Difficult painBMJ 2006; 332 doi: https://doi.org/10.1136/bmj.332.7549.1081 (Published 04 May 2006) Cite this as: BMJ 2006;332:1081
- Lesley Colvin, consultant anaesthetist,
- Karen Forbes, professorial teaching fellow in palliative medicine,
- Marie Fallon
Pain occurs in up to 70% of patients with advanced cancer and in about 65% of patients dying from non-malignant disease. In about 10% of these patients the pain is difficult to control. Their pain often falls into one of three categories: it responds poorly to opioids, it is episodic and breaks through despite background opioid analgesia, or it is caused by non-physical factors such as psychosocial distress.
Pain that responds poorly to opioids
The European Association for Palliative Care guidelines on the use of morphine and alternative opioids in cancer pain confirm oral morphine as the opioid of choice for moderate to severe pain. If the pain is uncontrolled with a dose of morphine that gives the patient intolerable side effects, suggested measures include exploring psychosocial issues, managing the side effects, reducing the dose of opioid, switching to an alternative opioid, or changing the route of administration. The use of adjuvant drugs or co-analgesics may be appropriate. Many such patients will have neuropathic pain.
Nociceptive pain results from real or potential tissue damage. Neuropathic pain is caused by damage to the peripheral or central nervous system. Pain may be described as aching, burning, shooting, or stabbing and may be associated with abnormal sensation; normal touch is perceived as painful (allodynia). It may be caused not only by tumour invasion or compression but also by surgery, radiotherapy, and chemotherapy. If neuropathic pain does not respond to opioids, patients will require additional measures.
The early addition of adjuvant analgesics, such as a tricyclic antidepressant or an anticonvulsant, should be considered. The number needed to treat is 3 for both categories. There is no evidence for a specific adjuvant for specific descriptors of neuropathic pain.
This article is adapted from the second edition of the ABC of Palliative Care, which will be published by Blackwells in the autumn and available from http://www.hammicksbma.com/ and all good medical bookshops
Patients may be overwhelmed by their situation and the central nervous system can express this as physical pain. Social, psychological, or spiritual factors may be major components of pain
In addition, there is no evidence for combining adjuvants. The adjuvant should be chosen for an individual patient based on all symptoms and potential side effects. Doses should be titrated to balance analgesia with adverse effects. If titration has reached a limit and pain has only partially responded then a second adjuvant may be added in some cases. This usually means a reduction in the dose of the first. A common example of combining adjuvants is gabapentin, which at maximum tolerated dose can sometimes be reduced to allow the addition of amitriptyline.
There are several non-pharmacological techniques for the management of neuropathic pain.
Psychological techniques—Psychological techniques, such as cognitive behavioural therapies, include simple relaxation, hypnosis, and biofeedback. These methods focus on overt behaviour and underlying cognitions and train the patient in coping strategies and behavioural techniques. Simple relaxation techniques should also not be forgotten.
Acupuncture has been used successfully in Eastern medicine for centuries. It seems to release endogenous analgesics within the spinal cord. Acupuncture is particularly useful for myofascial pain, which is a common secondary phenomenon in many cancer pain syndromes.
Transcutaneous electrical nerve stimulation (TENS) mayhavea similar mechanism of action to acupuncture. There is evidence to support its use in both acute and chronic pain.
Herbal medicine and homoeopathy are widely used for pain, but often with little evidence for efficacy. Regulations on safety for these treatments are limited compared with those for conventional drugs, and doctors should be wary of unrecognised side effects.
The term episodic pain is used to describe any acute transient pain that is severe and has an intensity that flares over baseline. Episodic pain thus encompasses breakthrough pain and incident pain. Breakthrough pain includes pain returning before the next dose of opioid is due or acute exacerbations of pain occurring on the background of pain usually controlled by an opioid regimen. Incident pain is usually defined as that occurring due to a voluntary action, such as movement or passing urine or stool. Pain due to bony metastases exacerbated by movement or weight bearing can be particularly problematic.
Patients with bony metastases in the spine, pelvis, or femora may have pain that escalates on movement, walking, standing, or even sitting. Opioid analgesics along with non-steroidal anti-inflammatory drugs are the mainstay of treatment, with the aim of making the patient comfortable at rest. Increasing the opioid dose is often unhelpful as a dose sufficient to make movement possible is too sedating when the patient is resting. Rescue or breakthrough doses of normal release opioid are usually used in anticipation of movement, along with non-drug measures such as radiotherapy, possible surgery, and appropriate aids and appliances.
Bisphosphonates are established in the prevention of skeletal events due to metastases from most solid tumours. In some patients, they provide short term analgesia.
Before invasive techniques are considered, it is important to exclude untreated depression, general anxiety, and distress (though untreated pain may also lead to any or all of these).
It is also worth considering a different drug. Methadone deserves a special mention in this context. It has unusual properties, which we do not fully understand. Its receptor binding profile differs from that of pure μ agonists and it can be remarkably potent at small doses.
Methadone often gives much better analgesia and reduced side effects. In addition, difficult elements of a pain—such as neuropathic or incident pain, or both—may become easier to control.
Invasive analgesic techniques
Despite appropriate use of analgesia and non-drug therapies, chemotherapy, and radiotherapy by multidisciplinary teams, a considerable number of patients will still have uncontrolled pain or unacceptable side effects, or both.
Such patients should be considered for some form of invasive analgesic technique. This may range from a simple nerve block to more invasive techniques such as regional or neurodestructive blocks.
The choice of technique is influenced by:
Prognosis and required duration of analgesia
Availability of experts and trained staff.
A basic rule is that the technique with the least likelihood of severe side effects should be chosen. In general, neurodestructive techniques should be reserved for when other measures have failed or when life span is obviously limited.
Spinal routes of drug delivery
With improvements in catheter and pump technology, use of spinal lines is becoming more common in pain control. If the technique is carried out by trained staff, complication rates are low, allowing flexible, long term analgesia that can be used in an outpatient setting. Catheters can be inserted either into the epidural space or into the subarachnoid (intrathecal) space, where the cerebrospinal fluid is found. The line may be tunnelled subcutaneously to reduce risks of infection and movement of the catheter. The choice of technique depends on several factors.
Agents not currently widely available in the UK that may be helpful in managing patients with cancer pain include:
Lidocaine patches are available in the US but limited in the UK. They produce few side effects and studies have shown efficacy in neuropathic pain. We have also used them for bone pain, particularly vertebral metastases, with some success.
Pregabalin has a similar pharmacological profile to gabapentin but is more potent. Randomised controlled trials have shown efficacy against some forms of neuropathic pain and an improved sleep pattern. Titration of dose is easier than with gabapentin.
N-methyl-D-aspartate (NMDA) subtype selective agents—Currently available drugs are non-selective. Animal research suggests particular subtypes of the NMDA receptor may have potential for analgesia with reduced side effects and opioid sparing effects.
Calcitonin gene-related peptide (CGRP) antagonists—CGRP is found in sensory neurones. Non-peptide analogues with a favourable pharmacokinetic profile may have potential as analgesics.
Starting or switching to methadone can be complicated in some patients, and specialist advice should usually be sought
The ABC of Palliative Care is edited by Marie Fallon, St Columba's Hospice chair of palliative medicine, University of Edinburgh and Geoffrey Hanks, professor of palliative medicine, University of Bristol.
Competing interests GM has received funding and honorariums from Anesta, Cephalon, Endo, Mundipharma, Napp, and Pfizer.