Frequently asked questions

Frequently Asked Questions: Table of Contents What clinical clues help distinguish between nociceptive and neuropathic pain? Can I combine treatments? Why should the treatment of chronic pain be multimodal? What is the gastrointestinal risk with nsNSAIDs/coxibs? What is the cardiovascular risk with nsNSAIDs/coxibs? Do nsNSAIDs/coxibs interfere with bone healing? What is the risk of addiction with opioids? What are the side effects to be expected with opioids? Why should antidepressants be used to treat pain? When should I refer patients to a specialist or pain clinic? Speaker’s Notes This slide lists some frequently asked questions about pain in general. Answers to these questions can be found on the following slides. Coxib = COX-2 inhibitor; nsNSAID = non-specific non-steroidal anti-inflammatory drug

What clinical clues help distinguish between nociceptive and neuropathic pain? Usually aching or throbbing and well-localized Usually time-limited (resolves when damaged tissue heals), but can be chronic Generally responds to conventional analgesics Pain often described as tingling, shock-like, and burning – commonly associated with numbness Almost always a chronic condition Responds poorly to conventional analgesics Speaker’s Notes With nociceptive pain, the painful region is typically localized to the site of injury and the pain is often described as throbbing, aching or pressure-like. Nociceptive pain is usually time limited and resolves when the damaged tissue heals (e.g., bone fractures, burns, and bruises). Although nociceptive pain is generally self-limiting, it can be chronic, as in osteoarthritis. Treatment with conventional analgesics is usually appropriate. Neuropathic pain is frequently described as a ‘shooting’, ‘electric shock-like’ or burning’ pain, commonly associated with ‘tingling’ and/or ‘numbness’. The painful region may not necessarily be the same as the site of injury. Pain occurs in the neurological territory of the affected structure (nerve, root, spinal cord, brain). In peripheral neuropathic pain, it is in the territory of the affected nerve or nerve root. In central neuropathic pain, it is related to the site of the lesion in the spinal cord or brain. Neuropathic pain is almost always a chronic condition and responds poorly to conventional analgesics. References Dray A. Neuropathic pain: emerging treatments. Br J Anaesth 2008; 101(1):48-58. Felson DT. Developments in the clinical understanding of osteoarthritis. Arthritis Res Ther 2009; 11(1):203. International Association for the Study of Pain. IASP Taxonomy. Available at: http://www.iasp- pain.org/AM/Template.cfm?Section=Pain_Definitions. Accessed: July 15, 2013. McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain 2011; 152(3 Suppl):S2-15. Dray A. Br J Anaesth 2008; 101(1):48-58; Felson DT. Arthritis Res Ther 2009; 11(1):203; International Association for the Study of Pain. IASP Taxonomy. Available at: http://www.iasp-pain.org/AM/Template.cfm?Section=Pain_Definitions. Accessed: July 15, 2013; McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006; Woolf CJ. Pain 2011; 152(3 Suppl):S2-15.

Common Descriptors of Neuropathic Pain Burning Tingling Pins and needles Electric shock-like Numbness Speaker’s Notes Verbal descriptors of pain can be important clues to the pathophysiologic mechanism behind the pain. For instance, with neuropathic pain, the pain is often described as burning, tingling or electric shock-like. Sensations of pins and needles or numbness are also frequently mentioned in conjunction with neuropathic pain conditions. References Baron R et al. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol 2010; 9(8):807-19. Gilron I et al. Neuropathic pain: a practical guide for the clinician. CMAJ 2006; 175(3):265-75. Baron R et al. Lancet Neurol 2010; 9(8):807-19; Gilron I et al. CMAJ 2006; 175(3):265-75.

