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Pharmacotherapy for Chronic Pain

Pharmacotherapy for Chronic Pain. Dr. Keith White, M.B., ChB Clinical Lead- Medication Reconciliation Clinical Care Management BC Patient Safety and Quality Council & Penny Miller, BSc.(Pharm.), M.A. Senior Instructor, Faculty of Pharmaceutical Sciences

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Pharmacotherapy for Chronic Pain

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  1. Pharmacotherapy for Chronic Pain Dr. Keith White, M.B., ChB Clinical Lead- Medication Reconciliation Clinical Care Management BC Patient Safety and Quality Council & Penny Miller, BSc.(Pharm.), M.A. Senior Instructor, Faculty of Pharmaceutical Sciences and Department of Family Practice, Faculty of Medicine, UBC Pharmacotherapeutic Consultant, Lifemark Health Chronic Pain Program

  2. Goal: Provide the physician with practical information to support the medication management of patients with chronic pain as one part of the multimodal treatmentto improve functioning, sleep and reduce pain. Learning Objectives: At the end of this session, the physician will demonstrate improved abilities to: Identify select medications that have evidence for the treatment of different types of chronic pain. Discuss when and how to use appropriate combinations of medications. Outline the importance for slow upward titrations and slow tapers off medications. Discuss the contraindications and controversies of medications used for chronic pain.

  3. Medications cannot eliminate pain & are merely a part of the overall treatment

  4. Treatment Principles • First consider non-drug measures. • Is a medication ESSENTIAL? (i.e. clear diagnosis) • Is the treatment GOAL/ outcome clear? • Initiate one drug at a time. Keep it simple. • Select pharmacologic classes with efficacy demonstrated (ideally) in multiple RCTs • Be aware that response will vary between patients • Start with very low doses and titrate slowly

  5. Treatment Principles… • When introducing a new treatment, consider overlap with old treatments to avoid deterioration in pain control. • If the new medication is well tolerated, then continue to titrate to effective or acceptable pain relief (30% to 50% reduction) • Consider adding a second agent with a different mechanism of action if the first agent is providing partial relief yet pain remains > or = 4/10 • If the medication is ineffective, then slowly taper off the medication

  6. Treatment Principles… • Consider side effects, drug interactions, cost and abuse potential • Be aware of comorbidities such as depression, anxiety and insomnia • Design a future plan to slowly taper off most medications for chronic pain • Educate patients about their medications • Regularly update the medication lists of patients (OTC, herbal, Rx)

  7. Choosing AnalgesicsThe choice of a pharmacologic agent is based upon the following factors: • Indication/ type and intensity of pain • Efficacy of agent for the specific indication (NNT) • Safety and experience of the agent (NNH) • Renal and hepatic function of patient NNT= numbers needed to treat NNH= numbers needed to harm Co-morbidities (e.g. depression, cardiac disease) Drug interactions Cost Dosing Schedule Dosage forms ( oral, topical, parenteral, etc.) & strengths available

  8. TCAs SSRIsSNRIs Alpha adrenergic agents Opioids Tramadol Descending Inhibitory Pathways(NE/5HT, enkephalins) Central Sensitization Spinal Cord Peripheral Sensitization Ca++: Gabapentin Pregabalin LVT OXC LTG NMDA: Ketamine DextromethorphanMethadone Memantine CBZOXC TCATPMLTG Lidocaine Na+ Medications affect pain differently TCA: Tricyclic antidepressant, SSRI: Selective serotonin reuptake inhibitor, SNRI: Serotonin and norepinephrine reuptake inhibitor, CBZ: Carbamazepine, OXC: Oxcarbazepine, TPM: Topiramate, LTG: Lamotrigine; GBP: Gabapentin; LVT: Levetiracetam; PREGAB: Pregabalin;.Adapted from Beydoun A., Backonja M.M; Mechanistic stratification of antineuralgic agents. Journal of Pain and Symptom Management, 2003:25:5S (p.S27) with permission from the U.S. Cancer Pain Relief Committee 18

  9. Gladys 55 years old Healthy Lifetime runner, mountain biker, skier Now has diffuse osteoarthritis Every joint hurts Choice of analgesic?

