The Pharmacological management of neuropathic pain: A review
Dr Gary McCleane MD FFARCSI, Consultant Anaesthetist, Pain Clinic, Craigavon Area Hospital
See also related article on Pain and Dissociation
neuropathic pain is caused by neural injury
the symptoms experienced by the patient with neuropathic pain differ to those experienced by the patients with nociceptive pain
analgesics that are effective for nociceptive pain have less effect in neuropathic pain
tricyclic antidepressants, anticonvulsants, membrane stabilisers and capsaicin can relieve neuropathic pain
anticonvulsants have differing modes of action and therefore failure to respond to one does not imply that others may not work
Tissue injury is usually accompanied by pain and is described as neuropathic if the initiating injury occurs to neural tissue. After injury occurs, symptoms are initially experienced distal to the site of injury: by contrast in non-neuropathic pain (nociceptive pain) symptoms are apparent, at least initially, at the site of injury. With time the margins between these types become blurred and each may coexist with the other. The consequence of neural injury is change in neural function both at the site of injury and proximal to it with the symptoms produced being manifestations of neural over or under activity. Typical features of neuropathic pain, regardless of the causal injury, include shooting / lancinating pain, burning pain, paraesthesia / dysaesthesia, numbness and allodynia (pain produced by a normally non-painful stimulus).
In addition to differing symptoms experienced with neuropathic and nociceptive pain, there are differences in those therapeutic agents which can produce pain relief. For example, it is accepted that nociceptive pain may be relieved by morphine and non-steroidal anti-inflammatory drugs (NSAIDs). However, with neuropathic pain some studies suggest analgesia with morphine (1,2) and NSAIDs (3,4) , while others demonstrate no analgesia with morphine (5, 6) or NSAIDs (7,8) .
The aim of this article is to highlight current therapeutic options for the treatment of neuropathic pain.
It has been recognised for almost 150 years that the topical application of extracts of the capsicum pepper can produce pain relief (9) . It is now recognised that the active pain killing constituent of the chili pepper is capsaicin, which when repeatedly applied topically in appropriate concentration causes reversible depletion of the neurotransmitter substance P (SP) from the sensory nerve endings (10) and hence pain relief, which may take several weeks to occur. Topical application of capsaicin has been shown to reduce the pain of a variety of conditions, including post herpetic neuralgia (11 - 13) , painful diabetic neuropathy (14 - 16) , chronic distal painful polyneuropathy (17) , surgical neuropathic pain (18) , post mastectomy syndrome (19) and osteoarthritis ( 20 - 23) . The major side effect is that of burning discomfort which may lead to poor patient compliance. The addition of glyceryl trinitrate (GTN) to capsaicin reduces the burning discomfort associated with application (24,25) and may improve compliance. GTN is also known to have an anti-inflammatory effect (26, 27) and this may augment the analgesia from the capsaicin.
It is widely accepted that oral tricyclic antidepressants (TCAs) have an analgesic effect in neuropathic pain (28, 29) with evidence of efficacy existing for amitriptyline (30 - 34) , imipramine (35), desimipramine (36 - 38) and clomipramine (39, 40) . This analgesic effect is independent of their antidepressant effect (41) and may be dose related (42,43) . TCAs have an effect of 5 hydroxytriptamine release (44) , the noradrenergic pathways (45) and a sodium channel blocking effect (46), the later effect being shared by the local anaesthetic and anticonvulsant groups.
Unfortunately, the undoubted analgesic effect of the TCAs is tempered by their side effect profiles with somnolence and dry mouth being the predominant side-effects. Recent work has highlighted a potential analgesic effect of topical doxepin, a TCA, in neuropathic pain (47,48) . The topical application of doxepin is associated with few side effects, and particularly central side-effects. Animal work has suggested a potential peripheral action of TCAs (49, 50) and may explain the analgesis seen in human studies.
It has long been appreciated that there a similarities between epilepsy and neuropathic pain (in 1885 Trousseau described trigeminal neuralgia as "epileptiform neuralgia 51) ) and that drugs that are effective in reducing seizure frequency may also have an analgesic effect in neuropathic pain (52, 53) . The first report of analgesia with an anticonvulsant in neuropathic pain was with phenytoin in 1942 (54). Subsequent randomised controlled trials (RCTs) has confirmed this case report evidence with phenytoin (55, 56) . In 1962 case report evidence of analgesia with carbamazepine emerged (57) , with subsequent support from RCTs in trigeminal neuralgia (58) and painful diabetic neuropathy (59) . Carbamazepine remains the most frequently used anticonvulsant for neuropathic pain (60) .
Anecdotal evidence points to a similar analgesic effect with lamotrigine (61 - 64) , although the evidence from the small number of RCTs so far reported is mixed (65, 66) . The analgesia from lamotrigine may be dose related and studies reporting no analgesia used low dosing regimes of this drug.
Gabapentin, a structural analogue of the inhibitory neurotransmitter gamma amino butyric acid (GABA), which paradoxically is thought not to exert its effect on GABA receptors (67) , has recently been demonstrated to reduce neuropathic pain (68 - 73) , and in particular post herpetic neuralgia (74) and painful diabetic neuropathy (75) , both conditions being archetypal neuropathic pain conditions. The potential advantage of lamotrigine and gabapentin over carbamazepine are their more favourable side effect profiles (76) .
When oral dose titration is not possible then parenteral administration may be necessary. Intramuscular fosphenytoin (a water soluble ester pro-drug of phenytoin, lacking its infusion related side-effects) produces analgesia where neuropathic pain is present (81) . Intravenous infusions of phenytoin and fosphenytoin both have a similar analgesic effect with the added advantage of relief that extends beyond the period of infusion and the intravascular half-life of the drug (82, 83) .
