Pain Management
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Diagnosis and management of neuropathic pain
Clara SM Wong1, Grace KM Hui1, Edmond KN Chung1 & Steven HS Wong*,1 Practice points ●●
Neuropathic pain is newly redefined as pain caused by a lesion or disease confining to the somatosensory nervous system.
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A number of clinician- and self-administered assessment tools are available for general screening purposes.
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Diagnosis of neuropathic pain should be to locate the lesion in the somatosensory nervous system based on clinical examination and supplemented by appropriate laboratory investigations.
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Like other chronic pain conditions, neuropathic pain should be managed in a multidisciplinary approach.
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Pharmacological management is targeted towards pain-generating mechanisms. A number of evidence-based guidelines are available.
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Psychological and physical interventions are effective supplementary treatment.
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Interventional procedures may be considered for refractory pain, but their evidences of efficacy are still limited.
Summary: A recent revision in the definition of neuropathic pain has highlighted this condition as a distinct disease entity. More accurate search for a lesion in the somatosensory nervous system as the pain-generating mechanism will help target the treatment by pharmacological agents. A multidisciplinary approach is recommended, with pharmacotherapy supplemented by psychological therapy and physical rehabilitation, and appropriate interventional treatment for selected refractory cases. Evolution in the definition of neuropathic pain There was no clear clue when the concept of neuropathic pain first emerged [1] . However, neuropathy and pain had been mentioned in the literature since 1920s [2,3] . At that time, ‘neuropathy’ often referred to all diseases of the nervous system, including psychiatric disorders. In 1994, Merskey and Bogduk first defined neuropathic pain as ‘pain initiated or caused by a primary lesion, dysfunction or transitory perturbation of the peripheral or central nervous system’ [4] . This definition has been often criticized. One of the reasons is due to the conceptual vagueness of the word ‘dysfunction’ [5] . 1 Department of Anaesthesiology, Queen Elizabeth Hospital, Hong Kong *Author for correspondence: Tel.: +852 2958 6176; Fax: +852 2782 4725; [email protected]
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Review Wong, Hui, Chung & Wong Neuropathic pain has been considered as a clinical description rather than a diagnosis. After years of debate, the International Association for the Study of Pain (IASP) adopted a revised definition of neuropathic pain as pain caused by a lesion or disease of somatosensory system [6] . This new definition of neuropathic pain is somehow more stringent. The word ‘dysfunction’ has been removed and the lesion or disease has been specified to be within the somatosensory system. The more restrictive definition means that some conditions will be excluded, e.g. fibromyalgia, interstitial cystitis. These dysfunctional conditions lack structural abnormalities and so do not fall into the definition of neuropathic pain. Neuropathic pain is one of the underlying causes for chronic pain. There is a great variability in these estimates as there is lack of good epidemiological studies and lack of operational and validated criteria resulting from ambiguity in previous definition of neuropathic pain. Current estimates of the population prevalence of neuropathic pain come from studies using validated screening tools that detect pain with possible neuropathic features [7] . They ranged from 1.5% up to approximately 8% of the general population [8–10] . Common causes of peripheral neuropathic pain include painful diabetic neuropathy, post-herpetic neuralgia and trauma after surgery or accident; causes of central pain include stroke, multiple sclerosis and spinal cord injury. Table 1 shows the prevalence of some common neuropathic pain conditions. Diagnosis of neuropathic pain The change in the definition of neuropathic pain has certain implications on the diagnosis of neuropathic pain. In the past, diagnosis of neuropathic pain remained a clinical diagnosis based mainly on the verbal descriptions of screening
tools. The new definition of neuropathic pain requires that an underlying lesion in the somatosensory nervous system be identified. This will mandate a more definitive work-up including a comprehensive neurological examination and the use of laboratory investigations. The following is an overview of the common assessment modalities used for the diagnosis of neuropathic pain (Table 2) . General screening tools Many of the neuropathic pain screening tools are based on pain descriptors of neuropathic pain. Any questionnaires should be interpreted in the context of global assessment of the patient. Common pain descriptors include lancinating (75.6%), burning (68.3%), pinsand-needles (65.9%), electric shock (64.6%), numbness (65.9%) and tingling (59.8%). Other less frequently used adjectives include squeezing (48.8%), painful cold (25.6%) and itching (29.3%) [19] . Table 1 summarizes the commonly used screening tools for neuropathic pain. These screening tools are easy to use by both clinicians and patients alike and both at clinic setting or over the phone. The screening test should be used in a validated language version to give the best result [28] . All screening tools should be applied to a specific area of pain for better discriminatory power. Thus, they are less accurate if used for patients with multiple area of widespread pain [29] . The above screening tools result should be employed for screening purpose at best, but they provide no clue to the cause and are not ideal to monitor therapeutic efficacy. Moreover, the screening tools may not be able to identify 10–20% of patients with neuropathic pain. Thus, the screening test should not replace a careful clinical examination [28] .
