Central or peripheral?

It should be remembered that the patient’s report of pain, the nature and severity, does not always distinguish between central and peripheral neuropathic pain; to the patient it feels the same irrespective of the location. Some tools can be used to distinguish neuropathic pain from non-neuropathic pain, which have usually been developed and tested on patients with peripheral neuropathic pain (Bennett et al., 2007) and have not been established in patients with central neuropathic pain with the exception of multiple sclerosis (MS) (Rog et al., 2007). Careful examination, quantitative testing and response to prior treatments can help elucidate the possible cause.

It is perhaps useful to refresh some of the definitions which are important in neuropathic pain (Merskey & Bogduk, 1994):

International Association for the Study of Pain definitions

Occasionally the sensations the patient reports might seem bizarre and may not fit the common definition of ‘pain’; this is immaterial to the patient. Some sensations can be extremely distressing even if we might not describe them as pain per se. We should also remember that patients with central neuropathic pain who usually have functional impairment, grossly altered biomechanics and ongoing secondary changes associated with neurological damage, are more likely to have co-existing pathologies and musculoskeletal pain problems. Each patient should be considered individually and the pain problem can be very complex. It should also be remembered that neuropathic pain may be persistent, paroxysmal (come and go without explanation), evoked (dependent on a stimulus) or any combination or all of these. Some peripheral neuropathic pains may start with a relatively trivial injury and the patient may have had trouble convincing health-care professionals of the veracity of their condition and consequently the condition goes undiagnosed for some time. A careful examination of the area is essential.

Central neuropathic pain

Central neuropathic pain can arise from primary injury or dysfunction within the central nervous system (CNS) (Merskey & Bogduk, 1994) and can arise at any level or even from more than one level. The recently suggested prerequisites for a diagnosis of the condition are:

It is important to distinguish the changes which may occur as a result of neuroplastic changes after damage to the peripheral nervous system (PNS) or which may occur in chronic pain states which may begin with an injury in another part of the body other than the CNS. In these conditions the dysfunction of the CNS is considered to be secondary to ongoing nociception rather than from a primary source in the CNS.

Central neuropathic pain states can be usefully classified into three main groups: (1) pain associated with progressive neurological conditions, e.g. MS; (2) pain following stroke; and (3) pain following spinal cord injury. Another group which does not necessarily fall into these is neuropathic pain associated with HIV infection. This may be due to damage caused by the HIV virus itself or by neuropathy as a result of the antiretroviral treatment (Cox & Rice, 2008). This last group will not be considered here.

The prevalence of pain for all causes in MS has been estimated at between 43% and 70% (Moulin et al., 1988; Solaro et al., 2004). One of the best estimates for the presence of central neuropathic pain is that over 27% of patients report the condition (Osterberg et al., 2005). It is commonly widespread with an increased prevalence in the lower limbs and a variable clinical picture but a low report of paroxysmal pain. A small proportion of patients report pain at the onset of their MS but in general the incidence for central neuropathic pain syndrome (CNPS) is reported to be higher in the early years. However, this may be an artefact of diagnosis, as additional musculoskeletal pain and pain associated with spasticity may predominate in the later stages of the disease masking the true prevalence of neuropathic pain. The actual cause of CNPS in MS is difficult to determine owing to the disseminated nature of the disease. Using MRI, Osterberg et al. (2005) demonstrated hyperintensity of activity in the lateral and medial thalamic regions in one-third of MS patients with CNPS and concluded that, although there is an indication that the cause of the pain may share some similarities with central stroke pain, they could not conclude that lesions in the thalamus were the cause of the pain and postulated that lesions in the spinal cord, particularly the spino- and quintothalamic pathways, are likely to be the cause. A previous hypothesis also suggested the importance of lesions in the neospinothalamic pathway, which may become hyperexcitable following lesioning.

Pain is also seen in Parkinson’s disease but the exact reason for this is yet to be determined. It is suspected that the basal ganglia and dopaminergic systems are involved in the processing of nociception to higher centres (see Ch. 6).

Post-stroke pain is the commonest CNPS seen in the population because of the common occurrence of stroke. Andersen et al. (1995) followed 207 new stroke patients who survived for 6 months and were able to participate in a quantitative sensory testing protocol. In this study abnormal sensory signs were common (47%) and 8% of patients were diagnosed with post-stroke pain. There does not appear to be a higher prevalence in either ischaemic or haemorrhagic strokes, but because more people sustain ischaemic strokes CNPS is more commonly seen in this group of patients in clinical practice (Andersen et al., 1995).