  10. Nonopioid Analgesics Simple Analgesic (Non-NSAID) • Para-aminophenols (Acetaminophen) NSAIDS • Salicylates (Acetylsalicylic acid i.e.Aspirin) • Propionic Acid derivatives (Ibuprofen, Naproxen, Naproxen sodium, ketoprofen) • PhenylAcetic Acid Derivatives (Diclofenac) • Indole acetic acid Derivatives (Indomethacin) • Oxicams (Piroxicam, Meloxicam) • Anthranilic acid (Mefenamic acid) • Pyrolizine carboxylic acid (Ketorolac) • Coxibs -COX-2 Selective Agents( Celecoxib)

  11. Acetaminophen (Tylenol®) Mechanism of Action: inhibits prostaglandin (COX-3) synthesis in CNS • Analgesic, antipyretic (not anti-inflammatory) Role in Therapy: • Monotherapy for mild pain • Combined with opioids and other adjuvants Precautions: • Hepatotoxic – In liver disease, chronic and binge alcohol use (maximum safe dose 2.6 gm – unknown?) • Do not exceed 4 grams daily (avoid OTC combination products e.g. cough & cold, muscle relaxants, etc) Pharmacotherapy 2007;27(9):1219-30 Advantages: • No effect on platelet function or GI tract Drug interaction: warfarin

  12. NSAIDs (Non-steroidal anti-inflammatory drugs) Mechanism of action: Inhibit the synthesis of prostaglandin (cyclooxygenase- COX) • anti-inflammatory, analgesic, antipyretic • COX-2 selective or non-selective inhibitors Role in Therapy: • Monotherapy for mild to moderate pain • Monotherapy for inflammatory conditions (osteoarthritis, rheumatoid arthritis, bursitis, tendonitis, gout, bony pain, low back pain) • Combination therapy with opioids • Also available topically (diclofenac), injectable (ketorolac, ibuprofen)

  13. NSAIDs Precautions: • Gastrointestinal- nausea, dyspepsia, GERD, erosions, ulcers, bleeding • Renal toxicity – hypertension, peripheral edema, CHF • Thrombosis (cardiovascular events)-platelet effects • Increased risk of MI and stroke with NSAIDs (especially Cox-2 selective inhibitors) • ASA combined with NSAIDs – antiplatelet effect antagonized (not typically seen with Celecoxib) • Allergies – ASA-sensitive bronchospasm (5%) in asthmatics, rashes (SJS, vasculitis) • Drug interaction: space ASA ingestion apart from NSAID

  14. NNT and NNH for NSAIDs • NNT 1.6 – 3 (for 50% pain relief) Oxford League Table • NNT Topical NNT 3.1 (BMJ 1998:316;333-338) • NNH 5 Endoscopic ulcer • NNH 70 Symptomatic ulcer • NNH 150 Bleeding ulcer • NNH 1300 Death from bleeding ulcer • Odds Ratio 1.6 – 2.0 Acute renal failure • CHF risk is double NSAIDs & Coxibs: Clinical Use Chapter 30 in Pharmacology and treatment of Pain. McMahon

  15. Risk factors for NSAID related GI ulcers • Advanced age > 70 yo • History of ulcer (hemorrhage) • Concomitant use of corticosteroids • Concomitant use of anticoagulants • High doses or use of more than one NSAID Other probable risk factors: • Helicobacter pylori infection • (Cochrane Database Syst Rev. 2006 Apr 19;(2):CD003840) • Cigarette smoking • Alcohol Consumption Circulation 2008;118:1894-1909

  16. Efficacy of PPIs to prevent NSAID induced ulcers • Both PPIs and double dose H2RAs were effective at reducing the risk of endoscopic duodenal and gastric ulcers (RR 0.44; 95% CI 0.26 to 0.74) and RR=0.40;95% CI; 0.32-0.51 respectively for gastric ulcer), and were better tolerated than misoprostol. • Standard doses of H2RAs were effective at reducing the risk of endoscopic duodenal (RR 0.36; 95% CI 0.18 to 0.74) but not gastric ulcers (RR 0.73; 95% CI 0.50 to 1.08). RostomA,DubeC,WellsGA, TugwellP,Welch V, JolicoeurE,McGowan J, Lanas A. Prevention of NSAID-induced gastroduodenalulcers. Cochrane Database of Systematic Reviews 2002, Issue 4. Art. No.: CD002296. DOI: 10.1002/14651858.CD002296.

  17. Risks associated with Proton Pump Inhibitors • Osteoporosis with a 29% increased risk of fracture, including 31% increased risk of hip fracture and a 54% increased risk of vertebral fracture. Ann Fam Med. 2011;9(3):257-267. • Two-fold increase in the risk of Clostridium difficilecolitis and a more than three-fold increase in the risk of other enteric infections.Am J Gastroenterol.2007;102(9):2047-2056 • May see increased risk of ambulatory pneumonia (controversial)Gastroenterology2010;139(4):1115-1127 • Risk of GI cancers has not been substantiatedGastroenterology 2010;139(4):1115-1127 • B12 deficiency not seen in elderly Aliment PharmacolTher. 2008;27(6):491-497.

