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Neuropathic Pain, Development & Treatment

Dr J C D Wells

Pain hurts! Recent functional Magnetic Resonance Imaging (fMRI) shows that most people who complain of chronic pain have very significant activation of part of the brain which lights up as a result of acute pain from experimental injury. It is now accepted by scientists and pain relief specialists that chronic pain is a condition in its own right and is often mediated by changes within the central nervous system, leading to activity in the limbic system which produces an unpleasant sensory and emotional disturbance. The amount of physical insult needed to promote unpleasant pain diminishes with chronicity so that patients experience both hyperalgesia, that is, severe pain on being provoked with normally mildly painful stimuli, and allodynia, which is pain being produced by normally non-painful stimuli, such as stroking or touching. We know and see these events in conditions such as post-herpetic neuralgia and post nerve injury, but it is becoming increasingly clear that these phenomena also occur in some patients with chronic back pain, fibromyalgia and similar chronic conditions.

Of course there are still those who malinger, that is, consciously complain of pain when none exists, in order to receive financial advantage, sign off work and the like, and it is difficult to distinguish sometimes between these and the genuine chronic pain sufferer, but just because there is no significant amount of physical disease at the time of examination, this does not mean that the patient is not experiencing real pain. The aforementioned fMRI shows that patients who have pain as a result of psychological and psychiatric disturbances (for example, depression or somatoform disorders) also feel and experience disturbances in the same part of their brain as the acute pain sufferer, the limbic system; ie, they are suffering from pain.

The limbic system not only experiences pain but also handles fear, anxiety, sleep, punishment and autonomic changes. It affects tension, which in turn affects the intensity of pain. Recent studies on antidepressants show that these produce regrowth of parts of the limbic system which have degenerated becuase of depression, further cementing the relationship between pain and depression and the response of pain to antidepressants. The complex nature of the sensation of pain was first appreciated by Melzack and Wall, who described the gate control theory of pain in the late '70s. At first their work was contested, but there has been gradual appreciation that pain is greatly attenuated both in the spinal cord and in the brain, and if there is lack of attenuation can lead to very severe and unremitting pain in the absence of significant nociception.

Throughout the last decade, the notion of central sensitisation and wind-up occurring as a result of repeated tissue or nerve damage, has been appreciated. This leads to a decreased threshold of peripheral stimulus, an expansion of the receptor field and increased spontaneous nerve firing. This, combined with the sensory aspect of pain, this modification by social and economic issues, makes pain very difficult to understand and to treat.

The neuromatrix in the limbic system is initially shaped by genetic programming and later by sensory input and experience. At the end of this process, the neuronal signature of each individual appears, not only affected by genetic, sensory and pain experiences, but also by cognitions and by chronic physical and psychological stress. There are major sex differences and gene therapy will probably become an important part of the treatment of chronic pain in the long term. As well as the limbic system, there are at least 25 other areas of the brain that are involved in pain, its transmission and ramifications, and further work is ongoing!

In the peripheral nervous system, if there is nerve damage, damaged axons sprout and form collateral nerve endings and areas which can be damaged or stimulated with light touch. Sodium channels become over-active and nociceptors become sensitised. Sleeping nociceptors, which are usually inert, awaken; basal cell firing increases, wallerian degeneration occurs and sympathetic fibres invade the dorsal root ganglia and sensitise the gate allowing the throughput of pain.

In the central nervous system, activity-dependent sensitisation occurs, plasticity (reorganisation of cortical representation) and disinhibition in the dorsal horn appears through descending pathways from the cortex. An adaptive process takes place throughout the neuraxis (brain and spinal cord) and in the dorsal horn, new pain fibres sprout.

It is not generally realised that pain causes greater negative effects on the quality of life than many other conditions. A report by Sprangers et al in the Journal of Clinical Epidemiology (Sprangers et al, 2000) reports quality of life more affected by musculo-skeletal conditions than renal disease, cerebro-vascular, neurological, gastro-intestinal and even cancer. Pain affects every aspect of a human's life, mood, activity, sleep, independence, fitness, social life and family life. Chronic pain patients become physically and psychologically impaired, overweight, unfit, depressed and anxious. They become socially disadvantaged and lose social contacts.

The cost of pain to the economy is immense. Not only is there a direct cost to the family (estimated at over 10,000 per year) but there is also a cost to the Health Service (6,000,000,000 per year) as well as social security, unemployment benefits and the like (Sleed and Eccleston,2005).

Pain treatment. Happily there now exist a number of effective treatments for neuropathic pain, and evidence is emerging that these can be useful for chronic pain conditions such as back pan and fibromyalgia, as well as the conditions we understand as being neuropathic, such as post-herpetic neuralgia and diabetic neuropathy. The number needed to treat is a treatment-specific measurement used for relative efficacy comparisons of medication versus placebo. For instance, a NNT of 2 means 50 out of 100 patients achieve more than 50 per cent pain relief because of the treatment, rather than a placebo reaction. We have to remember that NNTs for statins are about 20 and for gastro-protection are about 40 in order to appreciate the usefulness of treatments for neuropathic pain, where the NNTs range from 2 to 5. The lower the NNT, the better the drug.

Symptoms of neuropathic pain. The pain can be burning, shooting, stabbing or sharp. Hypersensitivity is common, including severe pain on mild painful stimuli and spontaneous pain with touch. Neuropathic pain is often seen in patients after shingles, with diabetic neuropathy and with complex regional pain syndromes. The pain can occur post-surgically, with trigeminal neuralgia and with multiple sclerosis.

Pain treatments for neuropathic pain. The most effective treatments for neuropathic pain have been shown to be tricyclic antidepressants (NNT = 2) and opioids (NNT = 2). Pregabalin and Gabapentin come out with an NNT of about 4. Lidoderm patches, which will become available in the UK next year, have a NNT of 2 to 4. Tramadol has a NNT of 4; Capsaicin, which will also be available as a patch in the UK before long, has a NNT of 6 and SSRIs have a NNT of 6+. All of these are good treatments.

However, of course the problem here is one of side-effects. Many of these drugs have significant side-effects; the NNH (number needed to harm) of tricyclics is 6, of opioids 8, of gabapentinoids 12, of Tramadol 15, Capsaicin 10 and of SSRIs 20. The safest by far is the Lidoderm patch, with a NNH of 40 - but guess what? It will cost more than the others! Thus treatment choices are going to be a balance between efficacy, which most of them have, side-effects, which most of them produce and cost, and remember that the newer ones are nearly always more expensive. In fairness, they have to be, because the pharma company has to reclaim its development costs.

In an algorithm described in the journal "Pain" in 2005, Finnerup recommended that Lidoderm patches should be used whenever there is allodynia and hyperalgesia; otherwise, patients should be commenced on tricyclics unless there is a specific contra-indication, when they should be commenced on Gabapentin or Pregabalin. The pair can be used in combination, but if there is failure due to lack of effect, or more likely due to side-effects, Tramadol and stronger opioids can be introduced. There is a relative chance of cholinesterase syndrome if high doses of tricyclics and Tramadol are used together, but in practice this is unusual. Most patients with neuropathic pain can be treated successfully with this simple algorithm;

Pain Clinics are usually glad to see patients where success has not been achieved, as often further medication changes, or the addition of other specific treatments, for instance, nerve blocks or Pain Management Programmes, can be successful in reducing pain and increasing activity

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