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Dr. Lucas K. Nyabero, PharmD

Disclosure •  I have nothing to disclose.

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Overview Ø Background Ø Safety & Efficacy Ø Case Studies on Topical Pain Control Ø Review Specific Compounds and why they work Ø Tool-kit: how to use in your practice 3

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Self Assessment Questions •  I will consider prescribing a pain patch –  (1) Yes

(2) No

(3) Maybe

•  I will consider prescribed a pain/numbing cream –  (1) Yes

(2) No

(3) Maybe

•  I have increased confidence that topical pain control route works –  (1) Yes

(2) No

(3) Maybe

•  I prefer oral over topical –  (1) Yes

(2) No

(3) Maybe 4

Background •  Pain is complicated and very subjective •  21-30% (NHI Survey) Adults reports pain lasting > 24hrs last month –  27% Low back pain –  15% Headaches and migraines –  15% Neck pain –  4% Facial pain

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Background •  260 million opioid prescriptions in 2012 (individualistic pain standard care!) •  Pain cost US economy $635 Billion/ year in productivity cost •  Chronic pain is the most common cause of disability •  100,000 patients admitted to hospital annually for NSAID related complications with a 5% mortality 6

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Pain •  We all agree that: –  Pain is a highly complex Multifaceted concept –  With a complex Individual perception –  Has a Cognitive component –  Has a Physical component –  Has an Emotional Component

•  Therefore calls for more individualized attention and a multifaceted treatment plans

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Current Regiments •  Current pain management is heavily relies on –  Oral route –  Parental route

•  Less on Topical route –  Topical will mostly be a patch –  Standard topical creams most Lidocaine related

•  Compounding provides room to individualize care 8

Challenges of Oral Agents •  •  •  •  •  •  •  •  • 

Gastro intestinal Renal Hepatic Cardio-vascluar Sedation and decreased cognitive Respitory depression Abuse and Addiction potential Decreasing efficacy hence higher doses Non-Compliance 9

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Compounded Preparation •  Compounded preparations include: –  Topical Creams –  Topical Gels –  Suppositories –  ODT/RDT preparation –  Patches –  Some oral

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Oral Vs Topical •  Oral pain regiment has been and is still considered as the gold standard so much so that majority of research dollars are devoted to developing more oral agents and fewer on topical. •  Medical, pharmacy and nursing schools spend limited time on topical agents. •  Topical route is a viable route that should be explored and developed as a good alternative of pain management.

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Oral Vs Topical •  Topical pain control is not a viable option for all. •  Some patients are good candidate others are not. •  There is no clear way to identify the good candidate.

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Benefits of Topical Agents 1)  2)  3)  4)  5)  6)  7) 

Avoids first pass therefore less hepatic effects Avoids GI side effects Avoid the decreased cognitive ability Very low chance of respiratory depression Low chances of dependency Less concentrations needed for desired effects Easier to customize/ individualize

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Limitation of Topical Agents 1)  Topical agents must have must be small enough and have the physiochemical properties for dermal and tissue penetration 2)  Skin permeability may vary in presence of tissue enzymes that metabolize drugs 3)  Disease states may alter dermal absorption 4)  Local dermal effects mat occur in response to drug or vehicle

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Targeting •  •  •  •  •  •  •  •  •  • 

NMDA (N-Methyl-D-Aspartate) Receptors AMPA (Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic) Receptors GABA-B (Gamma-Amino-Butyric Acid) Receptors NA (Sodium Channels) Channel Blockers Ca (Calcium Channels) Channel Blockers NorEpinepherine Receptors Alpha & Gamma Motor system Mu Receptors Substance P Non-Neural Cells (Transient-Receptor-Potential-Subfamily V) TRPV1, 3 & 4. 15

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Targeting •  NMDA –  Amantadine –  Dextromethorphan –  Ketamine –  Mg These agents inhibit the transfer of electrical signaling between neurons 16

Targeting •  GABA-B –  Baclofen Appears to be a Gaba-B receptor agonist on the C-Fiber terminal on the dorsal horn. Hence depressing release of glutamate and aspartate reducing muscle spasms

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Targeting •  Na Channel Blockers –  Lidocaine –  Tetracaine –  Prilocaine Augments pain relief by blocking the sodium channels

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Targeting •  Ca Channel Blockers –  Nifedipine –  Gabapentin (via alpha delta 2 sub-unit) Increases tissue perfusion necessary especially in neuropathic pain cases

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Targeting •  NorEpinephrine Receptor blockers –  Clonidine