Despite a common effect (reduction in seizure frequency and analgesia), anticonvulsants differ in their mode of action. Phenytoin has a sodium channel blocking effect (77) while lamotrigine has an effect on voltage gated cation channels (78) and glutamate release (79) , while gabapentin appears to exert its action via the alpha delta 2 sub unit of the calcium channel (80) . The clinical consequence of these differing modes of action is that a failed trial with one anticonvulsant does not mean that another in this class will not work.
Baclofen, like gabapentin, is structurally similar to the inhibitory amino acid gamma amino butyric acid (GABA) and yet seems to have a mechanism of action that differs to that of GABA (84, 85) . It is known to depress release of the excitatory neurotransmitters glutamate and aspartate (86, 87) . Isolated studies suggest an analgesic effect in trigeminal neuralgia (88, 89) .
The causes of incomplete analgesia with opiates in neuropathic pain are many. Among them are elevation of the anti-opioid peptide cholecystokinin (CCK) (90 - 92) . Neural injury produces an elevation in plasma CCK levels (93) , and if a CCK antagonist is administered, then opiate sensitivity in neuropathic pain may return. The obsolete anti-ulcer drug proglumide is a non-specific CCK antagonist (94) and has been shown to augment the analgesic effect of sustained release morphine in neuropathic pain (95, 96) . As well as reducing the analgesic effect of opiates, CCK is also elevated with chronic opiate administration, and hence more opiate is required to achieve the same level of analgesia with the passage of time (tolerance) (97 - 103) . CCK antagonists such as proglumide can reverse this tolerance. It may therefore be that opiates can be used to treat chronic neuropathic pain when co-administered with a CCK antagonist, although the debate will continue as to whether a dose limit be put on the sustained release morphine preparation.
For many years intravenous infusions of local anaesthetics have been used in the management of both acute and chronic pain: the analgesia of IV novocaine was described in 1943 (104) . Despite much anecdotal evidence of analgesia with IV lignocaine (105 - 8) there are few RCTs to verify this effect. It does seem that a short term infusion (e.g. 24 hours) may give relief in some patients for a sustained period (weeks to months). Parenteral local anaesthetics seem to suppress the activity of spontaneously active fibres in neuromas (109), , depresses C - afferent fibre evoked activity in the spinal cord (110) and silence dorsal root ganglion discharge without blocking nerve conduction (111) .
Parenteral administration of local anaesthetics may not always be feasible and there is some evidence to suggest that the oral equivalent mexiletene may also have an analgesic effect (112 ) .
Ketamine, a N-methyl D-aspartate (NMDA) receptor antagonist can have an analgesic effect in neuropathic pain (113 - 4). Its use is associated with side-effects that limit its use, but recent work has suggested an opiate potentiating effect that may be apparent at otherwise sub-therapeutic doses (115) .
The perineural injection of drugs seems to produce pain relief in some patients with neuropathic pain for varying lengths of time. Local anaesthetic injection may give only short term relief. However, the addition of corticosteroid may lengthen the pain relief produced. Steroids reduce inflammation by reducing prostaglandin synthesis (116 ) , suppress ectopic discharge (117) , have C fibre membrane stabilising effects (118) and stabilise the dorsal horn cell (119) and any or all of these effects may contribute to the pain relief produced. With the example of epidural steroid administration there is mixed evidence with some reports claiming benefit (120) , while others suggest less significant benefit in terms of extent and duration of relief (121 - 2)
The alpha adrenoreceptor agonist clonidine has been used for many years as an antihypertensive agent. When administered by the epidural or intrathecal route it has an effect on the descending noradrenergic pathways (123 - 4) which produces analgesia (125 - 8) . Unfortunately oral administration is not associated with such relief.
While many other agents may be used in treating neuropathic pain, their use is not verified by appropriate studies. It is hoped that the rational use of drugs increases the chance of achieving analgesia in the patient with neuropathic pain. However, when one considers the "numbers needed to treat" (N.N.T.), that is the numbers of patients needing to take the drug to achieve 50% reduction of that symptom in one patient, for the medication used in neuropathic pain it is clear that it is always greater than 2.5 (28,52) . Consequently, no one therapeutic intervention is guaranteed of success. This is similar to drugs used in nociceptive pain where the N.N.T. varies from 3.1 with paracetamol 500mg / codeine 60mg, to 3.6 with paracetamol 600 or 500mg, to 9.1 with codeine 60mg (129) . Consequently it may often be necessary to work ones way through a list of treatment options before analgesia is achieved. Inevitably any relief produced may be tempered by the associated side-effects of that drug so that improvement in quality of life (pain reduction, mood elevation, increased mobility, better sleep with minimal side effects from treatment) is the therapeutic goal. Poly pharmacy is a real danger, with patients staying on medication in hope of relief when none is actually apparent. Trials of medication for a defined period of time with assessment before and after may be more appropriate.
Pharmacological management will produce the desired analgesia in some, but not all, patients. In those who fail to respond, other modalities of treatment may be considered, ranging from behaviour modification and fostering of coping skills to the more major invasive medical techniques. It is still reassuring, however, to realise that in the future we have the prospect of additional agents which may or may not prove useful analgesics in neuropathic pain. These include agents with more specific sodium channel blocking effects, calcium channel blockers and new generation anticonvulsants and capitalise on the major expansion in knowledge generated from the work of the basic scientists.
It is hoped that this paper highlights the current outpatient therapeutic options and demonstrates a rational approach to the management of the patient with neuropathic pain.
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