P A I N. Learning Objectives Utilization of Topical Pain Creams. Epidemiology. Epidemiology. Is it a Problem? 4/14/18

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1 Learning Objectives Utilization of Topical Pain Creams Andy Ruiz, PharmD, MSc, FACA President/Partner Stonegate Pharmacy Review the epidemiology of pain Discuss the pharmacology of pain with emphasis on peripheral nociception Evaluate the various pharmacological agents utilized for topical pain management Given a patient case decide which therapy is most appropriate P A I N Is it a Problem? It is estimated that over 50 million people are partially or totally disabled due to pain Severe, unrelenting pain interferes with patients' quality of life, including their activities of daily living, their sleep, and their social interactions. Most elderly patients suffer from chronic pain. Most have pain in the last month of life Up to 50% of patients who are taking pain medication do not experience adequate relief Health economists from Johns Hopkins University writing in The Journal of Pain reported the annual cost of chronic pain is as high as $635 billion a year [1] This is more than the yearly costs for cancer, heart disease and diabetes. [1] Darrell J. Gaskin, Patrick Richard. The Economic Costs of Pain in the United States. The Journal of Pain, 2012; 13 (8): 715 DOI: /j.jpain

2 Percentage of US consumption of WORLDS opioid production in 2010: Hydrocodone 90% Oxycodone 80% Methadone 58% Hydromorphone 54% Fentanyl 59% Mepiridine 43% Condition Number of Sufferers Source Chronic Pain 100 million Americans Institute of Medicine of The National Academies [2] Diabetes Coronary Heart Disease (heart attack and chest pain) Stroke 25.8 million Americans (diagnosed and estimated undiagnosed) 16.3 million Americans 7.0 million Americans American Diabetes Association [3] American Heart Association [4] Cancer 11.9 million Americans American Cancer Society [5] Prevalence in the US Millions Suffering Chronic Pain Diabetes Coronary Heart Disease Stroke Cancer Prevalence in the US [2] Institute of Medicine Report from the Committee on Advancing Pain Research, Care, and Education: Relieving Pain in America, A Blueprint for Transforming Prevention, Care, Education and Research. The National Academies Press, [3] American Diabetes Association. [4] Heart Disease and Stroke Statistics 2011 Update: A Report From the American Heart Association. Circulation 2011, 123:e18-e209, page [5] American Cancer Society, Prevalence of Cancer: e_have_cancer.asp Medical Definition: What is Pain? Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. International Association for the Study of Pain, 1979 An unpleasant sensation induced by noxious stimuli and generally received by specialized nerve endings. CancerWEB,

3 Operative Definition: What is Pain? Pain is whatever the experiencing person says it is, existing whenever he/she says it does. Margo McCaffery, 1999 Acute Often obvious distress Presentation of Pain Can be sharp, dull, shock-like, tingling, shooting, radiation, fluctuating in intensity, and varying in location (occur in timely relationship to noxious stimuli) Comorbid conditions not usually present May see HTN, increased HR, diaphoresis, pallor Chronic Can appear to have no noticeable suffering Can be sharp, dull, shock-like, tingling, shooting, radiation, fluctuating in intensity, and varying in location (do NOT occur in timely relationship to noxious stimuli) Symptoms may change over time Usually NO obvious signs Emotions, Coping, and Pain Chronic pain is associated with higher levels of anger, fear, sadness, anxiety and stress, but often fewer observable outward physical changes/signs. Autonomic Response to Pain Grimacing Restlessness Guarding Increased respirations Increased heart rate Increased blood pressure Diaphoresis Pharmacology of Nociception 1. Transduction NSAIDs, Local Anesthetics & Anticonvulsants 2. Transmission Opioids, NMDA Antagonists 3. Perception Distraction, Relaxation, Imagery 4. Modulation Tricyclic Antidepressants Opioids GABA-Agonists Modified WHO Analgesic Ladder Proposed 4 th Step The WHO Ladder Step 1 Step 2 Step 3 Quality of Life Invasive treatments Opioid Delivery Pain persisting or increasing Opioid for moderate to severe pain Non-opioid Adjuvant Pain persisting or increasing Opioid for mild to moderate pain Non-opioid Adjuvant Pain persisting or increasing Non-opioid Adjuvant Pain Pain Severity

