Opioids - clinical applications in palliative care

Summary
Morphine is still the primary opioid for the management of chronic pain. Oral treatment with morphine mixture is preferred, but controlled-release formulations are available. Other routes of administration, such as intravenous and percutaneous, are reserved for specific cases. Morphine should be given regularly rather than as required. There are special considerations with the use of morphine in patients with renal failure and in the elderly. Alternative opioids may be needed.Recognition of opioid-insensitive pain, the addition of co -analgesics to the management, the rotation of opioids, and the use of epidural and intrathecal anaesthesia are useful strategies to control severe pain. The knowledge about the stimulation of NMDA receptors in severe pain and the recent development of the means to block them is offering new modalities of treatment.

Which opioid do I choose?
Morphine is the opioid of choice. There is extensive experience with this drug and there are various routes of administration. Oral medication is preferred and there are two commonly used oral formulations in Australia: morphine mixture and the much more expensive controlled-release tablets. As a general recommendation, morphine mixture is used first and the dose adjusted to maintain analgesia. Morphine doses correlate poorly with weight, height and surface area. The strengths of 2mg/mL, 5 mg/mL and 10 mg/mL are commonly used, but higher strengths are available. The higher strengths considerably reduce the volume of fluid that needs to be given for each dose. This may be important for patients with nausea, vomiting or difficulty with swallowing.

If the controlled-release preparation is needed, the daily dose of morphine mixture becomes the same daily dose of controlled-release morphine. Half the 24-hour dose is given 12-hourly. Therapy can begin with controlled-release morphine, but considerable judgement is required as giving a larger starting dose than necessary may lead to adverse effects and result in the patient rejecting morphine as a pain-relieving agent. The first dose should be in the range of 10 mg twice daily with the dosage titrated up to a level where the pain is relieved. Morphine mixture should be prescribed for any breakthrough pain which occurs while an adequate dose of controlled-release morphine is being achieved.

Renal failure
Oral morphine is absorbed in the small intestine but has a low bioavailability of approximately 30%. It is metabolised in the liver to a number of metabolites. Attention has focused on two metabolites, morphine-3-glucuronide (M3G) and morphine -6-glucuronide (M6G). M3G is present in the plasma in the highest concentration, M6G is next and morphine is present in the lowest concentration. M6G is an analgesic in its own right and is predominant when morphine is administered to patients with renal failure. In contrast, M3G may antagonise the analgesic effects of M6G and morphine in animals, but the extent of the interaction in humans is unclear.^1,2

The use of even 'average' doses of morphine in renal failure or in the elderly may result in an increase in the usual adverse effects and myoclonic jerks may become evident. Some patients also experience hyperaesthesia. These effects warrant a reduction in morphine dosage. Different formulations may contribute to the adverse effects in renal failure: higher concentrations of these metabolites occur with oral formulations and lower concentrations with subcutaneous preparations.³

Administration

Oral
Regular administration of opioids is fundamental to good pain relief in chronic pain syndromes. An 'as required' prescription is unlikely to be successful. Pain should not be allowed to cycle from severe, when the patient asks for pain relief, through the pain relief stage to severe again requiring the patient to ask for more pain relief. This cycling pain makes the patient more anxious and the pain more difficult to control. To counter this problem, an opioid regimen should consist of a 'regular' dose and a 'breakthrough' dose of opioids. The 'breakthrough' dose is usually one twelfth of the daily morphine dose and is given if pain occurs despite the 'regular' dose.

The 'regular' and 'breakthrough' analgesic requirements should be reviewed regularly, preferably daily, and the 'regular' dose increased by the 'breakthrough' dose so that the regular regimen covers the analgesic requirements and 'breakthrough' doses are kept at a minimum. Morphine mixture in regular4-hourly doses with a double dose at night to reduce waking with pain is the usual type of regimen.⁴ The patient with chronic pain should be assured that, with the use of opioids in palliative care, dependence is not a practical problem nor is tolerance.⁵

Non-oral routes
There are specific indications for the use of non-oral routes. These include:

• vomiting or severe dysphagia
• a need for rapid control when the patient has severe pain
• a need for spinal administration for pain unresponsive to opioids given by other routes
• in the last few days of life when swallowing may not be possible

Intravenous opioids are contraindicated in chronic pain management because this route seems to lead rapidly to tolerance. When oral treatment is not possible, the alternatives include the subcutaneous, rectal or percutaneous route. For the subcutaneous route, there is no evidence for delay in absorption in disease states nor does this route of administration limit the dosage.

When the dosage is high, small injection volumes can be given using the morphine tartrate formulation (120mg/1.5mL). Intermittent injections given 4-hourly using an in situ 'butterfly' needle or a subcutaneous infusion using a pump can be used. When converting to subcutaneous morphine, one third of the oral dose is used.

One study has shown that the same dose of controlled-release morphine can be given rectally as was given orally, but further studies are needed to confirm this finding.⁶ Oxycodone suppositories are also available.

