New(er) drugs in pain management - Vancouver - Island...

I want a new drug!I want a new drug!New(er) drugs in pain management

Dr Donna Kay Buna Pharm DDr. Donna Kay Buna, Pharm D

CDM forum‐ Update Pain Management

D b 12 2012December 12, 2012

Conflicts of InterestConflicts of Interest

• Clinical Coordinator VGHClinical Coordinator VGH

• I work in the VIHA Pain Program

• National Faculty Member• National Faculty Member, Knowledge Transfer, CPS

I h b id h i• I have been paid honorariums for educational presentations by Pfizer Merck GlaxoPfizer, Merck, Glaxo

copyright dkbuna 2012

Outline/Learning ObjectivesOutline/Learning Objectives

Pharmacology evidence for efficacyPharmacology, evidence for efficacy, tolerability profile, potential place in th ftherapy for…..

• Tapentadol IR & CR (Nucynta®)

• Oxycodone/Naloxone PR (Targin®)

B hi t d l (B T ®)• Buprenorphine transdermal (Bu‐Trans®)

I want a new drug!hHuey Lewis & the News

http://www.youtube.com/watch?feature=player_detailpage&v=N6uEMOeDZsA

I want a new drug! What other song and artist had similarities with this song in 1984 that Huey Lewishad similarities with this song in 1984 that Huey Lewis ended up suing Columbia Pictures for plagiarism?

69%1. What’s love got to do ith it? Ti Twith it? – Tina Turner

2. Footloose – Kenny LoginsLogins

3. Ghostbusters – Ray Parker Jr

4%10%

16%Parker Jr.

4. Dancing in the Dark –Bruce Springsteen

1 2 3 4

Bruce Springsteen

Answer Ghostbusters – Ray Parker Jr.Answer...Ghostbusters Ray Parker Jr.

TapentadolTapentadol(Nucynta®)IR 50 75 & 100mg tablets‐ IR 50, 75, & 100mg tablets

‐ ER 50, 100, 150, 200, 250mg tablets250mg tablets

Tapentadol (Nucynta®)Tapentadol (Nucynta )

• Synergistic dual mechanism of action (MOR‐Synergistic dual mechanism of action (MORNRI)– Weak mu opioid receptor (MOR) agonist– Weak mu opioid receptor (MOR) agonist

– Norepinephrine re‐uptake inhibitor (NRI)

• 50 x less affinity for receptor than morphine, yet provides ~1/3 analgesia that of morphine

Vadivelu N et al. Tapentadol extended‐release for treatment of chronic pain: a review. J Pain Res 2011;4:211‐218.

Tapentadol‐equi‐analgesic doseTapentadol equi analgesic dose

• Studies comparing TAP CR: Oxy CR2• Studies comparing TAP CR: Oxy CR2

–Ratio of 5:1

• Translates into oral TP: Morphine Oral1• Translates into oral TP: Morphine Oral1

–Ratio of 3.5:11. Product Monograph Nycynta CR. December 2, 2010. Janssen Inc. 2. Lange B, Steup A, Haufel T, et al. Efficacy and Safety of Tapentadol Prolonged R l f Ch i O t th iti P i d L B k P i Ad Th 1010 27(6) 381Release for Chronic Osteoarthritis Pain and Low Back Pain. Adv Ther 1010;27(6):381‐399.

Tapentadold l?improvement over tramadol?

• Does not require metabolic activation (likeDoes not require metabolic activation (like tramadol & codeine)

• Produces no active metabolites• Produces no active metabolites

• Has no significant drug interactions

• Not influence by genetic polymorphisms of the cytochrome P450 system

• Minimal serotonergic effects – significant reduced risk of serotonin syndromeyVadivelu N et al. Tapentadol extended‐release for treatment of chronic pain: a review. J Pain Res 2011;4:211‐218.

Systematic ReviewSystematic Review

Riemsma R et al. Systematic review of tapentadol in chronic severe pain. Curr Med Res Opin 2011; 27(10):1907‐1930.

Tapentadol IR‐Acute painTapentadol IR Acute pain

• Efficacious mod‐severe acute pain:Efficacious mod severe acute pain:– Third molar extraction

Bunionectomy– Bunionectomy

– Degenerative dx

50 70 ` t i f i ’ t 10 d• 50‐70mg ‐`not inferior’ to 10mg oxycodone

Hartrick CT, Hernandez J. Tapentadol for pain: a treatment evaluation. Expert OpinPharmacother 2012;13(2):283‐286.