•  Alpha & Gamma motor system –  Cyclobenzaprine

•  Mu Receptor –  Morphine –  Oxycodone –  Loperamide 20

Case Study •  FD 67yo male •  History of HTN, BPH, Radical Prostatectomy, Back Pain, Occational Leg numbeness & Pain –  Opana ER 10mg BID –  Oxycodone 30mg Q8H PRN –  Tizanidine 4mg Q8H –  Gabapentin 300mg BID –  Flexeril 5mg –  Senna 8.6mg BID –  Docusate 100mg BID Pain and discomfort from constipation hard to deal with. 21

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Case Study •  FD got a topical cream –  CDKLN –  Clonidine 0.2% + Gabapentin 6% + Ketamine 10% + Lidocaine 5% Nifedipine 2% –  Patient got relief but took time to get it

•  We added 2% DMSO (Dimethyl Sulfoxide) to the compound to increase penetration

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Case study •  New regiment –  –  –  –  –  – 

Opana ER 5mg BID Oxycodone 15mg Q8H PRN Tizanidine 4mg Q8H Gabapentin 300mg BID Flexeril 5mg Docusate 100mg BID

•  Patient reported sleeping better

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Case Studies •  NKL 40 yo Male •  Former college football and basketball star. •  Back and Hip pain –  Diclofenac 75mg BID –  Cyclobenzaprine 5mg TID –  Percocet 5/325 Q8H PRN –  Ibuprofen 600mg TID Non-Compliant with pain medication for fear of being dependent on pain meds.

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Case Study •  NKL •  CIKLP Cream –  Cyclobenzaprine 2% + Ibuprofen 6% +Ketoprofen 10% + Lidocaine 5% Piroxicam 2% –  Patient applied 3 to 4 times daily\

•  Patient had positive outcomes. Less pain better mobility.

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Case Study •  NKL New regiment –  Diclofenac 75mg BID –  Cyclobenzaprine 5mg BID –  Percocet 5/325 Q12H PRN

•  Patient reported less discomfort. •  Back to being active again

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Case Study •  BBM 35yo male •  History of MS, Back Pain, & Pain –  Opana ER 10mg BID –  Oxycodone 30mg Q8H PRN –  Tizanidine 4mg Q8H –  Gabapentin 300mg BID –  Flexeril 5mg –  Senna 8.6mg BID –  Docusate 100mg BID Pain and discomfort from constipation hard to deal with

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Case Study •  JPW 26 yo male •  History of HTN, BPH, Radical Prostatectomy, Back Pain, Occational Leg numbeness & Pain –  Opana ER 10mg BID –  Oxycodone 30mg Q8H PRN –  Tizanidine 4mg Q8H –  Gabapentin 300mg BID –  Flexeril 5mg –  Senna 8.6mg BID –  Docusate 100mg BID Pain and discomfort from constipation hard to deal with 28

Case Study •  KTZ 82yo Female •  History of Back degenerative spine condition –  –  –  –  –  –  – 

Ibuprofen 600mg 1 TID Oxycodone 15mg 1 Q4-6Hrs PRN Pain Tramadol 50mg 1 QID Lidocaine 2% gel Apply BID Oxymorphone ER 5mg 1 BID Senna 8.6 BID Miralax BID

•  Patient’s pain was not adequately covered 29

Case Study •  KTZ •  To supplement; –  We made a DBCT Cream •  Diclofenac 3% + Baclofen 2% + Cyclobenzaprine 2% + Tetracaine 2%

•  Did not provide much help –  Next We DCKLN Cream (Apply 1-2Gram 4-6 time daily) •  Diclofenac 5% + Clonidone 0.2% + Ketamine 10% + Lidocaine 5% +Nifedipine 2%

•  This provided better relief.

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Case Study •  KTZ: –  –  –  – 

Lidocaine was D/Cd Oxycodone 5mg Q8H PRN Tramadol 50mg BID Senna changed to PRN

•  KTZ could participate on the ADLs more freely •  KTZ’s anxiety of opioid dependency was slightly addressed by the reduction in dosing.

