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Non-Opioid Medications for Chronic Pain Family Medicine Wednesday School 2/13/19

Non-Opioid Medications for Chronic Pain Family Medicine Wednesday School 2/13/19. George D. Comerci, Jr., MD, FACP, Professor of Internal Medicine University of New Mexico School of Medicine Medical Director: Project ECHO Pain and Opioid Management Clinic. Objectives.

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Non-Opioid Medications for Chronic Pain Family Medicine Wednesday School 2/13/19

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  1. Non-Opioid Medications for Chronic PainFamily Medicine Wednesday School2/13/19 George D. Comerci, Jr., MD, FACP, Professor of Internal Medicine University of New Mexico School of Medicine Medical Director: Project ECHO Pain and Opioid Management Clinic

  2. Objectives At the end of this presentation the participant will: • Describe the role of non-opioid pain medications in the care of the patient with chronic pain • Name the various categories of non-opioid pain medications • Identify the indications, safe usage and contraindications of a prototypical medication from each category of non-opioid pain medications

  3. Disclosures I have no disclosures to report

  4. Pain Basics • Three types of pain • Somatic pain • Visceral pain • Neuropathic • Mixed

  5. The Nociceptor (Nature.2001)

  6. The Nociceptor (J Clin. Invest.2010)

  7. Spinal Pathways

  8. Non-Opioid Pain Medications:True Analgesic Medications Non-opioid medications that have analgesia as their primary indication: • NSAIDS: Aspirin, NSAIDS, APAP • Triptans • Corticosteroids • Local Anesthetics

  9. Non-Opioid Pain Medications:Adjuvant Pain Medications Non-opioid medications whose primary pharmacologic effect is not analgesia, but which have secondary effects that ameliorate pain • Antidepressants • Antiepileptics (membrane stabilizers) • Muscle relaxants • NMDA receptor blockers • Topicals • Miscellaneous

  10. WHO Analgesic Ladder: Still Valid?[Vargas-Schaffer G. Can Fam Phys. 2010]

  11. ASA, APAP and NSAIDs • Prototypical Drugs: Ibuprofen, Celecoxib, ASA and APAP • Act by the inhibition of COX-1/2/3 enzymes which convert arachidonic acid to prostaglandins • Indications and efficacy: • nociceptive pain • NNT 2-4 patients for a 50% reduction in moderately severe pain • All NSAIDs are probably equal in analgesic efficacy

  12. The Nociceptor (J Clin. Invest.2010)

  13. Salicylates • Aspirin: oral and topical • Diflunisal (Dolobid™) • Magnesium Salicylate (Doan’s™) • Salsalate (Disalcid™)

  14. NSAIDS Non-SelectiveSelective [COX-2] • Naproxen Celecoxib • Ibuprofen • Indomethacin Combinations • Ketorolac diclofenac/misoprostol • Piroxicam naproxen/esomeprazole • Meloxicam

  15. NSAIDs (cont.)*group Black Box Warning • Adverse effects: • GI:* ulcerations of gut, hepatitis (fulminant:APAP) • Renal: renal insufficiency and interstitial nephritis • Cardiac*: increased risk of MI, stroke, CHF • Fluid and electrolyte abnormalities • Contraindications • Acid peptic diseases • Increased Bleeding Risk: (i.e.. Anticoagulants) • Renal disease/cardiovascular disease • Caution with pregnancy (ductus arteriosus) • Sulfa-allergic patients (celecoxib)

  16. AcetaminophenUpToDate:2017 Acute: < 4000 mg/d Chronic: <3250 mg/d Elderly: <2000 mg/d Chronically Ill, etc. (prob. <2000 mg/d

  17. Anticonvulsants/Membrane Stabilizers

  18. Anticonvulsants/Membrane Stabilizers • Features shared by most of this class • Never stop them abruptly • All carry warning of increased suicidal thinking • All are primarily used for neuropathic pain • All cause somnolence • All have unique characteristics that clinicians must familiarize themselves with when using

  19. Anticonvulsants: Gabapentenoids • Prototypical Agents: Gabapentin, Pregabalin, • Act by a reduction of g-coupled influx of Ca++ necessary to release pre-synaptic neurotransmitters such as glutamate, NE, substance P dopamine and serotonin • Indications: Neuropathic pain • Actions: decrease nociceptor firing and improve non-REM sleep • NNT = 7.7 NNH = 13.9