Tapentadol‐extended releaseTapentadol extended release

• Comparable analgesia to Oxycodone CR in:Comparable analgesia to Oxycodone CR in:– OA knee

Chronic low back pain– Chronic low back pain

– Diabetic neuropathy

L id ff t l di t di ti ti• Less side effects leading to discontinuation

• Significantly improved GI tolerability

Vadivelu N et al. Tapentadol extended‐release for treatment of chronic pain: a review. J Pain Res 2011;4:211‐218.

Safety/Tolerabilityy/ y

• Potential for all typical opioid‐induced ADRs– Improved GI tolerability compared to others well documented but still is reported

– CNS‐ somnolence / dizziness

– Block NE uptake‐? Increase BP‐theoretical

– Respiratory depression‐ not reported

– Minimal abuse potential (CR designed to resist mechanical alteration)

– Mild withdrawal syndromeVadivelu N et al. Tapentadol extended‐release for treatment of chronic pain: a review. J Pain Res 2011;4:211‐218.Hartrick CT. Tapentadol for pain: a treatment evaluation. Expert Opin Pharmacother 2012: 13(2):283‐286.

Tapentadol‐ dosingTapentadol dosing

• Immediate release‐ acute painImmediate release acute pain– 50‐75mg = oxycodone 10mg

50 75mg q4 6h as required– 50‐75mg q4‐6h as required

– MAX: 600mg/day

E t d d l h i i• Extended release‐chronic pain– Opioid‐naïve‐ start with 50mg q12h

– Rotation: If on opioids < 140mg MEDD

– Maximum: 250mg q12h (500mg/day)

Hartrick CT et al. Tapentadol for pain: a treatment evaluation. Expert OpinPharmacother 2012;13(2): 283‐286.

Tapentadol‐dosingTapentadol dosing

• No dose adjustment mid‐mod renalNo dose adjustment mid mod renal impairment or mild hepatic impairment

• Reduce dose & frequency in moderate hepatic• Reduce dose & frequency in moderate hepatic impairment (C‐P score 7‐9;Class B)

N di d i l h i• Not studied in severe renal or hepatic impairment

• Contraindicated with MO inhibitors (NE potential leading to hypertensive crises)

Hartrick CT, Hernandez J. Tapentadol for pain: a treatment evaluation. Expert OpinPharmacother 2012;13(2):283‐286.

Place in TherapyPlace in TherapyStep 3‐ Strong opioid +non opioid + adjuncts

WHO Analgesic non‐opioid + adjuncts (morphine, HM, fentanyl)

St 2 75 T t d l

Stepladder

3 Severe

Step 2‐Mild opioid + non‐

Step 2.75 – Tapentadol = < 140mg MEDD

2 Moderate

N

Step 2‐Mild opioid + non‐opioid + adjuncts (codeine, tramadol)

1 MildNo

PainStep 1‐ Non‐opioid +adjunct


jWHO=World Health Organization

MEDD= Morphine Equivalent Daily Dose

Neuropathic Pain Algorithm p gadapted from CPS consensus statement 2007

Topical Lidocaine if focal or PHNor PHN

TCA or Gabapentin/Pregabalin

First Line Therapiesp / g

SNRI (Venlafaxine or Duloxetine)

Second Line Therapies)

Tramadol or CR Opioids Third Line Therapies?Tapentadol CRDPN l ?

p

MISC – minimal evidenceMoulin.et al. Pharmacological

DPN only?

