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Polypharmacy as a rational treatment approach for chronic pain

Polypharmacy as a rational treatment approach for chronic pain. Rollin M. Gallagher, MD, MPH University of Pennsylvania School of Medicine Philadelphia Veterans Medical Center Email: rgallagh@mail.med.upenn.edu. 1) To review mechanisms of acute pain and chronic pain diseases and conditions

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Polypharmacy as a rational treatment approach for chronic pain

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  1. Polypharmacy as a rational treatment approach for chronic pain Rollin M. Gallagher, MD, MPH University of Pennsylvania School of Medicine Philadelphia Veterans Medical Center Email:rgallagh@mail.med.upenn.edu

  2. 1) To review mechanisms of acute pain and chronic pain diseases and conditions 2) To discuss the rational use of polypharmacy and integrated multi-modality treatment for chronic pain Goals of This Presentation

  3. Medication selection in pain is based upon more than just pain severity • Diagnosis • Mechanisms of pain(s) • Efficacy • Clinical trial data • Comorbidities: medical and psychiatric • Prior treatment responses • Side-effect burden, toxicity risk, drug and disease interactions • Gallagher RM, Verma S. Sem Neurosurg. 2004;15:31-46. • Sindrup SH, Jensen TS. Pain. 1999;83:389-400. • Galer BS. Neurology. 1995;45(12 suppl 9):S17-S25.

  4. Medication selection in pain is based upon more than just pain severity • Ease of use • Dosing simplicity • Titration simplicity • Patient competence and convenience • Pain’s psychosocial context and the doctor-patient relationship: - stigma - cost - illness behavior - risk of treatment non-adherence - risk of medication misuse • Sindrup SH, Jensen TS. Pain. 1999;83:389-400. • Galer BS. Neurology. 1995;45(12 suppl 9):S17-S25. • Gallagher RM, Verma S. Sem Neurosurg. 2004;15:31-46.

  5. Public Health ChallengeHow do we prevent injuries from causing chronic pain? Injuries >> nerve damage >> pain >>acute distress continued nociception >> spinal cord damage >> fear, distress >>> brain damage >> >> chronic pain disease

  6. Neuro- plasticity Ectopic discharge Central sensitization Ectopic discharge Alteration of modulatory systems Phenotypical Changes ANS activation <<< Stress <<< Pain<<< BRAIN PROCESSING Spinal cord Damage Nerve injury +++ C fiber Abeta fiber Limb trauma Adapted from Woolf & Mannion, Lancet 1999 Attal & Bouhassira, Acta Neurol Scand 1999

  7. Pathology: • Muscle atrophy, • weakness; • Bone • demineralization; • -Depression THE END: CPRS Pain Cycle • Pathophysiology of Maintenance: • Radiculopathy • Neuroma traction • Myofascial sensitization Acute injury and pain • Psychopathology • of maintenance: • Encoded anxiety • dysregulation • - PTSD • -Emotional • allodynia • and mood • disorder Central sensitization Disability Less active Kinesophobia Decreased motivation Increased isolation Role loss Peripheral Sensitization: Na+ channels Lower threshold Neurogenic Inflammation: - Glial activation - Pro-inflammatory cytokines - blood-nerve barrier dysruption

  8. Challenges of OEF/OIF Veteran Cohort Recent evidence suggests that access to pain treatment after severe limb trauma leads to better outcomes.

  9. Does early intervention make a difference? Castillo et al. Pain 124 (2006): 321-329 • 567 severe single extremity trauma patients at 7 years • Predictors of poor outcome before injury include: • Alcohol abuse 1 month before injury • Older age, lower education, low self efficacy (Gallagher Pain1989) • Predictors of poor outcome at 3 months post-injury: • Acute pain intensity, anxiety, depression and sleep disturbance

  10. Opioid protective effect “Patients treated with narcotic medication for pain at three months post-discharge were protected against chronic pain, despite the fact that these patients had higher pain intensity levels and were thus at higher risk.” “The results presented here appear to lend support to the theory that… ..early aggressive pain treatment may protect patients from central sensitization and chronic pain.”

  11. Gabapentin in the Treatment of Postherpetic Neuralgia 100 Placebo (n=116) Gabapentin (n=109) 80 p<.001 59.5% 60 43.2% % of Patients 40 22.9% 17.4% 20 12.1% 8.6% 7.8% 2.8% 0 Moderately orMuch Improved MinimallyImproved No Change Worse Adapted from: Rowbotham M, et al. JAMA. 1998;280(21):1837-1842.

