The role of opioids in cancer pain

Step 3: Opioids for moderate to severe pain

Morphine is the drug of choice for managing moderate to severe cancer pain. No drug has been shown to have greater analgesic efficacy. Morphine is also the most cost effective analgesic.

Dose titration

Consider the following points when titrating the dose of oral morphine:

• Titrate the dose against the effect. Give the next dose before the effect of the previous one has worn off

• The starting dose is determined by previous analgesic requirements; patients moving from a step 2 analgesic will usually start with 5 mg morphine every four hours. Lower doses may be needed in elderly people and those with renal impairment

• Prescribe every four hours. A longer dosing interval may be needed for people with renal impairment

• During dose titration using the four hourly standard release morphine, use the full four hourly dose as needed as a “rescue” for breakthrough pain.7 Reassess pain control regularly. If pain is not controlled, increase the dose by 30-50%—for example, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, and 30 mg every four hours

• Increase the rescue dose at the same time and to the same level in line with the regular four hourly dose. Rescue treatment can be given every hour if necessary.7 Give a rescue dose before any procedure that is likely to exacerbate pain

• Morphine has no ceiling dose, but be cautious of incremental change at higher doses

• The systemic bioavailability of oral morphine varies between 15% and 60%. This explains why the effective analgesic dose varies widely between patients.8

Converting to sustained release morphine

Once the patient's pain has been adequately controlled and a stable dose achieved for 48 hours, convert to a sustained release morphine preparation (for example, MST Continus (Napp; Cambridge, United Kingdom) twice daily). Always prescribe rescue immediate release morphine equivalent to the four hourly dose.

Several modified release formulations of morphine are available. Evidence is lacking that the various 12 hourly oral formulations (tablets, capsules, and liquids) have significantly different potency or duration of effect.9

Many once a day formulations are also available. Although some show differences in kinetic profile,10 there is no evidence that this is clinically significant.7

Alternative routes of administration

• If patients are unable to take oral morphine, the preferred alternative route is subcutaneous

• Diamorphine is usually preferred for parenteral administration because it is more soluble than morphine (smaller volumes can be used for injection).11 Intramuscular opioid injections are not recommended in palliative care. Subcutaneous diamorphine is around three times more potent than oral morphine

• To convert a 24 hour dose of oral morphine to an equivalent dose of subcutaneous diamorphine divide by three—for example, 60 mg MST Continus twice daily is equivalent to 40 mg subcutaneous diamorphine in 24 hours

• Give appropriate breakthrough doses with subcutaneous injection equivalent to a four hourly diamorphine dose

• In a pain emergency or pain crisis, subcutaneous diamorphine may be more appropriate than oral analgesia because of its quicker onset of action

• Transdermal fentanyl may be used as an alternative to oral morphine for patients who require stable opioid doses

• Some patients prefer rectal administration. The bioavailability and duration of effect of rectal morphine is similar to that of oral morphine, and therefore the equianalgesic dose by both routes is the same.12

Side effects of morphine

It is important to warn patients about possible side effects. These can occur when taking weak opioids at step 2 of the analgesic ladder as well as when taking strong opioids at step 3.

Concerns about morphine

Morphine has long been feared by the general public and the medical profession.14 Underlying this fear is the mistaken belief that the potential for misuse of opioids is linked with their use as analgesics. Unfortunately, concerns about addiction, respiratory depression, and excessive sedation cause healthcare professionals to avoid using opioids or to use them in suboptimal doses. Clinical experience has shown that these fears are largely unfounded and that addiction is not likely if morphine is used to manage pain responsive to opioids in doses titrated to the degree of pain.11

Withdrawal symptoms indicate physical dependence and should not be confused with psychological dependence (addiction).

Opioid toxicity

Opioid toxicity can occur:

• When dose escalation is too rapid

• In patients with renal impairment

• If pain is not responsive to opioids

• After therapeutic pain relieving intervention—for example, chemotherapy, radiotherapy, or nerve block.

Warning signs include:

• Pinpoint pupils

• Hallucinations

• Vomiting

• Drowsiness

• Confusion

• Myoclonic jerks

• Micro sleeps.

If toxicity occurs, stop opioid analgesia. The patient may need to miss one or several four hourly doses, then:

• Restart at a reduced dose or

• Convert to an alternative opioid at a lower dose.

