Thinking outside the box: non-opiate pain medications and Customized medication options Dawn Ipsen, PharmD, Owner Kusler’s Compounding Pharmacy Snohomish, WA dawn@kuslers.com 360-568-1297 AANP Annual Convention July 27, 2016

Disclosure Compounded medications are “off-label” uses of FDA-approved drugs. No financial conflict of interest exists. When the FDA approves a specific drug as safe and effective, this determination applies only to the specific disease or condition for which the drug was tested. But physicians often prescribe medications for treatments for which they have not been specifically approved. Medical professionals do this because, in their judgment, the treatment is in the best interest of the individual patient.   Similarly, medical professionals often prescribe compounded medications because they believe it is the best medical option for their patients. It is estimated that one fifth of all prescriptions written for FDA-approved drugs are for uses for which they were not specifically approved.

objectives What is pain? Types of pain and pain assessment Background behind compounded medication recommendations Topical vs. Transdermal Categories of medications to consider Treatment approach techniques Patient case example

What is pain? McCaffery 1968 “Whatever the experiencing person says it is, existing whenever she/he says it does.” Subjective International Association for the Study of Pain “Unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” Complex and multi-dimensional 100-115 million US adults suffer from common chronic pain. Annual cost $600 million

Types of pain Acute Pain Alarm system, useful pain Short term, self-limiting Response to tissue trauma Resolves with healing and goal is to cure Nociceptive (may be neuropathic) May become chronic

Types of pain Chronic Pain Often 3-6 months or greater Pain extending past healing; cause not present Multi-dimensional; insomnia is common component Nociceptive, neuropathic, or both Goal is to rehabilitate and improve quality of life

Nociceptive pain Peripheral transduction from receptors Release inflammatory mediators Examples: burns, cuts, arthritis, tendonitis, appendicitis, post-op, pancreatitis, mechanical low back Sharp, pricking, burning, dull, aching, cramping Peripheral transduction from receptors in the skin, muscle, viscera, teeth, blood vessels, bones/joints Injury to tissue leads to release of inflammatory mediators Examples: burns, cuts, arthritis, tendonitis, appendicitis, pancreatitis, post-op, mechanical low back Described as: sharp, pricking, burning, dull, aching, cramping

Neuropathic Pain Nervous system injury or impairment Effecting signal processing Pain that serves no purpose Examples: neuropathy, phantom limb, trigeminal neuralgia, complex regional pain syndrome (CRPS) Burning, tingling, prickling, shooting, jabbing, electric shock-like, squeezing, deep aching, spasm, cold Nervous system injury or impairment effecting signal processing of peripheral or central nervous system that leads to pain that serves no purpose Causes: diabetic neuropathy, post-herpetic neuralgia, neuropathic low back, phantom limb, trigeminal neuralgia, complex regional pain syndrome Described as: burning, tingling, prickling, shooting, jabbing, electric shock-like, squeezing, deep aching, spasm, cold

Name that pain 42yo male presents to your clinic with pain that is described as burning, sharp and shooting pain that radiates from his low back and down his right leg. This started 6 months ago as the result of an overly aggressive basketball game. Acute or Chronic? Nociceptive, Neuropathic or Both?

Pain Assessment Pain assessment: P (provokes), Q (quality), R (radiates), S (severity), T (timeline) Pain scale: Active and at Rest

Pain Assessment Dermatome mapping – ‘show me where you hurt’

Assessment quiz True or False: It is important to assess both pain at rest and pain while active when quantifying the level of pain a person may be experiencing.

Transdermal vs. topical Penetration into the skin only Superficial or localized effect Minimal systemic effects Creams, lotions, gels, ointments, liquid spray, etc. powder spray, troche, medicated lollipop, mouthwash, enema

Customized Transdermal Options Penetration of drug(s) through the skin into the systemic circulation Bypass 1st-pass effect Local peripheral action Ability to combine multiple MOA in 1 delivery Less adverse effects than oral medications LipodermTM, Pluronic Lecithin Organogel (PLO), VanPenTM, Anhydrous Gels

Drug categories to consider NSAID’s Muscle relaxants Anticonvulsants Tricyclic antidepressants Anesthetics Alpha-2 agonist

NSAID’s Diclofenac, Ketoprofen, Piroxicam, Flurbiprofen, Ibuprofen, etc. MOA: Inhibit all cyclooxygenase (COX) activity Reduces production of prostaglandins Indications: Nociceptive pain Acute inflammation

