Transdermal Fentanyl: an update

Dr David Brooks

Macmillan Consultant in Palliative Medicine

• a case of fatal intoxication by the application of a transdermal fentanyl patch upon a superficial bleeding abrasion of a 2-year-old girl

– The grandmother applied the patch to cover the injury, unaware that she had used a fentanyl transdermal patch instead of simple band-aid.

• “The external examination revealed that 34 transdermal fentanyl matrix patches, with release rates differing from 25 up to 100 μg/h, were affixed on the woman’s body. – All patches were applied on parts of the body which

were in easy reach of the woman’s hands.

– The husband, having admitted that he supplied the patches to his wife but had not administered the patches to her skin, called the emergency physician once there was an obvious absence of life.

• woman aged 70 years

– suffered from chronic back pain

– 10 years transdermal fentanyl patches.

– applied fourteen 100 mg fentanyl patches with fatal intent,

• two 45 mg mirtazapine tablets

• concurrent therapeutic doses of tramadol and morphine

– after 24 hours, she awoke from a deep sleep to the sound of the telephone ringing

• 445 patients wearing the 72-h transdermal fentanyl – mean, 52.6 μg/h,

– range of 12.5 to 150 μg/h

• 10.1 % of all patients showed day 3 increase in PI-NRS of 30 % or more baseline PI-NRS

• 84.4 % were converted to the once-a day patch

Overall, fentanyl ITS provided equivalent analgesic efficacy to that with morphine PCIA, but was perceived to be more convenient/easier to use than morphine PCIA by patients, nurses and physical therapists and improved the ability of the patient to mobilize postoperatively.

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• Serum concentrations not a major determinant of pain control

• For adverse symptoms other than cognitive dysfunction, breakthrough opioid use was more important than serum fentanyl concentrations

• Serum fentanyl concentrations were not associated with cognitive dysfunction

• However, the MYD88 rs6853 variant was associated with significantly reduced risk of cognitive dysfunction,

• Thirty photographs of fentanyl/placebo TDS

– reflecting varying degrees of adhesion

– shown to 30 health professionals

– asked to score the photographs using the FDA scoring system.

• Validity was high for both series (≥ 0.954).

– Inter-reliability (k) ranged from 0.327 to 0.858 (average, 0.547) and 0.433-0.910 (average, 0.620) in series A and B, respectively.

FDA Scoring System for Patch Adhesion

Score Description Explanation

0 ≥90% adhered Essentially no lift off the skin

1 ≥75% to <90% adhered Some edges only lifting off the skin

2 ≥50% to <75% adhered Less than half of the patch lifting off the skin

3 >0% to <50% adhered but not detached

More than half of the patch lifting off the skin without falling off

4 0% adhered—patch detached

Patch completely off the skin

• 426 patients, 46 practices • The physicians assessed the adhesiveness of the transdermal fentanyl

(Fentavera){aka Fencino} matrix patch at one month and 2 months treatment. At both assessment intervals, more than 87% of cases exhibited “very good” or “good” adhesiveness, while there were rare cases of “poor” or “very poor” adhesiveness

Matrifen Durogesic Reservoir p

Adherence % (Variability %) 62.5 (19.4) 56.2 (21.0) <0.0001

• Adhesive Properties graded every 12 hours • 24 healthy volunteers

• 30 healthy males – FDA adhesion scores

• 0 - ≥90% 1 – ≥75% to <90%

Mean SD

Matrifen 0.5 0.7

Durogesic D-trans 0.2 0.5

Durogesic D-trans

Victanyl

• 9 healthy males

• 47 eligible patients • The median ORR from TDF mg/day to MEDD is 100 and from TDF

mcg/hour to MEDD is 2.4, suggesting that TDF 100 mcg/hour is equivalent to an MEDD of 240 mg.

• Fifty patients with cancer pain who had no previous opioid treatments – cognitive functions assessed using Addenbrooke's

Cognitive Examination (ACE-R) – 25 µg/h TDF – dose was increased so that VAS ≤2.

• Day 30 – attention-orientation, memory, fluency, language, and

ACER total scores showed a statistically significant improvement

– No significant change in visuospatial abilities. – No difference was detected in performance status

• One small study – complicated design.

• 258 study participants first received fentanyl (as one-day skin patches) for one month

• Titrated 12.5mcg/h to 50mcg/h

• Those who responded to therapy (achieved a predetermined level of pain relief) were then randomly allocated to continue fentanyl or placebo for 12 weeks.

– 163 participants randomised • one of three different types of neuropathic pain

• had not taken opioids before

• In the titration phase – 1 in 3 participants withdrew because of adverse

events or inadequate pain relief – almost 90% experienced adverse events.

