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RxFiles Q&amp;A Summary: Buprenorphine Transdermal Patch ­ Pg 1

BuTrans Patch

Buprenorphine Transdermal System (BTDS) for Weekly Application


{Semisynthetic, highly lipophilic opioid; derivative of morphine alkaloid thebaine; brain tissue levels far exceed serum levels}


Opioid analgesic (mu agonist; kappa &amp; delta antagonist). Narcotic and Controlled Drug (Canada). It is often considered a partial mu agonist; however some recent literature suggests full potent mu activity.3 Its action may more resemble a full mu agonist at lower doses, and partial mu agonist at higher doses. Controversial!

{Note, a related product, SUBOXONE consists of [buprenorphine 2mg + naloxone an opioid antagonist 0.5mg] as a SL tablet used to treat opioid dependence. Bioavailability of buprenorphine-variable: Transdermal 15%; SL= 30%-70%; Suboxone dosage range is 4-24mg/day buprenorphine. The amount of buprenorphine in 4 mg SL may equate to the amount in 16 BuTrans-20 patches. Only about 3% of the naloxone in Suboxone is absorbed; it will precipitate withdrawal if injected; useful in addiction med.}

Strengths Use/Place in Therapy Contraindications

(CI), official 1 CPS


{Patch provides sustained levels &amp; analgesia over 7 days.} {High affinity for mu receptor blockade may last &gt;24hrs. Effect not totally related to plasma levels.}


Drug Interactions


Metabolized via CYP3A4 to nor-buprenorphine (an active metabolite).

Adverse Events (AE)

{Most are similar to other opioids.}

Discontinuing / Withdrawal Other

Cost / 4 weeks:

5mcg/hr: $ 60 10mcg/hr: $ 105 20mcg/hr: $ 185

(includes markup &amp; dispensing fee)

Currently not covered by most drug plans!

