8th January 2024

Neuropathic agents

There are different agents which are preferred to opioids in the management of neuropathic pain. As discussed previously, patients with cancer often have more than one type of pain, and it is perfectly possible for neuropathic and nociceptive pain to co-exist within the same patient. Management of this can be difficult. Opioids do have some effect on neuropathic pain, so it is not unreasonable to follow the analgesic ladder and trial strong opioids first where there are multiple pains, particularly in cancer.

Clinical guidelines recommend the following escalation strategy where neuropathic agents are sought:

• Amitriptyline first line, 10mg at night, with slow titration to a maximum dose of 70mg.
• If ineffective, switch to gabapentin, 100mg three times a day, with titration in 300mg steps to 1200mg three times a day. This can be combined with amitriptyline if this has been partially effective.
• Duloxetine third line, 30mg a day slowly titrated to maximum 120mg.

We will go through the considerations of each drug in turn.

Amitriptyline

Amitriptyline is a tricyclic antidepressant (TCA) but is used at different doses for neuropathic pain than it is for depression. Neuropathic pain can be particularly troublesome at night, affecting sleep quality, which has a number of ramifications; amitriptyline helps sleep, hence its use as first choice.

Many drugs in palliative care can cause prolongation of the QT interval on ECG predisposing to potentially fatal arrhythmia such as Torsades de Pointes. Amitriptyline is one such drug, and the ECG must be checked prior to commencing therapy. Additionally, a history of arrhythmia, heart failure, or ischaemic heart disease would be a contraindication to amitriptyline.

Unfortunately, Amitriptyline is often not tolerated. Patients may experience delirium or sedation. There is also the risk of antimuscarinic side effects. If it is not tolerated, nortriptyline can be considered, but this would be guided by a specialist palliative care physician. Alternatively, patients may progress to the next step of treatment with gabapentinoids. Where patients have been on amitriptyline for more than 8 weeks, it must not be stopped abruptly.

Gabapentinoids

Gabapentin is the first choice in many guidelines, but many of you will also be familiar with pregabalin. They are classed as anti-epileptics, blocking presynaptic neurotransmitter release. Pregabalin has historically been a more expensive drug, but the difference is not as significant now. Pregabalin is advantageous as a twice-daily option, reducing tablet burden. Studies have shown similar efficacy for both drugs; local guidelines will play a role in choice.

Current guidelines recommend gabapentin as a second-line option for neuropathic pain (doses above). Pregabalin is recommended where there is a response to gabapentin, but side effects are intolerable. It is ordinarily commenced at 75mg twice daily. Dose reductions are recommended for frail patients or those with renal impairment.

Common side effects include drowsiness and confusion. As mentioned in ‘respiratory depression,’ gabapentinoids are a risk factor for opioid-induced respiratory depression, and studies have shown patients are more likely to suffer an opioid-related death when also taking gabapentin. Given the complex nature of cancer pain control, it is common for patients to be co-prescribed gabapentinoids and opioids. These patients must be closely monitored and have doses cautiously titrated.

Duloxetine

This is fourth line for neuropathic pain after trialling a combination of TCA and gabapentinoid. Earlier treatment is indicated in pain caused by diabetic neuropathy, for which it is specifically licensed. A serotonin noradrenaline reuptake inhibitor, it has shown a good effect in painful peripheral neuropathy – both related to diabetes and chemotherapy. It is commenced at 30mg daily and titrated to a maximum of 120mg a day.