(Cannabinoids, methadone, other anticonvulsants

management of chronic neuropathic pain‐ Consensus statement. Pain Res Manage 2007;12(1):13‐21

Tapentadol‐ in summaryTapentadol in summary

• “Mild” opioid with analgesic efficacyMild opioid with analgesic efficacy comparable to lower doses of strong opioids (less than 140mg MEDD)

• Advantages over Tramadol & Codeine• Used in ‘non‐responders’ to other mild opioidsUsed in non responders to other mild opioids in those that stronger opioids not desired

• Significantly improved GI tolerabilitySignificantly improved GI tolerability compared to stronger opioids (Oxycodone)

• Some evidence for DPNSome evidence for DPN

Oxycodone/Naloxone (Targin®)Oxycodone/Naloxone (Targin )• Developed to counteract opioid‐induced constipation (OIC)– Minimal tolerance to this OIC

– Significantly affects patient’s quality of life

– Sometimes difficult to manage with laxatives

– Often affects adherence and then subsequent pain control

Clemens KE, Mikus G. Combined oral PR oxycodone and naloxone in OICClemens KE, Mikus G. Combined oral PR oxycodone and naloxone in OIC dysfunction: Expert Opin Pharmacother 2010;11(2):297‐310.

Oxycodone /Naloxone CROxycodone /Naloxone CR• Combination of:

–Oxycodone‐ strong mu agonist analgesia

–Naloxone –mu receptor antagonist rapidNaloxone mu receptor antagonist rapid onset, high receptor affinity reverses opioid bindingbinding• IV – used as an antidote• Oral – effect predominantly in the gut can• Oral effect predominantly in the gut can reverse OIC

Leppert W. Role of oxycodone and oxycodone/naloxone in cancer pain management. Pharmacological Reports 2010;62: 578‐591.

Naloxone‐First pass ffeffect

1 O l d i i t ti1.Oral administration oxycodone/naloxone

2 NAL- high affinity for opioid2.NAL- high affinity for opioid receptors in gut reversing OIC

3.NAL-rapid/extensive pmetabolism only 2% bioavailable

4.OXY- significant portion available to elicit centrally mediated mu receptormediated mu receptor analgesia

Oxycodone /Naloxone CR 2:1 ratioOxycodone /Naloxone CR 2:1 ratio• Ratio 2:1 oxycodone/naloxone determined optimal:– 5mg/2.5mg CR tablet

– 10mg/5mg CR tablet



• Some diarrhea at higher doses‐ reversal ofSome diarrhea at higher doses reversal of OIC vs GI withdrawal symptoms


Evidence/studiesEvidence/studies

• Oxy/naloxone CR vs Oxycodone CR – No loss of analgesia

– Increase in spontaneous BM per week (median 3.0 p p (vs 1.0) after 4 weeks treatment

– Lower laxative intake

– Significant reduction in the Bowel Function Index (ease, completeness, judgment)

• 26.9 pts vs 9.4 pt (P<0.001)

Vondrackova D et al J Pain 2008;12(9):1144‐1154Vondrackova D et al. J Pain 2008;12(9):1144 1154Simpson K et la. Curr Med Res Opin 2008; 24(12):3503‐3512.Lowenstein O et al. Expert Opin Pharmacother 2009;10:531‐453.Sandner‐Kiesling A et al. Int J Clin Pract 2010;64:763‐774.

Safety/TolerabilitySafety/TolerabilityTable 3‐ Incidence of Adverse Events: Double‐blind safety population (Phase III study)Preferred term Placebo

N=158Oxycodone PRN=151

Oxycodone /NaloxonePR n=154

Overall ADR 83 (52.5%) 80 (53%) 86 (55.8%)

population (Phase III study)

Overall ADR 83 (52.5%) 80 (53%) 86 (55.8%)

Constipation 8 (5.1%) 18 (11.9) 13 (8.4%)

Diarrhea 7 (4.4%) 4 (2.6%) 8 (5.2%)

( ) ( ) ( )Nausea 11 (7.0%) 12 (7.9%) 10 (6.5%)

Vomiting 5 (3.2%) 7 (4.6%) 8 (5.2%)

Fatigue 4 (2.5%) 8 (5.3%) 4 (2.6%)

Dizziness 6 (3.8%) 9 (6.0%) 2 (1.3%)

Headache 11 (7.0%) 6 (4.0%) 5 (3.2 %)

Vondrackova D et al. Analgesic efficacy and safety of oxycodone in combination with naloxone as PR tablets in patients with moderate to severe chronic pain. J Pain 2008; 9(12):1144‐1154.

