Session # 7. Pharmacotherapy of Chronic Pain - Non-Opioid Options. Roman D. Jovey, MD

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2 Session # 7 Pharmacotherapy of Chronic Pain - Non-Opioid Options Roman D. Jovey, MD

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4 Learning Objectives Describe the differences in the initial pharmacotherapy of nociceptive vs. neuropathic pain. Discuss how the presence of central sensitization changes the pharmacological treatment approach Compare the risks and benefits of various non-opioid medications to treat pain. Discuss an approach to treating concurrent sleep, mood and anxiety problems in patients with pain.

5 Algorithms: Nociceptive Neuropathic Low Back Pain Fibromyalgia

6 Ellen: 1. Moderate to severe L knee OA Myofascial neck and shoulder girdle and left knee pain signs of central sensitization left leg 2. Mild renal insufficiency, hypertension, DM II, high NSAID GI and CV risk; L quadriceps muscle wasting and weakness; TrPts bil. trapezii and lev. scapulae 3. MDD in remission; sig. anxiety symptoms;? SUD EtOH 4. Moderate catastrophizing and passive approach to pain; previous divorce with loss of financial security and isolation 5. Moderate addiction misuse risk score ORT (5) 6. Moderately severe impact on function (PDI = 42/70)

7 Anthony 1. Mechanical low back pain with myofascial pain in the neck and shoulder girdle, lower lumbar and upper gluteal musculature 2. Mechanical / myofascial No central sensitization 3. Hypertension controlled on meds, tight hamstrings 4. Symptoms of depressed mood (HADs D= 13) with increasing isolation from family activities 5. Mild degree of catastrophization (PCS=26), family stress due to behaviours of eldest son 6. Moderate risk of med misuse (ORT=6) 7. Moderate impact of pain on function / QOL (BPI-I = 38)

8 Nociceptive Pain Management Specific treatment: where appropriate example: steroids for polymyalgia rheumatica appendectomy for appendicitis Mild to moderate nociceptive pain: try topicals, acetaminophen, NSAIDs / COXIBs +/- adjuvant medication Moderate to severe nociceptive pain: try opioid analgesics +/- adjuvant medications

9 Tapentadol Acet/codeine à Acet/oxycodone Buprenorphine TD Morphine, Oxycodone, Hydromorphone, Fentanyl TD, Methadone, Buprenorphine sl NSAIDs / COXIBS Acetaminophen Tramadol Mild Pain 0-3 Moderate Pain 4-7 Severe Pain 8-10 Adjuvants

10 Topical Analgesics Liniments work by closing the gate Capsaicin depletes Substance P locally Xylocaine - 5% patch (US only) NSAIDs 2.5% diclofenac (Penssaid) 1.16% voltaren (Emogel) 5% diclofenac in Lipoderm (compounded) Morphine Other compounded topical meds

11 Acetaminophen for Pain Great evidence in acute pain (ER, post-op) Inexpensive Fewer adverse effects than NSAIDs Little placebo-controlled evidence in CNCP Comparator drug in RCTs (e.g., NSAIDs or COXIBs) Concern over chronic use dosing limits: Increased risk of liver and UGI toxicity Risk of decline in renal function Hypertension may develop or worsen à increased CV risk Increased risk of hearing loss Doubles risk of asthma in adolescents Forman JP. Hypertension, 2005;Curhan GC, Arch Int Med, 2004; Chan AT. Circulation 2006; Garcia Rodriguez, Arthritis Res 2001; Zimmerman, 1995, 2000; Bromer, 2003; FDA Sept. 2002; Health Canada Feb. 2003; Dedier J, Hypertension, 2002; Curhan SG, Am J Med 2010; Beasley RW, Am J Resp Crit Care Med, 2010.

12 Paracetamol is ineffective in the treatment of low back pain and provides minimal short term benefit for people with osteoarthritis. These results support the reconsideration of recommendations to use paracetamol for patients with low back pain and osteoarthritis of the hip or knee in clinical practice guidelines. BMJ 2014;350:h1225 doi: /bmj.h1225

13 RCTs on knee OA comparing Acetaminophen, NSAIDs, IA steroids, IA hyaluronic acid, placebo 137 studies, 33,243 participants All treatments except acetaminophen showed clinically significant improvement from baseline pain. Ann Int Med 2015;162:46-54

