Commissioning Support Fentanyl Transdermal Patch For the treatment of chronic intractable non-cancer pain Committee’s Verdict: CATEGORY B (Q4) Category B: Suitable for restricted prescribing under defined conditions (The committee did not consider guidance for the use of transdermal fentanyl for cancer-related pain because this was considered to be restricted to specialist care) Commissioning and prescribing considerations When commissioning a pain management service, commissioners should consider specifying criteria for patients who may need to use patches for analgesia, for example: o patients who cannot tolerate tablet formulations, or have difficulty swallowing (although liquid formulations and subcutaneous morphine may be suitable for some of these patients) o patients with mental health problems o patients with compliance issues or for those who are socially isolated with limited access to care Fentanyl should be initiated by a specialist or a specialist pain management service, given the range of alternative treatments available for the management of chronic non-cancer pain. Continued prescribing can then occur in primary care. Patients receiving fentanyl patches should be assessed frequently e.g. after two weeks, for the efficacy of the treatment, improvements in functional status, compliance and tolerability of side effects. Q4 rating: The evidence for the efficacy of fentanyl transdermal patches (TDF) in cancer- and non-cancer pain was relatively weak, based on five open-label trials that compared TDF with morphine sustained-release Q2 Q1 (SR) and one double-blind, placebo-controlled trial. Overall, TDF was higher place higher place shown to be as effective as morphine SR, and more effective than weaker evidence stronger evidence placebo. However, the subjective nature of the outcome measures and the open-label design made the trials subject to potential bias. The cost of TDF compared with oral morphine gives it a low place in therapy. Q4 Q3 lower place lower place The Q rating relates to the drug’s position on the effectiveness indicator weaker evidence stronger evidence grid. The strength of the evidence is determined by the quality and quantity of studies that show significant efficacy of the drug compared with placebo or Place in therapy in primary care alternative therapy. Its place in therapy in primary care takes into account safety Strength of evidence for efficacy and practical aspects of using the drug in primary care, alternative options, relevant NICE guidance, and the need for secondary care input. MTRAC reviewed transdermal fentanyl because of the potential for its prescribing to increase in primary care Description of technology malignant pain although their use has been controversial because repeated administration may The fentanyl transdermal patch was first launched in cause dependence and tolerance. the 1990’s. Fentanyl is a strong opioid analgesic, and is a schedule 2 controlled drug. The licensed NICE issued a draft Clinical Guideline for consultation indications reviewed were for the treatment of chronic in December 2011 on the use of strong opioids for 4 intractable cancer- and non-cancer pain in adults.1 pain management in palliative care. Oral morphine The Medicines and Healthcare Products Regulatory SR was recommended as first-line maintenance Agency (MHRA)2 warned that “fentanyl patches therapy. NICE recommended that transdermal should be used only in patients who have previously preparations may be considered for patients in whom tolerated opioids because of a risk of significant oral opioids are unsuitable and analgesic respiratory depression in opioid-naïve patients”. requirements are not changing rapidly, supported by specialist advice where needed. The final guideline is Background information expected in May 2012. The World Health Organisation (WHO) recommends Clinical efficacy the use of strong opioids (e.g. oxycodone or morphine) for the management of moderate to severe There were six randomised controlled trials with over pain due to cancer, at step three of the WHO three- 100 participants that evaluated TDF (Durogesic®, 25 step analgesic ladder.3 Strong opioids are also µg/hour initial dose) for the relief of chronic pain in 5-7 sometimes used to manage chronic, severe non- patients with cancer-related pain (3 trials, n = 202, January 2012 Page 1 of 2 108, 131), osteoarthritis (1 trial,8 n = 416), low back Additional information pain (1 trial,9 n= 680) or any chronic non-cancer pain (1 trial,10 n = 256). Fentanyl is also available in injectable, buccal, sublingual and nasal delivery formulations. For the Five of the trials5-7,9,10 were open-label and compared transdermal formulation, the initial starting dose is a 12 TDF with morphine SR (60 mg/day initial dose); the or 25 µg/hour patch, replaced every 72 hours. See the sixth trial was a double-blind trial that used a placebo 1 SPC for full details of doses and dose equivalents. patch as comparator in patients with osteoarthritis.8 