Stick it to me: Topical and transdermal analgesics at the end of life

Stick it to me: Topical and transdermal analgesics at end of life Mary Lynn McPherson, PharmD, BCPS, CPE Kathryn A. Walker, Pharm.D, BCPS, CPE

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Nothing to Disclose

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Learning Objectives • Describe the evidence regarding efficacy and toxicity of topical analgesics, and proposed roles in caring for patients with advanced illness. • Describe patient- and agent-related variables that affect the selection and use of transdermal opioids (e.g., fentanyl and buprenorphine), including equianalgesic conversions and timing considerations when switching to and from a transdermal opioid.

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Learning Objectives • Given an actual or simulated case of a patient with an advanced illness, assess for the appropriateness of a topical or transdermal analgesic, and recommend dosing and monitoring strategies.

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Transdermal vs. Topical Analgesics • “Transdermal” analgesics – Fentanyl – Buprenorphine – Predominantly central (systemic) effects

• “Topical” analgesics – Applied to skin at site of pain – Predominantly a peripheral effect

So... What About Lidoderm?

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5% Lidocaine Patch (Lidoderm) • Indicated for treatment of post-herpetic neuralgia • Topical preparation • In patients with normal hepatic function, blood levels of the drug are minimal – On 12 hours, off 12 hours (max 3 patches) – Adequate trial is 2 weeks

• Only adverse effect is mild skin reactions (erythema or rash)

Davies PS, Galer BS. Drugs 2004;64(9):937-947.

Cochrane Review • May benefit some patients on an individual basis.

• Two studies showed improvement vs. placebo.

• There is stronger evidence for the use of other drugs.

• Side effects minimal; include irritation and redness.

• Unable to recommend as first line for PHN.

What else can we use it for?

Indication

Study design

Diabetic Polyneuropathy1 (> 3mo)

Open label flex dosing (3-8wks), up to 4 Significant improvements with patches applied for 18 hours minimal adverse effects, systemic accumulation did not occur

Low Back Pain2 (mod-severe, < 3 mo)

Open label non-randomized pilot (6 wks), up to 4 patches applied once daily

Significant improvements in avg pain intensity, QOL, 58% satisfaction, well tolerated

Myofascial Pain3

Randomized to lidocaine patch vs placebo patch vs trigger point injections

Subjective sx decreased with lidocaine patch and injections, >discomfort with injections, well tolerated

Knee OA4

Open label study, add-on therapy

2 week pain rating decreased by 29%

1, Barbano RL et al. Arch Neurol 2004;61:914-918.

2, Gimbel J, et al. Am J Therapeutics 2005;12:311-319.

3, Affaitati G, et al. Clin Therapy 2009;31(4):705-20.

4, Burch F, et al. Osteoarthr Cartil 2004;12(3):253-255.

Outcomes

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Pharmacokinetics and safety of continuously applied lidocaine patches 5% • Randomized, prospective, multiple-dose, openlabel pharmacokinetic study • Ten subjects – four lidocaine patches every 24 hours (group 1) • Ten subjects – four lidocaine patches every 12 hours (group 2) • Serum samples of blood drawn to assess pkin data and overall tolerability and safety were assessed with skin sensory testing Gammaitoni A et al. Am J Health-Syst Pharm 2002;59:2215-20.

Gammaitoni A et al. Am J Health-Syst Pharm 2002;59:2215-20.

Pharmacokinetics and safety of continuously applied lidocaine patches 5% • Mean steady-state Cmax values: – Group 1 (every 24 hours) = 186 ng/ml – Group 2 (every 12 hours) = 225 ng/ml

• 1/7 that of antiarrhythmic effect (~ 1500 ng/ml) • 1/25 that at which toxicity increases (~ 5000 ng/ml) • No sensory alterations at patch administration site

Gammaitoni A et al. Am J Health-Syst Pharm 2002;59:2215-20.

Capsaicin • The component of chili peppers that makes them HOT – Acts primarily as a counterirritant – Activates nerve fibers in the skin, which becomes desensitized over time as a result of depletion of substance P and calcitonin gene-related peptides – Desensitization due to reversible nerve degeneration – After therapy discontinued, epidermal nerve fibers are reinnervated over a 6 week period.

Capsaicin Efficacy

Drop-out rate: 19.3% vs 10.7%

• 12 week double-blind trial • 113 patients with mild-to moderate OA pain (primarily of the knee) randomized to: – Capsaicin 0.025% cream vs Vehicle cream QID

• Results: Capsaicin superior to vehicle, but not until week 4 • Conclusion: capsaicin provided modest analgesia in some patients with relatively mild baseline pain, but analgesia was neither rapid nor sustained and patients frequently selfmedicated to maintain adequate pain relief Altman RD et al. Semin Arthritis Rheum 1994;23(supple 3):25-33.

