A 73-year-old man was admitted to hospital for pain control. He had recently been diagnosed with a left upper lobe lung tumour which was invading the brachial plexus. His main complaint was that of a sharp left-sided chest pain. He described a severe deep burning pain which radiated down his left arm. He also described numbness and tingling in his arm. The pain was waking him at night and was affecting his power and thus his ability to perform his activities of daily living.

Questions 

• What type of pain is this likely to be?

• What are the causes of this type of pain and what are the clinical features?

• How would you make the diagnosis?

• How would you manage this patient?

• What are the pharmacological treatment options for this type of pain?

• What are the non-pharmacological and interventional treatment options?

What type of pain is this likely to be?

The most likely type of pain is neuropathic pain. The International Association for the Study of Pain (IASP) defines neuropathic pain (NP) as ‘pain initiated or caused by a primary lesion or dysfunction of the nervous system’ or in simpler terms it is ‘pain in an area of altered sensation’.¹

Neuropathic pain is frequently present in cancer patients either in isolation or in combination with nociceptive pain. Neuropathic pain is not a single entity but encompasses a variety of different complex clinical pictures with diverse pathophysiological mechanisms. 

The true prevalence of neuropathic pain in the general population is unknown. Some 15-20% of patients with cancer develop neuropathic pain during their illness with a higher percentage as the disease advances. Some studies suggest that up to 50% of difficult to manage cancer pains are neuropathic in nature. 

Neuropathic pain is a major cause of morbidity in patients and, when uncontrolled, it is often associated with anxiety, depression and reduced quality of life. No cure for neuropathy exists and for the majority who have it, the pain can persist lifelong.

What are the causes and the clinical features?

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).²

Rarely, if ever, can one single mechanism be claimed to be responsible. 

Many causes of neuropathic pain are implicated in patients with cancer including:

• Nerve compression

• Direct infiltration of a nerve or nerve plexus by a growing tumour

• Metabolic causes (diabetes, renal or hepatic dysfunction)

• Opportunistic infections, including herpes zoster infection

• Cancer treatment (surgery, radiotherapy or chemo-therapy)

• Paraneoplastic disorders.³

The severity of neuropathic pain ranges from mild discomfort to being severely debilitating, and the onset of symptoms can be sudden or can slowly progress over time. Patients often find it difficult to describe the character of the pain. 

Classically patients with neuropathic pain complain of spontaneous pains (arise without detectable stimulation) and evoked pains (abnormal responses to stimulation). The clinical features can include:

• Abnormal pain quality – burning, stabbing, gnawing

• Poorly localised pain, sometimes diffuse

• Paroxysmal pains

• Abnormal sensations, ie. tingling, pain, or numbness 

• Sensory impairment usually in an anatomical distribution, ie. loss of light touch, vibration, pinprick and thermal sensations

• Immediate or delayed onset after injury

• Allodynia, ie. pain due to a stimulus which does not normally provoke pain 

• Hyperalgesia, ie. whereby a noxious stimulus provides a painful sensation of abnormal severity

• Difficulty mobilising.

How would you make the diagnosis?

A thorough assessment is crucial in order to formulate an individualised management plan for each patient and to optimise pain control. 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) 

• A physical examination

• Exploration of potential aetiologies and treatable conditions, eg. spinal cord compression

• Patient education.

The diagnosis of neuropathic pain is based primarily on the clinical 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.⁴ Computed tomography (CT) and magnetic resonance imaging (MRI) scans can facilitate specific diagnoses, (eg. herniated disc, nerve infiltration by tumour). 

Pain assessment should be ongoing (occurring at regular intervals), individualised to each patient and clearly documented, so that all involved in the patient’s care understand the important issues. 

How would you manage this patient?

Due to the relatively poor understanding of the underlying mechanisms and limited efficacy of traditional analgesics, neuropathic pain can be challenging to treat. While many treatment options for this type of pain exist, there is no gold standard. 

A multidisciplinary bio-psycho-social management approach is recommended with appropriate assessment critical, focusing on identifying and treating underlying disease processes, assessing response to prior treatments and evaluating comorbid conditions, including depression, anxiety and sleep disturbances. 

Palliation of pain, restoration of therapeutic sleep, maintenance of function and improvements in overall quality of life remain the mainstays of treatment.⁵ Management of neuropathic pain includes medical options, surgical options (ie. decompression), invasive procedures and non-pharmacological approaches.

What are the pharmacological treatment options?

Analgesics used may vary in efficacy according to the type of neuropathic pain syndrome. 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 randomised controlled trials (RCTs) assessing efficacious medications for neuropathic pain, typically <50% of patients experience satisfactory pain relief.³ Burdensome side-effects (including inability to tolerate treatment) are also common.³

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. 

