This article is largely inspired by a presentation given by Dr Chris Kane, consultant in palliative medicine at Sue Ryder Hospice and the NHS Trust in Leeds, at the The Association of Supportive and Palliative Care Pharmacy annual conference in November 2018. It offered a thought-provoking view on a difficult symptom.
We have guidance from NICE(1) and Cochrane reviews (2,3) for neuropathic agents in cancer pain. In addition, Professor Nanna Finnerup and colleagues at the Danish Pain Research Center are known to provide the most comprehensive views on the management of neuropathic pain (NPP), and their most recent systematic review and updated recommendations conclude that there is inadequate response to drug treatment for this group of challenging pain syndromes, which results in a substantial unmet need for patients (4).
The facts are based on study data which compares NNT and NNH figures from studies and it should be remembered that opioids come out relatively well in this. NNT in this scenario is the number of patients who need to be treated before a benefit of more than that gained by placebo is seen, whilst NNH is the number who need to be treated before harm is detected. The closer the NNT and NNH to 1, the more effective the treatment. Both factors are important when making treatment decisions but with neuropathic pain inter-individual factors play a large part, so it is harder to predict response. The other challenge with NPP is that many agents that look promising from their pharmacology are not so effective in the clinical setting.
Clinical practice confirms that opioids are less effective in the management of pain with a neuropathic origin. Traditional analgesics which block ascending pain signals in the central nervous system work best when that system is intact. When the pathways have been damaged in some way, the response is diminished. This ‘failure’ of analgesia in NPP has necessitated the broader approach, and chance findings where antidepressants were found to be of benefit as co-analgesics led to case studies and more systematic trials. Research into the neurophysiology of pain has shown that the NMDA receptors in the spinal cord are involved in the generation of NPP so drugs with blocking action on this receptor, e.g. ketamine and methadone, should be of use. However, clinically, they have proven disappointing in many cases. Chris Kane makes a very valid point that in order for an NMDA receptor blocker to work, the receptor must first be activated by neuropathic pain so these drugs may only be effective when there is clear evidence of allodynia or hyperalgesia. The Cochrane review on methadone for cancer pain concluded that there was no evidence for or against it being effective for NPP(4).
Reproducible models used for NPP studies such as diabetic neuropathy are not necessarily transferable to the wide-ranging causes of NPP in cancer. Inter-individual differences present difficulties in studies in pain in general but these are even more diverse in NPP, so although some medicines help some pain for some patients, it is hard to predict which will be the right choice for the patient in front of you. The NICE guidance from 2013 (updated 2018) advises offering amitriptyline, duloxetine, gabapentin or pregabalin to the patient and if none of these are sufficiently effective, then to try one of the others. It provides a long list of medicines that should not be used based on a) lack of evidence of efficacy and b) the need for them to be initiated by specialists. So, if you have a patient who cannot tolerate amitriptyline due to its anticholinergic effects, and gabapentin and pregabalin have helped slightly but not much and they remain on a regular opioid around the clock, what is the next therapeutic move?
A systematic review from Japan(6) showed slightly more positive results with patients already on oxycodone who were given pregabalin 75mg BD and low dose amitriptyline, and another Japanese study(7) showed some benefit from adding an antidepressant to a gabapentinoid for painful bone metastases. Dr Kane has completed his own review(8) which showed gabapentin to be slightly better than pregabalin as an adjunct to an opioid but he believes that even judicious combinations of drugs can be tried but may not be much better.
The muscle relaxant action of benzodiazepines can be of some benefit in pain management but the evidence for anti-neuropathic activity for clonazepam is not backed up by evidence. Despite this, we know that it seems to be helpful in some cases.
Dr Kane gave us a different way of looking at the problem of NPP in cancer, which has parallels with the management of chronic pain. He feels that perhaps we should be supporting patients without over-burdening them with the drugs we cannot prove to be effective. Qualitative studies from 2002 and 2008(9,10) gave the somewhat surprising results that in spite of patients’ pain scores remaining high, they rated the satisfaction of their pain management as high when they felt:
- They understood the reason for the pain
- They knew what to expect
- They were being listened to by their healthcare team and the importance of their pain control was acknowledged
- They were being offered options
- Their side effects were managed
- They were not fearful of addiction.
So, in future studies, perhaps patients should be asked how the pain affects what they can do rather than use pain scores, and until newer, more effective medicines can be found, we might sometimes step back from increasing doses and drugs and ensure we are supporting the patient in their pain. Dr Kane also suggests that when the drugs are not working, we should not be afraid to stop as they can be started again.
- NICE guideline CG 173 Neuropathic pain in adults https://www.nice.org.uk/guidance/CG173
- Cochrane review of opioids in neuropathic pain. 2013 https://www.cochrane.org/CD006146/SYMPT_opioids-neuropathic-pain
- Cochrane review of gabapentin in chronic neuropathic pain 2017 https://www.cochrane.org/CD007938/SYMPT_gabapentin-chronic-neuropathic-pain-adults
- Cochrane review of methadone for neuropathic pain https://www.cochrane.org/CD012499/SYMPT_methadone-neuropathic-pain-adults
- Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Finerrup et al Lancet Neurology 2015 14: 162-73
- Anticonvulsants or antidepressants in combination pharmacotherapy for treatment of neuropathic pain in cancer patients: a systematic review and meta-analysis Guan j et al Clin J Pain 2016 32(8) 719-25
- Combinations of low-dose antidepressants and low-dose pregabalin as useful adjuvants to opioids for intractable, painful bone metastases Nishihara et al Pain Physician 2013 16(5) E547-52
- Opioids combined with antidepressants or antiepileptic drugs for cancer pain: Systematic review and meta-analysis Kane et al Palliative Medicine 2018 32(1) 276-86
- Probing the paradox of patients’ satisfaction with inadequate pain management. Dawson et al JPSM 2002 23(3) 211-20
- Opioid analgesics for cancer pain: symptom control for the living or comfort for the dying? Reid CM et al Ann Oncology 2008 19(1) 44-48