4 Pharmacology of Nociception Pharmacology of Nociception Algorithm for Chronic Pain (by Mode of Action) Proposed Mode of Action Therapeutic Category Medication Dose Route Regimen Alpha II-Agonist Hypotensive Clonidine 0.2% Lipoderm tid up to q2h prn Alpha II-Agonist Hypotensive Phenoxybenzamine 1.5-5mg/d Lipoderm qd AMPA-Na Channel Blocker Anticonvulsant Carbamazepine 10% Lipoderm tid up to q2h prn AMPA-Na Channel Blocker Anticonvulsant Gabapentin 6-10% Lipoderm tid up to q2h prn AMPA-Na Channel Blocker Anticonvulsant Gabapentin po b-tid max 800mg/d AMPA-Na Channel Blocker Anticonvulsant Gabapentin 300mg tid po 2-3gm/d AMPA-Na Channel Blocker Anesthetic Lidocaine Hcl 5-10% Lipoderm tid up to q2h prn AMPA-Na Channel Blocker Anesthetic Mexilitine Hcl 2% Lipoderm tid up to q2h prn Anti-inflammatory Corticosteroid Dex Sod Phos 2-40mg Lipoderm qd prn Anti-inflammatory Nsaids Diclofenac 2-10% Lipoderm qid prn Anti-inflammatory Nsaids Ibuprofen 20% Lipoderm qid prn Anti-inflammatory Nsaids Ketoprofen 10% Lipoderm tid prn Anti-inflammatory Nsaids Piroxicam 2% Lipoderm qd prn Calcium Channel Blocker Hypotensive Nifedipine 2-16% Lipoderm tid max 160mg/d Gaba Agonist Muscle Relaxant Baclofen 2% Lipoderm tid up to q2h prn Gaba Agonist Benzodiazepine Clonazepam 0.5-1mg S.L. qhs Increase Blood Flow Hemorheologic Pentoxifylline 2-5% Lipoderm tid prn Mu Agonist Antidiarrheal Loperamide 5-7% Lipoderm t-qid prn Mu Agonist Opiate Morphine Sulphate 10-30mg Lipoderm t-qid prn Mu Agonist Opiate Oxycodone 10-30mg Lipoderm t-qid prn NMDA-Ca Channel Blocker Antitussive Dextromethorphan 30-45mg SR po bid <400mg/d NMDA-Ca Channel Blocker Anesthetic Ketamine 50mg max 450/d Lipoderm tid may titrate NMDA-Ca Channel Blocker Anesthetic Ketamine 10-50mg/ml nasal 1-2 sprays prn NMDA-Ca Channel Blocker Anesthetic Ketamine 10% Lipoderm t-qid NMDA-Ca Channel Blocker Anesthetic Ketamine 10-30mg po or pr tid up to q2h prn NMDA-Ca Channel Blocker Muscle Relaxant Mg Cl 10-15% Lipoderm tid Substance P Analgesic Capsciacin 0.025%-2% Lipoderm t-qid prn Supplements Antiarthritic Glucosamine 10% Lipoderm q-tid Supplements Antiarthritic Glucosamine mg po q-tid Supplements Antoxidant Lipoic Acid mg po tid Supplements Analgesic Melatonin 1-10mg po qd Supplements Analgesic Methylcobolamin 1000mcg S.L. q-tid Supplements Muscle Relaxant Mg Glycinate 500mg po qd-tid Supplements Muscle Relaxant Mg Glycinate 500mg po q-tid Supplements Anti-inflammatory Omega-3 360mgEPA:240mgD po qd HA Supplements Analgesic Riboflavin mg po qd Supplements Analgesic Synergy Vitamin C 2.5-6gm po qd Tricyclic Antidepressant Antidepressant Amitriptyline 2-10% Lipoderm tid up to q2h prn Tricyclic Antidepressant Antidepressant Desipramine 2-10% Lipoderm tid up to q2h prn Tricyclic Antidepressant Antidepressant Imipramine 2-10% Lipoderm qd-qid Heir, Gary DMD, et al. IJPC 2004; 8: Alpha II Agonists Alpha II agonists have been in clinical use for decades, primarily in the treatment of hypertension. In recent years, alpha II agonists have found wider application, particularly in the fields of anesthesia and pain management. It has been noted that these agents can enhance analgesia provided by traditional analgesics, such as opiates, and may result in opiate-sparing effects. [6] This has important implications for the management of acute postoperative pain and chronic pain states. The alpha II agonists that are currently employed in compounding for pain management include clonidine and phenoxybenzamine. [6] Department of Anesthesia, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. hsmith3@caregroup.harvard.edu AMPA-Na Channel Blocker A number of lines of evidence suggest that AMPA receptor antagonists may have a role in attenuating features of neuropathic pain via the blockade of glutamate. Davar and colleagues described the prevention of hyperalgesia development in the chronic constriction injury (CCI) model by continual pre- and post-injury i.p. administration of the AMPA receptor antagonist MK-801.[7] AMPA-Na Channel Blocker Gabapentin Pts with central & peripherally mediated pain, migraine, and tremor were treated in an open-label study with GP, max. of 2,700 mg/day [8] 39 pts (65%) had moderate-to-excellent results, the best response in pts with peripheral pain [8] [7]Davar G, Hama A, Deykin A, Vos B, Maciewicz R. MK-801 blocks the development of thermal hyperalgesia in a rat model of experimental painful neuropathy. Brain Res 1991; 553: [8] Merren MD, Gabapentin for treatment of pain and tremor: a large case series, South Med J 1998 Aug; 91(8):