  18. Risk of MI and NSAIDs J Am Coll Cardiol. 2008 Nov 11;52(20):1628-36

  19. Commonly used NSAIDs Propionic Acids • Naproxen (Naprosyn®) 125 – 500 mg bid • Naproxen Na (Aleve®) 220 – 440 mg bid • Ibuprofen (Motrin®) 200 – 800 mg tid Phenylacetic Acid • Diclofenac (Voltaren®) 25 – 50 mg tid COXIB (COX-2 inhibitor) • Celecoxib (Celebrex®) 100 mg bid Carboxylic Acid • Ketorolac short term only 10 mg qid (IM and po) Ceiling effect when maximal dose is reached.

  20. Gladys Hurt back lifting a crate of Tylenol Arthritis in Costco Now has sciatica Choice of analgesic?

  21. Adjuvants / Coanalgesics • An adjuvant is a medication that is not primarily indicated for the treatment of pain, but which has been found to be useful in pain management • Tricyclic antidepressants • SNRIs (selectiveserotoninreuptakeinhibitors) • Anticonvulsants • NMDA blockers (N-methyl-D-aspartate)-dextromethorphan, ketamine 24

  22. Adjuvant Analgesics:Anticonvulsants/Neuromodulators For Chronic Neuropathic pain

  23. What is the efficacy evidence for anticonvulsants (neuromodulators)? • Gabapentin>1200 mg /day: • An updated Cochrane systematic review and meta-analysis of 29 studies (3571 patients) for 12 chronic pain conditions (PHN,PDN,Mixed NP) • NNT (for moderate benefit) was 5.8(95% CI 4.8 - 7.2);43% vs 26% placebo • NNTfor substantial benefitwas 6.8 (95% CI 5.6 -8.7); 31% vs 17% placebo Cochrane Database Syst Rev. 2011 Mar 16;3:CD007938. • Issues of 40% of trials were unpublished

  24. What is the efficacy evidence for anticonvulsants (neuromodulators)? • Pregabalin 300-600 mg/day for > 50% pain reduction. Meta-analysis of 25 RCTs resulted in: NNT 5.0 (95% CI 4-6.6) for PDN; NNT 11 (95% CI 7.1-21) for Fibromyalgia; NNT 3.9 (95% CI 3.1-5.1) for PHN Cochrane Database Syst Rev 2009;(3):CD007076 2. Issues of unpublished trials.

  25. What is the efficacy evidence for other anticonvulsants (neuromodulators)? • Carbamazepine is useful for trigeminal neuralgia • Cochrane Database Syst Rev. 2011;(1):CD005451. • NNT 1.8 (95% CI 1.4-2.8) • NNH 3.7 (95% CI 2.4-7.8) for minor harm. (Comparable to placebo for major harm) • There is insufficient data for benefit in other neuropathic states

  26. What is the efficacy evidence for other anticonvulsants (neuromodulators)? • Topiramate 50 mg bid may be useful for chronic migraine prevention (1.6 less headaches per month). • Arch Neurol. 2004;61:490–5 • Renal calculi, metabolic acidosis, weight loss, skin rash (10%), paresthesias (51%) , cognitive impairment • Cochrane Database Syst Rev. 2004;(3):CD003226. • Lamotrigine 200 – 400 mg daily- There is no convincing evidence this is effective in treating acute or chronic pain. Cochrane Database Syst Rev. 2011 Feb 16;(2):CD006044. • There is no evidence that anticonvulsants are effective for acute pain.

  27. Adjuvant Analgesics/ Co-analgesicsAnticonvulsants/Neuromodulators Gabapentin (Neurontin ®) Mechanism of action: binds to presynaptic alpha-2- delta subunit of voltage-gated calcium channels in dorsal horn, which results in a decreased release of glutamate and substance P (excitatory neurotransmitters: ) A structural analogue of the inhibitory neurotransmitter, GABA,-but does not bind to receptors or affect GABA. Role: a variety of neuropathic pain states (diabetic neuropathy, postherpetic neuralgia, mixed neuropathic states)

  28. Ca++ Channel Modulators Gabapentin and pregabalin Excitatory Neuron Modulation of Ca++ Channel by Pregabalin

  29. Adjuvant Analgesics/ Co-analgesicsAnticonvulsants/Neuromodulators: Gabapentin Dose: start at 100 mg at bedtime and increase slowly (every 3 days) to 1800 – 3600 mg daily as tolerated (divided as three times daily) • Adjust dose in renal impairment (clearance is decreased) • Absorption is inversely dependent on dosage: • Gabapentin oral bioavailability: 80% with100 mg tid 27% with 1600 mg tid • Analgesic effect seen at 2 to 3 weeks of therapeutic dose

  30. Adjuvant Analgesics/ Co-analgesicsAnticonvulsants/Neuromodulators: Pregabalin • Similar to Gabapentin • Linear pharmacokinetics (dose- response more predictable) • Analgesic effect is seen within first week of therapeutic dose • No generic products available • Dose: start with 25 mg qhs and increase slowly (every 3 to 7 days) as tolerated to 150 mg daily or 150 mg bid (Max 600 mg daily) • For all anticonvulsants, taperto elimination to avoid seizures even with no history of convulsive disorder.

