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Polypharmacy Approach for Pain Management Tracy M. Hagemann, Pharm.D., FCCP, FPPAG October 5, 2012 Objectives • Define polypharmacy as it relates to pain management • Identify patients at high risk for adverse effects with polypharmacy • Identify indications for the rational use of polypharmacy in treating acute and chronic pain What is it? Definition polypharmacy /poly·phar·ma·cy/ (-fahr´mah-se) • 1. administration of many drugs together. • 2. administration of excessive medication. – Duplication – Potentially inappropriate medications Dorland's Medical Dictionary for Health Consumers. © 2007 Polypharmacy and Pain • Multiple medications to treat a single condition • Using multiple drugs from the same class or multiple drugs with a similar mechanism of action to treat different conditions • Generally the RULE rather than the exception, especially for chronic pain When is it appropriate? • Not all polypharmacy is inappropriate – Co-morbidities – Different mechanistic pathways – Treatment of side effects Who is at risk for adverse events? • Those with co-morbidities • Older patients • Patients who are non-adherent to their medication/treatment regimens Rational Polypharmacy • Multimodal approach – achieve pain relief with minimal toxicity • Goals: – Use lower doses of > 1 drug to minimize adverse effects – Increase adherence – Maintain analgesic efficacy to prevent pain – Increase efficacy using > 2 drugs with different mechanisms of action – Target different but associated symptoms – Target different locations of the disease process Barriers to Rational Polypharmacy • Drug-Drug Interactions • Drug-Disease Interactions • Medication abuse, misuse and addiction Pain Medication Arsenal • Non-opioids • Opioids • Adjuvants – Anti-anxiety – Anti-depressant – Neuropathic pain treatments • Anticonvulsants (i.e. gabapentin) – Steroids – Topicals • Side effect management – Constipation – Nausea/vomiting – Sedation Considerations for Rational Polypharmacy • Know drug toxicities • Avoid overlapping/additive toxicities • Know drug mechanisms of action • Understand drug pharmacokinetics • Have convincing evidence that the combination is more effective than monotherapy Patient Factors • Age • Gender • Ethnicity Age • Physiologic aging impacts pharmacokinetics • Increased risk of drug-drug interactions with multiple drug use • Aging affects pharmacodynamics – Affects at receptor sites – Number of receptors binding capacity and biochemical reactions Age - Recommendations • Initiate treatment at lowest effective dose • Give as small a dose as possible for long-term therapeutic effect • Make SLOW changes in medications and doses Gender • Women use more medications – 4.8 Rx meds vs. 3.8 Rx meds – 81% vs. 74% – 12% of women over 65 years of age take at least 10 medications • 23% take at least 5 prescription medications Jorgensen et al 2001 Linjakumpu et al 2002 Kaufman et al 2002 Ethnicity • Associations – Ethnicity and other diseases like HTN, CV, malignancy – Ethnicity and drug metabolism (CYP 2D6) • 5-10% of Caucasians and 1-2% of African Americans and Asians are poor metabolizers – More likely to have frequent adverse events with standard doses • Fast Metabolizers – 10-15% Ethiopians and Saudi Arabians – 1-5% Caucasians – 2% African Americans – 0-2% Asians – More likely to have subtherapeutic effects with standard doses Drug-Related Variables • Mechanism of action/pharmacodynamics • Efficacy • Dosage forms available • Pharmacokinetics • Adverse effects • Drug Interactions • Cost Indications and Examples Indication #1 • To reduce drug intolerance by using a 2nd drug that allows a lower dose of 1st drug • May lead to increased adherence • Provide analgesic efficacy at certain times of day (giving IR with long-acting drugs) – Control breakthrough pain in a patient taking longacting opioids Indication #2 • To use a lower dose of a drug by using a 2nd drug – Example: opioid-sparing strategies, addition of anti-inflammatories Indication #3 • To address partial or non-response to 1 drug by adding a 2nd drug to increase efficacy – Example: use 2 medications with different mechanisms of action – Example: use a medication that has synergy with the 1st medication • Add an NMDA-type medication to a regimen containing an opioid Indication #4 • To target different symptom clusters that are a product of the disease or a comorbid disease – Example: pain associated with depression – Example: pain worsened by anxiety Indication #5 • To treat the comorbid disease by aggressively treating the index disease – Example: treat diabetes aggressively thereby reducing peripheral neuropathy severity Indication #6 • To address different locations of the disease process – Example: pain that has peripheral AND central mechanisms may require medications that use each pathway – Example: topical lidocaine patch with an antidepressant Indication #7 • To treat an adverse effect – Nausea/vomiting – Itching – Sedation – Constipation Approach to Rational Polytherapy • Consider: – Pain and non-pain medications – Prescription, OTC and homeopathies/others – PK/PD profile of all used medications – Therapeutic index of each medication – Route of elimination of the medications – Patient’s health status 5 Principles for Pain-Associated Comorbidity • Use drugs for comorbid disease that have proven analgesic efficacy • Your 1st target symptom should always be PAIN • Target all possible pain mechanisms • Do not shoot for absolute pain relief – Aim for tolerable pain levels (QoL) • Use drugs to address more than one comorbidity – Example: Sedating antidepressant for pain, sleep and depression Prescribing Guidelines for Polypharmacy • Anticipate the impact of adding the new medication • Avoid – Prescribing medications that significantly inhibit or induce CYP450 enzymes Prescribing Guidelines for Polypharmacy • Prescribe medications that: – Are eliminated through multiple pathways – Do not have serious consequences if their metabolism is prolonged – With different mechanisms of action from the patient’s existing medications Prescribing Guidelines for Polypharmacy • Remind patients to tell you when other physicians prescribe medications for them • Remember – Metabolism can create active or more active compounds that the parent drug – Generally, the older the medication, the less is known about it’s metabolism S.A.I.L. • SIMPLIFY the drug regimen as much as possible • Know the ADVERSE EFFECTS of each drug and the drug-drug interactions • Each medication should have a clear INDICATION and well-developed therapeutic goal • LIST the name and dosage of each medication in the chart and provide this information to the patient. Selected References • Werder SF, Preskorn SH. Managing polypharmacy: walking the line between help and harm. J Fam Prac 2003;2(2) • Maggiore RJ, Gross CP, Hurria A. Polypharmacy in older adults with cancer. The Oncologist 2010;15:507-22. • Chaparro LE, Wiffen PJ, Moore RA, Gilron I. Combination pharmacotherapy for the treatment of neuropathic pain in adults. Cochrane Database 2012;7:Article #:CD008943 • Gallagher RM. Rational integration of pharmacologic, behavioral, and rehabilitation strategies in the treatment of chronic pain. Am J Phys Med Rehabil 2005;84(3Suppl):S64-76. • Al-Shahri MZ, Molina EH, Oneschuk D. Medication-focused approach to total pain: poor symptom control, polypharmacy, and adverse reactions. Am J Hosp Palliat Care 2003;20:307-310. • Smith H, Bruckenthal P. Implications of opioid analgesia for medically complicated patients. Drugs Aging 2010;27(5):417-33. • Pergolizzi JV, Labhsetwar SA, Puenpatom RA, et al. Exposure to potential CYP450 pharmacokinetic drug-drug interactions among osteoarthritis patients: incremental risk of multiple prescription. Pain Practice 2011;11(4):325-36.