Table 1. Estimated prevalence of some common neuropathic pain conditions. Neuropathic pain conditions
Estimated prevalences (%)
Remarks
Diabetic polyneuropathy
8.3–41.9 [11]
In noninsulin-dependent diabetes (NIDDM) 13% in NIDDM; 15% in IDDM All ages Ages >70 5% in hernia repair 85% in amputation During 1st year after stroke Including 4.9% with trigeminal neuralgia Lasting more than 3 months
Postherpetic neuralgia Chronic post-surgical pain Central post-stroke pain Multiple sclerosis Spinal cord injury
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13–15 [12] 8 [13] 48 [14] 5–85 [15] 8 [16] 27.5 [17] 67 [18]
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Interviewing of symptoms Detection of physical signs Questions related to symptoms assessment
Portenoy -
Bouhassira et al. +
Krause and Backonja -
+ Six interview questions on pain: • Location • Temporal characteristics • Quality • Pain evoked by activity or body position • Nonpainful sensations • Current pain
Total 12 items: Gradation of pain from 0 (unnoticeable) to 5 (intensed) intensity for the 7 composite quantified items: • Burning • Tingling or prickling • Is light touch painful • Paroxysmal pain like electric shocks • Is cold or heat occasionally painful • Numbness • Slight pressure triggering pain Pain course patterns (-1, 0, 1) : • Persistent pain with slight fluctuation • Persistent pain with slight attacks • Pain attacks with pain-free interval • Pain attacks with pain attacks between them • Presence of radiating pain (no = 0; yes = 1 or 2)
Six yes/ no questions: • Pins and needles • Hot/burning • Numbness • Electric shocks • Aggravation of pain from light touch • Pain limited to joints
Seven yes/no questions: • Burning • Painful cold • Electric shocks • Tingling • Pins and needles • Numbness • Itching
12 quantified items (0 = no pain; 100 = worst imaginable pain) • Burning pain • Oversensitive to touch • Shooting pain • Numbness • Electric pain • Tingling pain • Squeezing pain • Freezing pain • Unpleasant • Overwhelming • Increased pain due to touch • Increased pain due to weather change
Five composite yes/ no items: • Strange, unpleasant sensations • Skin different from normal • Skin abnormally sensitive to touch • Paroxysmal pain or in burst • Pain as if skin temperature has changed abnormally
+
-
Standardized Evaluation of Pain (StEP) [27] Joachim Scholz +
+
+
+
Freynhagen et al. -
painDETECT [25]
-
+ (Short form of NPQ + (Short seven items + with only three items: version) [25] numbness, tingling and pain increase in response to touch) [24] + + +
ID Pain [26]
DN4 (Douleur Pain Questionnaire) [22]
NPQ (Neuropathic Pain Questionnaire) [21]
+
+
LANSS (Leeds Assessment of Neuropathic Symptoms and Signs) [20] Authors Bennett Clinician administered + patient self- administered for S-LANSS Patient self+ (S-LANSS) [23] assessment
Table 2. Common screening tools for neuropathic pain.
Diagnosis & management of neuropathic pain
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Sensitivity Specificity
Interpretation of scores
82–91% 80–94%
Neuropathic pain
If scores more than or equal to 12 = likely neuopathic pain; If < 12 = unlikely
Total scores = 24
Yes = 1–5; No = 0
LANSS (Leeds Assessment of Neuropathic Symptoms and Signs) [20] Physical examination Two items: findings at painful area • Allodynia: pain or unpleasant sensations (tingling, nausea) when stroking • Altered pinprick threshold
No data No data
The higher the scores, the more likely there is neuropathic pain
Summation of scores of 10 items Score > or = 4, likely neuropathic pain
80% 92%
Scores vary from -1 to 5
Yes = 1; No = 0
Individual items has different coefficient (0.008–0.020); Score of each item expressed as out of 100; Score x coefficient x -1.408 If > or = 0, likely neuropathic pain; If < 0, unlikely neuropathic pain 66% 74% 85% 80%
If less than or equal to 12, unlikely neuropathic pain; If between 13 and 18, uncertain degree of neuropathic pain
Total scores if more than or equal to 19; neuropathic pain likely;
None
None
Three items: • Hypoesthesia to touch • Hypoesthesia to prick • Pain caused or increased by brushing
None
painDETECT [25]
ID Pain [26]
DN4 (Douleur Pain Questionnaire) [22]
NPQ (Neuropathic Pain Questionnaire) [21]
Table 2. Common screening tools for neuropathic pain (cont.).