  31. Adverse Effects

  32. Anticonvulsant- Risk of suicidal thoughts and behaviour • 0.43% on Anticonvulsants versus 0.22% on placebo • Evident as early as 1 week after starting treatment • Risk is highest in Epileptic cases Neurology 2010; 75: 335-340 New Engl J Med 2010; 363: 542-451 CNS Drugs. 2009;23(4):281-92.

  33. Adjuvant Analgesics:Antidepressants For chronic pain

  34. What is the efficacy evidence for tricyclic antidepressants? • TCAs: Cochrane systematic review of 21 RCTs; for 50% pain reduction Cochrane Database Syst Rev 2012;12:CD008242 • NNT 4.6 (CI 95% 3.6-6.6) for PDN, Mixed NP, FM • TCAs: Systematic review of 16 RCT for 50% pain reduction J Pain Symptom Manage 2000;20(6):449-58 • NNT 3.4 (95% CI 2.6-4.7) for PDN • TCAs: Meta-analysis of 37 RCTs for 50% headache pain reduction BMJ 2010;341:5222-26 • Relative risk 1.41 (95% CI 1.02-1.89) for tension headaches • Relative risk of 1.80 (95% CI 1.24-2.62) for migraine headaches

  35. What is the efficacy evidence for SNRI antidepressants?Duloxetine • SNRIs: Duloxetine (60 – 120 mg /day): Cochrane review of 6 RCTs (n=220) for > 50% pain reduction at 12 weeks Cochrane Database Syst Rev 2009;(4):CD007115 • NNT 8 (95% CI 5 – 17) for PDN • NNT 6 (95% CI 1.34-2.03) for FM • SNRIs: Duloxetine (60 – 120 mg/day): systematic review of 12 RCTsPain Pract 2013;13(3):239-52 • NNT 6 For low back pain & osteoarthritis • NNT 8 For improved function

  36. What is the efficacy evidence for SNRI antidepressants?Venlafaxine • SNRIs: Venlafaxine(150 mg /day): Cochrane review of 4 RCTs for moderate pain reduction Cochrane Database Syst Rev 2010;(Jan 20):CD0054 • NNT 3.1 (95% CI 2.2-5.1) for NP • RR 2.2 (95% CI 1.5 to 3.1) • NNH for major adverse effects defined as an event leading to withdrawal from a study was 16.2 (95% CI 8 to 436) • NNHfor minor adverse effects was 9.6 (95% CI 3.5 to 13)

  37. Adjuvant analgesics/ Co-analgesics AntidepressantsTricyclic antidepressants (TCAs) Mechanism of action: inhibit the reuptake of norepinephrine and serotonin of descending pain pathway Role in Therapy: • Diabetic neuropathy, postherpetic neuralgia, central post-stroke pain, neuropathic pain, fibromyalgia, headache • Useful in co-morbid conditions ie. insomnia, depression, anxiety • Nortriptyline, Desipramine (secondary amines- greater Norepinephrine reuptake inhibition) NNT 2.6 NNH 20.4 • Amitriptyline (tertiary amine) NNT 2.4 NNH 1.4 • Side effects (especially anticholinergic effects)

  38. Antidepressants/ TCAs Adverse effects: • Anticholinergic side effects (dry mouth: 30% amitriptyline/10% nortriptyline), constipation, urinary retention, blurred vision, tachycardia, cognitive impairment) • Sedation (30% amitrip/2% nortrip), postural hypotension • Cardiac arrhythmias ( especially in overdose) • Weight gain Precautions: • Benign prostatic hypertrophy, closed angle glaucoma, CV disease • Screening EKG for cardiac conduction abnormalities if > 40 yo • Risk of suicide by overdose (> 750 mg or 15 - 20 mg per kg) Dose: start with 10 mg at bedtime and titrate slowly ( analgesic response typically seen with 10 – 75 mg daily)