Nsaid’s Ibuprofen Diclofenac potassium Piroxicam Side effects: 200-400mg po Q4-6H prn; max 1200mg/day for 10 days unless directed by prescriber Diclofenac potassium 25-50mg po TID; max 100-150mg/day Piroxicam 20mg/day po as single dose or divided Side effects: Hypertention; gastrointestinal bleeding and ulcers; liver toxicity; hearing loss; worsening of asthma; rash; SJS…

NSAID’s Evidence for Transdermal Application: Diclofenac commercially available topically Several transdermal NSAID’s licensed in UK Diclofenac, ibuprofen, ketoprofen, piroxicam Ketoprofen and diclofenac have the most evidence NSAID’s commonly used for peripheral analgesia by decreasing inflammation (Merry, et al. 1995) Ibuprofen can increase the absorption of other drugs – ionic surfactant (J Control Release 2004 Nov 24)

Nsaid’s Evidence for Transdermal Application Somberg JC, Molnar J. American Journal of Therapeutics. 2015(22):342-49. A retrospective study of 2,177 patients in 3 groups Cream I: Flurbiprofen 20%, Tramadol 5%, Clonidine 0.2%, Cyclobenzaprine 4%, Bupivicaine 3% Cream II: Flurbiprofen 20%, Baclofen 2%, Clonidine 0.2%, Gabapentin 10%, Lidocaine 5% Voltaren gel Pain decreased by 35%-37% vs. 19% Voltaren gel Adverse effects <2% for both compounded creams

Muscle relaxants Baclofen, Cyclobenzaprine, Guaifenesin MOA: Baclofen – Gaba-b receptor agonist; muscle relaxant and anti-spastic properties Cyclobenzaprine – Structurally related to TCA’s Indications: Trigeminal neuralgia Nociceptive pain Fibromyalgia

Muscle relaxants Baclofen: Cyclobenzaprine: Side effects: For spasticity 5mg po TID; may increase by 15mg/day q3 days; max 80mg/day (divided) Cyclobenzaprine: For muscle spasm 5mg po TID; may increase to 10mg po TID for up to 2-3 weeks Side effects: Drowsiness; constipation; nausea; dry mouth; dizziness; cardiac changes; edema; abnormal liver function

Muscle relaxants Evidence: Barton, et al. 2010 Adjunct with carbamazepine and phenytoin for TMJ (Baker, et al. 1985)

anticonvulsants Gabapentin, Carbamazepine MOA: Gabapentin – block glutamate (NMDA calcium channel) Carbamazepine - Block sodium channels AMPA Effects GABA

anticonvulsants Indications: 1st line for neuropathic pain Post-herpetic neuralgia Diabetic peripheral neuropathy Trigeminal neuralgia Mixed neuropathic pain Phantom limb Spinal cord injury Combo therapy only? 1st line agent for neuropathy

Anticonvulsants Evidence for transdermal application 2014 retrospective study of Gabapentin 6% in 23 patients. 20/23 benefited from topical 11/23 clinically meaningful pain reduction (>30%) 2008 retrospective study Gabapentin 2%-6% cream in 35 women with vulvodynia. Pain scores decreased by average 4.77 points 80% demonstrated at least 50% improvement in pain scores.

anticonvulsants Gabapentin Carbamazepine 300mg day 1, 300mg BID day 2, 300mg TID day 3; may increase to 1,800mg/day (divided TID) Carbamazepine 100mg BID day 1, may increase by 100mg q12h prn pain control; max 1,200mg/day

anticonvulsants Side effects: Gabapentin: Peripheral edema, nausea/vomiting, viral illness, ataxia, dizziness, nystagmus, somnolence, hostile behavior, fatigue, fever, SJS Carbamazepine: Hypotention, pruritus, rash, constipation, nausea/vomiting, xerostomia, asthenia, ataxia, dizziness, somnolence, blurred vision, nystagmus, AV block, CHF, SJS, metabolic imbalance, bone marrow depression, liver toxicity, angioedema…

Tricyclic antidepressants Amitriptyline, Desipramine and others MOA: Blocks re-uptake of norepinephrine & serotonin Effects on NMDA receptors, glutamate, sodium, potassium, calcium channels Indications: Peripheral diabetic neuropathy Post herpetic neuralgia Headache Facial pain Myofacial pain MOA: Blocks re-uptake of norepinephrine therefore down regulating nerve transmission

Tricyclic antidepressants Amitriptyline: 10-25mg po HS; may increase weekly to max 150-200mg/day Desipramine: 100-200mg/day po (single or divided doses) Nortriptyline: 25mg po TID-QID or single daily dose; max 150mg/day Side effects: Sedation; Weight gain; constipation; dry mouth; dizziness; headache; blurred vision; EKG changes; Liver toxicity; depression

