Chronic pain management requires an interdisciplinary approach. The elements of this approach include treating the underlying cause of pain, pharmacological and non-pharmacological therapies, and some invasive procedures.
Nociceptive and neuropathic pains are caused by different neurophysiological processes, and therefore tend to respond to different treatment modalities. Nociceptive pain is mediated by receptors on A-delta and C-fibres. These receptors serve a biologically useful role in localising noxious chemical, thermal and mechanical stimuli. Nociceptive pain can be somatic or visceral in nature. Somatic pain tends to be well localised, constant pain that is described as sharp, aching, throbbing or gnawing. Visceral pain tends to be vague in distribution, paroxysmal in nature and is usually described as deep, aching, squeezing and colicky in nature. Nociceptive pain usually responds to opioids and non-steroidal anti-inflammatory agents.
Neuropathic pain, in contrast to nociceptive pain, is described as "burning", "electric", "tingling" and "shooting" in nature. It can be continuous or paroxysmal in presentation. Nociceptive pain is caused by the stimulation of peripheral of A-delta and C-polymodal pain receptors (by substances such as histamine, bradykinin and substance P), whereas neuropathic pain is produced by damage to, or pathological changes in, the peripheral or central nervous systems.
Examples of pathological changes include prolonged peripheral or central neuronal sensitisation, central sensitisation-related damage to nervous system inhibitory functions, and abnormal interactions between the somatic and sympathetic nervous systems. The hallmarks of neuropathic pain are chronic allodynia and hyperalgesia.
Examples of neuropathic pain include: monoradiculopathies, trigeminal neuralgia, postherpetic neuralgia, phantom limb pain, complex regional pain syndromes and the various peripheral neuropathies.
Pathophysiology of neuropathic pain The mechanisms involved in neuropathic pain are complex and involve both peripheral and central pathophysiological phenomena. The underlying dysfunction may involve deafferentation within the peripheral nervous system (eg. neuropathy), deafferentation within the central nervous system (eg. post–thalamic stroke) or an imbalance between the two (eg. phantom limb pain).
Peripheral mechanismsFollowing a peripheral nerve injury (eg. crush, stretch or axotomy), sensitisation occurs. This is characterised by spontaneous activity by the neurone, a lowered threshold for activation and increased response to a given stimulus. Should the injured nerve be a nociceptor, then increased nervous discharge will equate to increased pain. Following nerve injury, C-fibre nociceptors can develop new adrenergic receptors and sensitivity, which may help to explain the mechanism of sympathetically maintained pain.
In addition to sensitisation following damaged peripheral nerves, the formation of ectopic neuronal pacemakers can occur at various sites along the length of the nerve. Increased densities of abnormal or dysfunctional sodium channels may be the cause of this ectopic activity. The sodium channels in damaged nerves differ pharmacologically and demonstrate different depolarisation characteristics. This may explain the rationale of treatment with lidocaine, mexiletine, phenytoin, carbamazepine and tricyclic antidepressants, each of which blocks sodium channels.
These ectopic pacemakers can occur in the proximal stump (e.g. neuroma), in the cell bodies of the dorsal root ganglion and in focal areas of demylenation along the axon. Neuromas are composed of abnormal sprouting axons and have a significant degree of sympathetic innervation. Neuromas have been reported to accumulate sodium channels at their distal ends, which can modulate their sensitivity. They can acquire adrenergic sensitivity, as indicated by increased pain following injection of norepinephrine into the neuroma. Neuromas can also acquire sensitivity to catecholamines, prostanoids and cytokines. Novel ion channels or receptors, not found in normal nerves, appear to be expressed in the regenerating terminal/axon.
Further animal investigations suggest that abnormal electrical connections can occur between adjacent demyelinated axons. These are referred to as ephapses. "Ephaptic cross talk" may result in the transfer of nerve impulses from one axon to another. Cross-talk between A and C fibres develops in the dorsal root ganglion. Nerve growth trophic factors may be important in the elaboration of these changes. A similar event referred to as "crossed after discharge" has also been described whereby "the sprouts of primary afferents with damaged axons can be made to discharge at high frequencies by the discharge of other afferents". It is also theorised that injured nerves may contain ephapses between sensory and sympathetic fibres, and such cross-connections may play a role in the pathogenesis of sympathetically mediated pain.
Inflammatory neuropeptides (substance P) and prostaglandins (PGE2) may be released from primary afferent nociceptors and sympathetic postganglionic neurons, respectively, activating nearby receptors and triggering a process of spreading activation. These mechanisms may explain the clinical response of some neuropathic pain patients to topical non-steroidal anti-inflammatory drugs, lidocaine and capsaicin.
The connective tissue sheath around peripheral nerves is innervated by the nervi nervorum. Injury, compression and inflammation of the sheath may cause pain. In cancer patients, pain associated with tumour compression of neural structures is clinically indistinguishable from non–malignant neuropathic pain. This nervi nervorum-related pain may resolve following tumour resection or treatment of tumour-induced inflammation. Anti-inflammatory medications have been shown to be effective in certain neuropathic pain conditions. The mechanism of pain relief may be decreased oedema at the tumour or injury site. However, these medications also have membrane stabilising effects and central analgesic effects. Therefore, it is extremely difficult to distinguish primary tumour-associated inflammation and involvement of the nervi nervorum from other mechanisms of neuropathic pain.