Patch (matrix): 5mcg/hr (0.12mg/day), 10mcg/hr (0.24mg/day), 20mcg/hr (0.48mg/day) o Persistent pain of moderate intensity in adults (40kg) requiring continuous opioid analgesia for an extended period of time (not suitable for unstable or widely fluctuating pain). [Higher patch strengths e.g. TRANSTEC 35-70mcg/hr (q3d) available in Europe for pain.4] o Can be used in opioid naïve patients (alternate to codeine, tramadol) and patients previously only on prn opioids o Considered when non-opioids provide inadequate relief and strong opioids undesirable in chronic non-cancer pain o Hypersensitivity, GI (ileus, surgical abdomen), mild/intermittent/acute pain, acute asthma/obstructive airway/respiratory depression, acute alcoholism/dependence, opioid dependence/acute opioid withdrawal, convulsive disorders, MAOIs within 14 days, myasthenia gravis, hepatic insufficiency, pregnancy/lactation; &lt;40kg o Begin at: 5mcg/hr patch applied once weekly; titrate up as necessary or if previously on opioid (up to 80mg oral morphine equivalent/day) may start on 5-10mcg/hr patch once weekly (medication for breakthrough pain should also be provided) o Dose adjustments: generally recommended after 7 days; and not more frequently than after 3 days. o Maximum dose: 20mcg/hr. (Patch applied for 7 days.) Doses 40mcg/hr may be associated with QT prolongation (but less than methadone)!5 o Breakthrough pain: may be managed by acetaminophen or NSAID +/- codeine or other breakthrough meds prn o Adjustments: Renal dysfx: NO dose adjustment required; (hepatic metabolism glucuronidation &amp; biliary excretion). o Apply to: non-irritated, dry, intact skin; upper outer arm, upper chest, upper back or side of chest (always above the umbilicus) o Do not apply creams or ointments etc. to skin &lt; 6hours prior to patch application as may affect adhesion. o If site irritation, consider a corticosteroid spray (e.g. beclomethasone or fluticasone) to skin area prior to patch; (this lacks data &amp; may affect absorption). {Alternately, steroid cream post-patch or well in advance (&gt; 6-12hr) of patch application.} o Rotate sites with each new patch; choose 4 or more sites and rotate; allow 3 weeks before reusing the same site o Avoid exposure of patch to direct sunlight ( absorption). Showering, swimming &amp; bathing should not affect patch. o 3A4 inhibitors: dose related toxicity of buprenorphine e.g. amiodarone, itraconazole, clarithromycin, fluconazole, erythromycin, grapefruit juice, protease inhibitors ritonavir, nelfinavir, amprenavir, verapamil, diltiazem o 3A4 inducers: likely to efficacy of buprenorphine: e.g. phenobarbital, carbamazepine, phenytoin, rifampin o CNS depressants: additive effects (e.g. sedation, alertness, confusion, dizziness) o E.g. alcohol, benzodiazepines, sedative/hypnotics, antipsychotics, antihistamines o Other: Warfarin INR; anesthetics hepatic blood flow &amp; [buprenorphine]; Benzodiazepines flunitrazepam: deaths reported in addict population o Common on initiation: nausea45%, dizziness27%, somnolence24%, constipation21%, pruritus, dry mouth o Most common in clinical trials (rates from crossover trials; for difference from placebo rates, see CPS or specific trial literature): o anorexia, application site erythema/pruritis25%, asthenia, constipation, dizziness27%, dry mouth, headache, hyperhydrosis16%, insomnia, nausea +/- vomiting, somnolence. [Potential QT prolongation with 40mcg/hr patch.] o Serious, but less common with careful dose titration: respiratory depression however ceiling effect in resp depression, hypotension o Consider tapering if higher doses to reduce withdrawal symptoms; withdrawal generally mild &amp; resolves in 2 weeks o After removal of patch, levels decline gradually; ~ 50% over ~12hours (10-24 hrs); administering a subsequent opioid after patch removal should generally be delayed until 24hours after removal o Steady state levels in ~3 days. Heat sources (external): will absorption &amp; risks (e.g. heat pad, hot bath, sauna, sunbathing, fever, etc.) o Advantages: long action useful for chronic-stable type pain; once weekly application &amp; kappa antagonist effect may result in less dsyphoria, psychological craving &amp; dependence {However, data from Norway suggests addiction concerns}6. May cause less withdrawal when stopped than other opioids; incidence of constipation may be lower. Compared to the fentanyl patch: lower abuse potential, mild withdrawal symptoms, may initiate in opioid naïve. o Disadvantages: long &amp; delayed action means it is not suitable for acute or fluctuating pain; adverse effects may be sustained for 24 hours after removal of patch.{If one holds that it is a partial mu agonist, this would limit the opioid effect resulting in both a ceiling dose &amp; potential withdrawal in patients dependent on other long-term opioids.}. Studies are short term (e.g. 12 weeks; most 4weeks); results modest &amp; benefits harms (NNT = 7-8 &amp; NNH for AE = 6-9). o CEDAC (Sept-2011 CDR Update): recommends against listing for coverage; high cost but no more effective than PO opioids o

Daily Opioid Dose*


Estimated Dose Equivalencies: BuTrans (BTDS) may be 25­110x more potent than oral morphine; individual variance; highly controversial!!!7

&amp; Approximate Cost/4wks

$43 $67 $56 $30 $64 $51 400 mg 300 mg 60 mg 30 -40 mg 12 ­ 15 mg 12 mcg/hr $89 $100 $42 $92 $72 $42 Acetaminophen + Codeine (30mg) ± Caffeine Codeine Cost/week based on Tramadol lowest cost Oral Morphine sustained release Oral Oxycodone (SR) formulations. Oral Hydromorphone Fentanyl Patch 6 (x30mg) tabs 100mg 15 mg 10 mg 3.75 mg 7-8 (x30mg) tabs 200 mg 150 mg 30 mg 15 ­ 20 mg 6 ­ 7.5 mg -