Tricyclic Antidepressants Tricyclic and tetracyclic antidepressants (TCAs)•• Drug Anticholinergic Drowsiness Insomnia/Agitation Orthostatic hypotension QTc prolongation* Gastrointestinal toxicity Weight gain Sexual dysfunction Amitriptyline 4+ 3+ 1+ (all TCAs see••) 3 to 4+ Amoxapine 2+ ND Clomipramine 1+ Desipramine Doxepin Imipramine Maprotiline Nortriptyline Protriptyline Trimipramine •• Gastrointestinal forms of anticholinergic side effects include: dry mouth, constipation, epigastric distress, decreased esophagogastric tone. Refer to "Anticholinergic" data for frequency rankings. * Risk of QTc prolongation or torsades de pointes is also elevated with advanced age, female sex, heart disease, congenital long QT syndrome, hypokalemia or hypomagnesemia, elevated serum drug concentrations (eg, drug overdose, interacting drugs, organ failure) and combination of drugs with QTc prolonging effects. Refer to topic on acquired long QT syndrome. Up To Date; 2014

Tricyclic antidepressants Evidence for Transdermal Application: Retrospective study Somberg JC, Molnar J, et al. American Journal of Therapeutics 2015(22):214-221. Amitriptyline 4%, Baclofen 2%, Bupivicaine 2%, Clonidine 0.2%, Gabapentin 6%, Ketamine 10%, Pentoxifylline, Tranilast +/- Nifedipine 2% in “Topical Cream” 208 patients Reduction in pain scores 35%-40% Excellent or good effect reported 70%-82% Reduction in oral pain medications 35% Avoidance of pain specialist referral 53% Patients did the best when the cream was used roughly 3-4 times daily. Adverse events were rare (5.7%) and mild or moderate in severity. (skin irritation, burning sensation, rash, flushing) Adding the calcium channel blocker, nifedipine, did not improve efficacy significantly.

Tricyclic antidepressants Evidence for Transdermal Application: A double-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA Barton DL, Wos EJ, et al. Support Care Cancer 2011(19):833-841 Amitriptyline 4%, Baclofen 1%, Ketamine 2% in PLO vs. placebo up to 4gm BID 208 patients Well tolerated and no detectable blood levels Statistically significant improvement in neuropathy

Tricyclic antidepressants Evidence for Transdermal Application: Topical amitriptyline, ketamine, and lidocaine in neuropathic pain caused by radiation skin reaction: a pilot study Uzaraga I, Gerbis B, et al. Support Care Cancer 2012 (20):1515-1524 Prospective, single-arm, cohort pilot study Compliance and effects 4ml of AKL in PLO TID through treatment Significantly reduced pain, both short and long term

Tricyclic antidepressants Evidence for Transdermal Application: Topical amitriptyline and ketamine in neuropathic pain syndromes: and open label study Lynch ME, Clark AJ, et al. The Journal of Pain, Vol. 6, No 10 (October), 2005:664-649 28 study subjects Amitriptyline 2% / Ketamine 1% in proprietary base Up to 4ml TID Decreased pain scores at 6 months (34%) and 12 months (37%) Minimal adverse effects and minimal systemic absorption

anesthetics Lidocaine, Tetracaine, Benzocaine, Bupivacaine, Prilocaine, others MOA: Decreased ionic flux through nerve membrane Stabilizing nerve cell membrane potential Blocks initiation and conduction of nerve impulse Indications: Post herpetic neuralgia Diabetic neuralgia Burn Generalized pain (sodium) Lidocaine is second line agent for localized peripheral neuropathy and postherpetic nerualgia

anesthetics Lidocaine 5% extended release topical patch Side effects: Apply up to 3 patches topically at one time, for up to 12 hours within a 24-hour period. Usually only 1 patch applied at a time. Side effects: Hypotension; nausea; cardiac arrest; cardiac dysrhythmia

anesthetics Evidence for Transdermal Application: Commercially available as patch Uzarage, et al. 2011 study Lidocaine absorption study dependent on concentration, time of application, salt vs. base, and solvents used (Akerman, et al. 1979) The lidocaine patch 5% effectively treats all neuropathic pain qualities: results of a randomized double-blind, vehicle-controlled, 3-week efficacy study with use of the neuropathic pain scale. Galer BS, et al. Clin J Pain 2002(18):297-301.