14 Network meta-analysis with 74 RCTs with a total of patients On the basis of the available data, we see no role for single-agent paracetamol for the treatment of patients with osteoarthritis irrespective of dose. We provide sound evidence that diclofenac 150 mg/day is the most effective NSAID available at present Lancet Mar 17. pii: S (16) doi: /S (16)

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18 Acetaminophen*- Suggested Dose Limits 4 gm/day short-term use in healthy patients (FDA Advisory Report 2009 lower the ceiling dose) 3.2 gm / day chronically in healthy patients (>10 d) 2.6 gm / day chronically in at risk patients *Daily alcohol consumption, warfarin, fasting, a low protein diet, cardiac or renal disease increase the risk of hepatotoxicity Zimmerman & Maddry, 1995 Seeff et al., 1986 Swarm et al., 2001 Bromer MQ, Black M. Acetaminophen hepatotoxicity. Clin Liver Dis 2003;7: Latta, 2000 Garcia Rodriguez, Arthritis Res 2001; Curhan 2002 Watkins et al., 2006.

19 Balancing Efficacy and Safety Antiinflammatory activity Analgesia Efficacy N S A I D S GI Tolerability GI Safety Cardiovascular Renal Safety

20 NSAIDS and COXIBs RCT Evidence in acute nociceptive, post-op, inflammatory arthritis & dental pain Useful for mild-moderate nociceptive pain and inflammatory pain

21 NSAIDs for Spinal Pain? Non-steroidal anti-inflammatory drugs for spinal pain: a systematic review and meta-analysis. NSAIDs are effective for spinal pain, but the magnitude of the difference in outcomes between the intervention and placebo groups is not clinically important. Machado G.C. et al. Annals Rheum Dis. Feb 2017

22 Risk Factors for NSAID Associated Serious GI Adverse Events Characteristic Odds Ratio (95% Interval) History of ulcer complications 13.5 ( ) Multiple NSAIDs 9.0 ( ) High-Dose NSAIDs 7.0 ( ) Concomitant anticoagulant use 6.4 ( ) Age 70 years 5.6 ( ) Age 60 years 3.1 ( ) Concomitant corticosteroid use 2.2 ( ) History of cardiovascular disease 1.8 ( ) SSRI 4.0 ( ) SSRI + NSAID 12.2 ( ) Adapted from Dr. Paul Harris Hunt RH et al. Recommendations for the appropriate use of anti-inflammatory drugs in the era of the COXIBs: defining the role of gastroprotective agents. Can J Gastroenterol Apr;16(4): Review.

23 NSAIDs and COXIBs Acute and chronic renal toxicity DeMaria AN. JPSM 2003 Double the risk of hospitalization for CHF Reproductive toxicity Chan VS Drug Safety 2004 Garcia-Rodriguez LA. Epidemiology 2003 Increased risk of hypertension Freis S. Hematology 2005

24 COXIBs No effect on platelets (good for post-op pain) (NOT post CABG surgery Stephens JM. Pharmacotherapy, 2004 ½ risk of complicated PUD (2%/yr) (VIGOR) Concurrent ASA reduces the GI protective effect (CLASS) Increased risk of CV events (MI & CVA)? Celebrex same as Ibuprofen and Naproxyn

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26 Prescribing NSAIDs

27 Nissen SE, et al. NEJM 2016;

28 Bally M, et al. BMJ 2017; 357:j1909

29 1. Hochberg et al. Arthritis Care Res (Hoboken). 2012;64: ACR pharmacologic recommendations: GI protection Subgroup Age >75 years History of upper GI ulcer but no bleed in past year History of upper GI ulcer with bleed in past year Recommendation Use topical rather than oral NSAIDs COX-2 or NSAID + PPI COX-2 + PPI When an NSAID is used for chronic management of patients with knee or hip OA... Consider adding a PPI to reduce risk of symptomatic or complicated upper GI events.