The original description of a possible cause of post-stroke pain was made over one hundred years ago (Dejerine & Roussy, 1906) and since that time the role of lesions of the thalamus in ‘thalamic pain’ has been well documented. The literature on the importance of lesions in and around the thalamus has grown. Lateral medullary infarctions are more likely to result in damage to the spinothalamic and trigeminothalamic pathways and have the highest incidence in the development of CNPS (MacGowan et al., 1997). The incidence of pain following damage to the thalamus is also high. In an MRI study of people with post-stroke pain a high proportion of them had thalamic lesions (>60%), but multiple lesions were seen in almost all of the patients and no thalamic involvement was demonstrated in others, so the specificity of the location is difficult to demonstrate (Bowsher et al., 1998).

Pain following spinal cord injury

About two-thirds or more of people who sustain a spinal cord injury report persistent pain, but this can be due to a number of reasons, not all of which are due to CNPS (Siddall et al., 2002). A proposed classification for spinal cord injury pain describes two broad groups: nociceptive and neuropathic. Nociceptive is further broken down into musculoskeletal and visceral (Siddall et al., 2002). Neuropathic is subdivided into:

In a 5-year follow-up of 73 patients with spinal cord injury Siddall et al. found 81% of patients reported pain; of these 41% had neuropathic pain at the level of the lesion and 34% had neuropathic pain below the level of lesion. Most patients reported more than one type of pain with musculoskeletal pain being the commonest (59%), although the least severe (Siddall et al., 2003).

At level neuropathic pain corresponds to the segmental level of the injury often involving two dermatomes above or below. At level neuropathic pain can be a result of damage to the nerve roots or the spinal cord and is characterized by allodynia and hyperalgesia in the affected dermatomes. The physiology is the same as by which peripheral neuropathic pain develops following damage or constriction of peripheral nerve roots in the affected area.

Below level pain is purported to be caused by changes in the spinal cord in or near the area of injury as described above and also as a result of what is sometimes termed a ‘supraspinal generator’. A loss of neurological input to higher centres, especially the thalamus, may result in abnormal activity, in particular spontaneous activity. However, the nature of the pain, which is often persistent without the spontaneous outburst of pain, suggests that there is more than one area of the brain implicated as a supraspinal generator.

Peripheral physiological changes

Central physiological changes

Following nerve injury an increase in DRG activity has been observed caused by spontaneous electrical activity or activity following low-intensity stimulation of the injured nerve. This increased activity is associated with hyperalgesia and parasthesia. Neurones may also demonstrate repetitive changes or oscillations in the resting potential also giving rise to hyperalgesia and spontaneous outbursts of pain. This also might explain the unpredictable nature of the condition, the variable response and dysesthesia.

Following injury, Wallarian degeneration occurs in myelinated neurones (Wallace & Rice, 2008). Activity or spontaneous activity in these may result in depolarization of adjacent uninjured unmyelinated neurones. Should this occur in mechanoreceptors, for example, stimulation of these through touch or movement may result in allodynia and hyperalgesia.

Key to the pathophysiology of neuropathic pain are the changes which take place in the ion channels of the nerve cell following nerve damage (Wallace & Rice, 2008). Perhaps the most important, or at least the best understood, is the alteration in the activation of sodium channels which alter the action potential of the cell membrane (Wallace & Rice, 2008). Much of the effectiveness of pharmacological treatment is attributed to the action of the drugs in producing sodium channel blockade (e.g. lidocaine, carbamazepine, tricyclic antidepressants). There are many different sodium channels in the DRG and the relevance of all is not understood. Some appear to increase in activity, whereas others reduce; some increase in number and others appear to change location on the cell. There are two main groups of channels classified by their sensitivity to tetrodoxin (TTX), a neurotoxin found in fish which binds to some voltage-gated channels; receptors are classified as sensitive (TTX-s) or resistant (TTX-r). TTX-s channels are found predominantly on A fibres, whereas TTX-r are seen specifically in the smaller C-fibre nociceptive neurones.

NICE guidelines on pharmacological therapies for neuropathic pain

Recent recommendations regarding the use of pharmacological agents in the management of neuropathic pain have been developed by NICE (2010). They describe three lines of possible pharmacological treatment for people with neuropathic pain. Patients with diabetic neuropathy should be treated specifically with duloxetine. It recommends all neuropathic pain from all other causes should be treated according to the guidelines.

The main classes of drugs used in the management of neuropathic pain are antidepressants, topical applications (capsaicin and lidocaine plasters) opioids and anticonvulsant medications. With the exception of duloxetine for the treatment of painful diabetic neuropathy, there is little evidence of condition-specific effects for these drugs.