  12. What happens above the spinal cord?

  13. Can we measure the impact of experience? Pain is conditionable:Expectation of Pain Activates the Anterior Cingular Gyrus Sawamoto et al. J Neurosci. 2000;20:7438.

  14. PAIN and EMOTION Serotonin and Norepinephrine inDepression and Pain PrefrontalCortex - anterior cingulate Limbic System Serotonin Pathways Locus Ceruleus Raphe Norepinephrine Pathways Verma S, Gallagher RM. Int Rev Psychiatry. 2000;12(2):103-114.Blier P, Abbott FV. J Psychiatry Neurosci. 2001;26(1):37-43.

  15. DIAGNOSIS There Are Many Painful Diseases and Pain Diseases Inflammatory / Immunological Mediation Nociceptive pain Caused by activity inneural pathways inresponse to potentiallytissue-damaging stimuli Neuropathic pain Initiated or caused by a primary lesion or dysfunction in the nervous system CANCER PAIN, LBP, CHRONIC FACIAL PAIN (mixed pain states) Peripheralneuropathy SENSITIZATION CRPS* Postoperativepain Arthritis Postherpeticneuralgia Trigeminalneuralgia Sickle cellcrisis Mechanicallow back pain Neuropathic low back pain Central post-stroke pain Diabeticneuropathy Sports/Exerciseinjuries Phantom tooth pain *Complex regional pain syndrome.

  16. Recognizing Neuropathic Pain Common signs and symptoms • Persistent burning sensation • Paroxysmal lancinating pains • Paresthesias • Dysesthesias • Hyperalgesias • Allodynias Galer BS. Neurology. 1995;45(suppl 9):S17-S25; Backonja M-M et al. Neurol Clin.1998;16:775-789.

  17. Pain Drawing & Neuropathy Types Boulton AJM et al. Med Clin North Am. 1998;82:909-929; Portenoy RK. Pain Management: Theory and Practice. 1996:108-113; Katz N. Clin J Pain. 2000;16:S41-S48

  18. 0 1 2 3 4 5 6 7 8 9 10 Numerical Rating Scale: Monitoring Patient Progress Severe Can’t function Moderate Bothersome Mild, in background Excruciating, ER time Burning at the stake !! Just Noticeable • Improvement can be monitored • Gives clinician and patient a consistent understandable measure with intra-rater reliability that facilitates discussion regarding: changes in pain, response to treatment • Reduction of 2 points represents a clinically important No pain Worst possible pain Adapted from Farrar JT et al. Pain. 2001;94:149-158.

  19. Efficacy – Medication Trials Disease specific vs Mechanism specific

  20. Effect of Medications on Pain in a Preclinical Model of Persistent Neuropathic Pain Late-Phase Pain Behavior in Formalin Model Vehicle control Duloxetine 100 Venlafaxine Gabapentin * Amitriptyline 75 * *p<.05 vs vehicle * Total Paw-Licking Time (Late Phase)(% of Control) 50 * * * * * * 25 * 0 0.1 1 10 100 Drug (ip, -30 Minutes, mg/kg, N=6-8) Simmons/Iyengar. Data on file, Eli Lilly and Company. This information concerns a use that has not been approved by the US FDA.

  21. Efficacy in Neuropathic Pain • Agents with consistent efficacy demonstrated in randomized, controlled trials for neuropathic pain • Lidocaine Patch 5%*(topical analgesic) • Anticonvulsants: gabapentin,* valproate, carbamazepine • Pregabalin • Tricyclics: nortriptyline,† desipramine,† amitriptyline • SNRIs: venlafaxine,† duloxetine* • Opioids: oxycodone,† tramadol† • GABA B agonist: baclofen† • * FDA approved for the treatment of neuropathic pain • † Not approved by FDA for this use

  22. Tricyclic Antidepressants • Multiple mechanisms (Na+ channels, 5-HT & NE reuptake blockade) • RCTs in diabetic peripheral neuropathy (DPN) and postherpetic neuralgia • Dosing: Initiate dose at 10 mg hs to 25 mg hs and ↑ as tolerated to 10 mg to 50 mg • If no effect at 2 weeks, continue to ↑ to ≥150 mg if needed • Documented, but limited, efficacy for fibromyalgia and chronic low back pain