Can I combine treatments? Lifestyle management Sleep hygiene Stress management Interventional pain management Not all pain therapies are pharmacological Physical therapy Pharmacotherapy Speaker’s Notes The 2011 Institute of Medicine (IOM) pain report suggested that a mind-body approach should be used when caring for patients with pain. The biopsychosocial approach, combining physical and emotional factors in assessing and treating chronic pain, offers a uniquely valuable clinical perspective. This mind-body perspective is now generally accepted by pain researchers and has been found useful by clinicians in various disciplines. This animated slide lists components that might be included in such a multimodal approach to pain therapy. References Gatchel RJ et al. The biopsychosocial approach to chronic pain: scientific advances and future directions. Psychol Bull 2007; 133(4):581-624. Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research.; National Academies Press; Washington, DC: 2011. Mayo Foundation for Medical Education and Research. Comprehensive Pain Rehabilitation Center Program Guide. Mayo Clinic; Rochester, MN: 2006. Occupational therapy Education Complementary therapies Biofeedback Gatchel RJ et al. Psychol Bull 2007; 133(4):581-624; Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research.; National Academies Press; Washington, DC: 2011; Mayo Foundation for Medical Education and Research. Comprehensive Pain Rehabilitation Center Program Guide. Mayo Clinic; Rochester, MN: 2006.

Why should the treatment of chronic pain be multimodal? Improved analgesia  doses of each analgesic  severity of side effects of each drug Opioid Potentiation Acetaminophen nsNSAIDs/coxibs α2δ ligands Ketamine Clonidine Nerve blocks Speaker’s Notes Optimal pain management that allows a patient to lead a normal life is unlikely to be achieved with a single analgesic. The concept of multimodal or balanced management pivots around the notion that by combining analgesics that work on distinct parts of the pain transmission circuit, pain management can be improved with lower doses of the individual analgesic and accordingly yield less side effects. Reference Kehlet H, Dahl JB. The value of "multimodal" or "balanced analgesia" in postoperative pain treatment. Anesth Analg 1993; 77(5):1048-56. Coxib = COX-2 inhibitor; nsNSAID = non-specific non-steroidal anti-inflammatory drug Kehlet H, Dahl JB. Anesth Analg 1993; 77(5):1048-56.

But… Patients with Chronic Pain of Just One Type of Pain Pathophysiology May be Rare Patients may have different pathophysiologic mechanisms contributing to their pain e.g., complex regional pain syndrome has multiple potential mechanisms, including nerve injury and inflammation – “mixed pain state” Therapies that will work better for a particular patient are likely to depend on the mechanisms contributing to the patient’s pain Speaker’s Notes Within any diagnostic category, individual patients may have different pathophysiologic mechanisms contributing to their pain. Both the drug and non-drug therapies that will work better for a particular patient are likely to depend on the mechanisms contributing to the patient’s pain. Thus, the assessment of pain has to include the determination of the type(s) of pain pathophysiology contributing to the patient’s pain. References Dowd GS et al. Complex regional pain syndrome with special emphasis on the knee. J Bone Joint Surg Br. 2007; 89(3):285-90. Vellucci R. Heterogeneity of chronic pain. Clin Drug Investig. 2012; 32(Suppl 1):3-10. Patients with mixed pain may benefit from combination therapy Dowd GS et al. J Bone Joint Surg Br 2007; 89(3):285-90; Vellucci R. Clin Drug Investig 2012; 32(Suppl 1):3-10.

What is the gastrointestinal risk with nsNSAIDs/coxibs? Pooled Relative Risks and 95% CIs of Upper Gastrointestinal Complications 100 18.5 11.5 REDO 10 7.4 3.9 4.1 4.1 4.1 4.4 Pooled relative risk log scale 3.3 3.5 3.8 2.9 2.3 1.8 1.4 1.5 1 Speaker's Notes The systematic review and meta-analysis included 28 observational studies to surmise relative risks (RR) of upper gastrointestinal complications associated with the use of 16 different NSAIDs. Using random-effects models, pooled RRs ranged from 1.43 (95% CI 0.65–3.15) for aceclofenac to 18.45 (95% CI 10.99–30.97) for azapropazone. Pooled RR was less than 2 for aceclofenac, celecoxib and ibuprofen; between 2 and less than 4 for rofecoxib, sulindac, diclofenac, meloxicam, nimesulide and ketoprofen; between 4 and less than 5 for tenoxicam, naproxen, indometacin and diflunisal; and greater than 5 for piroxicam, ketorolac and azapropazone. This analysis confirmed the variability in the risk of upper gastrointestinal complications among individual NSAIDs as used in clinical practice. Reference Castellsague J et al. Safety of Non-Steroidal Anti-Inflammatory Drugs (SOS) Project. Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS project). Drug Saf 2012; 35(12):1127-46. 0.1 Aceclofenac Celecoxib Ibuprofen Rofecoxib Sulindac Diclofenac Meloxicam Nimesulide Ketoprofen Tenoxicam Naproxen Indometacin Diflunisal Piroxicam Ketorolac Azapropazone NSAIDs 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(12):1127-46.