Capsaicin Efficacy • NNT = 8.1 – Topical NSAID NNT = 3.1 – Topical salicylates NNT = 5.3

• Given limited efficacy, topical capsaicin therapy may be limited to use as adjunctive therapy.

Altman RD et al. Semin Arthritis Rheum 1994;23(supple 3):25-33.

Capsaicin Safety • Not associated with serious adverse events, but accidental contact with the eyes or mucus membranes is extremely irritating • Adverse event rate = 54% – Placebo adverse event rate = 15%

• Wash hands immediately after use • Use of lidocaine jelly?

Altman RD et al. Semin Arthritis Rheum 1994;23(supple 3):25-33.

Non-oral diclofenac preparations available in U.S. • Diclofenac epolamine 1.3% topical patch (Flector®) • Diclofenac sodium 1.5% topical solution (Pennsaid®) • Diclofenac sodium 1% topical gel (Voltaren® Gel) • Diclofenac sodium 3% topical gel (Solaraze® Gel) Note: diclofenac epolamine 1.3% topical patch and diclofenac sodium 3% topic gel are not FDA approved for use in chronic musculoskeletal pain

Application of Voltaren 1% Gel

Voltaren 1% Gel Prescribing Information

Comparative Cmax of diclofenac Formulation

Cmax (ng/mL)

Diclofenac 50mg tablet

1298

Diclofenac 75mg tablet

2367

Diclofenac epolamine patch (Flector速)

8.8

Diclofenac gel 1% (Voltaren速 Gel)

53.8

Diclofenac gel 3% (Solaraze速) Diclofenac / DSMO soln. (Pennsaid速) Arthrotec [package insert]. New York, NY: Pfizer; 2010.

Flector [package insert]. Bristol, TN: King Pharmaceuticals; 2009.

Voltaren Gel [package insert]. Chadds Ford, PA: Endo Pharmaceuticals; 2009.

Solaraze [package insert]. Melville, NY: PharmaDerm; 2008.

Pennsaid [package insert]. St. Louis, MO: Covidien; 2010.

4 19.4

Diclofenac Adverse Effects • Cardiovascular risk – boxed warning

– Perioperative use in CABG contraindicated – May cause increased risk of MI and stroke, which can be fatal – Risk may be greater with longer duration and pre-existing CV disease

• Gastrointestinal risk – boxed warning

– Increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation.

– Events may occur at any time during use and be asymptomatic

• Elevated liver transaminases

Diclofenac 1% Gel (Voltaren® Gel) • Indicated for the relief of the pain of OA of joints amenable to topic treatment • Dosing – do not exceed 32 grams each 24hrs – Lower extremities – 2 grams QID – Upper extremities – 4 grams QID

• Avoid exposing application site to: – Sunlight or similar – Direct heat – Sunscreens, moisturizers, insect repellants, etc.

Voltaren Gel [package insert]. Chadds Ford, PA: Endo Pharmaceuticals; 2009.

Diclofenac gel (Voltaren速 Gel) in OA of the knee WOMAC Score at 12 weeks

0

WOMAC Pain

WOMAC Function

Pain on Movement

p = 0.01

p = .001

p < 0.002

-0.2

-0.4

-0.6

-0.8

-1

-1.2

-1.4

Barthel HR, et al. Semin Arthritis Rheum. 2009.

Diclofenac Placebo

n = 492

Diclofenac sodium topical solution 1.5% (Pennsaid®) • Indicated for the treatment of signs and symptoms of osteoarthritis of the knee • Dosing – 40 drops to affected knee QID – Dispense only 10 drops at once

• Avoid showering / bathing for 30 minutes • Avoid exposing application site to: – Sunlight or similar – External heat or occlusive dressings Pennsaid [package insert]. St. Louis, MO: Covidien; 2010.

