A number of alternative strong opioid analgesics are available which have their place in palliative care:

 

Morphine & similar drugs	Morphine Diamorphine Hydromorphone Oxycodone
Fentanyl & similar drugs	Fentanyl Alfentanil Sufentanil
Methadone	Methadone
Intermediate weak-strong opioid	Tramadol
Other opioids occasionally used	Dextromoramide Phenazocine Buprenorphine
Not recommended	Pethidine

 

Differences between these drugs are not fully understood, but include patient factors and drug factors. In clinical practice they may be divided into:

Morphine-like opioids

Oxycodone and hydromorphone, like morphine and diamorphine, are available in a wide range of doses in normal (4-hourly) and slow-release oral preparations. They can be used by CSCI, although neither are routinely available in injection form in the UK at present.

Although there may be small intrinsic differences between the side-effect profiles of these drugs (e.g. hydromorphone appears to cause less pruritus than morphine overall), inter-individual variability seems to be a greater factor in determining the clinical picture. Substituting one of these drugs for another may reduce side-effects in up to 75% of selected individuals.[1]

Oxycodone and hydromorphone may cause less toxicity than morphine in patients with renal failure, but neuro-excitatory side-effects are reported.

Fentanyl and its analogues

Fentanyl and its analogues (alfentanil, sufentanil and remifentanil) are selective μ-receptor agonists, unlike morphine. They cause less sedation, cognitive impairment and constipation than morphine-like drugs. They are largely inactive orally because of high first-pass hepatic metabolism, but can be used by transdermal patch, oral lozenge (buccal absorption) or CSCI.

Fentanyl does not appear to accumulate and cause toxicity in renal failure.

Methadone

Methadone is an agonist at the μ- and δ-opioid receptors, and also an NMDA receptor antagonist and monoamine reuptake inhibitor. These actions make it a useful treatment for neuropathic and other pain states not fully responsive to morphine. However, it has a long and variable elimination half-life, making it difficult to use safely, and should be reserved for neuropathic, ischaemic or inflammatory pain, or use as third- or fourth-line opioid.

Tramadol

Tramadol may be classed somewhere between the weak and strong opioids. It has additional pharmacological actions to its opioid effects. It is not classed as a 'controlled drug' which has some practical advantages for its prescribing.

Other opioid analgesics

Pethidine has a short duration of action, and when given regularly, active metabolites accumulate and can cause convulsions. Causes more dysphoria than morphine. Best avoided.

Dextromoramide is a short acting opioid that is occasionally used for incident pain that can be predicted e.g. painful dressing changes.

Most other opioid analgesics are too limited in their range of preparations, doses available, or routes of administration to have any routine place in cancer pain.

Indications for starting with an opioid other than morphine

• patient acceptability
• history of subacute/partial intestinal obstruction - to minimise constipation
• patient reluctant to take 'morphine' despite appropriate counselling
• patient reluctant to take oral medication regularly
• renal failure

Indications for changing to alternative opioids

This practice is known as opioid rotation or opioid substitution.

• unacceptable opioid side-effects
• renal failure

In daily clinical practice rotation to another opioid should be required in less than 2-3% of cases.[2]

Choice of alternative opioid

	Able to take oral medication	Unable to take oral
Pain well controlled and stablea	Fentanyl transdermal patch	Fentanyl transdermal patch
Pain uncontrolled or unstable	Oxycodoneb	Fentanyl CSCI (or alfentanil) - convert to patch when stable. Oxycodone CSCI suitable if available.

^a Also for patients starting strong opioid whose pain has increased slowly over time, is mild to moderate, and fairly stable.

^b Evidence is strongest for hydromorphone as causing less pruritus than morphine.[3,4]

Rationale

• Hydromorphone, oxycodone and fentanyl are useful alternatives to morphine and diamorphine.[5]
• Methadone is difficult to use safely, and should be reserved for neuropathic, ischaemic or inflammatory pain, or use as third- or fourth-line opioid.
• No other strong opioids have the range of doses and preparations needed to be suitable for routine use in cancer pain.
• Hydromorphone and oxycodone are available in a wide range of oral preparations, but parenteral preparations are not routinely available in the UK.
• There is little to choose between oxycodone and hydromorphone, but oxycodone is chosen in preference because:
  • a liquid normal release preparation is available
  • doses are simpler to calculate (e.g. 1.3mg versus 5mg)
  • there is less variation in the reported equianalgesic ratios for oxycodone
  • the manufacturer's recommended conversion of 7.5:1 for morphine to hydromorphone is higher than the more commonly used ratio of 5:1; this makes the tablet doses of 1.3mg even more complicated
• Fentanyl causes less side effects (sedation, cognitive impairment, constipation, myoclonus and pruritus) than any of the morphine family, and has greater patient acceptability.
• Transdermal patch or CSCI are the only methods of administering fentanyl regularly for chronic pain.
• Rapid dose titration for unstable pain control is more flexible and predictable with oral normal-release oxycodone than with fentanyl, even using fentanyl CSCI or OTFC lozenges.

Renal impairment / Renal failure

Metabolites of morphine accumulate in renal failure and can cause neurotoxic side effects such as myoclonus and confusion.[6,7] Fentanyl is mainly eliminated by hepatic metabolism to inactive metabolites, and case reports support its use in renal failure with less toxicity.

Oxycodone and hydromorphone do have active metabolites that are renally excreted, and their value in renal failure is less clear. However, case reports suggest they may be better than morphine, at least in individual patients switched from morphine.