Oxycodone /Naloxone CR (Targin®)‐ddosing

• Opioid naïve start 5/2 5 twice dailyOpioid naïve start 5/2.5 twice daily

• Max daily dose: 40/20mg twice daily

i O i id 20 80• Rotation: Opioids < 120mg MEDD or 80mg Oxy daily dose

• Concerns with any hepatic impairment would diminish first past effect & thereby reduce oxycodone effect


Place in TherapyPlace in Therapy

Step 3‐ Strong opioid +WHO Analgesic p g pnon‐opioid + adjuncts (morphine, HM, fentanyl)

Stepladder

®3 Severe

Step 2‐Mild opioid + non‐

Step 2.75 – Targin® ‐Oxy max dose: 80mg/day = ~120 MEDD

2 Moderate

N


1 MildNo

PainStep 1‐ Non‐opioid +adjunct



Oxycodone/Naloxone PR – In summary

• Comparable analgesia to Oxycodone CRComparable analgesia to Oxycodone CR

• Limits of dosing up to 80mg oxycodone/day = 120mg MEDD due to impact of naloxone on120mg MEDD due to impact of naloxone on gut (diarrhea)

I d GI l bili d• Improved GI tolerability compared to oxycodone alone

• Decreased risk of abuse/diversion

Buprenorphine (BUP)Buprenorphine (BUP)

• Semi‐synthetic opioid analgesicSemi synthetic opioid analgesic– Sublingual – Suboxone®

• Buprenorphine/Naloxone• Buprenorphine/Naloxone • Approved for opioid withdrawal managementmanagement

– Low dose transdermal (Bu‐Trans®)10 & 20 /h d h• 5, 10 & 20 mcg/hour 7 day patch

• Approved for chronic pain

BUP‐partial agonist in vitroPure agonist action in vivo

Low intrinsic activityNo activityFull activity

High affinity

Buprenorphine‐ PharmacodynamicsBuprenorphine Pharmacodynamics

• Low instrinsic activity –ceiling effect (12‐Low instrinsic activity ceiling effect (1216mg)

• Main antinociception spinal cord less effect• Main antinociception spinal cord less effect on brain (? Less abuse potential)

Sl i i ( k )• Slow association (take‐up on receptor)

• Slow dissociation (off receptor)– Reduced severity of withdrawal

– May require naloxone infusion to detox

Plosker GL. Buprenorphine 5, 10 and 20 ug/hr transdermal patch. Drugs 2011:71(18): 2491‐2509.

Buprenorphine‐ PharmacodynamicsBuprenorphine Pharmacodynamics

• Mu receptor occupancy rate low (< 50%):Mu receptor occupancy rate low (< 50%):– Allows co‐administration other opioids– Reduced refractory period if rotating to anothery p g

• Antagonistic at the Kappa receptortranslates into reduced dyspnea/dependencey p / p

• Main active metabolite (norbuprenorphine) potent delta receptor agonist:p p g– Efficacy in bone pain (delta opioid receptors are present on pain fibre within bone)


Buprenorphine low dose transdermaldEvidence

• Osteoarthritis hip or kneeOsteoarthritis hip or knee– Better than placebo

Equivalent to sublingual BUP– Equivalent to sublingual BUP

– Noninferior to acetaminophen + Codeine (regularly scheduled)(regularly scheduled)

– Noninferior to CR tramadol (up to 200mg/day)

• Lo back pain• Low back pain– Better than placebo dose > 5 mcg/hr


Buprenorphine Safety/TolerabilityBuprenorphine Safety/Tolerability

• Mild to moderate intensity/mostly 1st monthMild to moderate intensity/mostly 1 month

• Most frequently reported ADRs (> 10%)Headache (more frequent in younger popln)– Headache (more frequent in younger popln)

– Dizziness

– Somnolence M f tl– Somnolence

– Constipation

– Dry mouth

More frequently reported in older patientsDry mouth

– Nausea/Vomiting

– Application site reactions‐ pruritis/erythemia (25%)Application site reactions pruritis/erythemia (25%)

Plosker GL, Lyseng‐Williamson KA. BP 5, 10 and 20 ug/hr Transdermal Patch: A guide to Its Use in Chronic Non‐Malignant Pain. CNS Drugs 2012:26(4):367‐373.