Initial BuTrans patch dose 5 mcg/hr 5 mcg/hr 5-10 mcg/hr if on previous opioid. + something for breakthru + something for breakthru Estimate of Eventual BuTrans® Patch Strength 5 mcg/hr $60 10 mcg/hr $105 20 mcg/hr * $185 *Monograph does not recommend starting &gt; than 10 mcg/hr (as per &quot;dosing&quot; above). Table serves as a guide; actual dosing requires careful individualization &amp; reassessment! ** Can patients on high doses of morphine &amp;/or strong opioids be switched to transdermal buprenorphine? (See also extras under page 3 of this Q&amp;A online.) Currently this is not recommended in Canada and there is concern about opioid withdrawal. However, one study successfully switched cancer patients on oral morphine (120-240mg/d) and transdermal fentanyl (50-100mcg/hr) to BTDS using a potency ratios of 70:1 for morphine and 0.6:0.8 for transdermal fentanyl. 10 Note, due to transdermal route, there is less bioavailability variance than oral opioids. Anecdotally, some physicians report success with direct switching of &lt;40-60mg/day morphine equivalent opioid regimens. Approach 1: wean patient over several weeks to about half their opioid dose, then convert to estimated equivalent buprenorphine dose +/- fast acting opioid. Approach 2: Apply first dose of equivalent dose buprenorphine patch at same time as taking last dose of long-acting opioid +/- fast acting opioid.

Note however that opioid withdrawal may occur for patients taking long-term and/or higher doses of opioids after switching to buprenorphine!**

RxFiles Q&amp;A Summary: Buprenorphine Transdermal Patch ­ Pg 2


Table 1: Randomized controlled trials (RCT): buprenorphine transdermal system (BTDS) - BuTrans (7 day) patch, chronic non-cancer pain




Results (primary; other)

VAS: 37.6 +/- 20.7 vs 43.6 +/- 21.2 p=0.049 use of breakthru tabs: 1.8 vs 2.4/day (NS ) also improved: pain +: sleep, disability, etc. AE &quot;severe&quot; as per patient: 53% vs 42% NNH=9 AE: &gt;20%: (nausea, somnolence, pruritis, asthenia,

constipation, insomnia, dizziness)


Low back pain, mod-sev (VAS BTDS 5, 10, 20mcg/hr vs Pl + i-ii ACC30 q4-6h prn lower dose for BTDS 2/5) for 6wks &amp; not well controlled. (most had long hx) DB, crossover @4wk Not ITT (only evaluated if 2 n=53 (28 ; 25 ); age ~54 wks tx completed) baseline pain: 62.1 +/- 15.5 Low back pain, mod-sev, on prior opioid (78 randomized) PP: n=53 (20 ; 30 ); age ~51 Osteoarthritis (hip or knee); mod-sev n=135; age ~64 baseline pain: 4 (BS-11) on acetaminophen 4g/day Osteoarthritis (hip or knee); mod-sev n=238 at run in; 102 42% analysed (~65% ); age ~64 baseline pain: 4 (BS-11); no recent strong opioid Osteoarthritis (hip or knee); n=315 at run-in;15549% analyzed age ~ 60, (67% ) previously on opioid (90mg or lack of relief with NSAID Non-cancer pain 2 months; on previous combination oral opioids n=588 at run-in; n=267 45% actually randomized; (~62% ); age ~57 Osteoarthritis (hip or knee); mod-sev n=199; age ~63

morphine equivalent; not more than 12doses of short-acting opioid/day)



BTDS 10, 20, 40mcg/hr vs Pl + i-ii Acetaminophen q4-6h prn DB, crossover @4wk Not ITT BTDS 5, 10, 20mcg/hr vs Tramadol CR 150 - 400mg/day (+ acetaminophen prn) x 12 wk Open label; non-inferiority BTDS 5, 10, 20mcg/hr vs buprenorphine SL 0.2-0.4mcg q68h (+ acetaminophen 1g prn) DB, x 4wks BTDS 5, 10, 20mcg/hr vs Pl (no rescue medication allowed) DB, parallel group; x 5 wks (1 wk run[blinding was broke for 1 patient] BTDS 5, 10, 20mcg/hr vs Pl (+ acetaminophen 500mg prn) DB, parallel-group x 2 wks (discontinue early if require 1g acetaminophen/day, or unable to continue with patch) BTDS 5, 10, 20mcg/hr vs Pl x 6 mo

(NSAID continued; + acetaminophen prn)

in, 3wk titration, 1wk maintenance)



Mean dose = 29.8mcg/hr vs 32.9mcg/hr PP: Pain on 0-4 point scale: 1.9 vs 2.2 p=0.044; no difference in pain disability index BS-11: no difference; - 2.26 vs -2.09 (ITT) also rescue med; sleep; QOL AE: 226 vs 152; AE DC: 14.5% vs 29.2% AE-BTDS: nausea 30%; constip. 19%; dizzy 16% AE-Tramadol: nausea25%, fatigue18%, pain 12% BS-11: scores considered equivalent (per protocol) for morning, midday &amp; evening AE: patch associated with less nausea, vomiting &amp; dizziness Discontinuation (ITT): 53% vs 55% p=0.7; 42% discontinued due to AE patient satisfaction scale (0 ­ 4) at final visit: 44% vs 32% (ITT) satisfied score &gt;2; OR=1.66 NNT=8; AE: 70% vs 53%; NNH=6. (nausea, headache,

dizziness, somnolence, pruitis at site, constipation.)