30 30 NSAIDs / COXIBs and GFR GFR >60 ml/min Okay to use GFR ml/min Use with caution and careful monitoring Weight Blood pressure Electrolytes Creatinine, egfr GFR <30 ml/min Don t use

31 ACR 2012 OA Guidelines: Knee OA Pharmacological Treatment Summary An adult with symptomatic knee OA without cardiovascular comorbidities, current or past upper GI problems or chronic kidney disease IF there is an inadequate response to intermittent use of OTC acetaminophen, OTC NSAIDs or OTC nutritional supplements. Conditionally recommend ü Acetaminophen ü ü Oral NSAIDs Topical NSAIDs Conditionally recommend that patients should not use the following û û û Chondroitin sulfate Glucosamine Topical capsaicin IF there is an inadequate response to full-dose acetaminophen Strongly recommend ü ü Oral or Topical NSAIDs Intraarticular corticosteroid injections Conditionally recommend ü ü ü Tramadol Duloxetine Intraarticular hyaluronan injections IF there is an inadequate response to both nonpharmacologic and pharmacologic treatments and total joint arthroplasty is not an option. Strongly recommend ü Opioid analgesics Conditionally recommend ü Duloxetine ü ü Traditional Chinese acupuncture Transcutaneous electrical stimulation Hochberg et al, Arthritis Care & Research 2012;64( 4):

32 ACR 2012 OA Guidelines: Knee OA Pharmacological Treatment Summary An adult with symptomatic knee OA without cardiovascular comorbidities, current or past upper GI problems or chronic kidney disease IF there is an inadequate response to intermittent use of OTC acetaminophen, OTC NSAIDs or OTC nutritional supplements. Conditionally recommend ü Acetaminophen ü Oral NSAIDs ü Topical NSAIDs Conditionally recommend that patients should not use the following û Chondroitin sulfate û Glucosamine û Topical capsaicin IF there is an inadequate response to fulldose acetaminophen Strongly recommend ü ü Oral or Topical NSAIDs Conditionally recommend ü ü ü Intraarticular corticosteroid injections Tramadol Duloxetine Intraarticular hyaluronan injections IF there is an inadequate response to both nonpharmacologic and pharmacologic treatments and total joint arthroplasty is not an option. Strongly recommend ü Opioid analgesics Conditionally recommend ü ü ü Duloxetine Traditional Chinese acupuncture Transcutaneous electrical stimulation Hochberg et al, Arthritis Care & Research 2012;64( 4):

33 ACR 2012 OA Guidelines: Knee OA Pharmacological Treatment Summary An adult with symptomatic knee OA without cardiovascular comorbidities, current or past upper GI problems or chronic kidney disease IF there is an inadequate response to intermittent use of OTC acetaminophen, OTC NSAIDs or OTC nutritional supplements. Conditionally recommend ü ü ü Acetaminophen Oral NSAIDs Topical NSAIDs Conditionally recommend that patients should not use the following û û û Chondroitin sulfate Glucosamine Topical capsaicin IF there is an inadequate response to full-dose acetaminophen Strongly recommend ü Oral or Topical NSAIDs ü Intraarticular corticosteroid injections Conditionally recommend ü Tramadol ü Duloxetine ü Intraarticular hyaluronan injections IF there is an inadequate response to both nonpharmacologic and pharmacologic treatments and total joint arthroplasty is not an option. Strongly recommend ü Opioid analgesics Conditionally recommend ü Duloxetine ü ü Traditional Chinese acupuncture Transcutaneous electrical stimulation Hochberg et al, Arthritis Care & Research 2012;64( 4):

34 ACR 2012 OA Guidelines: Knee OA Pharmacological Treatment Summary An adult with symptomatic knee OA without cardiovascular comorbidities, current or past upper GI problems or chronic kidney disease IF there is an inadequate response to intermittent use of OTC acetaminophen, OTC NSAIDs or OTC nutritional supplements. Conditionally recommend ü ü Acetaminophen Oral NSAIDs ü Topical NSAIDs Conditionally recommend that patients should not use the following û Chondroitin sulfate û û Glucosamine Topical capsaicin IF there is an inadequate response to full-dose acetaminophen Strongly recommend ü ü Oral or Topical NSAIDs Conditionally recommend ü ü ü Intraarticular corticosteroid injections Tramadol Duloxetine Intraarticular hyaluronan injections IF there is an inadequate response to both nonpharmacologic and pharmacologic treatments and total joint arthroplasty is not an option. Strongly recommend ü Opioid analgesics Conditionally recommend ü ü ü Duloxetine Traditional Chinese acupuncture Transcutaneous electrical stimulation Hochberg et al, Arthritis Care & Research 2012;64( 4):

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36 add Duloxetine

37 37 Abnormal pain processing/central sensitization Suspect when: Pain seems out of proportion to objective findings Aggravation of pain causes pain severity and duration out of proportion to precipitating event Pain spread beyond usual area Testing in area of pain reveals Painful response to lightly brushing the skin Excessive pain after a pinprick compared to an unaffected area and the ability to still feel the pinprick long after it is removed (after pain)

38 Case: R.H.

39 Mr. RH A 72 y.o. man presents 6 months after the onset of a blistering rash in the R flank and lower R chest area. He initially complained of a pricking sensation over the rash radiating around to the R side of his abdomen. The rash healed after 2 weeks but the pricking, burning sensation remains. He complains that even the touch of a shirt against his skin is painful.

