As a result of advances in the investigation and management of cancer, survival rates are much improved in this patient population. Consequently, a large number of patients are now reporting reduced quality of life, often relating to cancer pain. Therefore, it is becoming increasing important that all physicians caring for patients diagnosed with cancer, whether in the community or hospital-based, should be aware of different and evolving treatment modalities in cancer-related pain.

Mechanisms of cancer pain

Our understanding of the mechanisms of cancer-related pain is predominantly derived from animal models. Historically, animal models have proven beneficial in understanding the mechanisms underlying other pain modalities, such as neuropathic and chronic pain. Cancer pain can be considered to be multifactorial in origin, meaning it is without a single somatic, sympathetic or neuropathic pain state. It may be understood as having an inflammatory, ischaemic and neuropathic component. 

Inflammatory pain may be due to the release of a number of growth factors, cytokines, interleukins and endothelins, which directly activate primary afferent fibres.^1,2 Neuropathic pain can be attributed to different aetiologies, such as infiltration of the nerves by tumour mass and treatment-related, (eg. surgery, chemotherapy). This helps explains why certain medications for neuropathic pain, such as gabapentin and amitriptyline, show some efficacy in the management of cancer pain. 

The pathophysiology of cancer pain has features in common with other pain states, however, there are some unique differences. In animal models with bone cancer pain, there are reported alterations on the amount of nociceptive-specific cells and wide dynamic range (WDR) neurons, those that respond to both innocuous and noxious stimuli. Models showed an increased proportion of WDR neurons that displayed hyperexcitability to thermal and mechanical stimuli.³ These similarities suggest that while some treatment modalities in other pain states may be beneficial, there is an even wider range of treatment options that may be available to patients with cancer-related pain.

Cancer pain management 

Treatment of cancer-related pain is approached using a bio-psycho-social model. This may involve patient education, altering expectations, modifying activities, community supports and cognitive therapy aimed at improving mood and sleep patterns. Historically, the primary way of managing cancer pain was treatment of the underlying pathological process, eg. bone pain secondary to metastatic prostate cancer may be improved by anti-androgen treatment; chemotherapy may reduce the mechanical/ischaemic pain associate with tumour burden; and radiotherapy has a proven role in palliation for bone metastasis.⁴

The WHO analgesic ladder was originally published as a method for relief of cancer pain.⁵ The ladder is essentially a set of guiding principles that involve a stepwise approach to the use of analgesic drugs. Step one involves non-opioid based regimes (eg. paracetamol, NSAIDs); step two involves a weak opioid (eg. codeine); and step three involves a strong opioid (eg. morphine). If a patient were to present with moderate to severe pain, it is appropriate for them to commence on strong opioids immediately rather than progress through the earlier steps. The original monograph would emphasise the importance of using strong oral opioids in the management of moderate to severe cancer pain. 

The underlying principles of the WHO method to relieve cancer pain – ‘by the clock’, ‘by the mouth’, ‘by the ladder’, and ‘for the individual’ – are of paramount importance. It is also vital to note that, with the advent of other treatment modalities, each stage in the ladder may be supplemented by other interventions, such as disease-modifying medications and nerve blocks, often considered the fourth step of the ladder. 

The WHO ladder is still considered the gold standard in cancer pain management. Nevertheless, since its introduction, other opioid-based medications and different formulations have emerged that also have a role to play, such as fentanyl, buprenorphine, hydromorphine and oxycodone. 

However, recent guidelines published by the European Association of Palliative Care cautioned that, due to a low level of evidence, no one opioid could demonstrate superiority over another in the treatment of cancer-related pain.⁶ Despite this, morphine still remains the most commonly used opioid (both oral and parenteral) for the management of moderate to severe pain.⁷

Interventional therapies 

Although systemic pharmacotherapy is the mainstay of treatment for cancer-related pain, there are many limitations to this strategy; not only the opioid-based side-effects (constipation, nausea and vomiting, cognitive impairment), but more specifically an inability to provide adequate pain relief for what can be an advancing and worsening pain state (opioid unresponsive pain). For these reasons, interventional pain techniques can play an essential role in cancer pain management.⁸

Interventional procedures can be classified under three headings: peripheral, sympathetic and central neuroaxial techniques. They may also be re-classified as either being neuromodulatory, such as the intrathecal administration of local anaesthetic, or neurodestructive, such as the use of toxic agents, cold/heat energy or radiofrequency ablation aiming to obliterate neural function.  

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Before considering any of these techniques it is of paramount importance that the physician must have an accurate knowledge of the patient’s pain history, the disease process, the response to first-line pain management strategies, and also patient expectations. These therapies should only be considered as an adjunct to systemic pharmacotherapy and should not be used as first-line or monotherapy in the treatment of cancer-related pain. 