>90% >90%
Standardized Evaluation of Pain (StEP) [27] Ten physical tests • Skin touch • Blunt pressure • Brush pressure • Brush movement • Vibration • Pinprick • Warm temperature • Cold temperature • Temporal summation • Straight leg raising test Signs of positive discriminatory value include straight leg raising test, deficit in cold detection and reduced pinprick sensation [16]
Review Wong, Hui, Chung & Wong
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Diagnosis & management of neuropathic pain Clinical examination Clinical examination can never prove or disprove the existence of pain as it is a subjective sensation. It serves the purpose to verify and reject the hypothesis where a part of the somatosensory system has a lesion [30] . It also helps to assess whether the pain is from central or peripheral nervous system and or from other non-nervous system [31] . A comprehensive bedside clinical neurological examination should be performed to map out areas of abnormal somatosensory functions. Both positive and negative phenomena of neuropathic pain should be assessed. Positive phenomena refer to qualitative alteration of pain sensation (allodynia or dysesthesia) and quantitative alteration of pain sensation (hypo- or hyper-aesthesia) [32] . Negative symptoms include loss of sensation to specific stimuli such as touch (cotton wool), vibration (128-Hz tuning fork), joint movement, temperature (thermorollers) and pin-prick sensations (wooden cocktail stick). The threshold of detection of these stimuli can be further determined using quantitative sensory testing [31] . The border of the sensory abnormalities should be defined. The area of sensory abnormalities should be within the innervation area of a peripheral nervous system of a plexus, root or peripheral nerve, or within a topographic representation of a body part in central nervous system. Comparison of the unilaterally painful area with contralateral limb or comparing proximal area with distal area is important [28] . This step is very important to confirm that the pain is consistent with a lesion or disease of the somatosensory nervous system [33] . Neuroelectrodiagnostic tools Nerve conduction study is used to find out the electrical conduction velocity of motor or sensory nerves, usually over a numbed or weak area [34] . Needle electromyography looks for evidence of denervation and reinnervation in affected muscle fibres. The above two tests evaluated the function of large myelinated nerve fibres (i.e., α and β fibres) and not pain fibres (i.e., δ and C fibres). A normal study does not rule out neuropathic pain. Somatosensory evoked potential is a noninvasive means to assess the function of somatosensory system. It is a test of large myelinated fibres and dorsal column. If we can locate lesion in somatosensory system, it will further support the diagnosis of neuropathic pain. The tests result could also tell us the nature of pathology such as in case of axonal or demyelinating injury and allow us to monitor progress of treatment or
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recovery. These tools should be regarded as first line investigations in neuropathic pain especially in case of possible traumatic or iatrogenic nerve lesion [25] . Neuroelectrodiagnostic tools have advantage of independence of bias from patient’s response as it is a pure electrophysiological testing. But there is no information on small fibres and there would be discomfort on patient’s side. Quantitative sensory testing Quantitative sensory testing (QST) is a psychophysiological method for measurement of threshold of sensation in response to various pre-determined mechanical and thermal physical stimuli. It is used in diagnosis and follow-up of small fibre neuropathy and in early diagnosis of diabetic neuropathy [35,36] . The stimuli can be divided into two groups: thermal stimuli such as cold, heat, cold pain, heat pain; mechanical stimuli such as tactile, vibration, blunt pressure and pinprick. German Research Network protocol is the most widely adopted protocol in performing this investigation [37] . Clinical judgment should be exercised in selection of appropriate aspect of QST to test in order to yield useful information for clinical use. The drawback of QST is lack of blinding [38] . QST changes are also detected in patients without neuropathic pain such as in various rheumatological diseases, fibromyalgia or inflammatory arthromyalgias [21] . European Federation of Neurological Societies (EFNS) guideline recommends QST as helpful tool to quantify treatment effects on allodynia and hyperalgesia and may help to reveal differential efficacy of treatments on different pain components. Limitations of QST lie in the fact that it only helps to delineate the types of nerve fibres involved but not the level of lesion in the nervous system [28] . It is also time-consuming to perform. As a number of factors are involved including the instructions from the examiner, cooperation by the patient, and technical factor of test-retest variability, precautions should be taken in the performance of the testing and interpretation of the results [39] . QST remains a research tool. Its wider application in clinical settings awaits further standardization and validation [40] . Microneurography Microneurography is a minimally invasive method to evaluate single-axon recordings from peripheral nerve in awake subjects [41] .
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Review Wong, Hui, Chung & Wong The advantage of this method is the ability to discriminate action potential in single, identified peripheral fibres and provide a direct link between activity in peripheral nerve fibres and pain perception [42] . It is the only clinical measure to record and quantify positive sensory phenomena mediated by large myelinated fibres (tactile paraesthesia and dysesthesia), small thinly myelinated fibres and unmyelinated fibres (spontaneous pain) [42] . The shortcoming is that this method is time consuming and labor-intensive. Laser evoked potential & contact heat evoked potential Laser evoked potentials (LEP) and contact heat evoked potentials (CHEP) are measures used to specifically locate lesion in Aδ and C fibres without activating mechanoreceptive and Aβ fibres. Both Aδ and C fibres are thermosensitive. Cortical responses are measured during radiant heat stimulation by laser or rapidly delivered adjustable heat pulses temperature. LEP has been suggested in EFNS guideline on neuropathic pain assessment as a versatile and reliable tool to assess function of subcortical nociceptive pathways in all skin territory [43] . Pain-related reflexes Pain-related reflexes are useful to evaluate a specific subgroup of neuropathic pain, the facial pain. The trigeminal reflexes mediated by Aβ fibres are established as helpful for diagnosis of trigeminal pain diagnosis [44] . They are abnormal in structural lesion as in trigeminal neuropathy, symptomatic trigeminal neuralgia and postherpetic neuralgia, and normal in patients with classical trigeminal neuralgia [28] . Recent AAN-EFNS guideline on trigeminal neuralgia confirmed that Aβ mediated trigeminal reflexes (early R1 blink reflex and early SP1 masseter inhibitory reflex) are efficient tools to evaluate symptomatic forms of trigeminal neuralgia with an overall specificity of 94% and sensitivity of 87% [45] . In a study on patients with ophthalmic postherpetic neuralgia, use of pain related reflexes R1 blink reflex has specificity of 100% and sensitivity of 73% [46] . Skin biopsy Immunostaining of standardized 3-mm punch skin biopsy helps to visualize C fibres [47] as they specifically penetrate epidermis and assess the density, morphology and pathology of C fibres together with other skin appendages such