The duration of the trials was variable: there were two At current prices, the costs of one year’s treatment are: cross-over trials with treatment arms lasting 2 or 4 o fentanyl transdermal patch (Matrifen) 25 to 100 weeks,5,10 three parallel trials lasting 4 to 6 weeks8-10 µg/hour, £310 to £993 and a parallel trial in patients with low back pain o fentanyl transdermal patch (Durogesic DTrans) lasting 13 months.9 25 to 100 µg/hour, £439 to £1,412 o morphine SR (Morphgesic) 10 to 100 mg twice The main outcome measures in the trials focussed on daily, £47 to £347 pain relief, tolerability and quality of life. (Other fentanyl transdermal patches are available) Results: Non-cancer pain Pain control: TDF treatment showed significantly Reference greater pain relief vs. a placebo patch in patients with 8 osteoarthritis. Compared with morphine SR, TDF 1. Janssen-Cilag Ltd. Durogesic DTrans 12/25/50/75/100 treatment showed significantly greater improvement in mcg/hr Transdermal Patch. SPC 2011 pain intensity in one trial,10 and was of similar efficacy http://www.medicines.org.uk/emc . in a second trial.9 One trial reported significantly 2. Medicines and Healthcare Products Regulatory Agency. greater use of rescue medication in TDF-treated Fentanyl patches: serious and fatal overdose from 10 dosing errors, accidental exposure, and inappropriate patients. use. Drug Safety Update. 2011. Quality of life: Two trials reported significantly greater http://www.mhra.gov.uk/home/groups/pl- improvements in some domains of the SF-36 for TDF- p/documents/publication/con025632.pdf <accessed treated patients than comparator-treated patients.8,10 12/2011> There were no significant differences in the third trial.9 3. World Health Organisation. WHO's pain ladder 2009. http://www.who.int/cancer/palliative/painladder/en/ Results: Cancer-related pain <accessed 7/2009> Pain relief: Three trials evaluated TDF vs. morphine 4. NICE clinical guideline draft for consultation. Opioids in SR in patients with cancer-related pain, and found no palliative care: safe and effective prescribing of strong significant differences between treatment groups for opioids for pain in palliative care of adults. NICE. 2011. any patient-rated pain measures. Two trials reported http://www.nice.org.uk/nicemedia/live/12953/57394/5739 greater use of immediate-release morphine as rescue 4.pdf <accessed 12/2011> 5. Ahmedzai S, Brooks D. Transdermal fentanyl versus medication in TDF-treated patients than in those 5,7 sustained-release oral morphine in cancer pain: receiving morphine SR. preference, efficacy, and quality of life. The TTS- Quality of life: There were no significant differences Fentanyl Comparative Trial Group. J Pain Symptom between treatment groups, in the two trials where Manage 1997;13:254-61. quality-of-life measures were reported.5,6 6. Mercadante S, Porzio G, Ferrera P et al. Sustained- release oral morphine versus transdermal fentanyl and oral methadone in cancer pain management. Eur J Pain 2008;12:1040-6. Adverse effects 7. van Seventer R, Smit J, Schipper R et al. Comparison of TTS-fentanyl with sustained-release oral morphine in Adverse events commonly reported in the trials were the treatment of patients not using opioids for mild-to- those usually associated with opioid use: nausea, moderate pain. Curr Med Res Opin 2003;19:457-69. vomiting, diarrhoea, constipation, dizziness and 8. Langford R, McKenna F, Ratcliffe S et al. Transdermal drowsiness or sedation. The incidences of adverse fentanyl for improvement of pain and functioning in effects varied across the trials and there were few osteoarthritis: a randomized, placebo-controlled trial. significant differences between the treatment groups. Arthritis Rheum 2006;54:1829-37. The incidence of constipation was significantly lower 9. Allan L, Richarz U, Simpson K et al. Transdermal with TDF than with morphine SR in three trials (p < fentanyl versus sustained release oral morphine in 7,9,10 strong-opioid naive patients with chronic low back pain. 0.001). See the Summary of Product Spine (Phila Pa 1976 ) 2005;30:2484-90. Characteristics (SPC) for full details of adverse 1 10. Allan L, Hays H, Jensen NH et al. Randomised events. crossover trial of transdermal fentanyl and sustained release oral morphine for treating chronic non-cancer pain. BMJ 2001;322:1154-8. Launch date: 1995 Manufacturer: Janssen Cilag WARNING: This sheet should be read in conjunction with the Summary of Product Characteristics This guidance is based upon the published information available in English at the time the drug was considered. It remains open to review in the event of significant new evidence emerging. MTRAC can be contacted at the Dept. of Medicines Management, School of Pharmacy, Keele University, Keele, Staffs ST5 5BG Tel: 01782 734131 Email: [email protected] Web: www.mtrac.co.uk RELEVANT NICE GUIDANCE WAS NOT AVAILABLE AT THE TIME OF ISSUE OF THIS VERDICT Date: January 2012 ©Midlands Therapeutics Review & Advisory Committee .