Alpha-2 agonist Clonidine MOA: Reduces sympathetic CNS outflow Inhibit glutamate Inhibit substance P Activate serotonin

Alpha-2 agonist Indications: Evidence for Transdermal Application: Neuropathic pain Synergistic with other agents Prevent NMDA antagonist problems Hyperalgesia CRPS diagnosis Evidence for Transdermal Application: Following nerve injury, sympathetic stimulation can excite primary afferent fibers via alpha-adrenoceptors (McLachlan, et al. 1993)

Alpha-2 agonist Evidence for Transdermal Application: Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy. Campbell CM, Kipnes MS, et al. Pain. 2012 Sep; 153(9):1815-23 Randomized, double-blind, placebo-controlled, parallel-group, multicenter Nociceptive response tested 0.1% clonidine gel vs. placebo TID x 12 weeks Significantly reduced foot pain in patients with functional nociceptive response.

Evidence based medicine please Which of the following lists of medications appear to have some, if limited, evidence based medicine supporting their use as a possible transdermal treatment for pain? A) Cyclobenzaprine, baclofen B) Gabapentin, amitriptyline, clonidine C) None of the above D) All of the above

Treatment approach Acute vs. Chronic Look closely at oral (traditional) therapies both current and past Analyze current medication and supplement list Lifestyle and Supplement considerations Look for 3+ different MOA’s for best results with compounded transdermal therapies Patient counseling Fair expectations Proper application and dosing Who, What, When, Where, How and Why Acute vs. Chronic Consider NSAID at least short term (about 2 weeks) Look closely at oral (traditional) therapies both current and past Partial responses? Limited by side effects? Analyze current medication and supplement list Do not change current oral therapies Watch max doses for some drugs (NSAID’s, gabapentin) Look for 3+ different MOA’s for best results

Dermatomes Helpful for medication application Apply where it hurts? Where is the source or cause of the pain?

Pain…A complicated matter bending treatment walking worried burning working better sleep feels lasts dull pain gnawing Shooting medicine cramping aches sharp day sciatic radiating support pulsating stabbing head Gets worse when bothering knees stiffness

Patient case example 49 yo female referred by local pain specialist MD for pharmacy consult Fell off 25-30 foot ladder 3 years prior Shattered right heel and ankle extending up into tibia and fibula 3 surgeries since injury No work, no hobbies, can’t drive longer than 1 hr.

Patient case example Aggravators: standing, walking, weight bearing pressure Alleviators: include elevation and rest Allergies: sulfa’s, oxycodone, codeine, hydrocodone Concomitant medical conditions: depression, anxiety, fibromyalgia

Patient case example (cont.) Medications, supplements, over-the-counters, etc. Omega fish oil Chromium picolonate Sertraline 100mg tid B complex Bupropion SR 150mg bid Calcium Acacia berry Atenolol 25mg am Vitamin D 20,000IU daily Clonazepam 0.5mg bid Gabapentin 600mg tid OTC’s creams and medications barely help Baclofen prn Methocarbamol prn Arnica gel is useful Multivitamin Medical Marijuana helps Atenolol 25mg am (anxiety) Chromium picolonate (sugar cravings) Methocarbamol prn (causes drowsiness)

Patient case example (cont.) Pain scores: Active: 7-9 (primarily 7); Rest: 5-6 Subjective description: Stiff, painful, freezing cold areas and burning areas, ‘falls asleep’, nerve firing, intense dull pain, burning, bone-on-bone grinding, pressure pain on heel, shoots up leg, arthritic

Patient case questions Acute or chronic? Nociceptive, neuropathic or both? Medications for transdermal therapy to consider?

Patient case example (cont.) Plan: Ketoprofen 10%, Gabapentin 10%, Amitriptyline 2%, Baclofen 2% in Lipoderm® cream 1-2 pumps to affected area 3-4 times daily.

Patient case example (cont.) 1 week pharmacist follow-up: Dizzy/floating feeling first couple doses Settled at 1 pump BID 40% reduction of pain during activity 80% reduction of pain during rest Her quality of life and daily activities have greatly improved!! Patient is very pleased with outcome!

Summary thoughts Improving lives one patient at a time Be a patient advocate Listen to what patients have to say Know what is important to your patient What are their ‘pains’, what are their ‘joys’ This is their journey and you can have a positive impact along the way!

Kusler’s Compounding Pharmacy Thank you! Dawn Ipsen, PharmD Kusler’s Compounding Pharmacy 700 Avenue D, Suite 102 Snohomish, WA 98290 (360) 568-1297 dawn@kuslers.com