LETTER TO THE EDITOR

Utilisation of transdermal fentanyl in Germany from 2004–2006 byEdeltraut Garbe and colleagues

E. Garbe and colleagues report on critical issuesregarding the utilisation of transdermal fentanylpatches for pain management in Germany.1 Theirreport and conclusion was the major impetus for theDrug Commission of the German Medical Associa-tion to publish a warning letter on the non-criticaluse of transdermal fentanyl and related severe sideeffects.2 The data used in this analysis is compellingdue to the amount of data which could be analyzed.The authors demonstrated a trend towards initialuse of transdermal fentanyl in higher dose ranges.Their major concern was the inappropriate pre-scribing pattern including high initial doses ina high-potency-opioid naïve (HPO-naïve) patientpopulation, as well as the lack of adequate clinicalindication for a transdermal route of opioid administra-tion. These findings—since adopted by the GermanDrug Commission---raise serious concerns aboutsafety issues.However, there are some shortcomings in the meth-

odology as well as in the interpretation of the data. Thepotential limitation of the study is an overestimation ofproblems as a result of the frequent utilisation of trans-dermal fentanyl in Germany. Garbe et al. defined aHPO-naïve patient as a patient having no high-potentopioid (e.g. morphine, hydromorphone, oxycodone+/� naloxone, pethidine, piritramide, levomethadoneor buprenorphine) in a period of 3months precedingthe index date.1 However, this definition excluded allpatients who have been on so-called “low-potencyopioids” (e.g. codeine, tramadol, tilidine) before. Thisexclusion of patients who have been on low-potencyopioids is not in line with the international litera-ture.3–5 The discrimination of opioids in WHO-class3 and 2 (high and low-potency) classes is in fact morean administrational as a clinically relevant differentia-tion. By this process, additional 13.865 patients wereclassified as HPO-naïve resulting in a total of 84.5%(n= 29.793) of all new transdermal fentanyl usersbeing opioid-naïve. Taking into account that theterm “opioid-naïve” should describe the absence ofall opioids, the prevalence of potential inadequate

fentanyl application was estimated artificially higherthan a realistic clinical approach would generate.The second issue in the interpretation of the study

relates to opioid therapy initiation. Starting opioidtherapy with higher doses than the lowest available doseof transdermal fentanyl (delivery rate 12.5mg/hvs. ≥25mg/h) was regarded as problematic andpotentially harmful. In 71.2% of the HPO-naïve newtransdermal fentanyl users, the initial dose exceededthe lowest available dose of 12.5mg/h.1 A questionunanswered related to the exceeded dose is: Howmany of those patients have been on WHO-step-2opioids previously? If a patient failed on weaker opioids(e.g. 400–600mg tramadol), switching to transdermalfentanyl should result in an initial dose of 25mg/h atleast. Another issue which has been mentioned in thestudy but which was not considered adequately is thatcancer diagnosis among the so-called HPO-naïvepatients was identified in 34.5% (n=10.283). Theexperience of uncontrolled pain due to inadequateopioid therapy, requiring a significant dose increase orswitching to a more potent opioid, is not uncommonamong cancer pain patients. Therefore, it might benecessary to start with doses exceeding 12.5–25mg/h toachieve adequate pain relief. In a study byVielvoye-Kerkmeer and colleagues,WHO-Step-2 wasskipped in 14 opioid-naïve cancer pain patients, and theinitial transdermal fentanyl dose was 25mg/h. Only onepatient dropped out due to side effects on day 2, whereasa dose increase was needed in 9 of 14 cancer patientswithin 3–6days.6 Klepstad et al. concluded in theirsystematic review that the optimal initial dose for titrationof opioids in adult patients with pain due to cancer is12.5–25mcg/h.7 Therefore, even when accepting thedefinition of HPO-naïve patients by Garbe et al.,in 2006, approximately 80% of the incident fentanylprescriptions were in this range.1

The identification of prescription patterns, whereHPO-naïve patients received one fentanyl patch andno other HPO prescription afterwards led to theconclusion that transdermal fentanyl was used to treatacute pain only.1 However, another interpretation of

Copyright © 2012 John Wiley & Sons, Ltd.

pharmacoepidemiology and drug safety 2012; 21: 902–903Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/pds.3315

the data is possible but was disregarded. This groupmight have also consisted of patients treated withWHO-Step-2 opioids or WHO-Step-1 analgesics wheretransdermal fentanyl was administered for the first timeand due to side effects (e.g. drowsiness, nausea andvomiting) the fentanyl patch administration was discon-tinued without prescribing other strong opioids.Treatment discontinuation when prescribing strongopioids for the first time is not uncommon and seemsto be more frequent in opioid-naïve patients comparedto those previously consuming weak opioids.6,7

The transdermal route of application has a particularadvantage for patients unable to take oral opioids dueto difficulties in swallowing or severe nausea andvomiting. 72.5% of the HPO-naïve patients had beenidentified as having no difficulties with the oral route,and Garbe et al. concluded that transdermal fentanylwas not indicated.1 However, the use of transdermalfentanyl is not restricted to these conditions only. Trans-dermal fentanyl could be used in any case of moderateto severe chronic pain, where the use of a strong opioidis regarded as appropriate.8,9 Regarding the efficacy andtoxicity of different strong opioids, there is no evidenceof significant differences comparing oral morphine andtransdermal fentanyl.10 Therefore, it might be con-cluded that the use of transdermal fentanyl is notrestricted to conditions as defined by Garbe et al. only.Garbe and colleagues concluded that before initia-

tion of transdermal fentanyl, patients with chronic painshould be titrated to adequate pain relief with short-acting oral or parenteral HPOs.1 According to theGerman SPC of Durogesic SMAT, it is suggested toperform a titration with immediate-release opioids,such as morphine or tramadol (!), in opioid-naïvepatients before starting with fentanyl patches in equia-nalgesic doses.9 However, given the present availableknowledge, there is also evidence supporting an opioidtitration by using slow-release formulations.7 Sincedose initiation with immediate-release opioids is veryuncommon in Germany, the citation of studies reflect-ing the US-American situation is not helpful whendiscussing German problems of strong opioids use.1