5 AMPA-Na Channel Blocker Gabapentin Other conditions that showed some improvement were benign essential/familial tremor, Restless Legs Syndrome, centrally mediated pain, and periodic nighttime leg movements [9] Carlton: GP has a peripheral site of action & may offer a novel therapeutic agent for topical treatment of pain [10] [9] Merren MD, Gabapentin for treatment of pain and tremor: a large case series, South Med J 1998 Aug; 91(8): [10] Carlton SM, Zhou S, Attenuation of formalin-induced nociceptive behaviors following local peripheral injection of gabapentin, Pain 1998 May;76(1-2):201-7 Anti Inflamatory NSAIDS Blockade of Cox-1 and Cox-2 enzymes. These enzymes play a key role in making prostaglandins. decrease prostaglandin production = less swelling and less pain. Anti Inflamatory Corticosteroids Glucocorticoids reduce pain by inhibiting prostaglandin synthesis, which leads to inflammation, and reducing vascular permeability that results in tissue edema. Ex. dexamethasone sodium phosphate Calcium Channel Blocker calcium channels have been recognized as key targets in controlling pain through modulation of the entry of calcium into neurons. [11] When a pain signal is initiated, calcium channels open and the influx of calcium ions trigger the release of neurotransmitters, which thereby potentiates the signal to the brain where it is perceived as pain. Ex. Nifedipine 2-16% [11] Vanegas H, Schaible H. Effects of antagonists to high-threshold Ca channels upon spinal mechanisms of pain, hyperalgesiaand allodynia. Pain. 2000;85(1-2):9-18. Gaba Agonist A lack of inhibition, particularly that mediated by gamma-amino butyric acid (GABA) is responsible for many pain states. The inhibition of pain transmission via GABA receptor activation is the mechanism by which pain is relieved Ex. baclofen, clonazepam MU Agonist The opioid system controls pain, reward and addictive behaviors. Opioids exert their pharmacological actions through three opioid receptors, mu, delta and kappa. When an opioid binds to the mu-receptor it induces a change in shape which in turn induces a change in the ion channels of the associated cell membrane mu-receptor activation opens the ion channel allowing potassium ion outflow causing hyperpolarization. This hyperpolarization causes difficulty for an action potential to be reached and decreases the firing of the neuron. Ex. Morphine, oxycodone 5

6 NMDA-Ca Channel Blocker The NMDA receptor is an ionotropic receptor that allows for the transfer of electrical signals via calcium influx Blocking the NMDA receptor decreases the neurons ability of potentiating a signal and decreases pain [12] NMDA-Ca Channel Blocker It is clear that NMDARs are critically involved in the induction and maintenance of neuronal hyperexcitability after noxious events. Until recently, only central NMDARs were a primary focus of investigations. With the recognition of peripheral somatic and visceral NMDARs, it is now apparent that the role of NMDARs in pain is much greater than previously thought. [13] [12] Kim AH, Kerchner GA, Choi DW (2002). "Blocking Excitotoxicity". In Marcoux FW, Choi DW. CNS Neuroprotection. New York: Springer. pp [13] Petrenko, Andrei B. MD; Yamakura, Tomohiro MD, PhD; Baba, Hiroshi MD, PhD; Shimoji, Koki MD, PhD, FRCAThe Role of N-Methyl-d-Aspartate (NMDA) Receptors in Pain: A Review Anesthesia & Analgesia: October Volume 97 - Issue 4 - pp Tricyclic Antidepressants TCAs that inhibit the reuptake of norepinephrine or both norepinephrine and serotonin, such as amitriptyline and desipramine, have demonstrated efficacy in the treatment of chronic pain conditions such as diabetic neuropathy, fibromyalgia, chronic headaches, and post-herpetic neuralgia [14]. Tricyclic Antidepressants Their ability to relieve pain in these conditions appears to be independent of their antidepressant effect and may be directly related to their effect on neuronal reuptake of serotonin and norepinephrine and in part by the increased duration or concentration of serotonin and norepinephrine in synapses associated with central pain integration [15]. [14] Onghena P, Van Houdenhove B. Antidepressant-induced analgesia in chronic non-malignant pain: a meta-analysis of 39 placebo-controlled studies. Pain. 1992;49: [PubMed] [15] McHugh JM, McHugh WB. Pain: neuroanatomy, chemical mediators, and clinical implications. AACN Clin. Issues. 2000;11: [PubMed] Route Oral Rectal Sub lingual Topical / Transdermal Medications Class Quantity Timing Route Oral Tablets / Capsules Sustained release Immediate release Special patient considerations 6