Odds ratio/relative risk for ulcer complications Risk Factors for Gastrointestinal Complications Associated with nsNSAIDs/Coxibs 1 1 1 2 1 3 4 3 1 Speaker’s Notes Most anti-inflammatory drugs have been associated with gastrointestinal side effects. Gastrointestinal mucosa damage can range from endoscopic lesions with no clinical manifestations to serious upper gastrointestinal complications that, in some instances, may be fatal. This graph provides the relative risk of a variety of factors for gastrointestinal complications associated with nsNSAIDs/coxibs. Previous upper gastrointestinal bleeding s the single most important predictor of future upper gastrointestinal bleeding. References Bardou M, Barkun AN. Preventing the gastrointestinal adverse effects of nonsteroidal anti-inflammatory drugs: from risk factor identification to risk factor intervention. Joint Bone Spine 2010; 77(1):6-12. Gabriel SE et al. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis. Ann Intern Med 1991; 115(10):787-96. García Rodríguez LA, Hernández-Díaz S. The risk of upper gastrointestinal complications associated with nonsteroidal anti-inflammatory drugs, glucocorticoids, acetaminophen, and combinations of these agents. Arthritis Res 2001; 3(2):98-101. García Rodríguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994; 343(8900):769-72. 3 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(8900):769-72; 2. Gabriel SE et al. Ann Intern Med 1991; 115(10):787-96; 3. Bardou M. Barkun AN. Joint Bone Spine 2010; 77(1):6-12; 4. Garcia Rodríguez LA, Hernández-Díaz S. Arthritis Res 2001; 3(2):98-101.

Gastrointestinal risk Guidelines for nsNSAIDs/Coxibs Use Based on Gastrointestinal Risk and ASA Use Gastrointestinal risk Not elevated Elevated Not on ASA nsNSAID alone Coxib nsNSAID + PPI On ASA Coxib + PPI Speaker’s Notes In 2006, the Third Canadian Consensus Conference recommended that all patients on ASA who are prescribed either a coxib or a nsNSAID should also receive a PPI, regardless of their level of gastrointestinal risk. While this recommendation proved to be controversial, the rationale was that ASA is prescribed to patients with comorbidities that are themselves gastrointestinal risk factors. Of note, some patients may take ASA because they believe it to be beneficial without necessarily having any comorbidities. Reference Tannenbaum H et al. An evidence-based approach to prescribing nonsteroidal antiinflammatory drugs. Third Canadian Consensus Conference. J Rheumatol 2006; 33(1):140-57. 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(1):140-57.

What is the cardiovascular risk with nsNSAIDs/coxibs? Speaker’s Notes The objective of this study was to analyse available evidence on the cardiovascular safety of nsNSAIDs and coxibs. Data were extracted from all large scale randomized controlled trials comparing any non-steroidal anti-inflammatory drug (NSAID) with other NSAIDs or placebo. The primary outcome was myocardial infarction. Secondary outcomes included stroke, death from cardiovascular disease, and death from any cause. The composite endpoint was non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death compared with placebo. The analysis included data from 31 trials (n = 116,429 patients) with >115,000 patient-years. Patients were allocated to naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, lumiracoxib or placebo. All drugs seemed to be associated with increased risks of the composite endpoint. All NSAIDs except naproxen had an estimated rate ratio greater than 1.3, which is the generally accepted indicator of clinically relevant increase in risk. The authors concluded that although uncertainty remains, little evidence exists to suggest that any of the investigated drugs are safe in cardiovascular terms. Naproxen seemed least harmful. Cardiovascular risk needs to be taken into account when prescribing any NSAID. Reference Trelle S et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 2011; 342:c7086. Composite includes non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death compared with placebo; chart based on network meta-analysis involving 30 trials and over 100,000 patients. Coxib = COX-2 inhibitor; nsNSAID = non-specific non-steroidal anti-inflammatory drug Trelle S et al. BMJ 2011; 342:c7086.