When utilised in the appropriate patient-specific clinical scenario, they have the potential to improve analgesia, function and enhance quality of life.⁹ Essentially, when pain relief cannot be achieved through pharmacological means, interventional approaches become a viable alternative. 

Nerve blocks for pain relief

Peripheral neural blockade encompasses any procedure whereby an agent is delivered with the purpose of modulating nociceptive afferent input to the central nervous system. They can be further sub-classified as diagnostic, prognostic and therapeutic. 

A diagnostic nerve block may be performed for the purposes of determining the source of pain. The location of a noxious stimulus is clinically important and may be elicited by performing a nerve block of a somatic nerve (involves both sensory and motor function). If pain persists despite accurately blocking the neural input from the painful area then one can conclude that the pain is not originating in the periphery and may have its origin in the central nervous system. 

Prognostic nerve blocks are those that are performed in order to elicit whether performing neurolysis of a nerve is likely to offer appropriate pain relief. In essence, they attempt to emulate the sensory loss that will occur once denervation occurs and determine whether this level of sensory loss is tolerable by the patient. However, the results of these blocks should be interpreted with caution, as pain relief from local anaesthetic to nerves does not preclude that a neurodestructive procedure will have the same outcome. More appropriately, one should conclude that if a prognostic block had no meaningful benefit for a patient, then a subsequent neurolysis should not be attempted. 

A therapeutic nerve block aims to treat the underling cause of a patient’s pain, eg. epidural steroids for disc-related back pain. These types of block, therefore, have roles to play in non-cancer pain. 

Examples of peripheral nerve blocks include:

• Intercostal nerve block for metastatic chest wall disease, which may be performed via a standard infrarib approach or via paravertebral approach
• Interscalene nerve block for use in tumours invading areas of the brachial plexus, such as pancoast tumour or upper limb bony metastasis. 

Non-neurolytic blocks can be performed as a single shot injection of local anaesthetic or involve placement of a catheter for continuous infusion. It has been observed that patients receive pain relief that often exceeds the predicted pharmacological duration of the local anaesthetic. The mechanism behind this phenomenon has not yet been fully discovered. 

The placement of a catheter is generally considered for a short-term basis, typically only a few days. However, longer infusions may be considered in special circumstances under the guidance of an experienced pain specialist, eg. an interscalene catheter that blocks the brachial plexus for persistent severe shoulder pain. 

Conversely, neurolytic blocks operate by destroying neural pathways whether that be afferent nerves or sympathetic efferents implicated in the transmission of pain. There are many ways of achieving this, including thermal coagulation, radiofrequency ablation, cryotherapy, and chemical neurolysis (glycerin, phenol, alcohol). The extent of neurolysis and the resulting duration of therapeutic effect can vary between techniques. 

These methods all result in Wallerian degeneration of the nerves, therefore, if the axon itself remains intact there is always the possibility of regeneration and emergence of a new pain state. Since it is difficult to predict the incidence of this complication, it once again highlights the importance of proper patient selection for these procedures. Other complications include damage to local tissues as a result of the neurolytic mechanism. Consequently, many neurolytic blocks have become less popular compared to the more conservative non-neurolytic blocks, with the notable exception of the coeliac plexus or superior hypogastric plexus block.

Sympathetic blocks, as the name suggests, involves blockade of efferent sympathetic fibres and the afferent nociceptive fibres that run parallel to them in the same nerve. These types of blocks are especially suited for visceral cancer pain. Examples include the stellate ganglion block, which supplies sympathetic outflow to the upper extremities (head, neck and intrathoracic structures); the coeliac plexus block, frequently used for upper abdominal malignancy (eg. pancreatic cancer);¹⁰ and the superior hypogastric plexus block for visceral pelvic pain. 

Conclusion

Opioid-based therapy guided by the WHO analgesic ladder remains the cornerstone of treatment of patients with cancer pain. There is a substantial subpopulation of cancer patients that remain refractory to this approach and they may be considered for further interventional techniques at different stages throughout their disease process. 

There have been many advances in the techniques and pharmacological agents available to pain physicians to help deal with these circumstances. However, the practicality and appropriateness of such interventions must always be considered before embarking on any treatment plan. 

It is important that any clinician dealing with the prospect of cancer pain be aware of the potential benefits, but also limitations, of interventional approaches. Therefore, the ability to liaise with colleagues in oncology, palliative medicine, radiology and pain medicine is vitally important and serves to advance understanding and ultimately improve patient outcome. The unique combination of multiple stakeholders and complex patient populations makes this challenging but very rewarding work.

References 

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