(General: industry sponsored trials) Exclusions: multiple (e.g. if expected to exceed max BTDS dose) 79 patients enrolled; 53 patients evaluated per-protocol most patients (59%) titrated to highest dose (titrations weekly) 82% of patients chose to continue for 6 month open label followup where pain and QOL improvements were sustained similar improvements in opioid &amp; opioid naïve patients BTDS had modest benefit vs PL considering prior opioid hx Some +ve 2° outcomes: e.g. get out of bed, sit in chair. 6mo follow-up open label, 27/40 completed +ve. limitations: not ITT; AEs 1wk screening, 12 wk treatment; 2 week follow-up phases; 172 screened, 135 randomized. baseline pain: BS-11: 6.16 3.92 vs 6.21 4.10 (ITT) patient and assessor ratings of pain favoured BTDS 21 day run-in 6 serious adverse events: 1 fatal MI, not deemed related to BTDS; 1

hospitalization for biliary colic/spasm &amp; 1 hospitalization for dizziness &amp; asthenia.

patch site redness 55% &amp; irritation 25%; some complaints of patch buckling or curling. 7 day run-in on ibuprofen &amp; inadequate relief on ibuprofen artificial type of trial a number of 2° endpoints did not have significant differences but some &quot;trends&quot; supportive; subgroup: benefit only seen in knee subgroup, not hip Purdue sponsored; odd/unique design; very short! Open label run-in with BTDS for 7-21 days; only those tolerating BTDS entered &amp; randomization was at dose achieved during run-in (may underestimate harm &amp; overestimate efficacy)


proportion of subjects with ineffective tx: 51.2% vs 65%; NNT=7 ;(OR = 1.7995% CI: 1.09-2.95) AE: pruritis at patch site 9.3% vs 5.1%; headache 3.9% vs 2.2% ; somnolence 2.3% vs 0.7%. (Openlabel run-in withdrawal &amp; early completion of study serve to underestimate true AE risks.)


WOMAC OA Index of Pain (1°): NS some 2°s improved: daytime movement pain pain mental health &amp; vitality; QOL

BTDS: ?less effective in very severe OA; ?patient preferred no difference in BTDS &amp; Pl in mean dose or titrations required - dose higher than available in Canada 6day open-label run-in with buprenorphine SL 0.8­1.6mg/day prn 72hr patch improved sleep reported 72hr patch used need for prn: 56.7% vs 8%; 72hr patch used. 239 patients chose to continue BTDS in open follow-up study

Select Studies with different dose (e.g. 35-70mcg/hr) or dosage form (e.g. 3-4 day patch) than available in Canada; but of interest

1. 18 2. 19 3. 20 4. 21 Chronic cancer pain open label; + tramadol 200mg/day prn Chronic cancer &amp; non-cancer pain n=137 (90 BTDS; 47 Pl) (~50% ) Chronic cancer &amp; non-cancer pain not controlled on weak opioids n=157 (55% ); age 59 Chronic cancer &amp; non-cancer pain n=445 BTDS 35 mcg/hr vs Buprenorphine SL &amp; Pl BTDS 35 - 70 mcg/hr vs Pl (+ buprenorphine SL 0.2mg prn) DB; x 9 days BTDS 35 ­ 70 mcg/hr vs Pl (+ buprenorphine SL 0.2mg prn) DB; x 15 days BTDS 35 - 70 mcg/hr vs Pl ? breakthru pain as reflected by need for prn: use of buprenorphine 0.6 mg vs 0.4mg p=0.03. patient's assessment of pain: NS. nausea, dizzy &amp; vomiting 43.5% patients reported good pain relief vs 32.4% (NNT=9); response rate higher at 35-52.5mcg/hr, but NS at 70mcg/hr. 78% overall reported 1 AE (CNS &amp; GI) ?greater pain relief vs Pl

