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October 2001, Volume 23, No.10
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Original Article
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Clinical management of neuropathic painK F Chin 錢劍輝 HK Pract 2001;23:439-448 Summary Neuropathic pain is a common clinical problem. It is crucial to differentiate between organic and psychogenic pain. Every effort should be spent to find the cause of neuropathic pain. Once neuropathic pain is suspected, there are a number of useful modalities to help the patients and these include local measures, a variety of drugs other than ordinary analgesics, surgical procedures and psychological counselling. 摘要 神經痛是一種常見的臨床問題。應儘一切努力找出神經性疼痛的原因，並且區別是器質性還是心理性疼痛。神經性疼痛，可以採用局部治療措施，多種藥物治療包括止痛藥在內、外科療法以及心理療法等方法幫助病人。 Introduction Pain is the commonest symptom in medicine, usually a signal to the development of some potentially damaging lesion. For the majority of pain, adequate symptomatic treatment can be easily achieved, but in certain situations pain becomes an intractable problem. This may occur because of incurable underlying disease, because it is due to damage of the peripheral or central sensory nervous system, or occasionally, because it is a manifestation of unrecognised psychiatric disturbance. Nowadays "Pain Clinics" exist in some of the major hospitals in Hong Kong. Pain clinics are usually composed of a physician in charge (usually director of the pain clinic or his deputy), anaesthetist, neurologist, neurosurgeon, radiotherapist and psychiatrist. This multi-disciplinary approach helps to solve many difficult pain syndromes and offers great relief to patients with chronic pain. Otherwise, chronic pain sufferers may easily develop secondary depression and even commit suicide. In the medical profession, one of our major duties is to make patients feel more comfortable even though the condition is incurable. Control or even partial relief of pain can offer patients a much more tolerable and enjoyable life and this gives the medical professionals involved great job satisfaction. Amongst the pain syndromes, neuropathic pain is the most interesting and complicated problem. I will try to highlight some of the important aspects in clinical management which hopefully can help us to improve our care of patients with problems of pain.
Definition Pain may be defined as an unpleasant sensation that is perceived as arising from a specific region of the body and is commonly produced by a process that damages or is capable of damaging body tissue.1 The second part of this definition refers to pain that is within everyone's experience and is termed nociceptive pain, that is, pain due to peripheral tissue damage signalled by an intact nervous system. This contrasts with the less common, but important, disorders that comprise neuropathic pain, that is, pain due to damage of the nervous system itself. Neuropathic pain is much more difficult to treat than nociceptive pain for two reasons. Firstly, because many of the causes produce irreversible damage to either the peripheral or Central Nervous System (CNS) and secondly, because the mechanism responsible for neuropathic pain is quite different to those of nociceptive pain and is less well understood. Thus, neuropathic pain is often intractable, even though the incidence of neuropathic pain is much less than that of nociceptive pain. Peripheral mechanism of nociceptive pain Type of fibre and sensation Fast conducting myelinated sensory fibre (conduction velocity 30-100m/s) have receptors with low thresholds while slow conducting myelinated delta fibres (conduction velocity 4-10m/s) and unmyelinated afferents (conduction velocity less than 2.4m/s) have receptors that are activated by noxious stimuli. Selective stimulation of single afferents by microneurography in man shows that large Fibre activation causes pressure or tickling sensation; A delta and larger C-Fibre activation causes brief sensation often described as pricking, activation of slower C-Fibres causes diffuse severe pain, often with a burning quality. Hyperalgesia and chemical sensitisation of receptors Hyperalgesia, that is exaggerated response to stimuli above the normal pain threshold, often results from tissue damage. Both peripheral receptor sensitisation and secondary central sensitisation contribute to hyperalgesia. Receptor sensitisation Substances mediating inflammation including bradykinin, 5-hydroxytryptamine (5-HT), histamine, and prostaglandin released to injury, are extremely algesic. They act synergistically to lower the threshold of C-Fibres and increase their activity. Central sensitisation When there is a prolonged nociceptor activation in the periphery, dorsal horn cells in the spinal cord may change in the way they are stimulated. Those that are normally only activated by nociceptors begin to respond to low-threshold afferents, so that innocuous peripheral stimuli may evoke painful sensations. Such activity is probably in part the basis of allodynia (all types of stimuli produce painful sensation) and hyperpathia (summation of pain sensation with repetitive stimulation and pain persisting after cessation of stimulation). Central nervous system Dorsal horn
Spinal cord pharmacology
Several peptides have been identified in afferent C-Fibres and their terminals in the dorsal horn, and there is strong evidence that some at least have a neurotransmitter function. They include substance P, vasoactive intestinal polypeptides, somatostatin and angiotensin. Substance P is present in about 20% of dorsal root ganglia cells, their terminals in Laminae 1 and 2. Only noxious peripheral stimuli cause its release. Other peptides may have a similar function. Capsacin, the pungent extract of red pepper, desensitises C-Fibres, depletes substance P, and abolishes cutaneous inflammation induced by chemical irritants. Topical application of capsaicin is useful in the treatment of some hyperalgesic stage, particularly post-herpetic neuralgia. Opiate receptors and endorphins are widely distributed in the nervous system. Several endorphins have been identified of which beta endorphin is a relatively stable compound probably having a "gain control function" such as that suggested for substance P, contrasting with the encephalines which are unstable and more likely to be classical neurotransmitters. Both the periaqueductal grey and the nucleus raphi Magnus contain high corretration of opiate receptors and encephalins. However it has also been shown that 5-HT and noradrenaline are the neuro-transmitters involved in the pathway from the nucleus raphi magnus to the dorsal horn, and the projection from the locus coeruleus to the dorsal horn is noradrenergic. Neuropathic pain Definition The term neuropathic pain is used to embrace all pain due to lesions of the sensory pathway, both peripheral and central. The many causes of neuropathic pain are all shown in Table 1. Taken together, those conditions affecting the primary sensory neurons (including the dorsal root ganglion and dorsal root) are much more common than the central causes. Malignant disease is a relatively unusual cause of neuropathic pain. However, the majority of the non-malignant conditions listed are not amenable to complete and permanent cure. Neuropathic pain is therefore a severe chronic problem for many patients.