Voltaren 1% Gel 3/5 Pack • Three 100 g tubes = $82.98 • Five 100 g tubes = $138.30

www.drugstore.com

Diclofenac / DSMO (Pennsaid速) solution in OA of the knee 0

WOMAC Pain

WOMAC Function

WOMAC Score at 12 weeks

-2

WOMAC Stiffness p = 0.112 p = 0.035

-4 -6 -8 -10

T-Diclo

p = 0.015 p = 0.009

O-Diclo DSMO

-12

Placebo

-14

n =775

-16 -18 -20

Simon LS, et al. Pain. 2009.

p = 0.034 p = 0.026

T-Diclo: topical diclofenac; O-Diclo: oral diclofenac; DSMO: dimethyl sulfoxide

Adverse Effects AE

Topical (n=154) %

Placebo (n=157) %

Vehicle (n=161) %

Oral (n=151) %

Topical + Oral (n=152) %

Any

62.3

57.3

60.2

62.3

64.5

Abdominal Pain

3.2

0.6

3.1

7.3

2.0

Dyspepsia

2.6

3.8

3.7

4.0

3.3

Nausea

0

0

0.6

2.0

3.3

LFT abnormality

1.9

0.6

3.7

7.9

7.2

Digestive System

Simon LS, et al. Pain. 2009.

Questions Unanswered • Can topical diclofenac be safely administered to – those with cardiovascular disease?

– those with history of peptic ulcer disease?

– those with history of NSAID associated upper gastrointestinal bleeding?

– those on concurrent anti-platelet or anticoagulation therapy?

NO DATA!

Salicylates • Mechanism of action – counterirritant – May interfere with transcription factors and kinases involved in inflammatory processes – Do not appear to work through COX inhibition • 100 fold less potent than COX-2 inhibitors

• Trolamine salicylate – undetectable in serum • Methyl salicylate applied for four days – BenGay, Icy Hot – Achieved a low systemic serum concentration

• Efficacy – poor in chronic pain states Altman R, Barkin RL. Postgraduate Medicine 2009;121:139-147.

Salicylates • Safety – Methyl salicylate has been associated with severe toxicity and deaths after topical application or with accidental or deliberate ingestion – Methyl salicylate potentiates effects of warfarin, increasing bleeding risk – Adverse side effects more similar to oral NSAIDs compared to other topical products • Must consider safety profile when using in patients (decision to avoid ORAL NSAIDs is a reason to avoid using topical salicylates) Altman R, Barkin RL. Postgraduate Medicine 2009;121:139-147.

Compounded Opioids for Wound Care • MOA: act on peripheral opioid receptors that are expressed in inflamed tissues • Dose:

– 10 mg of IV morphine sulfate + 8 grams of intrasite gel (compound pharmacy) – Apply to wound 1-3 times daily

• Side effects: site irritation (e.g. itching, burning, redness) • Limited systemic absorption

Topical Opioids • There is conflicting data regarding the efficacy of topical opioids (morphine) in the treatment of ulcers compared to placebo.

– Recent trials published in 2009 and 2011 did not find statistically significant data regarding the use of topical morphine – However, numerous other studies and case reports have shown the efficacy of topical morphine for wound pain reduction

• Conclusion:

– Although there exist contradictory data, topical morphine can be an effective alternative to treat patients with wound pain in palliative care – Safe with very little to no systemic absorption 33

Topical Opioids • Little data on using topical opioids for systemic absorption and pain control – Case Report of a 90 year old male was treated with hydromorphone 4mg/0.2mL (dosed PRN every hour up to a max of 16mg/hr or 32mg/4 hours), which was rubbed into the skin at healthy sites – Patient experienced pain relief within 15 minutes

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Topical Opioids in Palliative Care • Review of literature concludes: – There is support for the use of topical opioids – No clear direction to make clinical recommendations regarding • • • • •

Ideal opioid Starting dose Interval of administration Methods of titration Carrier

LeBon B et al. J Pain Sx Manage 2009;37(5):913-917.

Fentanyl • Synthetic pure mu opioid agonist • 75-100 times more potent than morphine (mg-to-mg basis) • Greater lipid solubility than morphine – Facilitates rapid diffusion across the BBB – Quick onset of action

• Parenteral – IV injection, IV infusion, SQ infusion, IM injection (no, no, bad dog), TD, TM 36

Transdermal Fentanyl • Apply every three days for stable chronic pain • Low MW and high solubility in both fat and water, therefore good candidate for TD administration.

• 12 mcg/h, 25 mcg/h, 50 mcg/h, 75 mcg/h, 100 mcg/h • Gel-containing reservoir, drug-in-adhesive matrix, matrix membrane patch 37

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Variables that affect absorption • Area of application / hair • Increased body temperature • Cachexia / low body weight patients – Poor fat stores, debilitated patients, muscle wasting and altered clearance

• After TDF removal, about half the drug has been eliminated after 17 hours 39

Indications • Management of persistent, moderate to severe chronic pain in opioid-tolerant patients 2 years of age or older who require a total daily dose of opioid at least equivalent to TDF 25 mcg/h: – – – –

Oral morphine 60 mg/d for > 1 week Oral oxycodone 30 mg for > 1 week Oral hydromorphone 8 mg/d for > 1 week Oral oxymorphone 25 mg for > 1 weeks