7 Route Rectal suppositories BASE TYPE Immediate release Special patient considerations Route Sub Lingual Liquid drops Rapid Dissolve Tablets Avoid 1 st pass metabolism Immediate release Special patient considerations Topical Route: Advantages Avoids the GI tract and hepatic first-pass metabolism Reduces systemic side effects Improves compliance Allows concentration of Rx at site of application Plasma concentrations of <10% compared to oral route Topical Route: Drawbacks Variations in the stratum corneum barrier Delivery dosing may require adjustment Rate of absorption may vary Rash is most common SE May be difficult when treating larger areas [16] Heir, Gary DMD, et al. IJPC 2004; 8: Heir, Gary DMD, et al. IJPC 2004; 8: Electronic and Electro Mortar & Pestles The electronic mortar & pestle provides pharmacists with the modern way to compound creams, gels, ointments and suspensions. Ointment Mill The ointment mill mixes powders, crystals and creams into a smooth, finished product 7

8 Examples of MOA Norepinephrine / serotonin inhibitors TCAs, Amitriptyline Na channel Anti-arrhythmics, Anticonvulsants Ca Channel Nifedipine NMDA antagonists (the Ca channel) Ketamine, DM, Amantadine, Orphenadrine COX-II inhibitors - NSAID s Ketoprofen, piroxicam Examples of MOA Substance P inhibitors Capsaicin, Opioids Alpha-2 Agonists Clonidine Alpha-1 Antagonists Prazosin, Phentolamine Modalities of Topical Pain Treatment NSAID s ketoprofen, piroxicam, meloxicam Treat pain and inflammation Higher drug levels at site of application Eliminate GI distress and complications Neuropathic agents Gabapentin Treats neuropathic pain as a AMPA-Na Channel Blocker Examples Anesthetics Before Needle Sticks / Laser treatments Benzocaine 20%/Lidocaine 6%/Tetracaine 4% Phenylephrine HCl 0.01% Topical PLO Why phenylephrine? Examples Neuropathic Pain Amitriptyline HCl 2%/Baclofen 5%/Ketamine HCl 5%/Ketoprofen 10% in PLO Transdermal Gel Amitriptyline HCl 2%/Baclofen 2% PLO Transdermal Gel Ketoprofen 20%/Ibuprofen 2%/Ketamine 2%/Clonidine 0.2%/ Amitriptyline HCl 2%/Guaifenesin 2% Topical Lipoderm Baclofen 5%/Ketoprofen 10%/Lidocaine 5%/Gabapentin 5% Topical Lipoderm Ketamine 10%/Gabapentin 6%/Clonidine 0.2%/ Nifedipine 2% Topical Lipoderm Gabapentin 10%/Clonidine HCl 0.2%/Baclofen 1% Topical Anhydrous Lipoderm Rheumatoid Arthritis / Joint Pain Ketoprofen 10% in PLO Transdermal Gel Soft Tissue Inflammation Ibuprofen 20% PLO Transdermal Gel Diclofenac Sodium 10% PLO Transdermal Gel Ibuprofen 20%/Piroxicam 1% PLO Transdermal Gel 8

9 Multiple Modalities of Treatment Ketoprofen 20%/Ibuprofen 2%/Ketamine 2%/ Clonidine 0.2%/Amitriptyline 2% Ketoprofen NSAID Ibuprofen NSAID Ketamine - NMDA Receptor Antagonist Clonidine - Alpha -2 Agonist Amitriptyline - NE Reuptake inhibitor Need More Information? Andres Ruiz, PharmD, MSc, FACA President/Partner Stonegate Pharmacy andyruiz@stonegaterx.com 9