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as blood vessels and sweat glands [48] . In postherpetic neuralgia, the density of intradermal nerve fibres is lower than that in nonaffected skin area [31] . Functional neuroimaging Magnetic Resonance Imaging (MRI) is a very useful tool to delineate lesion in central nervous system [31] , such as anatomy of the concerning nervous structure, any space occupying lesion in vicinity of the nerve and other associating denervation changes in musculoskeletal system [49] . However, any MRI findings should be interpreted in clinical context of the patient as imaging abnormalities may not necessarily explain the pain. Positron emission tomography (PET) and functional MRI (fMRI) are novel techniques of great research value in evaluating neuropathic pain [31] . The rationale behind is to measure regional changes in cerebral blood flow and metabolic rate in response to noxious stimuli [50] . Studies have shown decreased resting regional cerebral blood flow in contralateral thalamus and reversal of this abnormality by analgesic procedures. Hypoperfusion at thalamus could be employed as future marker of neuropathic pain and restoration of thalamic blood flow used for monitoring treatment effect [51] . A grading system for diagnosis of neuropathic pain A grading system has been proposed [33] . If the distribution of pain is neuroanatomically plausible and the history suggests a relevant lesion or disease, the pain is considered ‘possible’ neuropathic pain. Two further confirmatory tests are needed. If there are positive or negative sensory signs confining to the innervation territory of the lesioned nervous structure, and diagnostic tests could confirm a lesion or disease to explain the pain, then it is considered ‘definite’ neuropathic pain. If only one of the above confirmatory tests is positive, it is only considered ‘probable’ neuropathic pain. Management of neuropathic pain Like other chronic pain conditions, neuropathic pain is often managed in a multidisciplinary approach, which is centred around pharmacological treatment and in combination with nonpharmacological treatment regimens such as cognitive-behavioural, physical and occupational therapy. For refractory neuropathic pain,
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Diagnosis & management of neuropathic pain more invasive interventional treatment may be considered. While the primary objective of treatment is reduction of pain, other outcome measures in chronic pain management should be considered, for example, Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials outcome measures [52] . Pharmacological management The implementation of a new definition of neuropathic pain, which involves the need to look for a lesion in the somatosensory nervous system, will have impact on the pharmacological management of neuropathic pain. Without a structural lesion to substantiate the diagnosis of neuropathic pain, use of pharmacological treatment for neuropathic pain may not be justified. As different analgesics have different mechanisms of action, it is sometimes difficult to predict the treatment response to any particular analgesic [53] . Identifying the underlying mechanism of neuropathic pain will allow the use of pharmacological agents targeted at specific pain mechanisms. Different guidelines have been developed by different international institutions for the treatment of neuropathic pain. These include the Neuropathic Pain Special Interest Group
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(NeuPSIG) of the IASP, the EFNS and the National Institute for Health and Care Excellence (NICE) in the UK [54–56] . In establishing the guidelines, randomized controlled trials (RCT), systematic reviews and existing guidelines on pharmacological management of neuropathic pain were reviewed and evaluated [57,58] . Medications are recommended in the guidelines, basing on degree of evidence of analgesic efficacy, safety, ease of use and cost-effectiveness. Table 3 summarizes the recommendations for pharmacological treatment of neuropathic pain based on various guidelines. The following is an account of some of the drugs that are commonly used for treatment of neuropathic pain. ●●Tricyclic antidepressants (TCAs)
The efficacy of TCAs is established mainly in painful diabetic neuropathy (PDN) and postherpetic neuralgia (PHN). Their analgesic efficacy is probably mediated by action on descending modulatory inhibitory controls [59] , although a peripheral effect on sodium channels has also been reported [55] . The most common side effects are anticholinergic (e.g., dry mouth, constipation, blurred vision, orthostatic hypotension and urinary retention). Examples include
Table 3. Drugs recommended for treatment of neuropathic pain based on various guidelines (adapted from O’Connar AB & Dworkin RH [57])
NeuPSIG [54]
EFNS [55]
NICE [56]
Tricyclic antidepressants
First line
First line (except TN)
SSNRI Calcium channel α2-δ ligands Lidocaine 5% patch
First line First line
First line for PPN. PHN and CP Second line for PPN First line for PPN, PHN and CP First line for PHN
Not mentioned
Second to third line for PPN and PHN
Consider only if acute rescue therapy is needed
Second to third line for PPN, PHN and CP First line for TN
Should not be used in nonspecialist settings First line for TN
Tramadol
Strong opioids Carbamazepine
First line for localized peripheral NP Second line (exception: First line in acute NP, exacerbation of NP, adjunct during titration with First line drugs, and neuropathic cancer pain) Same as for tramadol Third line (except TN)
First line (except TN) First line (except TN)
CP: Central pain; NP: Neuropathic pain; PHN: Postherpetic neuralgia; PPN: Painful polyneuropathy; SSNRI: Selective serotonin–norepinephrine reuptake inhibitor; TN: Trigeminal neuralgia.