  20. The Nociceptor (J Clin. Invest.2010)

  21. Anticonvulsants: Gabapentin • Approved Indications • Epilepsy • Post Herpetic Neuralgia (PHN) • Off-Label Uses • Fibromyalgia • Diabetic Peripheral Neuropathy (DPN) • “other” pain states

  22. Anticonvulsants: Gabapentin • Dosing: start low, go slow • Strive for a dose of 1200-3600 mg/day • Stack doses at nighttime • Adjust for renal creatinine clearance • Better absorption with divided dosages • Adverse Effects • Somnolence, dizziness, edema, weight gain • Can cause leucopenia, thrombocytopenia • Contraindications: hypersensitivity • Extreme Caution: renal insufficiency, dialysis

  23. Anticonvulsants: Pregabalin (C-V) • Approved Indications: • PHN, DPN, Fibromyalgia, spinal neuropathic pain • Epilepsy • Off label: • other neuropathic pain states

  24. Anticonvulsants: Pregabalin (C-V) Dosing • better absorption • 150mg/d in divided doses…up to 600mg/d maximum effect • Adjust for decreased creatinine clearance Adverse Effects • Somnolence, dysphoria, euphoria, edema • Increased risk of angioedema-caution with ACE-I • Still under patent

  25. Anticonvulsants: Topiramate • Raises threshold of activation of the sodium/potassium channels resulting in “stabilization” of the neuron and reduced neuronal depolarization (“firing”) • Approved Indications: • Epilepsy • Migraine prophylaxis • Off label: • Cluster HA, DPN • other neuropathic pain states,

  26. The Nociceptor (J Clin. Invest.2010)

  27. Anticonvulsants: Topiramate Dosing • 25-100mg daily Adverse affects: • Acidosis, hyperammonemia, • nephrolithiasis, increased intraocular pressure • Diminished cognition, paresthesia • Reduce dose with renal insufficiency

  28. Antidepressants(Kremer M. 2016) • Prototypical Agents: Tricyclic Antidepressants Serotonin-Norepinephrine Reuptake Inhibitors Thought to cause enhancement of endogenous descending antinociceptive systems via inhibition of reuptake of norepinephrine and serotonin

  29. Antidepressants

  30. Spinal Pathways

  31. Antidepressants: Common Features Shared by Drugs in the Class • All can potentially cause the serotonin syndrome • All have Black Box warning for increased suicidal thinking • All have complex drug-drug interactions • TCAs have unique cardiotoxic side-effects • TCAs meet AGS criteria for potentially inappropriate usage in the elderly • All are associated with “withdrawal syndrome” • All can potentially worsen other psychiatric comorbidities • Effects observed after prolonged treatment

  32. Tricyclic Antidepressants: TCAs Approved Indications: • Depression Off-label Uses: • Neuropathic pain (peripheral >central) • Fibromyalgia, DPN, PHN, etc. • Migraine Prophylaxis • NNT (TCA) = 2-4 for 50% reduction in pain. (Cochrane Review.2010)

  33. Antidepressants: TCAs • Doxepin, and amitriptyline: most sedating and anticholinergic • Imipramine, nortriptyline: less sedating and fewer anticholinergic side effects • Desiprimine and protriptyline: most activating Dosing • Dose low and go slow: (10 mg-25mg) • For pain: 75mg-100mg

  34. Antidepressants: TCAs Adverse Effects • Anticholinergic: sedation, dry mouth, blurred vision, urinary retention • orthostatic hypotension • Weight gain

  35. TCAs: Cardiac Effects • Type I Anti- arrhythmics: i.e.. quinidine • Prolong PR, QRS and QTc intervals • Doses below 100mg/d probably safe (Clin Pharmacol Ther, 2004;75:234-44) • Safe in patients with chronic pain (Rev Bras Anesteiol.2009;1:46-55) • EKG for patients >40 years • Caution with other QT prolonging drugs • Antifungals, macrolides, etc.

