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

2. 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.

3. 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

4. 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
million US adults suffer from common chronic pain.
Annual cost $600 million

5. 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

6. 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

7. 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

8. 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

9. 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?

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

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

12. 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.

13. 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

14. 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

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

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

17. Nsaid’s Ibuprofen Diclofenac potassium Piroxicam Side effects:
mg po Q4-6H prn; max 1200mg/day for 10 days unless directed by prescriber
Diclofenac potassium
25-50mg po TID; max mg/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…

18. 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)

19. Nsaid’s Evidence for Transdermal Application
Somberg JC, Molnar J. American Journal of Therapeutics. 2015(22):
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

20. 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

21. 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

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

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

24. 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

25. 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.

26. 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

27. 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…

28. 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

29. Tricyclic antidepressants
Amitriptyline:
10-25mg po HS; may increase weekly to max mg/day
Desipramine:
mg/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

30. 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

31. Tricyclic antidepressants
Evidence for Transdermal Application:
Retrospective study
Somberg JC, Molnar J, et al. American Journal of Therapeutics 2015(22):
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.

32. 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):
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

33. 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):
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

34. 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:
28 study subjects
Amitriptyline 2% / Ketamine 1% in proprietary base
Up to 4ml TID
Decreased pain scores at 6 months (34%) and months (37%)
Minimal adverse effects and minimal systemic absorption

35. 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

36. 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

37. anesthetics Evidence for Transdermal Application:
Commercially available as patch
Uzarage, et al 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):

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

39. 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)

40. 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 Sep; 153(9):
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.

41. 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

42. 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

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

44. 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

45. Patient case example
49 yo female referred by local pain specialist MD for pharmacy consult
Fell off 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.

46. 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

47. 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)

48. 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

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

50. 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.

51. 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!

52. 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!

53. Kusler’s Compounding Pharmacy
Thank you!
Dawn Ipsen, PharmD
Kusler’s Compounding Pharmacy
700 Avenue D, Suite 102
Snohomish, WA
(360)