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Review Wong, Hui, Chung & Wong amitriptyline, nortriptyline and imipramine. The average dosage for amitriptyline is 75 mg/day, but effective dosages vary from one patient to another (e.g,. 25–150 mg).
However, on reviewing the evidence for analgesic efficacy of lidocaine patches, the results are conflicting [66] . A meta-ana-lysis shows that its efficacy is modest when compared with placebo [67] .
●●Selective serotonin–norepinephrine
●●Tramadol
reuptake inhibitors (SSNRIs)
The efficacy of tramadol, including the combination with paracetamol, is established predominantly in PDN [55,58,68,69] . Typical dosage starts from 50mg daily to maximum 400 mg daily, with precaution in renal and hepatic dysfunction. Side effects of tramadol include dizziness, dry mouth, nausea, constipation, and somnolence. Serotonin syndrome may occur if tramadol is used in combination with other serotoninergic medications (particularly selective serotonin reuptake inhibitors, but also other antidepressants).
The SSNRIs, duloxetine and venlafaxine, have well documented efficacy in painful polyneuropathy [60–62] . Duloxetine has been shown to be consistently effective in painful diabetic peripheral neuropathy [54] . However, duloxetine has not been thoroughly studied in other types of neuropathic pain, and so its efficacy in such conditions is unclear. Frequent side effects associated with duloxetine are nausea, dry mouth and constipation. Discontinuation rates are approximately 15 to 20% across studies.
●●Strong opioids ●●Calcium channel alpha-2-delta ligands
The efficacy of gabapentin and pregabalin is established in PDN and PHN [63–65] . The analgesic effect is mainly mediated through a decrease in central sensitization and nociceptive transmission through action on the alpha-2delta subunit of calcium channels [55] . Common side effects include dizziness, somnolence, peripheral oedema and weight gain. Effective dosages for neuropathic pain are 1800–3600 mg/day for gabapentin and 150–600 mg/day for pregabalin. ●●Lidocaine 5% topical plasters
Its efficacy is established mainly in PHN. This mediates its analgesic effect, possibly by reducing ectopic discharges through its sodium channel blocking properties. Lidocaine 5% plasters are generally safe and have little systemic absorption.
The use of strong opioids in chronic neuropathic pain is debatable. However, several randomized controlled trials (RCTs) have now established that strong opioids (oxycodone, methadone, and morphine) have efficacy in PDN and PHN at dosages ranging from 10–120 mg for oxycodone, the most studied drug in neuropathic pain [55,58,69] . However, the analgesic effect achieved for neuropathic pain is not necessarily associated with improvement in aspects such as quality of life, psychological comorbidities and sleep. Problems with prolonged used of opioids include immunological changes, hypogonadism [58] and risk of addiction [70] . Opioid induced hyperalgesia, was found in animal models, and it is worried that it might also occur in humans [71] . Owing to the above reasons, opioids are considered to be second-line treatment for noncancer neuropathic pain in all current recommendations [55,58,72] .
Table 4. Step-by-step approach to the management of neuropathic pain† Step 1
Step 2
Step 3
Step 4
a. Establish diagnosis of neuropathic pain. If uncertain of diagnosis, refer to pain specialist b. Treat the cause of neuropathic pain a. Start therapy for the disease causing neuropathic pain b. Start symptom treatment with one or more of the first line drugs c. Consider nonpharmacological treatments a. Reassess pain b. If pain responsive to treatment, continue treatment c. If partial pain response, add one other first line drugs d. If minimal pain response at target dosage after an adequate trial, switch to an alternative first line drug a. If trials of first line drugs and in combination fail, consider second and third line drugs or referral to pain specialist
Adapted from [54].
†
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Diagnosis & management of neuropathic pain ●●Other drugs
Certain antidepressant medications (e.g., citalopram and paroxetine), certain antiepileptic medications (e.g., carbamazepine, lamotrigine, topiramate and valproic acid) and topical low concentration capsaicin have shown efficacy for treatment of neuropathic pain, either in a single RCT or inconsistently across multiple RCTs. Most of the guidelines recommend that these drugs should be reserved for patients who cannot tolerate or who do not respond adequately to first and second line drugs [54–56] . ●●Combination therapy
A few placebo-controlled trials found the efficacy of combining different analgesic agents over single agent. Examples include gabapentin combined with nortriptyline or morphine compared with gabapentin monotherapy in a mixed group of patients with PDN and PHN [73,74] . It was demonstrated that the combination therapy using lower dosages of individual agents had lower side effects compared with using higher dosage of a single agent. Another example is gabapentin in combination with oxycodone, being superior to gabapentin alone, in diabetic neuropathic pain [75] . This was further supported by another study using combination of duloxetine and pregabalin for the treatment of PDN [76] . Nonpharmacological treatment Psychological and physical interventions are effective means for rehabilitation of patients with chronic pain. Cognitive-behavioural therapy has been shown to have a positive impact on shortterm psychological outcomes following spinal cord injury [77] . Physical and occupational therapies are often recommended for patients with chronic pain disorders but evidence of their effectiveness in neuropathic pain is lacking. Interventional treatment Interventional treatment refers to invasive procedures to deliver drugs to the targeted body areas, as well as ablation or modulation of targeted nerves. A lot of these procedures have been performed for References
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patients with refractory neuropathic pain. These include epidural block with local anaesthetics and steroids for herpes zoster and spinal radiculopathy; sympathetic blockade, intrathecal methylprednisolone and pulsed radiofrequency treatment for PHN; spinal cord stimulation (SCS) and deep brain stimulation (DBS) for neuropathic pain due to spinal cord injury and central post-stroke pain; adhesiolysis and SCS for failed back surgery syndrome (FBSS); microvascular depression, radiosurgery and radiofrequency rhizotomy for trigeminal neuralgia. However, most evidences of efficacy were mainly from anecdotal reports or poor quality studies. A recent recommendation concluded weak recommendations could only be made on the use of steroid injections for acute neuropathic pain associated with herpes zoster and radiculopathy, and SCS for FBSS [78] . ●●Step-by-step approach to management of
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shows a step-by-step approach to the management of neuropathic pain, based on the recommendations by NeuPSIG.