Clinical features of neuropathic pain Neuropathic pain is often paroxysmal, shooting or shock-like pain in addition to continuous background pain. Emotional change and fatigue may cause the pain to vary over short periods. The onset of neuropathic pain may be immediate following the initiating cause, but is often delayed. For example, it is characteristic for thalamic pain to develop at an interval of 2 or 3 months after thalamic infarction, and myelopathic pain may take many months to develop following spinal cord trauma. Neuropathic pain and associated hyperalgesia, allodymia, and hyperpathia are not necessarily confined to the territory of an affected nerve or root and may radiate widely, causing diagnostic difficulty. However, there is often a clear anatomical correlation of pain and sensory abnormality and the presence of sensory loss is often helpful in distinguishing neuropathic from nociceptive pain. Abnormalities of local or regional sympathetic activity are common in association with neuropathic pain, particularly with peripheral nerve lesions, but may also occur with root, cord or thalamic lesions. Mechanisms of pain in peripheral neuropathy Review of the clinical evidence indicates that pain seems to be related to the acuteness of the degenerative condition and preferential involvement of small fibres by the underlying disease process (for example, small-fibre diabetic neuropathy and amyloid neuropathy), particularly when there is also marked regenerative activity in the nerves.2 Ischaemia can readily be shown to provoke pain and paraesthesia in certain situations, for example carpal tunnel syndrome. It is likely that ischaemia is a contributory factor in some neuropathies, for example, diabetic mononeuropathy and mononeuropathies associated with connective tissue disease which have a microangiopathic state. Abnormal sympathetic activity is certainly important in maintaining causalgia. Sympathetic block may relieve pain and associated allodynia and hyperpathia in patients with causalgia and other types of post-traumatic neuralgia, whether or not there are signs of abnormal sympathetic function in the affected limb. Pain due to lesions of the CNS The CNS lesions that lead to neuropathic pain usually involve the spino-thalamic tract and its rostral thalamoparietal projections. Within the thalamus, lesions causing thalamic pain (usually infarcts) involve the main sensory nuclei, which receive both the medial leminiscal pathway and pain sensation from the spino-thalamic tract. Pure dorsal column leminiscal system lesions, do not cause chronic neuropathic pain, although cervical dorsal column lesions most commonly demyelinating plaques, may provoke a Lhermitte's symptom which can cause an unpleasant sensation. There is usually sensory impairment accompanying central neuropathic pain although loss may be subtle and is often of associated spinothalamic type. As with peripheral neuropathic pain, there is no clear correlation between the severity of pain and the degree of sensory loss. Guidelines to treatment of neuropathic pain It is difficult to describe treatment of many individual pain syndromes. I shall list out some general principles of management and point out some of the important aspects in individual pain syndromes.4 Local measures Counter stimulation including heat and cold, vibration, ultrasound, TENS and acupuncture have been used for treating chronic pain. Neuropathic pain tends to be exacerbated by cold and decreased by heat but an exception is post-herpetic neuralgia in which regular application of cold packs for 20 minutes may reduce troublesome allodynia for up to several hours. TENS, acting by segmental inhibition, has been shown to be effective in a wide range of different chronic pain but is probably more effective for neuropathic than nociceptive pains. Acupuncture probably works by segmental inhibition and by diffuse noxious inhibitory control. Cerebrospinal fluid endorphin levels are also raised by acupuncture and the diffuse noxious inhibitory control may be partly opiate-mediated. Topical local anaesthetic Simple lignocaine ointment is sometimes helpful in areas of severe allodynia and hyperpathia, particularly in some patients with painful scar syndromes tender amputation stumps and post-herpetic neuralgia.