For a small proportion of patients with opioid-sensitive pain who are troubled with opioid adverse effects, the spinal route may be useful. The doses required by this route may be substantially less than the oral/subcutaneous route. Epidural or intrathecal routes are available and the decision to use them should be made in conjunction with an anaesthetist specialising in pain management. Often the analgesic effect of morphine can be enhanced by the addition of a co-analgesic such as bupivicaine and/or clonidine. The catheter may be tunnelled under the skin so that it exits in a convenient location and, with skilled nursing care, can remain functioning for many months.

Adverse effects
Some of the adverse effects wear off in days. Nausea and vomiting usually settle over the first week of treatment, as does drowsiness. It is not routine to use a drug to control nausea, but it may be necessary to use metoclopramide or haloperidol to control nausea or vomiting over the first few days of treatment. The doses are then reduced and stopped, if possible, because of their long-term adverse effects.

Constipation, gastric stasis and hallucinations may not be self -limiting. Every patient who takes opioids regularly needs a laxative. Docusate sodium with senna is a good choice to start with, but there are a large number of preparations to choose from, each with different pharmacological actions and latency. Gastric stasis is important to recognise because it responds to treatment with cisapride or another prokinetic agent.

Hallucinations may be precipitated by morphine and other drugs and can be part of a delirium. Their presence always requires a clinical review of the patient and often the help of a psychiatrist. Hallucinations may require treatment with haloperidol and/or benzodiazepines. The opioid may need to be reduced or stopped.

What about the alternatives to morphine?
Some patients have had reactions to morphine and they cannot be persuaded to have further treatment with the drug. Codeine may have a useful place in early stages of pain, but it is important to be aware that approximately 10% of Caucasians cannot convert codeine to morphine and therefore may get little analgesia. Codeine is best used in conjunction with paracetamol or aspirin.

Oxycodone or methadone are alternatives to morphine. Neither of these drugs is metabolised to morphine. Oxycodone can be given as a tablet and has a useful suppository formulation. Methadone has a variable half-life of 8-80 hours which does not seem to correlate with the duration of its analgesic effect of 6-12 hours. Methadone accumulates with repeated doses. This may be a major problem in elderly patients. It is best to begin with twice daily doses and monitor the patient while the drug is accumulating over the first 5-10 days. Increasing the doses at short intervals is a frequent cause of toxicity and should be avoided.

At present, fentanyl patches are available in Australia through the Special Access Scheme. They deliver 25-100 microgram/hour over 72 hours percutaneously. Fentanyl seems to be a useful alternative to morphine in patients who are intolerant of morphine because of drowsiness or constipation. Subcutaneous fentanyl can be used for patients who need an alternative to subcutaneous morphine.

Pethidine may be suitable for postoperative pain control, but it is not suitable for ongoing pain management. Its metabolite, norpethidine, has a long half-life and may accumulate in patients with impaired renal function.

Pentazocine (high incidence of dysphoria and hallucinations), dextromoramide (variable effect and short duration of action) and buprenorphine (may precipitate withdrawal in patients who have received morphine) have currently no place in the management of chronic pain.

Opioid-insensitive pain
Opioids do not seem to be equally effective for all types of pain. Attempts to control opioid-insensitive pain may lead to toxicity before the pain is controlled. The recognition of bone pain, e.g. due to metastases, may enable the use of co -analgesics such as non-steroidal anti-inflammatory drugs. Neuropathic pain has a variable response to opioids, and co -analgesics such as antidepressants or anticonvulsants should be added. Recent evidence suggests that a change to an alternative opioid may assist in controlling pain or reducing adverse effects or both.

There is recent evidence of excessive stimulation of glutamate receptors in persistent pain. One of these receptors is the NMDA (N-methyl-D-aspartate) receptor. The hypothesis is that with severe persistent pain, opioid administration alone will not stop the pain because of the excitation of these glutamate receptors in neurons in the brain and spinal cord. Ketamine, a non-competitive NMDA receptor antagonist, shows promise in relieving morphine-resistant pain.^7,8

Conclusion
Gaining expertise with the use of morphine for chronic pain management should be the primary goal of those managing pain in the terminally ill patient. There is a wide choice of routes of administration and the adverse effects may be minimised by careful dose adjustment, particularly in patients with renal failure or in the elderly. When alternatives are indicated for more severe pain, oxycodone or methadone may be used, but fentanyl seems to have potential advantages although it is not yet generally available.

When a patient is not responding to opioids, review the pain diagnosis with the causes of opioid-insensitive pain in mind, particularly bone and neuropathic pain. Rotation of the opioid to another should be considered. Co-analgesics or one of the recently developed NMDA receptor antagonists may also be required.

Further reading

Doyle D, Hanks GW, MacDonald N, editors. Oxford textbook of palliative medicine. Oxford: Oxford University Press, 1993.

Cancer pain relief. 2nd ed. Geneva: World Health Organization, 1996.