• Contraindicated in post-operative pain, mild pain, intermittent pain • Caution with 3A4 inhibitors 40

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Conversion to TDF

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Fentanyl Tidbits • Converting from oral LA opioid to TDF – If patient not taking oral morphine, convert to oral morphine – Using the 2 mg oral morphine/day ~ 1 mcg/h TDF, calculate TDF patch strength – Advise patient to take one last dose of the oral longacting opioid at the same time the first TDF patch is applied – Increase TDF if necessary in 3 days, and every 6 days thereafter McPherson ML. Demystifying Opioid Conversion Calculations: A Guide For Effective Dosing. Amer Soc of Health-Systems Pharm, Bethesda, MD, 2009.

Fentanyl Tidbits • Converting from ATC SA opioid to TDF – If patient not taking oral morphine, convert to oral morphine – Using the 2 mg oral morphine/day ~ 1 mcg/h TDF, calculate TDF patch strength – Advise patient to take two or three scheduled doses of their oral SA opioid after TDF patch application: one at the time of patch application, another 4 hours later, and another 4 hours later if needed – Increase TDF in 3 days if necessary, then every 6

McPherson ML. Demystifying Opioid Conversion McPhersonCalculations: ML. Demystifying A Guide Opioid For Conversion Calculations: A Guide For Effective Dosing. Amer Soc of Health-Systems EffectivePharm, Dosing.Bethesda, Amer SocMD, of Health-Systems 2009.

Pharm, Bethesda, MD, 2009.

Fentanyl Tidbits • Titrating TDF upward – After initiation of TDF therapy, evaluate use of rescue opioid on days 2 and 3. If patient using > doses of rescue opioid, calculate TDD of rescue opioid and increase TDF patch in equivalent amount – Increase by 25-50 mcg/h, but not to exceed a 100% increase. No dosage increase should exceed 50 mcg/h • Increase from 25 to 50 mcg/h • For patients on > 50 mcg/h, increase by 50 mcg/h

McPherson ML. Demystifying Opioid Conversion Calculations: A Guide For Effective Dosing. Amer Soc of Health-Systems Pharm, Bethesda, MD, 2009.

Fentanyl Tidbits • Converting from TDF to an oral opioid – Based on the TDF patch strength, calculate oral morphine evaluate (2 mg oral morphine/day ~ 1 mcg/h TDF) – Once the new opioid product is in the patient’s home, remove TDF patch – For the first 12 hours after patch removal, use only the previously prescribed rescue opioid – 12 hours after patch removal begin with 50% calculated scheduled opioid regimen; rescue available – 24 hours after patch removal, increase to 100% calculated opioid regimen; rescue available McPherson ML. Demystifying Opioid Conversion Calculations: A Guide For Effective Dosing. Amer Soc of Health-Systems Pharm, Bethesda, MD, 2009.

Fentanyl Tidbits • Converting from TDF to IV fentanyl – Establish IV access, remove TDF patch – Allow “as needed” bolus dose of fentanyl – Six hours after TDF patch removal, begin 50% of IV fentanyl infusion (which should be 50% of the patch strength); bolus option remains in place – Twelve hours after TDF patch removal, increase IV fentanyl infusion to 100% of prescribed amount (which should be equal to the TDF patch strength); bolus option remains in place

McPherson ML. Demystifying Opioid Conversion Calculations: A Guide For Effective Dosing. Amer Soc of Health-Systems Pharm, Bethesda, MD, 2009.

Fentanyl Tidbits • Converting from IV fentanyl to TDF – Apply TDF patch in same strength as IV fentanyl infusion – Six hours after application of TDF, reduce IV fentanyl infusion by 50%; bolus option remains in place – Twelve hours after application of TDF, discontinue IV fentanyl infusion; bolus option remains in place – Twenty-four hours after application of TDF, discontinue IV fentanyl bolus

McPherson ML. Demystifying Opioid Conversion Calculations: A Guide For Effective Dosing. Amer Soc of Health-Systems Pharm, Bethesda, MD, 2009.

Butrans (BU-tranz) • Transdermal buprenorphine indicated for the management of moderate to severe chronic pain in patients requiring a continuous, around-the-clock opioid analgesic for an extended period of time – Osteoarthritis, low back pain

• Available as 5 mcg/h, 10 mcg/h, 20 mcg/h • Schedule III

Butrans • Each patch is meant to be worn for 7 days • Apply to upper outer arm, upper chest, upper back or the side of the chest. Do not re-use site for 21 days.

