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 Goals of This Presentation 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 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 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 Public Health Challenge How 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 THE END: CPRS Pain Cycle Challenges of OEF/OIF Veteran Cohort Recent evidence suggests that access to pain treatment after severe limb trauma leads to better outcomes. 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.” Gabapentin in the Treatment of Postherpetic Neuralgia What happens above the spinal cord? Pain is conditionable: Expectation of Pain Activates the Anterior Cingular Gyrus Serotonin and Norepinephrine in Depression and Pain DIAGNOSIS There Are Many Painful Diseases and Pain Diseases Recognizing Neuropathic Pain Pain Drawing & Neuropathy Types Numerical Rating Scale: Monitoring Patient Progress • 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 Efficacy – Medication Trials Disease specific vs Mechanism specific Effect of Medications on Pain in a Preclinical Model of Persistent Neuropathic Pain Efficacy in Neuropathic Pain Tricyclic Antidepressants 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 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 Efficacy Comparison, Neuropathic Pain: Number-Needed-to-Treat Analyses 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? Lidocaine Patch 5% in Postherpetic Neuralgia Efficacy of Controlled-Release Oxycodone in Postherpetic Neuralgia (N=50) Analgesic Therapy in PHN: A Quantitative Systematic Review Summary based on 56 blinded RCTs: Efficacy Comparison, Neuropathic Pain: Number-Needed-to-Treat Analyses 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 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 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 Depression and Pain Comorbidity CHOOSING MEDICATION Expect partial effects: use multiple agents with different mechanisms: – from different classes – from the same class Target – keeping pain below 5 to enable quality of life • 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 Algorithm for Medication Selection in Chronic Pain With and Without Comorbid Depression Prioritized Problem List And Goal-oriented Management Plan Osteoarthritis, spinal stenosis in 60-year-old executive/grandmother Prioritized Problem List And Goal-oriented Management Plan Osteoarthritis, spinal stenosis in 60-year-old executive/grandmother Prioritized Problem List And Goal-oriented Management Plan Osteoarthritis, spinal stenosis in 60-year-old executive/grandmother 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. 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 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.