  36. Antidepressants: SNRIsVenlafaxine (Alyer.2017) • Approved Indications: • Depression • Off-Label Uses • Fibromyalgia, headache prophylaxis, other neuropathic pain states • Dosing: • 150 mg/d or greater for pain effect • Maximum/d = 225 mg • NNT = 6.4 NNH = 11.8

  37. Antidepressants: SNRIVenlafaxine • Adverse Effects • Hypertension • Agitation/anxiety, nausea, dry mouth • Caution with renal and hepatic impairment • Rarely cardiotoxic effects an hyponatremia (SIADH) • Caution with other serotonin drugs

  38. Antidepressants: SNRIDuloxetine • Approved Indications • Diabetic peripheral neuropathy • Fibromyalgia • Chronic Musculoskeletal Pain 60mg-90 mg/d NNT:6-8 • Off-label Uses • Other neuropathic pain states

  39. Antidepressants: SNRIDuloxetine • Dosing • 60-120 mg/d • Adverse Effects • Nausea is the most common reason for discontinuation • Dry mouth, somnolence, dizziness • Transaminitis (Inc. AST/ALT) is not uncommon • Do not use in patient with severe renal insufficiency, or chronic liver disease

  40. Tramadol (C-IV) Centrally acting analgesic: Dual MOA • Acts as opioid: (10 x less affinity for Mu receptor than codeine) • activation of descending inhibitory pain systems like TCAs and SNRIs (100-1000 x less than imipramine) • Metabolized to 0-demethylated metabolite (CYP2DR) which is crucial for activity

  41. Tramadol (C-IV) • Approved Indications • Pain severe enough to require the use of an opioid analgesic • Off-Label Uses • Restless legs syndrome • Dosing • 50 to 100 mg every 4 to 6 hours (maximum: 400 mg/day). • Dosing Adjustments: • Cirrhosis: 50 mg/q 12 hr. (max = 100mg/d) • Renal Insufficiency: (Clcr , 30cc/min)50-100 q12 hr. (max = 200mg/d)

  42. Tramadol (C-IV) • Side effects: N/V, dizziness, constipation, somnolence, seizures (increased by SSRIs and to an extent TCAs) • Black Box Warnings • Addiction/abuse/overdose potential • Neonatal withdrawal • Severe respiratory depression in children • Extensive P-450 metabolism • Interaction with benzodiazepines

  43. Skeletal Muscle Relaxants[Beebe. 2005] Anti-spasticity Drugs • Spasticity: loss of descending inhibition to spinal motor neuron due to upper motor neuron disease • Act directly on the motor unit or motor arc Anti-spasmodic Drugs • Ostensibly, act by relieving muscle spasm caused by local tissue trauma from acute muscle damage or strain • In reality, action poorly understood, probably centrally anti-nociceptive

  44. Reflex Arc[Google Image. Balint Roxana]

  45. Skeletal Muscle Relaxants

  46. Anti-Spasticity Drugs Baclofen: (GABA-mimetic agent) • Inhibits spinal interneuron that stimulates muscle contraction in the reflex arc. • Approved for “spasticity”, especially Multiple Sclerosis, other central spastic conditions • Little evidence for other pain conditions resulting from muscle spasm • Dose low, go slow: maximum dose = 80 mg/d • withdrawal syndrome can occur if stopped abruptly [black box warning]

  47. Anti-Spasticity Drugs Tizanidine: • centrally acting agonist which causes presynaptic inhibition of motor activity • Approved for “spasticity” • Off-label: other pain syndromes such as myofascial pain, low back pain and even neuropathic pain • Dose low, go slow: 4mg q 6-8hr • maximum dose = 36mg/d • Can cause hypotension (like clonidine) • Monitor ALT 1, 3, 6 months post starting therapy

  48. Anti-Spasticity Drugs Diazepam: • inhibits skeletal muscle tone by means of the benzo. receptor on postsynaptic GABA neurons • Increased risk of hip fracture in elderly • Do not use with opioids Dantrolene: (use with extreme caution) • interferes with muscle contraction via inhibition of Ca++ release • Approved for chronic spasticity • Black Box: liver injury Botox: • binds to Acetylcholine receptor on muscles inhibit action of acetylcholine

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