• 163 were 'responders' entered the randomised withdrawal phase. – The number of participants completing the study (and

therefore continuing on treatment) without an increase of pain by more than 15/100 • 47/84 (56%) with fentanyl • 28/79 (35%) with placebo.

• Because only 63% responded sufficiently to enter the randomised withdrawal phase, this implies

– only a maximum of 35% of participants entering the study would have had useful pain relief and tolerability with transdermal fentanyl,

– compared with 22% with placebo.

• Satisfaction (were 'satisfied' and 'very satisfied' at the end of the study) – Almost 60% of participants taking fentanyl – compared with about 40% with placebo.

• The most common adverse events were – Constipation – Nausea – Somnolence – Dizziness.

• Authors' conclusions – There is insufficient evidence to support or refute the suggestion that

fentanyl works in any neuropathic pain condition. – We downgraded the quality of the evidence to very low

• Nine studies

– 1244 patients.

– often small

– used different study designs

– compared fentanyl with many different drugs.

• Most patients went from moderate or severe to no worse than mild pain when using transdermal fentanyl.

• Only 3 in 10 patients were constipated using transdermal fentanyl – compared with 5 in 10 using oral morphine – useful and significant reduction in complaints about

constipation – risk ratio of 0.61 (95% CI 0.47 to 0.78) – NNT to prevent constipation was 5.5 (95% CI 3.8 to 10)

• We could not analyse the data in a meaningful way regarding harmful (adverse) events such as – nausea – abdominal pain – gastrointestinal bleeding – confusion.

• Only 3 in 10 patients were constipated using transdermal fentanyl – compared with 5 in 10 using oral morphine – useful and significant reduction in complaints about

constipation – risk ratio of 0.61 (95% CI 0.47 to 0.78) – NNT to prevent constipation was 5.5 (95% CI 3.8 to 10)

• We could not analyse the data in a meaningful way regarding harmful (adverse) events such as – nausea – abdominal pain – gastrointestinal bleeding – confusion.

• Authors' conclusions • The randomised trial literature for effectiveness

of transdermal fentanyl is limited • Most studies < 100 participants

– and did not provide data appropriate for meta‐analysis.

• Only a few reported how many patients had good pain relief – but, where data were reported, a majority had no

worse than mild pain within a reasonably short time period.

• Authors' conclusions

• The evidence pointed to a useful and significant reduction in complaints about constipation for transdermal fentanyl compared with oral morphine.

• The quality of evidence in these studies is severely limited. – Overall, the methodological quality of the included

trials was poor with a median quality score of two (range one to three) on the Oxford Quality Scale.

• Nine reviews – 152 included studies – 13,524 participants

• The amount and quality of evidence around is disappointingly low,

• In around 19 out of 20 people – moderate or severe pain reduced to mild or no pain within 14 days.

• Most people will experience adverse events – Between 1 in 10 and 2 in 10 people will find these adverse events

intolerable

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• RCT 520 step III opioid naïve patients

• Therapy Impact Questionnaire

Fig. 3

Journal of Pain and Symptom Management 2000 19, 348-356DOI: (10.1016/S0885-3924(00)00130-5)

Fig. 3

Journal of Pain and Symptom Management 2000 19, 348-356DOI: (10.1016/S0885-3924(00)00130-5)

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After Robert Twycross, 1997

What have we learnt

• Fentanyl related deaths are rising – Not related to diversion in the UK but maybe in Aus

• Mums wearing patches shouldn’t sleep with their babies – And keep them hidden from elderly child carers

• You can use them for assisted suicide – But they don’t always work

• Remove them before MRIs • Once daily may be good for end of dose failure

– But not available in the UK yet

What have we learnt

• If you are switching from a subcut infusion half the dose at six hours and stop at 12 – But the kinetics look like stopping at six may be even

better

• Fentanyl may increase your brain power – But your genes may too

• On the way back 25mcg/h is equivalent to 60mg Oral morphine – But we knew that already

• Fentanyl isn’t great for neuropathic pain – What a surprise for an opioid

• There are differences in adhesiveness – But the evidence base is not great

What have we learnt

• Fentanyl definitely causes less constipation… …nausea, vomiting, drowsiness, and urinary retention – But more skin reactions than morphine

• NICE still think the best evidence is the price tag • The rate of achieving therapeutic levels for the

smaller patches is not as slow as we thought – And not vastly different from syringe drivers

• We have to be aware of the potential for accumulation in patients with severe heart or liver failure – Especially if they are thin