Table 4
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Review For reprint orders, please contact: [email protected]
Diagnosis and management of neuropathic pain
Clara SM Wong1, Grace KM Hui1, Edmond KN Chung1 & Steven HS Wong*,1 Practice points ●●
Neuropathic pain is newly redefined as pain caused by a lesion or disease confining to the somatosensory nervous system.
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A number of clinician- and self-administered assessment tools are available for general screening purposes.
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Diagnosis of neuropathic pain should be to locate the lesion in the somatosensory nervous system based on clinical examination and supplemented by appropriate laboratory investigations.
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Like other chronic pain conditions, neuropathic pain should be managed in a multidisciplinary approach.
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Pharmacological management is targeted towards pain-generating mechanisms. A number of evidence-based guidelines are available.
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Psychological and physical interventions are effective supplementary treatment.
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Interventional procedures may be considered for refractory pain, but their evidences of efficacy are still limited.
Summary: A recent revision in the definition of neuropathic pain has highlighted this condition as a distinct disease entity. More accurate search for a lesion in the somatosensory nervous system as the pain-generating mechanism will help target the treatment by pharmacological agents. A multidisciplinary approach is recommended, with pharmacotherapy supplemented by psychological therapy and physical rehabilitation, and appropriate interventional treatment for selected refractory cases. Evolution in the definition of neuropathic pain There was no clear clue when the concept of neuropathic pain first emerged [1] . However, neuropathy and pain had been mentioned in the literature since 1920s [2,3] . At that time, ‘neuropathy’ often referred to all diseases of the nervous system, including psychiatric disorders. In 1994, Merskey and Bogduk first defined neuropathic pain as ‘pain initiated or caused by a primary lesion, dysfunction or transitory perturbation of the peripheral or central nervous system’ [4] . This definition has been often criticized. One of the reasons is due to the conceptual vagueness of the word ‘dysfunction’ [5] . 1 Department of Anaesthesiology, Queen Elizabeth Hospital, Hong Kong *Author for correspondence: Tel.: +852 2958 6176; Fax: +852 2782 4725; [email protected]
10.2217/PMT.14.7 © 2014 Future Medicine Ltd
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Review Wong, Hui, Chung & Wong Neuropathic pain has been considered as a clinical description rather than a diagnosis. After years of debate, the International Association for the Study of Pain (IASP) adopted a revised definition of neuropathic pain as pain caused by a lesion or disease of somatosensory system [6] . This new definition of neuropathic pain is somehow more stringent. The word ‘dysfunction’ has been removed and the lesion or disease has been specified to be within the somatosensory system. The more restrictive definition means that some conditions will be excluded, e.g. fibromyalgia, interstitial cystitis. These dysfunctional conditions lack structural abnormalities and so do not fall into the definition of neuropathic pain. Neuropathic pain is one of the underlying causes for chronic pain. There is a great variability in these estimates as there is lack of good epidemiological studies and lack of operational and validated criteria resulting from ambiguity in previous definition of neuropathic pain. Current estimates of the population prevalence of neuropathic pain come from studies using validated screening tools that detect pain with possible neuropathic features [7] . They ranged from 1.5% up to approximately 8% of the general population [8–10] . Common causes of peripheral neuropathic pain include painful diabetic neuropathy, post-herpetic neuralgia and trauma after surgery or accident; causes of central pain include stroke, multiple sclerosis and spinal cord injury. Table 1 shows the prevalence of some common neuropathic pain conditions. Diagnosis of neuropathic pain The change in the definition of neuropathic pain has certain implications on the diagnosis of neuropathic pain. In the past, diagnosis of neuropathic pain remained a clinical diagnosis based mainly on the verbal descriptions of screening
tools. The new definition of neuropathic pain requires that an underlying lesion in the somatosensory nervous system be identified. This will mandate a more definitive work-up including a comprehensive neurological examination and the use of laboratory investigations. The following is an overview of the common assessment modalities used for the diagnosis of neuropathic pain (Table 2) . General screening tools Many of the neuropathic pain screening tools are based on pain descriptors of neuropathic pain. Any questionnaires should be interpreted in the context of global assessment of the patient. Common pain descriptors include lancinating (75.6%), burning (68.3%), pinsand-needles (65.9%), electric shock (64.6%), numbness (65.9%) and tingling (59.8%). Other less frequently used adjectives include squeezing (48.8%), painful cold (25.6%) and itching (29.3%) [19] . Table 1 summarizes the commonly used screening tools for neuropathic pain. These screening tools are easy to use by both clinicians and patients alike and both at clinic setting or over the phone. The screening test should be used in a validated language version to give the best result [28] . All screening tools should be applied to a specific area of pain for better discriminatory power. Thus, they are less accurate if used for patients with multiple area of widespread pain [29] . The above screening tools result should be employed for screening purpose at best, but they provide no clue to the cause and are not ideal to monitor therapeutic efficacy. Moreover, the screening tools may not be able to identify 10–20% of patients with neuropathic pain. Thus, the screening test should not replace a careful clinical examination [28] .