Consider using the opioid antagonist naloxone if life threatening respiratory depression occurs. Use with care, however, as it may increase the patient's pain.

Give naloxone as an intravenous injection as follows:

• Dilute ampoule of naloxone 400 μg/ml to 10 ml 0.9% sodium chloride injection

• Administer 0.5 ml (20 μg) every two minutes until the respiratory rate is satisfactory

• Give further boluses if necessary every 30 to 60 minutes because naloxone has a short duration of action.

Respiratory depression is unlikely unless doses much higher than prescribed have been given.

Giving morphine to patients with renal impairment

>Take care when prescribing opioid analgesics for people with renal impairment because these patients are extremely sensitive to opioids. Seek specialist advice from the palliative care team.

Remember:

• Do not prescribe sustained release preparations of morphine unless renal function and dose requirements are stable

• Prescribe small doses of immediate release morphine

• The dosing frequency may need to be decreased

• To consider opioid alternatives that are not renally excreted (for example, subcutaneous alfentanil).

No opioid is truly safe in patients with renal impairment, usually because of the accumulation of toxic metabolites. Of the opioids mentioned, alfentanil by subcutaneous injection seems to be the best tolerated opioid in this clinical context.15

Hydromorphone and oxycodone

Hydromorphone and oxycodone are available in similar normal release and modified release formulations as morphine. The efficacy and tolerability of morphine and hydromorphone seem similar.20

Oxycodone is an effective alternative to morphine.7 Its side effect profile and analgesic efficacy is similar to that of morphine.21 Oxycodone has better systemic bioavailability (60-90%) and the equianalgesic dose of oral oxycodone is between one half to two thirds that of oral morphine.22

Methadone

Methadone is also a potent opioid analgesic. It is widely available and seems to have similar efficacy and a comparable side effect profile to morphine.23 However, it has complex pharmacokinetics, which varies between people. Also there is a risk of drug accumulation owing to its long half life. Therefore, experienced doctors need to take responsibility for starting and monitoring the prescribing of methadone.23

Fentanyl

Fentanyl is a lipid soluble synthetic opioid, which can be delivered in a transdermal controlled systemic delivery formulation for up to 72 hours.24 Transdermal fentanyl has been shown to be effective for treating cancer pain.25^–27 Although the drug is an effective alternative to oral morphine, it is less flexible and needs to be used with caution in patients with unstable pain.

Because of the unique delivery system of fentanyl, it takes 12-24 hours for serum levels to stabilise after starting the patch or changing the dose.24 Some evidence shows that transdermal fentanyl may cause less constipation than morphine.25 28

The European Association for Palliative Care recommends that transdermal fentanyl is reserved for patients who require stable opioids doses.7 Opioid toxicity has been reported with inappropriate prescribing of transdermal fentanyl.29 In addition, owing to limitations in patch size, small increments in dose are not possible. The dose is effectively doubled when increasing from 25 μg/h to 50 μg/h patches, and clinical problems have been reported with this dose increment.30

Oral transmucosal fentanyl citrate produces a rapid onset of analgesia in five to 15 minutes, with a duration of action of about two hours. It is a relatively new treatment for breakthrough pain and has been shown to be effective.31 Expense, however, limits widespread use.

Buprenorphine

Transdermal buprenorphine is licensed for the treatment of moderate to severe cancer pain. It has been shown to be more effective than placebo in a double blind randomised controlled trial.32 It is not clear how its efficacy compares with that of oral morphine.

Evidence for the effectiveness of switching opioids when managing cancer pain is limited. This was highlighted by a recent systematic review.33 If a clinician thinks that a patient needs a different opioid they should seek help from the palliative care team.

Opioids and neuropathic pain

The use of opioids for neuropathic pain has been intensely debated, but reports suggest they have a role.34 In the management of cancer related neuropathic pain, opioids are used in conjunction with adjuvant agents such as antidepressants and anticonvulsants.35

The role of non-steroidal anti-inflammatory drugs has been well established in the treatment of mild cancer pain and in association with opioids in the treatment of moderate to severe pain.36 Non-steroidal anti-inflammatory drugs have been shown to have a relevant opioid sparing effect.37

This article is based on a module that is available on the BMJ Learning website (http://www.bmjlearning.com/). Access to the site is free but registration is required