Pain is one of the most prevalent and distressing symptoms experienced by patients with cancer and has been shown to impact significantly on the physical, emotional and functional wellbeing of patients.¹ Pain is a complex phenomenon and the aetiology of pain is often multifactorial. Pain may be broadly classified into nociceptive and neuropathic categories, but many patients with cancer have mixed-pain syndromes, ie. a combination of nociceptive and neuropathic pain.

Definition of neuropathic pain

Neuropathic pain (NP) is defined as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system”.² NP is not a single entity but encompasses a variety of different complex clinical pictures with diverse pathophysiological mechanisms. 

No cure for NP exists and, for the majority of those with NP, the pain can persist lifelong. Comorbidities, such as depression and impaired quality of life, are common. Palliation of pain, restoration of therapeutic sleep, maintenance of function and improvements in overall quality of life remain the mainstays of treatment.³

Causes

Neuropathic pain can occur as a result of injury or dysfunction to peripheral nerves and posterior roots (peripheral NP), or to the spinal cord and brain (central NP).⁴ Rarely, if ever, can one single mechanism be claimed responsible. Many causes of NP are implicated in patients with malignancy (see Table 1).

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Signs and symptoms 

The severity of NP ranges from mild discomfort to being severely debilitating, and the onset of symptoms can be sudden or slowly progress over time. Patients often find it difficult to describe the character of the pain. Classically, patients with NP complain of spontaneous pains (arise without detectable stimulation) and evoked pains (abnormal responses to stimulation [see Table 2).

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Assessment and diagnosis 

A thorough pain assessment is crucial to optimal pain management interventions. Evaluation of a patient’s pain is a multidimensional process and should include:

• A comprehensive pain history and identification of clinical features (eg. insomnia, autonomic neuropathy) that might help individualise treatment
• A physical examination
• Exploration of potential aetiologies/treatable conditions, eg. spinal cord compression
• Patient education.

The diagnosis of NP is based primarily on the history (eg. underlying disorder and distinct pain qualities) and the findings on physical examination (eg. pattern of sensory disturbance). Electromyography and nerve conduction studies may provide objective evidence of nerve injury or dysfunction.⁵ CT and MRI scans can facilitate specific diagnoses (eg. herniated disc, nerve infiltration by tumour).⁵ Pain assessment should be ongoing (occurring at regular intervals), individualised, and clearly documented so that all involved in the patient’s care understand the important issues. 

Management

Due to the relatively poor understanding of the underlying mechanisms and limited efficacy of traditional analgesics, NP is challenging to treat. Many treatment options are available for NP but there is no gold standard (see Table 3). A multidisciplinary bio-psycho-social approach to the treatment of NP is thus warranted. The choice of medication for each patient depends on a number of factors, including the potential for adverse effects, treatment of comorbidities (eg. depression, sleep disturbances), drug interactions, risks of misuse and abuse, and cost.⁶ Analgesics may vary in efficacy according to the type of NP syndrome.

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Guidelines for management

The International Association for the Study of Pain recently published evidence-based guidelines on the management of NP based on synthesising results from multiple randomised controlled trials (RCTs).⁶ Because most of the NP trials have investigated patients with post-herpetic neuralgia or painful diabetic neuropathy, much of the efficacy data that guide clinical practice are thus extrapolated from patients with non-malignant NP. Few trials have reviewed cancer-related NP. Additional consensus guidelines from the European Federation of Neurological Societies and the Canadian Pain Society have also been published.^7,8

Pharmacological interventions

Antidepressants

Among the first-line treatments for NP are tricyclic antidepressants (TCADs) and selective serotonin-noradrenaline reuptake inhibitors (SNRIs). The efficacy of TCADs for treating a variety of NP types has been established in multiple RCTs.^6,7,9,10 Secondary amines such as nortriptyline and desipramine provide pain relief comparable to amitriptyline and other tertiary amine TCADs while causing fewer adverse effects.¹¹ TCADs are limited, however, by anti-cholinergic side-effects (eg. dry mouth, blurred vision and urinary retention), a slow onset of action (analgesia in days to weeks) and the potential for cardiac toxicity. TCADs should be started with low doses and titrated to effect and should be used with caution in the elderly. Selective SNRIs, including duloxetine and venlafaxine, have also shown consistent efficacy in NP.^10,12-14

Anti-convulsants

Anti-convulsants such as gabapentin and pregabalin appear to be more effective in the treatment of NP than traditional anti-convulsants such as carbamazepine and sodium valproate. Pregabalin and gabapentin appear similar in terms of adverse effects, actions and efficacy, but pregabalin is reported to have a shorter onset of action (< 1 week) and dose titration can occur more rapidly.¹⁰ Dose-related dizziness and sedation are common adverse effects that can be ameliorated by starting with low doses and titrating cautiously.¹¹ Both require dose reduction in patients with renal insufficiency.⁶

Opioids

The role of opioid analgesics in NP has been controversial. NP has been considered refractory to opioids but, more recently, much research has supported use of these agents.^15-17 The extent to which pain responds to opioids varies depending on both patient and pain characteristics.¹⁸ Methadone is a synthetic opioid agonist at the µ- and ∆-receptors and an antagonist at the N-methyl-D-aspartate (NMDA) receptor. Its NMDA receptor antagonist properties have led to the clinical impression that methadone is of particular benefit in patients with NP.^19,20 Clinical studies of tramadol, an atypical opioid analgesic, have also confirmed its effectiveness in NP.^21-26

Topical agents

Topical agents can produce local analgesic effects, especially if the region of NP is relatively small and circumscribed. The lidocaine 5% patch is effective in the management of post-herpetic neuralgia and in patients with allodynia due to other types of peripheral NP.^12,14 Because of the small amounts of lidocaine absorbed, systemic side-effects do not occur. Topical application of capsaicin appears to be effective in the management of post-herpetic neuralgia, but can cause burning, stinging and erythema and thus can be intolerable to a number of patients.^27,28

Combination therapy

While monotherapy may be desirable for both ease of administration and reduction of potential side-effects, this approach may not achieve satisfactory analgesic control. In RCTs assessing efficacious medications for NP, typically < 50% of patients experience satisfactory pain relief.¹¹ Burdening side-effects (including inability to tolerate treatment) are also common.¹¹ Because no one medication is universally effective, the combination of two or more agents with different mechanisms of action to achieve synergistic pain efficacy is not uncommon. 

Invasive treatments

More invasive treatments such as epidural injections of local anaesthetics or corticosteroids, implantation of epidural and intrathecal drug delivery systems, neural ablative procedures and insertion of spinal cord stimulators may be considered for patients with intractable NP. 

Non-pharmacological interventions

Non-pharmacological treatment options in the management of NP include exercise, physiotherapy, acupuncture and transcutaneous electrical nerve stimulation (TENS). Evidence supporting efficacy of these options is, however, limited.⁵ Psychological treatment options include relaxation/diversion, counselling and education, cognitive behavioural therapy, stress management and pain management programmes.

Conclusion

Neuropathic pain is a common and debilitating condition. Thorough assessment and careful management is thus required. Pain management is a continuous dynamic process. The disease state and factors that influence pain are not static. Optimal pain control in patients with NP requires an integrated approach. The array of medications and other treatment interventions with demonstrated efficacy in NP is expanding, presenting the clinician with many different options for the management of this debilitating condition.

References

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