Table 1. Estimated prevalence of some common neuropathic pain conditions. Neuropathic pain conditions
Estimated prevalences (%)
Remarks
Diabetic polyneuropathy
8.3–41.9 [11]
In noninsulin-dependent diabetes (NIDDM) 13% in NIDDM; 15% in IDDM All ages Ages >70 5% in hernia repair 85% in amputation During 1st year after stroke Including 4.9% with trigeminal neuralgia Lasting more than 3 months
Postherpetic neuralgia Chronic post-surgical pain Central post-stroke pain Multiple sclerosis Spinal cord injury
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13–15 [12] 8 [13] 48 [14] 5–85 [15] 8 [16] 27.5 [17] 67 [18]
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Interviewing of symptoms Detection of physical signs Questions related to symptoms assessment
Portenoy -
Bouhassira et al. +
Krause and Backonja -
+ Six interview questions on pain: • Location • Temporal characteristics • Quality • Pain evoked by activity or body position • Nonpainful sensations • Current pain
Total 12 items: Gradation of pain from 0 (unnoticeable) to 5 (intensed) intensity for the 7 composite quantified items: • Burning • Tingling or prickling • Is light touch painful • Paroxysmal pain like electric shocks • Is cold or heat occasionally painful • Numbness • Slight pressure triggering pain Pain course patterns (-1, 0, 1) : • Persistent pain with slight fluctuation • Persistent pain with slight attacks • Pain attacks with pain-free interval • Pain attacks with pain attacks between them • Presence of radiating pain (no = 0; yes = 1 or 2)
Six yes/ no questions: • Pins and needles • Hot/burning • Numbness • Electric shocks • Aggravation of pain from light touch • Pain limited to joints
Seven yes/no questions: • Burning • Painful cold • Electric shocks • Tingling • Pins and needles • Numbness • Itching
12 quantified items (0 = no pain; 100 = worst imaginable pain) • Burning pain • Oversensitive to touch • Shooting pain • Numbness • Electric pain • Tingling pain • Squeezing pain • Freezing pain • Unpleasant • Overwhelming • Increased pain due to touch • Increased pain due to weather change
Five composite yes/ no items: • Strange, unpleasant sensations • Skin different from normal • Skin abnormally sensitive to touch • Paroxysmal pain or in burst • Pain as if skin temperature has changed abnormally
+
-
Standardized Evaluation of Pain (StEP) [27] Joachim Scholz +
+
+
+
Freynhagen et al. -
painDETECT [25]
-
+ (Short form of NPQ + (Short seven items + with only three items: version) [25] numbness, tingling and pain increase in response to touch) [24] + + +
ID Pain [26]
DN4 (Douleur Pain Questionnaire) [22]
NPQ (Neuropathic Pain Questionnaire) [21]
+
+
LANSS (Leeds Assessment of Neuropathic Symptoms and Signs) [20] Authors Bennett Clinician administered + patient self- administered for S-LANSS Patient self+ (S-LANSS) [23] assessment
Table 2. Common screening tools for neuropathic pain.
Diagnosis & management of neuropathic pain
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Sensitivity Specificity
Interpretation of scores
82–91% 80–94%
Neuropathic pain
If scores more than or equal to 12 = likely neuopathic pain; If < 12 = unlikely
Total scores = 24
Yes = 1–5; No = 0
LANSS (Leeds Assessment of Neuropathic Symptoms and Signs) [20] Physical examination Two items: findings at painful area • Allodynia: pain or unpleasant sensations (tingling, nausea) when stroking • Altered pinprick threshold
No data No data
The higher the scores, the more likely there is neuropathic pain
Summation of scores of 10 items Score > or = 4, likely neuropathic pain
80% 92%
Scores vary from -1 to 5
Yes = 1; No = 0
Individual items has different coefficient (0.008–0.020); Score of each item expressed as out of 100; Score x coefficient x -1.408 If > or = 0, likely neuropathic pain; If < 0, unlikely neuropathic pain 66% 74% 85% 80%
If less than or equal to 12, unlikely neuropathic pain; If between 13 and 18, uncertain degree of neuropathic pain
Total scores if more than or equal to 19; neuropathic pain likely;
None
None
Three items: • Hypoesthesia to touch • Hypoesthesia to prick • Pain caused or increased by brushing
None
painDETECT [25]
ID Pain [26]
DN4 (Douleur Pain Questionnaire) [22]
NPQ (Neuropathic Pain Questionnaire) [21]
Table 2. Common screening tools for neuropathic pain (cont.).