  23. Other NP agents Voltage gated Calcium channels: • Gabapentin: Every 3-5 days • 0 0 300 mg • 300 0 300 mg • 300 300 300 mg • 300 300 600 mg • 600 300 600 mg • 600 600 600 mg • Pregabalin: Every 1-2 weeks as tolerated • 50 mg TID or 75 mg BID • 100 mg TID or 150 mg BID

  24. Other NP agents Serotonin – Norepinephrine Reuptake Inhibitors (SNRIs) for diabetic neuropathy • Duloxetine • 20 mg or 30 mg in AM • In 1- 2 weeks, if tolerated, increase to 40 – 60 mg in AM • Target dose 60 mg for 3 weeks. • Maximum dose 120 mg 2) Venlafaxine (Effexor) LA (check BP) 1. 137.5 mg in AM for 5 days, then increase by 37.5 mg every 5 days until 150 mg for 3 weeks 2. Increase after 2 weeks to 225 mg . 3. Increase after 2 weeks to 300 mg

  25. Efficacy Comparison, Neuropathic Pain: Number-Needed-to-Treat Analyses 4.4 Lidocaine Patch 5% (Meier et al, 2003) 2.7 Opioids (Raja et al, 2002) 4.0 Tricyclic Antidepressants (Raja et al, 2002) Drug or Therapeutic Class 3.2 Gabapentin (Rowbotham et al, 1998) 5.0 Gabapentin (Rice and Maton, 2001) 5.3 Capsaicin (Sindrup and Jensen, 1999) ∞ 15 20 10 0 5 Number-needed-to-treat (NNT) Mean ±95% Cl Meier et al. Pain. 2003;106:151–158.

  26. Evidence for Disease Specificity in Efficacy Trials for NP Pain EFFICACY: SPECIFIC FOR DISEASE? • Postherpetic neuralgia • Spinal cord injury pain • Painful HIV neuropathy • Chemotherapy neuropathy • Diabetic neuropathy • Phantom tooth pain? GENERALIZED TO NEUROPATHIC MECHANISM?

  27. Lidocaine Patch 5%in Postherpetic Neuralgia 5 Observational only 0 Vehicle Change in VAS (mm) -5 ** ** -10 Active * * * * † * * * † N=35 † † -15 0.5 2 4 6 9 12 Postapplication Time (Hours) VAS=visual analog scale.*P=.0001 to P=.021, active vs observational only. **P=.016 and P=.041, vehicle vs observational only. † P<.001 to P=.038, active vs vehicle from 4 to 12 hours. Adapted from: Rowbotham MC et al. Pain. 1996;65:39-44.

  28. Analgesic Therapy in PHN: A Quantitative Systematic Review Summary based on 56 blinded RCTs: Number Needed to Treat Hempenstall K et al. PLoS Med. 2005;2:628-644.

  29. Efficacy Comparison, Neuropathic Pain: Number-Needed-to-Treat Analyses 4.4 Lidocaine Patch 5% (Meier et al, 2003) 2.7 Opioids (Raja et al, 2002) 4.0 Tricyclic Antidepressants (Raja et al, 2002) Drug or Therapeutic Class 3.2 Gabapentin (Rowbotham et al, 1998) 5.0 Gabapentin (Rice and Maton, 2001) 5.3 Capsaicin (Sindrup and Jensen, 1999) ∞ 15 20 10 0 5 Number-needed-to-treat (NNT) Mean ±95% Cl Meier et al. Pain. 2003;106:151–158.

  30. Amitriptyline in SCI pain Cardenas DD et al. Pain. 2002;96:365-373. • Sample: 84 patients with SCI and chronic pain • Design: Double-blind, RCT with amitriptyline vs. active placebo, benztropine • Results: – No significant differences were found among the groups in pain intensity or pain-related disability. – The findings do not support the routine use of amitriptyline in the treatment of chronic pain in patients suffering from SCI

  31. Nortriptyline vs Placebo in Chemotherapy-induced Painful Paresthesias Hammack JE et al. Pain. 2002;98:195-203. • Sample: 51 patients with painful paresthesias from chemotherapy -induced neuropathy • Design: 4-week, double-blind, RCT with cross-over after 1-week washout • Dose: Target dose = 100 mg/day • Outcome: – no differences in pain intensity or quality of life, slight improvement in sleep on NT – SE burden higher on NT • Conclusion: NT provides modest improvement, at best, in chemotherapy- induced painful paresthesias