EMLA Containing a mixture of lidocaine and prilocaine has been successfully used under an occlusive dressing in post-herpetic neuralgia and the transdermal patch administration should be considered a simple and convenient means of supplying a centrally acting drug. Capsacin, a pungent component of hot pepper can enhance the release and inhibit the reuptake of substance P and other neuropeptides from terminals of unmyelinated polymodal afferents. The cream therefore works through its action of desensitising afferent C-Fibres for long periods. However, it may produce intolerable burning pain in some patients. 2 Local nerve block may be useful in three ways. First the origin of a particular pain may be more accurately defined. Secondly, injection into a peripheral trigger zone may reduce widely radiating pain; and thirdly, failure to relieve pain with an adequate nerve block may indicate an element of secondary central pain. Epidermal injection of a local anaesthetic, with or without an opiate can produce analgesia over a wide area. Low back pain with root pain not amendable to surgery, arachnoiditis, and brachialgia with neck pain may respond well to such treatment. Intravenous injection of the short-acting sympathetic blocker phentolamine has some value in indicating which patients have sympathetically maintained pain and in predicting the response to other types of sympathetic block. Systemic drugs
Simple analgesics (such as paracetamol and aspirin), the NSAIDs, weak opiates (including codeine, dihydrocodeine, and dextropropoxyphene), partial opiate agonis (such as buprenorphine), mixed agonist-antagonist drugs (for example, pentazocine) and strong opiates may have a beneficial effect on nociceptive pain. However, all these analgesics are much less effective for neuropathic pain. The drugs must be prescribed as a regular dose and not on an 'as required' basis, otherwise the analgesic effect will be much reduced. Many patients with neuropathic pains, both of peripheral and central origin, will report some lasting analgesia after taking the drugs, and many may well wish to take simple analgesics or weak opiates on a long-term basis. However, the prescription of morphine and other strong opiates should always be resisted in patients with pain of non-malignant origin. Depression is a fairly common accompaniment to chronic pain. Antidepressant treatment will help depressed patients whatever the type of pain. The tricyclic antidepressant have an enhancing effect on the descending bulospinal 5HT-mediated analgesic pathway to the dorsal horn, and thus theoretically have an analgesic action independent of any antidepressant effect. An analgesic effect of amitriptyline has been shown convincingly in some neuropathic pain, notably post-herpetic neuralgia. The newer serotonin re-uptake inhibitor drugs have not been shown to be superior to amitriptyline except that they are less sedative than amitriptyline. Benzodiazepines such as diazepam, oxazepam, lorazepam and chlordiazepoxide may be helpful for short-term relief of anxiety and muscle spasm. However, the side effects such as drowsiness, dependence and severe withdrawal effects limit their use in chronic pain. Antiepileptic drugs are useful in neuropathic pain. Carbamazepine has been proven to be effective in trigeminal neuralgia. Although claims have been made for other drugs like phenytoin, valproate and clonazepam in a variety of neuropathic pain, positive results have, on the whole, only emerged from poorly controlled short term trials. Gabapentin which is a newer drug seems to be quite effective in neuropathic pain, and is much less sedative than carbamazepine. Intravenous infusion of lignocaine at doses as small as 1mg/kg have been shown to reduce neuropathic pain and associated allodynia and hyperpathia, but this is not a practical long-term treatment. Oral drugs with local anaesthetic like membrane-stabilising properties such as mexiletine have been shown to have a short-term analgesic effect in painful diabetic peripheral neuropathy. Role of surgery in the treatment of chronic pain The indications for surgical treatment for chronic pain are now very limited. Procedures such as peripheral neurolysis, rhizotomy (section of dorsal roots), dorsal root entry zone lesions, anterolateral cordotomy, thalamotomy and even leucotomy are rarely indicated nowadays. CNS stimulation Dorsal column stimulation may be particularly useful in unilateral lower limb pain, for example, persistent lumbrosacral root pain after failed back surgery or when arachnoiditis is present. Segmental inhibition at dorsal horn levels is a possible mechanism of the action of dorsal column stimulation, as is more rostral inhibition at the thalamic level. Periaqueductal grey stimulation is relatively ineffective in neuropathic pain and is currently little used. For thalamic stimulation, the results are unpredictable and analgesia is often short lived. Psychological measure Leaving aside the psychiatric disorders associated with pain discussed above and which call primarily for psychiatric treatment, psychological intervention has a role in the management of other chronic pain problems. Psychological counselling and psychological interventions including relaxation therapy, biofeedback, and cognition and behavioural methods are all useful in many chronic pain syndromes. Hypnosis has a limited role in the treatment of chronic pain but may be successful in susceptible individuals. Specific management of common neuropathic pain
Conclusion Neuropathic pain is a fairly common clinical problem. We should always pay careful attention to the symptoms described by the patient and analyse them accordingly. Even if the symptoms sound unusual at first, we should not always assume that the pain is "psychogenic". Once a clinical diagnosis is made, there is a lot that we can offer. We can help the patients deal with the problem and hence fulfil one of our greatest missions "to make our patients feel more comfortable and improve their quality of life".
K F Chin, MBBS, FRACP, FHKAM, FHKCCM Correspondence to: Dr K F Chin, Room 1001, Champion Building, 301-309 Nathan Road, Kowloon, Hong Kong. References
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