Some of the drugs currently used in the management of neuropathic pain are not licensed in the UK for this use (e.g. amitriptyline and nortriptyline) and patients might often be confused why such medications are prescribed when pain is not explicitly described as an indication for prescription on the accompanying medical information. It is essential that the reason for prescription of these medications is made clear to the patient. Failure to receive appropriate information about medication may result in non-compliance with drug therapy.

The first line of treatment should be either the antiepileptic pregabalin or the tricyclic antidepressant amitriptyline. The dose of pregabalin starts at 150 mg/day divided into two or three equal doses, increasing to an effective dose or maximum tolerated dose to no more than 600 mg/day. Amitriptyline commences at 10 mg/day and increases to no more than 75 mg/day according to effect and patient tolerance. Because of the sedating effects of amitriptyline this is taken some time before going to bed. The dose of amitriptyline may be increased further but only in consultation with a pain specialist. If amitriptyline proves to be effective but the adverse effects (typically drowsiness and dry mouth) prove intolerable the patient may be trialled on nortriptyline or imipramine,which may be tolerated better. There is some evidence of cardiac toxicity from amitriptyline and so high doses should be avoided in people with an increased cardiac risk. The possibility of causing falls in elderly or unsteady people should also be considered.

If the first-line treatment fails to provide sufficient effect at the maximum tolerated dose, pregabalin can be added to or substituted for amitriptyline, and vice versa, following the above guidance on dosage. Both pregabalin and gabapentin are calcium channel α2-δ ligands which bind to the α2-δ component of the calcium channels reducing the release of glutamate, norepinephrine (noradrenaline) and substance P. Both pregabalin and gabapentin have been seen to improve sleep. Dizziness, somnolence and cognitive impairment are the main side effects.

The NICE guidance does not recommend the use of opioids as a first-line treatment for neuropathic pain and only recommends them in coordination with a referral to a specialist pain service. The drug of choice in this situation is tramadol; a μ-opioid which also blocks the reuptake of serotonin. This is given as either a monotherapy in place of the first- and second-line therapies or in conjunction with the treatments described above. In either case a referral to a specialist pain service is recommended. The side effects of tramadol are the same as other opioids; constipation, somnolence and nausea. The NICE guidelines do not recommend the use of other opioid therapies without the opinion of a specialist pain service.

These guidelines reflect the management recommended by non-pain specialists and do not cover all the pharmacological options available. For example a previous review of the literature recommended the use of cannabinoids as a second-line therapy in the management of neuropathic pain associated with MS, although concerns about the long-term safety and the risk of precipitating psychosis may have been a factor in not recommending them in the NICE guidance.

Injectable drugs

Sustained infusions into the blood stream (parenteral therapy) or directly into the space surrounding the spinal cord (intrathecal injections) have been performed with positive effects on central stroke pain. Parenteral injections of lidocaineanticonvulsants, the N-methyl-D-aspartic acid (NMDA) antagonist ketamine (Eide et al., 1995) and the opioid alfentanil (Eide et al., 1995) have all been demonstrated to be effective in randomized controlled trials. Intrathecal injections of morphine combined with clonidine have been demonstrated as useful in combination but not alone. The anti-spasticity drug Baclofen, a derivative of gamma-aminobutyric acid, has been demonstrated to provide pain relief, but this may be mainly due to its effect on musculoskeletal pain (Loubser & Akman, 1996), although one RCT has demonstrated a central effect on neuropathic pain (Herman et al., 1992).

Intrathecal injections are not without problems. They might be technically difficult to insert in the correct place, especially in people with spinal cord injuries, and the risk of infections associated with indwelling cannulae can be a significant concern. The difficulty with all injection therapies is that they do not represent a long-term solution to the problem, but might be helpful in allowing rehabilitation or providing relief during severe episodes of pain.

Mirror box therapy

For patients with chronic regional pain syndrome of a single limb, rehabilitation using the unaffected limb reflected in a mirror to ‘trick’ the brain into seeing the limb moving without pain has been developed (Moseley et al., 2008). Patients with neuropathic pain frequently experience severe pain on movement and tactile stimulation of the affected limb. Mirror box therapy allows the patient to observe the impression that the affected limb is moving or being touched. The mechanism for this remains speculative but seeing the limb being touched activates the visual or visuotactile cells in the secondary somatosensory cortex (SII) which facilitates SI neurones and promotes inhibition, and probably facilitates inhibition at the thalamic level. Giving a sense of normalization of sensory input may promote neural reorganization which leads to an improvement in tactile acuity and a reduction in pain (Moseley et al., 2008).