Do nsNSAIDs/coxibs interfere with bone healing? Some animal and in vitro studies suggest nsNSAIDs may delay bone healing, though results are contradictory However, clinical experience and most in vivo studies do not substantiate this Balance of evidence suggests short-duration nsNSAID/coxib use is safe and effective for post-fracture pain control Speaker’s Notes The available literature indicates that prostaglandins have fundamental roles in multiple steps along the fracture-healing and remodeling cascade. It is also well acknowledged that non-steroidal anti-inflammatory drugs (NSAIDs), through their actions on the prostaglandin network, can effectively manage acute pain and reduce regional swelling with less side effects compared to opioids. Many clinicians have however begun steering away from using NSAIDs to manage post-fracture pain. While not all in accord, the collective evidence from in vitro and predominantly rodent-based studies evidence demonstrates a strong trend towards NSAIDs significantly retarding the intrinsic fracture-healing process and suppressing reparative biomechanical remodelling and union. Although one clinical study has shown that short-term perioperative administration of celecoxib, rofecoxib, or low-dose ketorolac had no significant deleterious effect on non-union, there are no data from large, prospective randomized studies exploring the effect of NSAID use on fracture repair. In the absence of solid and convincing parallel clinical evidence, it remains controversial as to whether the pre-clinical data reported can reliably or should be extrapolated to the human condition considering the differing physiology, treatment compliance and comorbidity load. Accordingly, despite the theoretical concerns, the available evidence contends that short-term use of NSAIDs is safe for post-fracture pain control. However, there is still no clear consensus with regards to the “true” safe interval and duration during which such therapy can be confidently applied. Furthermore, there is no clear data concerning long-duration NSAID use. References Kurmis AP et al. The effect of nonsteroidal anti-inflammatory drug administration on acute phase fracture-healing: a review. J Bone Joint Surg Am 2012; 94(9):815-23. Pountos I et al. Do nonsteroidal anti-inflammatory drugs affect bone healing? A critical analysis. ScientificWorldJournal 2012; 2012:606404. Coxib = COX-2 inhibitor; nsNSAID = non-specific non-steroidal anti-inflammatory drug Kurmis AP et al. J Bone Joint Surg Am 2012; 94(9):815-23; Pountos I et al. ScientificWorldJournal 2012; 2012:606404.

What is the risk of addiction with opioids? One review of 24 studies (involving 2507 chronic pain patients) indicated there is a 3.3% risk of developing addiction to prescription opioids Speaker’s Notes Sixty-seven studies were reviewed to address the development of abuse/addiction and aberrant drug-related behaviors in chronic pain patients with non-malignant pain on exposure to chronic opioid analgesic therapy. Within these 67 studies, 24 were classified under the abuse/addiction heading and comprised 2507 chronic pain patients with a calculated abuse/addiction rate of 3.27%. Further analysis of this sub-group revealed that the percentage of abuse/addiction was 0.19% when only patients with for no history of abuse/addiction were included. In conclusion, chronic opioid analgesic therapy exposure will lead to abuse/addiction in a very small percentage of patients and this percentage can be dramatically decreased by preselecting chronic pain patients with no history of drug/alcohol abuse/addiction. Reference Fishbain DA et al. What percentage of chronic nonmalignant pain patients exposed to chronic opioid analgesic therapy develop abuse/addiction and/or aberrant drug-related behaviors? A structured evidence-based review. Pain Med 2008; 9(4):444-59. Fishbain DA et al. Pain Med 2008; 9(4):444-59.

What are the side effects to be expected with opioids? System Adverse effects Gastrointestinal Nausea, vomiting, constipation CNS Cognitive impairment, sedation, lightheadedness, dizziness Respiratory Respiratory depression Cardiovascular Orthostatic hypotension, fainting Other Urticaria, miosis, sweating, urinary retention Speaker’s Notes The use of opioids in pain management can be associated with a variety of adverse effects, as shown on this slide. Gastrointestinal side effects can include nausea, vomiting and constipation, while central nervous system effects may include cognitive impairment, sedation, lightheadedness, and dizziness. Respiratory depression, orthostatic hypotension, fainting, urticaria, miosis, sweating and urinary retention are among the other potential adverse effects of opioids. References Moreland LW, St Clair EW. The use of analgesics in the management of pain in rheumatic diseases. 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. 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.

