a less than satisfactory opioid regimen in cancer pain Different types Multipurpose Neuropathic pain Bone pain Musculoskeletal pain Bowel obstruction pain Lussier D et al. Oncologist. 2004;9:571-91.
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Types of Co-Analgesics for Management of Cancer Pain Lussier D et al. Oncologist. 2004;9:571-91.
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Summary: Co-Analgesics and Cancer Pain Lussier D et al. Oncologist. 2004;9:571-91. Consider optimizing opioid therapy before adding co-analgesic Consider burdens and potential benefits vs. other analgesic techniques Select most appropriate drug based on comprehensive patient assessment Prescribe based on knowledge of drug’s pharmacological characteristics, actions, approved indications, unapproved indications, likely side effects, potential serious adverse events, and drug-drug interactions Use the co-analgesic with the best risk:benefit ratio Avoid initiating several co-analgesics simultaneously Initiate treatment with low doses; titrate according to analgesic response and adverse effects Reassess efficacy and tolerability regularly Taper/discontinue medications if no additional pain relief Consider combining multiple co-analgesics in selected patients
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Drug Availability and Adherence
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Prevalence of Non-adherence to Cancer Pain Therapy Miaskowski C et al. J Clin Oncol. 2001;19(23):4275-9.
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Barriers to Optimal Management of Cancer Pain Institutional Regulations regarding supply, prescription, and administration of opioids Healthcare professionals (HCPs) Lack of knowledge in key areas of pain management Lack of continuity of care among different HCPs Patients and their family/caregivers Beliefs and perceptions about pain and pain medications Jacobsen R et al. Scand J Caring Sci. 2009;231:190-208.
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Patient Barriers to Adherence to Cancer Pain Therapy Fear of addiction Fear of tolerance Concern analgesics side effects are inevitable and unmanageable Fear of injections Fatalistic belief about cancer pain or belief that it is impossible to control Belief that “good” patients do not complain about pain Belief that healthcare professionals find it annoying to talk about pain and that this talk distracts from treating the cancer Jacobsen R et al. Scand J Caring Sci. 2009;231:190-208. Patients believe there is a trade-off between treating the pain and treating the cancer
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Healthcare Provider Barriers to Effective Management of Cancer Pain Insufficient knowledge of pain management Insufficient assessment of pain Unwillingness to prescribe opioids Nurses unwilling to give opioids to patients Insufficient time to pay attention to patients’ pain needs Patients unwilling to report pain Patients refuse to take opioids Families unwilling to permit patients to take opioids Patients unable to pay for medications Nimmaanrat S et al. Palliative Care: Research and Treatment. 2010;4:11-7.
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Guidelines
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WHO Pain Ladder for the Management of Cancer Pain World Health Organization. WHO's cancer pain ladder for adults. Available at: http://www.who.int/cancer/palliative/painladder/en/. Accessed 22 January 2015.
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NCCN Guidelines for Management of Cancer Pain in Opioid-Naïve Patients* Ongoing care Ongoing care * NCCN = National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Adult Cancer Pain. 2014
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NCCN Guidelines for Management of Cancer Pain in Opioid-Tolerant Patients NCCN = National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Adult Cancer Pain. 2014
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NCCN Guidelines for Subsequent Pain Management in Patients with Cancer* NCCN = National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Adult Cancer Pain. 2014 Ongoing care
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ESMO Clinical Practice Guidelines for Management of Cancer Pain ESMO = European Society For Medical Oncology Ripamonti CI et al. Ann Oncol. 2012;23 Suppl 7:vii139-54.
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EAPC Guidelines for the Use of Opioids for Cancer Pain EAPC = European Association for Palliative Care; NSAID = non-steroidal anti-inflammatory drug; WHO = World Health Organization Caraceni A et al. Lancet Oncol. 2012;13:e58-68. For patients with mild to moderate pain or whose pain is not controlled by paracetamol or an NSAID, addition of a WHO step 2 opioid given orally may provide good pain relief Alternatively, low doses of a step 3 opioid may be used There are no important differences between step 3 opioids given orally; any one may be used as the first choice for moderate to severe cancer pain Weak recommendation that immediate-release and slow-release oral formulations of morphine, oxycodone, and hydromorphone can be used for dose titration Transdermal fentanyl and buprenorphine are alternatives to oral opioids
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EAPC Guidelines for the Use of Opioids for Cancer Pain Weak recommendation that methadone can be used as a step 3 opioid for moderate to severe cancer pain Weak recommendation that patients not achieving adequate pain relief on a step 3 opioid may benefit from switching to an alternative opioid Strong recommendation that breakthrough pain should be treated with additional doses of immediate-release oral opioids Appropriate titration of around-the-clock therapy should always precede the recourse to potent rescue opioid medications Weak recommendation to add NSAIDs to step 3 opioids to improve analgesia or reduce opioid dose required for pain relief Use of NSAIDs should be restricted due risks of serious adverse events Strong recommendation that amitriptyline or gabapentin should be considered for patients with neuropathic cancer pain that is only partially responsive to opioids EAPC = European Association for Palliative Care; NSAID = non-steroidal anti-inflammatory drug Caraceni A et al. Lancet Oncol. 2012;13:e58-68.
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