BuprenorphineRespiratory Depression

• Low risk of respiratory depression

• Ceiling effect demonstrated in trials in healthy volunteers

• Possibly related to kappa receptor antagonist

• Potentially problematic if used with other CNS y pdepressants or in overdose situation

Buprenorphine‐more advantagesBuprenorphine more advantages

• Anti‐hyperalgesic effectAnti hyperalgesic effect

• Low risk/mild withdrawal due to slow receptor dissociation & gradual decline in levels whendissociation & gradual decline in levels when patch removed

L d• Low term advantages– Lacks effect on HPA and HPG axis

– Lacks immunosuppression effects shown with other opioids

Buprenorphine‐QTc ProlongationBuprenorphine QTc Prolongation• Studies in healthy volunteers showed QTci l l i b 9 2 i h hinternal prolongation by 9.2 msec with the 40mcg/hour transdermal

• Caution: Long QT syndrome; co‐admin with Class 1A/III antiarrthymics; unstable cardiac dx

Torsades de Pointe

QT prolongation

Buprenorphined /dose initiation/titration

• Supplemental IR analgesia during titrationSupplemental IR analgesia during titration

• Opioid‐naïve – start with 5 mcg/hr patch

i• Rotation: (patients on < 80mg MEDD)

MEDD < 30 mg MEDD 30‐80 mg

5 mcg/hr 10 mcg/hr

20 mcg/hr

BUP transdermal‐ PK‐AbsorptionBUP transdermal PK Absorption• Absorption‐affected by application site

– Recommended‐outer arm, upper chest, upper back and side of chest (26% less than others)

N d i ( bd hi h OA i )– Non‐approved sites (abdomen, thigh, OA site)‐less absorption

Lo bod fat less absorption– Low body fat – less absorption

Site Rotation importantp• Repeated use of same site can doubles drug exposure/site reactionsexposure/site reactions

• Manufacturer provides an “Application Site Tracker”• Two methods of disposal

FF f ld ti k id t th d fl h d t il t• FF= fold sticky sides together and flush down toilet• PDU = patch disposal unit provided by manufacturer

Week Date applied

Date Removed

DisposalFF /PDU

Upper outer arm

Upper back

Upperchest

Upper side of chestarm chest

One Nov 1 Nov 8 FF L

Two Nov 8 Nov 15 PDU R

hThree Nov 15 Nov 22 FF R

Four Nov 22 Nov 29 PDU L

BUP‐PharmacokineticsBUP Pharmacokinetics• Peaks in 3 days – Do not titrate dose up before peak is achieved and effects assessedpeak is achieved and effects assessed.

• Wear continuously for 7 days

What cytochrome P450 isoenzymemetabolizes the largest percentage of

drugs?drugs?

56%1. CYP 2C91. CYP 2C9

2. CYP 2D6

3 CYP 3A431%

3. CYP 3A4

4. CYP 1A2

2%

11%

1 2 3 4

2%

Answer.....Answer.....

• What cytochrome P450 isoenzymeWhat cytochrome P450 isoenzymemetabolizes the largest percent of drugs?– CYP 2C9– CYP 2C9

– CYP 2D6

CYP 3A4 50 % Ab i CCB BZ–CYP 3A4– CYP 1A2

50 %‐ Abx, statins, CCB, BZD

BUP‐ EliminationBUP Elimination

• Metabolized by cytochrome P450‐3A4 toMetabolized by cytochrome P450 3A4 to norbuprenorphine – active metabolite– ~40 fold lower effects– 40 fold lower effects

– Only clinically relevant interactions with protease inhibitors atazanavir and efavirenzinhibitors atazanavir and efavirenz

• NO dosage adjustment required in renal impairmentimpairment

Place in TherapyStep 3‐ Strong opioid +non‐opioid + adjuncts (morphine HM fentanyl)

WHO Analgesic (morphine, HM, fentanyl)Step 2‐3 alternativesTAP < 140 MEDD

Stepladder

3 Severe TARGIN® < 120 MEDDBUP LDTD< 80mg MEDD

2 Moderate

N


1 MildNo

Pain

( , )

Step 1‐ Non‐opioid +adjunct



Buprenorphine Low dose transdermalIn summary

• Comparable to lower dose opioids < 80mgComparable to lower dose opioids < 80mg MEDD

• Convenient once weekly dosing• Convenient once weekly dosing

• Suitable for patients with swallowing diffi l idifficulties

• Generally safe in elderly/renal impairment

• Low risk ceiling effect for respiratory depressionp

• Antihyperalgesic effect can be beneficial

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