  39. Antidepressant (TCA) Monitoring • Efficacy for improved sleep (immediate) • Efficacy for improved pain control (1 -2 weeks)Raskin et al Pain Med 2005 • Efficacy for improved mood (6 – 8 weeks) • EKG baseline prior to initiation in patients over 40 years old • Must taper off to avoid antidepressant discontinuation syndrome

  40. Drug Interactions with TCAs • TCA + Codeine – TCA block hepatic cytochrome 2D6 isoenzyme so inhibit conversion of codeine to morphine (also, tramadol conversion to active metabolite) • TCA +CNS depressants (alcohol, opioids)->sedation • TCA + other anticholinergic – paralytic ileus • TCA + SSRI or SNRI + Triptan = serotonin syndrome • TCA + SSRI or SNRI + tramadol = serotonin syndrome

  41. Adjuvant analgesics/ Co-analgesicsAntidepressants- SNRI- serotonin-norepinephrine reuptake inhibitors Mechanism of action: increase levels of norepinephrine ( and serotonin) to stimulate the descending pain pathway Duloxetine (Cymbalta ®) • Start at 15 mg once daily (mix 30 mg capsule with apple sauce) and titrate slowlyup to 60 mg daily • Dosage adjustment not necessary in renal dysfunction; caution with hepatic insufficiency Venlafaxine (Effexor ®) • Start at 37.5 mg once daily and titrate slowly up to 150 mg (225 mg) daily • Adverse effects: nausea, headaches, stimulation/sedation, sweating, increased blood pressure Minimal anticholinergic side effects

  42. Other Antidepressants • SSRIs (selective serotonin reuptake inhibitors) • NNT 6.7 Very weak Analgesic potential • Bupropion (Wellbutrin®) (dopamine/noradrenalin reuptake inhibitor) – single trial of analgesic benefit at 150 mg to 300 mg daily. No sexual dysfunction or weight gain. Side effects: insomnia, psychosis, seizures. • Trazodone (serotonin-2 antagonist/reuptake inhibitor) – no analgesia. Very sedating so is useful as sleep aid. • Side effect: priapism,rarely(0.1-0.01% with 50 – 150 mg dose) • J Clin Psychiatry 2005;66: 469-76.

  43. Combination Therapy In cases of partial but insufficient pain relief by a single drug, some combinations are more beneficial. • gabapentincombined with nortriptylineLancet 2009;374:1252–61 ormorphineN Engl J Med 2005;352:1324–34 versus monotherapy(RCTs) • in a mixed group of patients with PDN and PHN, with either combination providing better efficacy at lower dosages without any increase in side effects • Gabapentin combined with oxycodone In diabetic neuropathic pain, combinationwas found superior to gabapentin alone. EurJ Pain 2008;12:804–13. Lancet Neurol 2013;12:1084-95

  44. Muscle Relaxants

  45. Muscle Relaxants • May be useful combined with analgesics for acute short-term (2 weeks) management of muscle spasms in non-specific low back pain • Not recommended for chronic use. • Efficacy : The pooled relative risk for cyclobenzaprine, tizanidine, dantroleneversus placebo after 2 to 4 days was 0.80 (95% confidence interval: 0.71 to 0.89) for pain relief and 0.49 (95% confidence interval: 0.25 to 0.95) for global efficacy Systematic review (Cochrane Database Syst Rev. 2003;(2):CD004252

  46. Skeletal Muscle Relaxants: Antispasmodics

  47. Skeletal Muscle Relaxants:Antispasticity agents

  48. Cyclobenzaprine & Amitriptyline

  49. Skeletal Muscle Relaxants • Adverse effects: (relative risk of 2.04) • Drowsiness, dizziness • Headache • Blurred vision • Nausea, vomiting • Withdrawal symptoms (with seizures) • Anticholinergic effects (cyclobenzaprine, orphenadrine) • Hepatic reactions in some (chlorzoxazone, dantrolene, tizanidine) • QT prolongation & increased intraocular pressure – cyclobenzaprine Pharmacotherapy. 2008 Feb;28(2):207-13 Systematic review (Cochrane Database Syst Rev. 2003;(2):CD004252)

  50. Skeletal Muscle RelaxantsRecommendations for practice • C -Skeletal muscle relaxants are not considered first-line therapy for musculoskeletal conditions. • B -Skeletal muscle relaxants may be used as adjunctive therapy for acute low back pain • C - Antispasmodic agents should be used short-term (two weeks) for acute low back pain. • B -There is no clear evidence that one skeletal muscle relaxant is superior to another for musculoskeletal spasms. • C - Choice of skeletal muscle relaxant should be based on individual drug characteristics and patient situation. A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series Am Fam Physician. 2008 Aug 1;78(3):365-370.

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