Why should antidepressants be used to treat pain? Brain Inhibiting reuptake of serotonin and norepinephrine enhances descending modulation Perception Ascending input Descending modulation Ectopic discharge Nerve lesion Speaker’s Notes The main analgesic effect of antidepressants is thought to occur by increasing the amounts of serotonin and noradrenaline available in the synaptic clefts at the spinal and supraspinal levels, and thereby enhancing the inhibitory effects of the descending modulatory pathways. It is interesting to note that at therapeutic concentrations, antidepressants have very little analgesic effect on nociception, suggesting they may help “normalize” the function of an altered pain system rather than inhibiting pain transmission. Reference Verdu B et al. Antidepressants for the treatment of chronic pain. Drugs 2008; 68(18):2611-2632. Transmission Glial cell activation Nociceptive afferent fiber Spinal cord Verdu B et al. Drugs 2008; 68(18):2611-2632.

When should I refer patients to a specialist or pain clinic? Evaluate for patients presenting with pain the presence of red flags! Speaker’s Notes It is also important to screen patients presenting with pain for red flags indicative of a serious underlying condition. Depending on the condition suspected, clinicians should then initiate appropriate investigations or refer the patient to a specialist. Reference Littlejohn GO. Musculoskeletal pain. J R Coll Physicians Edinb 2005; 35(4):340-4. Initiate appropriate investigations/ management or refer to specialist Littlejohn GO. J R Coll Physicians Edinb 2005; 35(4):340-4.

Look for Red Flags for Musculoskeletal Pain Older age with new symptom onset Night pain Fever Sweating Neurological features Previous history of malignancy Speaker’s Notes It is also important to screen patients presenting with pain for red flags indicative of a serious underlying condition. Depending on the condition suspected, clinicians should then initiate appropriate investigations or refer the patient to a specialist. Reference Littlejohn GO. Musculoskeletal pain. J R Coll Physicians Edinb 2005; 35(4):340-4. Littlejohn GO. R Coll Physicians Edinb 2005; 35(4):340-4.

Clinical Approach to Suspected Neuropathic Pain Are verbal descriptors and history suggestive of neuropathic pain?1 Whenever possible, treat the underlying cause/disease Yes No Can you detect sensory abnormalities using simple bedside tests?1,2 Yes No Can you identify the responsible somatosensory nervous System lesion/disease2 Probable nociceptive pain Yes No Speaker’s Notes Confirming the presence of neuropathic pain involves: Identification of a cluster of common verbal descriptors and history leading to the suspicion of neuropathic pain Finding sensory abnormalities (either a deficit, such as hypoesthesia, or an excess of function, such as allodynia, hyperalgesia) in the painful area adding support for a neuropathic origin of the pain, particularly if the pain and the sensory abnormality are within a neuroanatomical territory Identification of the responsible neurological lesion/disease If a neuropathic pain syndrome is diagnosed, the underlying cause should be treated and appropriate analgesic therapy should be initiated. Occasionally sensory abnormalities may not be detected and/or the somatosensory nervous system lesion/disease cannot be easily identified. If neuropathic pain is still suspected, specialist referral should be considered (and appropriate pain treatment initiated in the interim period). References Freynhagen R, Bennett MI. Diagnosis and management of neuropathic pain. BMJ 2009; 339:b3002. Haanpää ML et al. Assessment of neuropathic pain in primary care. Am J Med 2009; 122(10 Suppl):S13-21. Treede RD et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 2008; 70(18):1630-5. Consider specialist referral and if neuropathic pain is still suspected, consider treatment in the interim period3 Neuropathic pain is likely: initiate treatment3 1. Freynhagen R, Bennett MI. BMJ 2009; 339:b3002; 2. Haanpää ML et al. Am J Med 2009; 122(10 Suppl):S13-21; 3. Treede RD et al. Neurology 2008; 70(18):1630-5.