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41 Herpes Zoster (Shingles) Due to a reactivation of the Herpes Zoster virus from a previous Chicken Pox infection Affects 20% of people over our lifetime Pain can precede the rash by up to 14 days

42 Herpes Zoster (Shingles) Post-herpetic neuralgia (PHN) can affect 20% of all people with shingles but 40% of patients with shingles >60 y.o. Using anti-viral meds (ie. acyclovir, famcyclovir) within 72 hrs of the rash shortens the duration of acute zoster HZV vaccine approved in Canada 2009 for people > 50 y.o.

43 CCDR - A Publication from the Public Health Agency of Canada

44 Zostavax Recommended Use Target Age Group Recommendation Comments Persons age ³ 50 years without contraindications Recommended Grade A, good Administer irrespective of prior chickenpox history or documented varicella infection (Grade A, good) Routine testing for varicella antibody not recommended Duration of protection is unknown beyond 4 years; uncertain whether vaccination at age will provide ongoing protection January Statement on the recommended use of the herpes zoster vaccine. Canada Communicable Disease Report. An Advisory Committee Statement (ACS). Can Commun Dis Rep. 2010;36(ACS-1):

45 HZ Risk Factors Age > 50 Female Immunosuppression (disease or meds) Family history Diabetes / COPD Statins

46 Treatment of Neuropathic Pain

47 Pharmacologic Treatment of Neuropathic Pain TCAs Gabapentinoids SNRIs Tramadol or CR Opioid Analgesic Cannabinoids * Add additional agents sequentially if partial but inadequate pain relief** Fourth Line Agents * * e.g., carbamazepine, methadone, lamotrigine, topiramate ** In using multiple agents, be aware of synergistic or additive adverse effects Moulin DE et al. Pain Res Manage 2014; 19(6):328-35

48 Painful Polyneuropathy PHN Peripheral Nerve Injury HIV neuropathy Central Neuropathic Pain Mixed Neuropathic Pain

49 Evidence for the Pharmacotherapy of Neuropathic Pain NNT Tricyclics Opioids Gabapentin Pregabalin Tramadol Venlafaxine / Duloxetine Cannabinoids BOTOX-A Capsaicin 8% (NNT= # of patients treated to get 1 with a 50% pain reduction) (NNH = # patients treated for 1 to drop out of the study) NNH Finnerup N.B. et al. Lancet Neurol 2015; 14:

50 Topical Treatments for NePain Capsaïcin cream Lidocaine 5% patch (U.S. only) Xylocaïne 10% Cream: 10 g of xylocaine powder (Xenex ) 90 g Glaxal base q 4 h prn warn re: toxicity symptoms NSAIDs ( Diclofenac 1.5% w/v, 1.16% gel, up to 5% compounded) Others

51 Compounded Topical Treatment Options 5-15% lidocaine 5-15% diclofenac 5-25% ketoprofen 5-25% ketamine 2-5% amitriptyline % clonidine 2-5% carbamazepine 6-15% gabapentin 5 % loperamide 3-8% baclofen % capsaicin In VersaPro TM cream or gel or PLO or Lipoderm

52 Tricyclic Antidepressants (TCAs) Amitriptyline most evidence + most side effects Nortriptyline, desipramine preferred in older pts Start at 10mg qhs and titrate to side effects or maximum tolerated dose Use serum levels to titrate above 150mg/d Benefits evident in 1-2 weeks To decrease am drowsiness, take at least hrs before wake time, not bedtime Caution: glaucoma, BPH, cardiac conduction, severe liver disease, suicide risk

53 SNRIs Less effective than TCAs but better tolerated Venlafaxine approved for MDD and GAD - need to dose above 200mg/d for pain - monitor BP Duloxetine - approved for DPN, FM, LBP,OA - approved for MDD and GAD - less effect on BP (Desvenlafaxine, Milnacipran)