  32. Chronic facial pain and depression Gallagher, R.M., Marbach, J., Raphael, K., Dohrenwend, B., Cloitre, M.: Is there co-morbidity between temporomandibular pain dysfunction syndrome and depression?: A pilot study. Clinical Journal of Pain, 7: 219-225, 1991 Gallagher, R.M., Marbach, J., Raphael, K., Handte, J., Dohrenwend, B.: Seasonal Variation in chronic TMPDS Pain and Mood Intensity Pain, 61[1]: 113-120, 1995. Dohrenwend, B., Marbach, J. , Raphael, K., Gallagher, R.M.: Why is depression co-morbid with chronic facial pain? A family study test of alternative hypotheses. Pain 83:183-192, 1999

  33. Depression and Pain Comorbidity Pain, A condition or symptom that causes or activates depression Pain Remission Recovery Response Relapse Recurrence Relapse “Normalcy” Progression to disorder Depression Symptoms DEPRESSIVE ILLNESS Acute Continuation Maintenance Treatment Phases Kupfer DJ. Depression. J Clin Psychiatry. 1991;52(suppl):28-34. Dohrenwend BP, et al. Facial Pain and depression. Pain. 1999;83(2):183-192. Gallagher & Verma, Pain and depression. Prog Pain Res Man 2004 Raphael et al, Fibromyalgia. Pain 2004

  34. CHOOSING MEDICATION Expect partial effects: use multiple agents with different mechanisms: – from different classes – from the same class

  35. 0 1 2 3 4 5 6 7 8 9 10 Target – keeping pain below 5 to enable quality of life Severe Can’t function Moderate Bothersome Mild, in background Excruciating, ER time Burning at the stake !! Just Noticeable • Improvement can be monitored • Gives clinician and patient a consistent understandable measure with intra-rater reliability that facilitates discussion regarding: changes in pain, response to treatment • Reduction of 2 points is clinically meaningful No pain Worst possible pain Adapted from Farrar JT et al. Pain. 2001;94:149-158.

  36. Algorithm for Medication Selection in Chronic Pain With and Without Comorbid Depression Neuropathicpain Nociceptivepain Pain condition +depression Secondary depression Primary D. Secondary sleepdisturbance Evaluate risks Persists afteradequateanalgesia Evaluate risks Persists afteradequateanalgesia NSAIDs,Cox-IIs,opioids, lidocaine p.? doxepin cr.? SSRI trial Evaluate risks Evaluate risks Lidocaine patch;gabapentin & other AED (Ca+ & Na+ channels); alpha 2 agonists (tizanidine, clonidine);opioids SNRIs: venlafaxine, duloxetine Antihistamine,zolpidem,etc. Trazodone Low-doseTCA Titrate TCAs (Na+ channels and SNRI) : desipramine, nortriptyline, Adapted from Gallagher RM, Verma S. Semin Clin Neurosurgery. 2004. This information concerns uses that have not been approved by the US FDA.

  37. Prioritized Problem List And Goal-oriented Management PlanOsteoarthritis, spinal stenosis in 60-year-old executive/grandmother Immediate Problems Goal Statement Plan

  38. Prioritized Problem List And Goal-oriented Management PlanOsteoarthritis, spinal stenosis in 60-year-old executive/grandmother Pivotal Problems Goal Statement Plan

  39. Prioritized Problem List And Goal-oriented Management PlanOsteoarthritis, spinal stenosis in 60-year-old executive/grandmother Background Problems Goal Statement Plan

  40. Final Thoughts • A medication that is effective in one neuropathic pain disorder may not be effective in others. But it may be, so try it. • Mechanisms of neuropathic pain may differ in different diseases and within diseases, accounting for variability in study results. • Be aware of drug interactions in patients with several chronic conditions.

  41. Final Thoughts Success in rational polypharmacy requires: • Establish appropriate goals—pain relief and quality of life • Know mechanism and disease-specific data related to efficacy • Present recommendations with confidence based upon evidence, not just charisma • Establish patient and doctor responsibilities

  42. Final Thoughts Success in rational polypharmacy requires: • Run sequential clinical trials of medications based on efficacy, SE burden and toxicity, comorbidities, ease of use, and patient adherence. • If partial effects, maintain on minimal effective dose while pursuing additional medication trials, one at a time. • Look for additive benefit of several medications, targeting different mechanisms, to obtain control of pain to improve quality of life.

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