ACC30=acetaminophen/caffeine/codeine 30mg AE=adverse events BS-11=box score 11 point rating system CR=controlled release DB=double-blind ITT=intention to treat NNH=number needed to treat to harm one patient NNT=number needed to treat to benefit one patient NS=not statistically significant OR=odds ratio Pl=placebo QOL=quality of life SL=sublingual VAS=visual analogue scale Additional References &amp; Links o Pharmacist's Letter. Onsolis (Fentanyl Buccal Film) and BuTrans (Buprenorphine Patch). Aug 2010. NPS (Australia) Summary of buprenorphine patch Norspan: o RxFiles: Opioid Comparison Chart in RxFiles Drug Comparison Charts ­ 8th Edition; accessed online at: ; RxFiles Opioid Newsletter 2005: ; Opioid Treatment Agreement: ; Switching to BuTrans Anecdotes22; Canadian Opioid Guidelines 2010 (National Pain Centre): References

1 2 3

Prepared by Loren Regier, Sep 2010 (Update Dec/2011)for RxFiles Academic Detailing Thanks to the many reviewers who provided input.

CPS 2010 Product Monograph - BuTrans Heit HA, Gourlay DL. Buprenorphine: new tricks with an old molecule for pain management. Clin J Pain. 2008 Feb;24(2):93-7. Review. Erratum in: Clin J Pain. 2008 May;24(4):370. Pergolizzi J, Aloisi AM, Dahan A, Filitz J, Langford R, Likar R, et al. Current Knowledge of Buprenorphine and Its Unique Pharmacological Profile. Pain Pract. 2010 May 17. 4 NHS-York Hospitals - Palliative care analgesic dose conversion chart 5 Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MC. QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial. Arch Intern Med. 2007 Dec 10;167(22):2469-75. 6 Skurtveit S, Furu K, Kaasa S, Borchgrevink PC. Introduction of low dose transdermal buprenorphine -- did it influence use of potentially addictive drugs in chronic non-malignant pain patients? Eur J Pain. 2009 Oct;13(9):949-53. 7 Kress HG. Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine. Eur J Pain. 2009 Mar;13(3):219-30. Epub 2008 Jun 24.. 8 Sittl R, Likar R, Nautrup BP. Equipotent doses of transdermal fentanyl and transdermal buprenorphine in patients with cancer and noncancer pain: results of a retrospective cohort study. Clin Ther. 2005 Feb;27(2):225-37. 9 Palliative Care Formulary 3 (Twycross et al, 2007) 10 Mercadante S, Casuccio A, Tirelli W, Giarratano A. Equipotent doses to switch from high doses of opioids to transdermal buprenorphine. Support Care Cancer. 2009 Jun;17(6):715-8. 11 Gordon A, Rashiq S, Moulin DE, Clark AJ, Beaulieu AD, Eisenhoffer J, et al. Buprenorphine transdermal system for opioid therapy in patients with chronic low back pain. Pain Res Manag. 2010;May-Jun;15(3):169-78. 12 Gordon A, Callaghan D, Spink D, Cloutier C, et al. Buprenorphine transdermal system in adults with chronic low back pain: a randomized, double-blind, placebo-controlled crossover study, followed by an open-label extension phase. Clin Ther. 2010. May;32(5):844-60. 13 Karlsson M, Berggren AC. Efficacy and safety of low-dose transdermal buprenorphine patches (5, 10, and 20 microg/h) versus prolonged-release tramadol tablets (75, 100, 150, and 200 mg) in patients with chronic osteoarthritis pain: a 12-week, randomized, open-label, controlled, parallel-group noninferiority study. Clin Ther. 2009 Mar;31(3):503-13. 14 James IG, O'Brien CM, McDonald CJ. A Randomized, Double-Blind, Double-Dummy Comparison of the Efficacy and Tolerability of Low-Dose Transdermal Buprenorphine (BuTrans((R)) Seven-Day Patches) With Buprenorphine Sublingual Tablets (Temgesic((R))) in Patients With Osteoarthritis Pain. J Pain Symptom Manage. 2010; Aug;40(2):266-278. 15 Munera C, Drehobl M, Sessler NE, Landau C. A randomized, placebo-controlled,double-blinded, parallel-group, 5-week study of buprenorphine transdermal system in adults with osteoarthritis. J Opioid Manag. 2010;6(3):193-202. 16 Landau CJ, Carr WD, Razzetti AJ, Sessler NE, Munera C, Ripa SR. Buprenorphine transdermal delivery system in adults with persistent noncancer-related pain syndromes who require opioid therapy: a multicenter, 5-week run-in and randomized, double-blind maintenance-of-analgesia study. Clin Ther. 2007Oct;29(10):2179-93. Erratum in: Clin Ther. 2009 Mar;31(3):677. 17 Breivik H, Ljosaa TM, Stengaard-Pedersen K, Persson J, et al. A 6-months, randomiseed, placebo-controlled evaluation of efficacy &amp; tolerability of a low-dose 7-day buprenorphine Transdermal patch in OA naïve to potent opioids. Scaninavian J of Pain 2010;122-141. (not available on pubmed as of Nov 23, 2010. 18 Pace MC, Passavanti MB, Grella E, Mazzariello L, Maisto M, Barbarisi M, Baccari E, Sansone P, Aurilio C. Buprenorphine in long-term control of chronic pain in cancer patients. Front Biosci. 2007 Jan 1;12:1291-9. 19 Sorge J, Sittl R. Transdermal buprenorphine in the treatment of chronic pain: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study. Clin Ther. 2004 Nov;26(11):1808-20. 20 Sittl R, Griessinger N, Likar R. Analgesic efficacy and tolerability of transdermal buprenorphine in patients with inadequately controlled chronic pain related to cancer and other disorders: a multicenter, randomized, double-blind, placebo-controlled trial. Clin Ther. 2003 Jan;25(1):150-68. 21 Böhme K. Buprenorphine in a transdermal therapeutic system--a new option. Clin Rheumatol. 2002 Feb;21 Suppl 1:S13-6.