• In opioid-naïve patients the initial dose should always be 5 mcg/h • Converting to Butrans:

www.butrans.com; Prescribing Information

Butrans • The oral morphine : transdermal buprenorphine equipotency ratio is between 1:70 and 1:100 (1:75 most commonly published).

• mg buprenoprhine/day x 75 = mg oral morphine/day • For example, consider the Butrans 10 mcg/hour patch: • (buprenorphine 10 mcg) x (24 hr) x (1 mg) = hr day 1000 mcg • 0.24 mg buprenorphine x 75 = 18 mg oral morphine/day

Butrans â&#x20AC;˘ Mercadente et al determined ratio is 1:70

McPherson ML. Demystifying Opioid Conversion Calculations: A Guide for Effective Dosing, ASHP 2010

Butrans (BU-tranz) • Advantages over TDF:

– Lower abuse potential – Less dangerous in an overdose – Causes fewer withdrawal symptoms

• Contraindications and Precautions

– Significant respiratory depression, asthma, paralytic ileus – Acute post-op, mild, or intermittent pain

• Cost for 4 patches (1 month) AWP – 5 mcg/hour - $151.20 – 10 mcg/hour - $226.80 – 20 mcg/hour - $401.52

Mrs AG • 81 yo AAF with progressive dementia. She was admitted because of a mental status change at ALF, medical team suspected aspiration pneumonia however found lung mass c/w cancer • PMH: ESRD on HD, OA, COPD, CAD • Meds PTA included percocet 5/325 for arthritic pain but daughters could not quantify use • Family: four daughters all involved in her care 54

Mrs AG • PE: cachectic, appears sedated and unresponsive, two stage II ulcers • Pain Regimen: Hydromorphone 1mg IV q2hours (receiving 5/day)

• Consultation requested and family meeting held to discuss options – Daughters recognize decline of pt and have realistic expectations considering likely cancer dx – Primary family concern was sedation and pain SCr 5.7

Hct 32

BUN 92

Hgb 10

WBC 12.5

ABG on pH 7.43 FiO2 pCO2 38 24% pO2 77

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Mrs AG Patient Related Variables

Agent Related Variables

COPD- not CO2 retainer

Long acting opioid

ESRD on HD

No active metabolites

Unresponsive/ NPO

No tablet formulation No TDB bc >80 mg morphine

Transdermal Fentanyl?

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Mrs AG • 5 mg IV HM= 100 oral morphine= 50 mcg/hr fentanyl patch • Individualize dose: – decrease by 25-50% sedation and cross tolerance

• Start Fentanyl 25 mcg/hr TD q72 hours

Is that all?

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Mrs AG • Orders: – Start Fentanyl patch 25 mcg/hr TD q72 hours- place now (9 am) – Give oxyfast (oxycodone concentrate 20 mg/ml) 10 mg buccally q4 hours standing x3 doses then change to q2h prn

• Next day patient appeared much more comfortable to our team, staff and family • Discharged to NH with palliative plan (no hospital transfer) with family agreement 58

Mrs AG...

One Month Later • She is admitted from NH after a fall leading to a hip fx. She is s/p hip repair and spent one week in ICU requiring ventilator support postop. We are consulted and meet with family because she is not weaning off ventilator.

– Primary concern: “we think she is suffering, can’t you do something about the pain?”

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Mrs AG • Pain Regimen: Fentanyl 75 mcg/hr TD q72 hours – At NH increased from 25 mg/hr patch to 50 mcg/hr patch after one week – Two weeks later increased to 75 mcg/hr

Appropriate titration?

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Mrs AG • Team is concerned that she may not wean off the vent (trach or w/d?) and also noting pain – IV fentanyl drip and boluses

• Considerations – TD  IV conversion – Given titration in cachectic patient, how much credit do we give the current patches?

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Mrs AG • Go back to what you last knew... TDF 25 mcg/hr patch worked and well tolerated – 25 mcg/hr patch = 25 mcg/hr IV fentanyl

• Started a 25 mcg/hr fentanyl drip with 25 mcg IV q1hr prn (D/C’d patch) • At 6 hours, start continuous infusion at 12 mcg/h; at 12 hours increase to 25 mcg/h; keep bolus • She did not require further titration and after next family meeting, a terminal ventilator withdrawal was scheduled for the next day.

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And Palliative Care!

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Stick it to me: Topical and transdermal analgesics at end of life Mary Lynn McPherson, Pharm.D., BCPS, CPE mmcphers@rx.umaryland.edu Kathryn A. Walker, Pharm.D., BCPS, CPE kwalker@rx.umaryland.edu University of Maryland School of Pharmacy 64