Fentanyl is a selective μ-receptor agonist (morphine acts on μ and κ). It causes less constipation, sedation, and cognitive impairment than morphine or hydromorphone[1-6] (and probably oxycodone). Fentanyl may be associated with a slightly higher incidence of nausea than morphine.[7]

As it has inactive metabolites and is metabolised mainly in the liver it is less likely to cause adverse effects in uraemic patients (who accumulate morphine).[8] The disposition of fentanyl does not appear to be significantly affected in liver disease.[9]

As it is more selective than morphine, fentanyl will not relieve pain that is insensitive to morphine, but may help in patients with morphine-responsive pain who develop intolerable side effects.

Fentanyl is inactive when swallowed and is only available as a transdermal patch, oral lozenge (buccal absorption), or CSCI.[10-12]

CSCI is better than a patch for establishing effective blood levels rapidly, and should be used when speed is important, or when more flexibility is desired.

Converting a patient from morphine to fentanyl can lead to a modified withdrawal syndrome of shivering, diarrhoea, bowel cramps, sweating and restlessness, even though pain relief is maintained. These symptoms can be relieved with morphine given PRN for a few days.[13-16]

Fentanyl toxicity from too high doses is subtler than morphine toxicity due to a lack of hallucinations, myoclonus etc. and may present as vagueness, drowsiness or 'not feeling well'.

Indications

• Alternative opioid when morphine causes unacceptable side-effects.
• Starting a strong opioid in a patient with:
  • a history of subacute bowel obstruction - not if obstructed (less constipating than morphine)
  • renal failure (which can lead to myoclonus or confusion with morphine due to metabolite accumulation)
  • biliary colic/obstructed bile duct (see additional notes below)
• First-line strong opioid for reasons of patient acceptability.[7,17]

Transdermal fentanyl patch

• Start with 25µg/h, or convert dose from morphine.
• It takes 12-24h to achieve therapeutic blood levels, and approximately 72h to reach steady-state:
  • CSCI of fentanyl or alfentanil will achieve more rapid blood levels
• If converting from morphine, give last dose of 12-hourly SR morphine when applying patch (or 3 more doses morphine elixir) except when accumulation of opioids in renal failure has occurred.
• If converting from morphine, continue to use morphine PRN for withdrawal symptoms:
  • may just present as restlessness
  • may occur over next 24h (or more)
  • not necessarily pain
• Change patches every 72h.
• Up to 25% patients need patch changing every 48h.[6]
• Use either oral morphine or oral transmucosal fentanyl for breakthrough pain.
• Fever may increase drug absorption due to vasodilation.[18]
• Sweating may decrease drug absorption because it prevents the patch from sticking to the skin.
• After removal of the patch, blood levels decrease by 50% in 18h.
• Mild to moderate skin erythema or pruritus have been reported in <5% of patients.[7,19]

Subcutaneous fentanyl

• Calculate dose as equivalent to transdermal patch[12] e.g. 25µg/h = 600µg/24h; for convenience (and considering the widely variable absorption from a patch[20]) use 500µg/24h CSCI ≈ 25µg/h patch.
• Large volumes are needed for high doses: consider substituting alfentanil (see next section).
• Compatible in a syringe driver with most commonly used drugs in palliative care.

Oral transmucosal fentanyl citrate (OTFC)

Fentanyl lozenges (on a stick)[20,21] are rapidly absorbed through the buccal mucosa, leading to onset of pain relief within 5-10 minutes. The maximum effect is reached within 20-40 minutes, and a duration of action of 1-3h. Bioavailability is about 50%.[22] One comparative study suggests they may give better results than normal-release oral morphine.[23]

Indication

• Breakthrough pain in patients on regular strong opioid therapy.

Use

The optimal dose is determined by titration, and cannot be predicted by a patient's regular dose of opioid.[24,25]

Approximately 25% of patients fail to obtain relief even at the highest dose, or have unacceptable adverse effects.

• Lozenge should be placed in the mouth and sucked, constantly moving it from one cheek to the other.
• Should not be chewed.
• Water can be used to moisten the mouth beforehand.
• Aim to consume the lozenge within 15minutes.
• Partially consumed lozenges should be dissolved under hot running water, and the handle disposed out of reach of children.

Dose titration

• Initial dose is 200µg, regardless of dose of regular opioid.
• A second lozenge of the same strength can be used if pain is not relieved after 15 minutes.
• No more than two lozenges should be used to treat any individual pain episode.
• Continue with this dose for a further 2-3 episodes of breakthrough pain, allowing the second lozenge when necessary.
• If pain still not controlled, increase to the next higher dose lozenge.
• Continue to titrate in this manner until dose is found that provides adequate analgesia with minimum adverse effects.
• No more than 4 doses per day should be used (regular strong opioid dose should be increased).