A recent review concluded that there was good evidence to support the use of mirror box therapy combined with a graded motor imagery programme and recommended its use be included in future guidelines (Daly & Bialocerkowski, 2009) for chronic regional pain syndrome. There is little evidence thus far to support its use in central neuropathic conditions. One study on a limited number of subjects with pain following spinal cord injury demonstrated that using a mirror and back projection of walking legs to give and impression the patient was walking led to a reduction in pain on a single exposure which was greater than imagined activity or watching a film. A further mean reduction in pain was observed over 3 weeks of daily exposure to the visual illusion of walking. However, this study used only five patients and one had to withdraw due to distress on the first exposure to the visual illusion (Moseley, 2007).

Cognitive behavioural therapy

Pain management programmes base on the principles of cognitive behavioural therapy are one of the mainstays of the management of chronic intractable pain. There are only limited data on the role of pain management programmes in the management of pain in neurological conditions. Traditionally pain management programmes run with a heterogeneous group of patients, the assumption being that the difficulties faced by people withchronic pain are common irrespective of the cause or nature of their condition. This has been questioned recently and there do appear to be subtle differences in the way in which people with a neuropathic pain problem deal with their pain when compared to those with low back pain, the commonest reason for referral to pain management (Daniel et al., 2008). The most notable difference is that those with neuropathic pain are more likely to report their pain is as a result of damage. Pain management programmes often try to avoid the term damage as it is unhelpful and focus on causes of pain that do not focus on tissue damage. However, reference to the role of previous damage as a cause of the onset of pain and to explain the continuance of pain as a consequence of damage in the past rather than ongoing injury might be useful in explaining pain to those with neuropathic pain.

Persistent pain has significant physical, social and psychological consequences. Often those patients with pain from a neurological condition may have additional physical or cognitive difficulties compounding their condition.

It is important to understand that pain management is not delivered as an alternative to medical treatments but the two should be delivered in a complimentary way.

The main aims of a pain management approach (Watson, 2004) are to:

The main outcomes of a pain management programme are:

Note that a reduction in pain is not listed above as an outcome. However, a reduction in pain is reported in the literature as a common outcome (Eccleston et al., 2009; Morley et al., 2008), although the effects are modest and not as large as the effects on mood.

Pain management requires a full biopsychosocial assessment of the patient. This will include a physical examination to guide any specific physical exercises required to address specific deconditioning and dysfunction as part of the programme. The patient’s understanding of their condition and their beliefs about it and how this affects their current behaviour is assessed. The current coping strategies are identified to help elucidate both helpful and unhelpful behaviours. The role of significant others is also assessed. For a full account of the assessment at management of chronic pain see specific texts such as Main et al. (2008).

Goal setting and pacing

Patients with neuropathic pain may have limited activity as a consequence of the initial cause of the pain, as in the case of stroke or spinal cord injury. Limited physical capacity, due to inactivity, and lowered pain tolerance also restrict function. Engaging in certain activities often increases pain and this increase may remain for some time after the activity has ceased. Some people restrict their activity so much that they become more restricted over time due to the effects of physical deconditioning. Although there is much debate about the effect or even the fact of deconditioning, many people with neuropathic pain are severely limited in their physical activity in the affected body part and frank deconditioning and degeneration of physical abilities are often seen at the local level.

Resumption of physical activity is a mainstay of pain management programmes, but the effects attributed to physical activity alone are very modest and recent authors have suggested a more systematized approach of activity scheduling (Main et al., 2008; Sullivan, 2008). Appropriatescheduling of activity has been demonstrated to result in reductions in fear of pain, disability and depression, although none of the data relates specifically to patients with pain from neurological conditions. It involves identifying avoided activities, setting a baseline for participation (time and intensity) and allocating time during the day to perform the activity. These activities are typically activities of daily living rather than just specific physical exercises. The patient only discontinues the activity after the agreed goal has been completed regardless of the level of pain. If the goals are chosen well it should be unlikely that the patient will discontinue the activity due to intolerable pain.

The goals are chosen so that the patient participates in desired and valued activities. Setting and achieving goals in valued activities helps to mitigate the effect of interference of pain on lifestyle and reduces pain- and disability-associated depression (Morley & Sutherland, 2008).

Physical exercise and increasing fitness are common goals for pain management and can be useful to offset specific problems as a result of the pain or those associated with the primary condition. It is most useful if the majority of exercises used are those which the patients will be able to practice without the help of the therapist. Therapist contact time is limited and the establishment of a self-help programme is an essential aim of pain management (Watson, 2004).