54 Gabapentin Gabapentinoids Blocks a2d receptor of N-Type Ca channels Neuropathic pain, migraine, mood stabilizer, Ciguatera poisoning, ê EtOH /drug craving Least side effects of AEDs: (drowsiness, dizziness, ataxia, dysarthria, diarrhea) No known adverse drug interactions Synergistic effect with opioids (Gilron, 2005) 100mg hs test dose then titrate by 300mg q3 days up to 3600mg+ (tid dosing) Adjust dosing in renal insufficiency

55 Pregabalin Gabapentinoids (2) Action same as GPN Officially indicated for neuropathic pain (PHN, DN) RCT evidence for PNP, FM Linear absorption kinetics BID dosing Side effects similar to GPN Start 50-75mg qhs then bid x7; 150mg bid x7à 300 bid x 7 Effects seen within 1 week of adequate dosing Adjust dosing in renal insufficiency

56 AEDs Topiramate Multiple mechanisms of action Migraine, mood stabilizer, (diabetic neuropathy) Main S/E cognitive impairment (occurs early) Other S/E: renal stones, metabolic acidosis, depression Start at 25mg hs x 1wk then titrate weekly by increasing the dose by 25mg on a bid regimen Average dose: mg/d (pain or epilepsy) Migraine average dose: mg/d Oral hypoglycemic drug à weight loss

57 Lamotrigine AEDs Proven efficacy in neuropathic pain caused by neurotoxic anti-retroviral therapy in HIV-positive patients Placebo-controlled trials showed efficacy in patients with diabetic neuropathy and central pain Highest incidence of skin rashes and Stevens- Johnson Syndrome of all AEDs Need to titrate dose very slowly (25mg per week)

58 Classification of Pain by Primary Mechanism Nociceptive Inflammation or mechanical damage in tissues Any combination of mechanisms may be present in a patient with CNCP Neuropathic Damage or dysfunction of peripheral nerves Centralized Pain Central disturbance in pain processing Phillips, K and Clauw, D Best Practice & Research Clinical Rheumatology 25 (2011)

59 Treating Pain Based on Mechanisms any combination may be present NSAIDs Opioids Peripheral Neuropathic (nociceptive) Pain Centralized Pain Surgery/ Injections Tricyclics SNRIs Gabapentinoid Cannabinoid Clauw IASP 2016

60 Algorithm for the symptombased management of fibromyalgia Boomershine CS. Nat Rev Rheum 2009; 5:191-99

61 Evidence-based treatments for FM Non-pharmacotherapy Aerobic exercise walk, bike, swim CBT, interdisciplinary pain programs, patient education groups Pharmacotherapy TCAs / Cyclobenzaprine SNRIs duloxetine Pregabalin Tramadol (Nabilone, Na-Oxybate, Mg) Guidelines/resources Canadian fibromyalgia guidelines Algorithm for the symptom based management of fibromyalgia 2 Fibromyalgia treatment CAM therapies 3 1..Fitzcharles et al. Pain Res Manag. 2013;18: Boomershine and Crofford. Nat Rev Rheumatol. 2009;5:191-9; 3. Ablin et al. Evid Based Complement Alternat Med. 2013;2013:

62 LDN is a promising treatment approach for chronic pain conditions thought to involve inflammatory processes. The clinical data supporting its use are very preliminary, and more research is needed...

63 Chronic Pain Co-morbidity Sleep Depression Anxiety

64 Rational Polypharmacy Taper off of sedating medications i.e. sedatives, muscle relaxants, sleeping meds For sleep try: tricyclics (amitriptyline, doxepin), trazodone, gabapentin, pregabalin, mirtazepine, tizanidine, cannabinoids, quetiapine INSTEAD OF BENZOs Optimize anti-depressant therapy (TCAs, venlafaxine, bupropion, duloxetine) For anxiety and pain try SNRIs, SSRIs, gabapentin or pregabalin before resorting to benzos

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66 Park. BMJ. 2015; 350: h2698

67 What is in the pipeline for the pharmacotherapy of pain?

68 Future Pharmacotherapies? CGRP antagonists NMDA blockers Cannabinoids COX inhibitors Bradykinin antagonists Glutamate antagonists Substance P and Neurokinin antagonists Omega conotoxins / Nicotinic agonists TRPVR1 agonist Glial cell function modulators

69 Summary Knowing pain mechanisms can allow you to start treating pain even though you may not have a clear diagnosis Central sensitization can be involved in all pain types All medications have risks and benefits Pain co-morbidities need to be treated to optimize the outcomes of pain management

70 Questions?