The choice of pharmacological agent used in neuropathic pain depends on:

• Potential adverse effects 

• Potential drug interactions

• Comorbidities that may be relieved, such as depression or sleep disturbance

• Cost

• Potential risk of abuse and misuse.

Antidepressants

Among the first-line treatments for neuropathic pain are tricyclic antidepressants (TCADs) and selective serotonin-noradrenaline reuptake inhibitors (SNRIs). Secondary amines such as nortriptyline and desipramine provide pain relief comparable to amitriptyline and other tertiary amine TCADs, while causing fewer adverse effects.³

These agents have documented pain-control efficacy, but are limited by anticholinergic side-effects (such as dry mouth, blurred vision and urinary retention), a slow onset of action (analgesia in days to weeks) and the potential for cardiac toxicity.³

TCADs should be started with low doses and titrated to effect, and should be used with caution in older people. Selective SNRIs, including duloxetine and venlafaxine, have also shown consistent efficacy in managing neuropathic pain.³ Abrupt withdrawal should be avoided.

Anticonvulsants

Anticonvulsants, such as gabapentin and pregabalin, appear to be more effective in the treatment of neuropathic pain than traditional anticonvulsants such as carbamazepine and sodium valproate. 

Pregabalin binds to the voltage gated calcium channel with a higher binding affinity than gabapentin. 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.³

Pregabalin may be dosed on a twice daily schedule but may require three times daily dosing, similar to gabapentin. Dose-related dizziness and sedation are common adverse effects that can be ameliorated by starting with low doses and titrating cautiously.³ Both require dose reduction in patients with renal insufficiency.

Opioid analgesics

The role of opioid analgesics in neuropathic pain has been controversial; NP has long been considered refractory to opioids, but more recently, much research has supported the use of these agents.^6,7,8 The extent to which pain responds to opioids varies depending on both patient and pain characteristics.⁹ Opioids other than morphine shown to be effective include tramadol, fentanyl and oxycodone. 

Methadone is a synthetic opioid agonist at the mu- and delta-receptors and an antagonist at the N-methyl-D-aspartate (NMDA) receptor. Methadone’s NMDA receptor antagonist properties have led to the clinical impression that methadone is of particular benefit in patients with neuropathic pain.^10,11 

Methadone can be considered different from the other opioids with respect to neuropathic pain; it can either be tried as an alternative to a first-line opioid or introduced later, when other options have failed.

Ketamine

Ketamine is a dissociative anaesthetic agent and a non-competitive NMDA receptor antagonist. Ketamine has been shown to improve analgesia in neuropathic pain caused by cancer; however central nervous system adverse effects are reported. While there is much clinical experience supporting the use of ketamine in neuropathic pain states, the evidence base is not well established to date.

Topical agents

Topical agents can produce local analgesic effects, especially if the region of neuropathic pain 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 neuropathic pain.^12,13 The patch is applied to the area where the greatest pain is experienced. Only a small proportion of lidocaine contained in the patch is absorbed through the skin and because of the small amounts of lidocaine absorbed, systemic side-effects do not occur. 

Capsaicin cream, an ingredient of hot peppers, has also been used effectively in the management of neuropathic pain.^14,15 It can cause burning, stinging and erythema which can be intolerable to some patient.^14,15 Mixing the capsaicin with EMLA cream or GTN paste may help.

Miscellaneous medications

Several additional medications have shown efficacy for the treatment of neuropathic pain. These include anti-depressants (eg. buproprion, citalopram and paroxetine), anticonvulsants (eg. carbamazepine, lamotrigine), topical low concentration capsaicin, memantine (an NMDA receptor antagonist used in the treatment of Alzheimer’s disease) and mexiletine (a class IB anti-arrythmic). Further research is warranted in order to demonstrate the true efficacy of these agents.

What about non-pharmacological options?

Non-pharmacological treatment options are extremely important in the management of neuropathic pain and include exercise, physiotherapy, acupuncture and transcutaneous electrical nerve stimulation (TENS). Evidence supporting efficacy of these options is however limited.⁴

Psychological treatment options include: 

• Relaxation/diversion

• Counselling and education

• Cognitive behavioural therapy (CBT)

• Stress/pain management programmes.

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 neuropathic pain. 

Consideration of these invasive treatments is generally reserved for patients with no surgically treatable pathology in whom conservative management has not been effective.

References

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14. Bernstein JE, Korman NJ, Bickers DR et al. Topical capsaicin treatment of chronic postherpetic neuralgia. J Am Acad Dermatol 1989; 21(2, pt 1): 265-270
15. Alper BS, Lewis PR. Treatment of postherpetic neuralgia: a systematic review of the literature. J Fam Pract 2002; 51: 121