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Interesting Use For Compounds •  Pain control in wound care •  Pain control using a dextrose/ mannitol/ •  Use of Mg Compound for pain control on Fibromyalgia and MS •  Pain and scar preparations

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Compound Suggestions •  Starting regiment: –  KGCB (Ketamine 5% + Gabapentin 5% + Clonidine 0.2% + Baclofen 2%)

•  Neuropatic Pain –  KBCGL (Ketamine 10% + Baclofen 2% + Cyclobenzaprine 2% + Gabapentin 6% + Lidocaine 5%) –  You can add: Orphenadrine, Diclofenac, Tetracaine Less than 25% load

•  Nerve Pain –  Amtriptyline 2% + Clonidine 0.2% + Gabapentine 6% + Ketamine 10% + Lidocaine 10%

•  Spasm Pain –  Baclofen 5% + Cyclobenzaprine 5% + Diclofenac 5% + Lidocaine5% 33

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Support for dose choices? Drug

%

Study

Ketamine

10%

Finch et al: Pain. 2009; 146: 18-25

Clonidine

0.1%

Campbell et al: Pain. 2012; 153: 1815-1823

Doxepin

3.3%

McCleane et al: Br J Clin Pharmacol. 2000; 49:574-9

Amitriptyline

2-5%

Ho et al: Clin J Pain. 2008; 24: 51-55

Gabapentin

2-6%

Boardman et al: Obstet Gynecol. 2008; 112:579-585

Baclofen

2%

Nyirjesy et al: J Low Genit Tract Dis. 2009;13: 230-6

Lidocaine

5%

Uzaraga et al: Support Care Cancer 2012;20:1515-24

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Conclusion •  Topical preparations are a viable arrow in the pain management quiver.

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Self Assessment Questions •  I will consider prescribing a pain patch –  (1) Yes

(2) No

(3) Maybe

•  I will consider prescribed a pain/numbing cream –  (1) Yes

(2) No

(3) Maybe

•  I have increased confidence that topical pain control route works –  (1) Yes

(2) No

(3) Maybe

•  I prefer oral over topical –  (1) Yes

(2) No

(3) Maybe 36

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Questions

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References 1.  2.  3.  4.  5.  6.  7. 

8.  9.  10.  11. 

Brandvold A, Carvallo M (2014) Pain Management Therapy: The Benefits of Compounded Transdermal Pain Medication. J Gen Practice 2014, 2:6 Jorge, LL, Feres CC, Teles VEP (2011) Topical Preparations For Pain Relief: Efficacy and Patient Adherence. J Pain Research 2011: 4 11-24 De Leon-Casasola OA (2007) Multimodal Approaches To The Management of Neuropathic Pain: The Role of Topical Analgesia. J Pain Symptom Manage (2007) Mar;33(3)356-364 Campbell CM, Kipnes MS, Stouch BC, Brady KL, Kelly M, Schmidt WK, Petersen KL, Rowbotham MC, Campbell (2012) Randomized Control Trial of Topical Clonidine for Treatment of Painful Diabetic Neuropathy. J Pain (2012) 153 1815-1823 Dong XD, Svensson P, Cairns BE (2009) The Analgesic Action Diclofenac may Be Mediated Through Peripheral NMDA Receptor Antagonism. J Pain (2009) 144 36-45 Peppin JF, Albrecht PJ, Argoff C, Gustorff B, Pappagallo M, Rice FL, Wallace MS (2015) Skin Matters: A Review Of Topical Treatments For Chronic Pain. Part One: Skin Physiology and Delivery Systems Pain Ther (2015) 4:17-32 Simon LS, Grierson LM, Naseer Z, Bookman AAM, Shainhouse JZ (2009) Efficacy And Safety Of Topical Diclofenac Containing Dimethyl Sulfoxide (DMSO) Compared With Those Of Topical Placebo, DMSO Vehicle and Oral Diclofenac For Knee Osteoarthritis. J Pain (2009) 143 238-245 Sawynok J (2014) Topical Analgesic For Neuropathic Pain: Preclinical Exploration, Clinical Validation, Future Development. Eur J Pain (2014) 18: 465-481 Trevisani M, Szallasi A (2010) Targeting TRPV1: Challenges and Issues in Pain Management. The Open Drug Discovery Journal (2010) 2: 37-49 Anand P, Bley K, (2011) Topical Capsaicin For Pain Management: Therapeutic Potential and Mechanisms Of Action Of The New High-Concentration Capsaicin 8% Patch. British Journal of Anaesthesia (Advance Access published August 17, 2011 Zur E, (2014) Topical Treatment of Neuropathic Pain Using Compounded Medication. Clin J Pain (2014) Vol 30:1 73-91

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•  If you need further guidancePlease feel free to reach out •  Dr. Lucas K Nyabero PharmD •  CEO & PIC •  NewSpring Pharmacy LLC

•  [email protected]

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