Copyright 2010 RxFiles, Saskatoon Health Region; All Rights Reserved. DISCLAIMER: The content of this newsletter represents the research, experience and opinions of the authors and not those of the Board or Administration of SHR. Neither the authors nor SHR nor any other party who has been involved in the preparation or publication of this work warrants or represents that the information contained herein is accurate or complete, and they are not responsible for any errors or omissions or for the result obtained from the use of such information. Any use of the newsletter will imply acknowledgment of this disclaimer and release any responsibility of SHR , it employees, servants or agents. Readers are encouraged to confirm the information contained herein with other sources.

RxFiles Q&amp;A Summary: Buprenorphine Transdermal Patch ­ Pg 3


Comments (anecdotal) from clinicians on switching from other opioids to BuTrans o Officially not recommended in Canada, but some experience has been positive o Limited experience; if done, most success with tapering down the other opioids prior to switch to Butrans 5 or 10 and then titrated up as necessary. Direct opioid rotations mostly only for doses &lt;40-60 mg/day of morphine. o Encourage non-drug therapy complementary approaches in addition to drug therapy; essential for long term success of CNCP o Relative potency for switching is not well established: o BuTrans 5 = .12 mg/day 10 mg/day morphine or 7.5 mg/day oxycodone o BuTrans 10 = .24 mg/day 20mg/day morphine or 15 mg/day oxycodone o BuTrans 20 = .48 mg/day 40 mg/day morphine or 30 mg/day oxycodone o Example- pt on 40 mg morphine (Meslon 20mg bid) with poor pain relief (VAS 8/10) o Option #1 (preferred?) Wean patient down to 20mg/day (10 mg am 15mg pm X 1-2 weeks the 15mg BID X 1- 2 weeks the 10 mg am 15mg pm X 1-2 weeks then Sat am take last does of 10mg M-Eslon and apply BuTrans 10mg patch. Use MS-IR 5 mg bid prn for any withdrawal or severe pain o Option 2 = Patient on 20 mg M-Eslon bid; Sat am apply BuTrans 20 patch and take last dose of 20mg M-Eslon. Then use MS-IR 5-7.5 mg bid-tid severe pain or withdrawal. [MS-IR = immediate release morphine sulphate]


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