In summary, the paper of Garbe et al. gives impor-tant information regarding the use of transdermalfentanyl in Germany, even though some of the estimatesand calculations seem to be to high due to the methodol-ogy. Strong opioids, such as transdermal fentanyl,should be used carefully, and the patients have to bemonitored to avoid (severe) side effects.2 Transdermalfentanyl has the highest prescription rate compared toother strong opioids in Germany. In 2010, 60.4 Milldefined-daily-doses (DDDs) of transdermal fentanylhad been prescribed compared to 28.6 Mill DDDs of

oxycodone.11 Keeping in mind that there is still majorlack of knowledge on opioids in the health community,and knowing, that there is still no evidence of theefficacy of long-term opioid treatment especially innon-cancer pain patients at all, monitoring prescriptionpatterns of opioids to detect inappropriate use seems tobe very important.12–14

CONFLICT OF INTEREST

Rainer Sabatowski is a member of a scientific advisoryboard of a Jansen-Cilag award for young scientists.

REFERENCES

1. Garbe E, Jobski K, Schmid U. Utilisation of transdermal fentanyl in Germanyfrom 2004 to 2006. Pharmacoepidemiol Drug Saf 2012; 21: 191–198.

2. Arzneimittelkommission der Deutschen Ärzteschaft. Die unkritische Anwendungvon Fentanylpflastern erhöht das Risiko für schwerwiegende Nebenwirkungen.Deutsches Ärzteblatt 2012; 109: B628–629.

3. Cepeda MS, Fife D, Chow W, Matrogiovanni G, Henderson SC. Opioid ShoppingBehavior: HowOften, How Soon,Which Drugs, andWhat PaymentMethod. J ClinPharmacol [Epub 1 February 2012]. DOI: 10.1177/0091270012436561

4. Cepeda MS, Etropolski M, Weinstein R, Fife D, Boston R, Matcho A. Dosepatterns in commercially insured subjects chronically exposed to opioids: a largecohort study in the United States. BMC Palliat Care 2010; 9: 14.

5. Mercadante S, Porzio G, Ferrera P, et al. Low doses of transdermal buprenor-phine in opioid-naïve patients with cancer pain: a 4-week, nonrandomized,open-label, uncontrolled observational study. Clin Ther 2009; 31: 2134–2138.

6. Vielvoye-Kerkmeer APE, Mattern C, Uitendaal MP. Transdermal fentanyl inopioid-naive cancer pain patients: an open trial using transdermal fentanyl forthe treatment of chronik cancer pain in opioid-naive patients and a group usingcodein. J Pain Symptom Manage 2000; 19: 185–192.

7. Klepstad P, Kaasa S, Borchgrevink PC. Starting Step III opioids for moderate tosevere pain in cancer patients: Dose titration: A systematic review. Palliat Med2011; 25: 424–430.

8. Heads of Medicines Agencies. Fentanyl Transdermal Patch SPC. http://www.hma.eu/fileadmin/dateien/pipar/de763765fentanyl/spc_de763765fentanyl.pdf(accessed 18 April 2012)

9. Janssen-Cilag. Durogesic SMAT: Fachinformation. Janssen-Cilag: Beerse, 2011.10. Caraceni A, Pigni A, Brunelli C. Is oral morphine still the first choice opioid for

moderate to severe cancer pain? A systematic review within the European PalliativeCare Research Collaborative guidelines project. Palliat Med 2011; 25: 402–409.

11. Schwabe U, Paffrath D (ed.). Arzneiverordnungs-Report 2011. Springer Verlag:Stuttgart, 2012.

12. Pflughaupt M, Scharnagel R, Gossrau G, Kaiser U, Koch T, Sabatowski R.Physicians’ knowledge and attitudes concerning the use of opioids in thetreatment of chronic cancer and non-cancer pain. Schmerz 2010; 24: 267–275.

13. Reinecke H, Sorgatz H. S3 guideline LONTS. Long-term administration ofopioids for non-tumor pain. Schmerz 2009; 23: 440–447.

14. Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften(AWMF). Langzeitanwendung von Opioiden bei nicht-tumorbedingten Schmerzen(LONTS). http://www.awmf.org/uploads/tx_szleitlinien/041-003l.pdf (accessed 18April 2012).

RAINER SABATOWSKI*

RÜDIGER SCHARNAGEL

Comprehensive Pain Center, Technical UniversityDresden, Dresden, Germany

* R. Sabatowski, Comprehensive Paint Center, UniversityHospital “Carl Gustav Carus,” Technical University

Dresden, Fetscherstr. 74, 01307Dresden, Germany.

E-mail: rainer.sabatowski@uniklinikum-dresden.de

letter to the editor 903

Copyright © 2012 John Wiley & Sons, Ltd. Pharmacoepidemiology and Drug Safety, 2012; 21: 902–903DOI: 10.1002/pds