>90% >90%
Standardized Evaluation of Pain (StEP) [27] Ten physical tests • Skin touch • Blunt pressure • Brush pressure • Brush movement • Vibration • Pinprick • Warm temperature • Cold temperature • Temporal summation • Straight leg raising test Signs of positive discriminatory value include straight leg raising test, deficit in cold detection and reduced pinprick sensation [16]
Review Wong, Hui, Chung & Wong
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Diagnosis & management of neuropathic pain Clinical examination Clinical examination can never prove or disprove the existence of pain as it is a subjective sensation. It serves the purpose to verify and reject the hypothesis where a part of the somatosensory system has a lesion [30] . It also helps to assess whether the pain is from central or peripheral nervous system and or from other non-nervous system [31] . A comprehensive bedside clinical neurological examination should be performed to map out areas of abnormal somatosensory functions. Both positive and negative phenomena of neuropathic pain should be assessed. Positive phenomena refer to qualitative alteration of pain sensation (allodynia or dysesthesia) and quantitative alteration of pain sensation (hypo- or hyper-aesthesia) [32] . Negative symptoms include loss of sensation to specific stimuli such as touch (cotton wool), vibration (128-Hz tuning fork), joint movement, temperature (thermorollers) and pin-prick sensations (wooden cocktail stick). The threshold of detection of these stimuli can be further determined using quantitative sensory testing [31] . The border of the sensory abnormalities should be defined. The area of sensory abnormalities should be within the innervation area of a peripheral nervous system of a plexus, root or peripheral nerve, or within a topographic representation of a body part in central nervous system. Comparison of the unilaterally painful area with contralateral limb or comparing proximal area with distal area is important [28] . This step is very important to confirm that the pain is consistent with a lesion or disease of the somatosensory nervous system [33] . Neuroelectrodiagnostic tools Nerve conduction study is used to find out the electrical conduction velocity of motor or sensory nerves, usually over a numbed or weak area [34] . Needle electromyography looks for evidence of denervation and reinnervation in affected muscle fibres. The above two tests evaluated the function of large myelinated nerve fibres (i.e., α and β fibres) and not pain fibres (i.e., δ and C fibres). A normal study does not rule out neuropathic pain. Somatosensory evoked potential is a noninvasive means to assess the function of somatosensory system. It is a test of large myelinated fibres and dorsal column. If we can locate lesion in somatosensory system, it will further support the diagnosis of neuropathic pain. The tests result could also tell us the nature of pathology such as in case of axonal or demyelinating injury and allow us to monitor progress of treatment or
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recovery. These tools should be regarded as first line investigations in neuropathic pain especially in case of possible traumatic or iatrogenic nerve lesion [25] . Neuroelectrodiagnostic tools have advantage of independence of bias from patient’s response as it is a pure electrophysiological testing. But there is no information on small fibres and there would be discomfort on patient’s side. Quantitative sensory testing Quantitative sensory testing (QST) is a psychophysiological method for measurement of threshold of sensation in response to various pre-determined mechanical and thermal physical stimuli. It is used in diagnosis and follow-up of small fibre neuropathy and in early diagnosis of diabetic neuropathy [35,36] . The stimuli can be divided into two groups: thermal stimuli such as cold, heat, cold pain, heat pain; mechanical stimuli such as tactile, vibration, blunt pressure and pinprick. German Research Network protocol is the most widely adopted protocol in performing this investigation [37] . Clinical judgment should be exercised in selection of appropriate aspect of QST to test in order to yield useful information for clinical use. The drawback of QST is lack of blinding [38] . QST changes are also detected in patients without neuropathic pain such as in various rheumatological diseases, fibromyalgia or inflammatory arthromyalgias [21] . European Federation of Neurological Societies (EFNS) guideline recommends QST as helpful tool to quantify treatment effects on allodynia and hyperalgesia and may help to reveal differential efficacy of treatments on different pain components. Limitations of QST lie in the fact that it only helps to delineate the types of nerve fibres involved but not the level of lesion in the nervous system [28] . It is also time-consuming to perform. As a number of factors are involved including the instructions from the examiner, cooperation by the patient, and technical factor of test-retest variability, precautions should be taken in the performance of the testing and interpretation of the results [39] . QST remains a research tool. Its wider application in clinical settings awaits further standardization and validation [40] . Microneurography Microneurography is a minimally invasive method to evaluate single-axon recordings from peripheral nerve in awake subjects [41] .
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Review Wong, Hui, Chung & Wong The advantage of this method is the ability to discriminate action potential in single, identified peripheral fibres and provide a direct link between activity in peripheral nerve fibres and pain perception [42] . It is the only clinical measure to record and quantify positive sensory phenomena mediated by large myelinated fibres (tactile paraesthesia and dysesthesia), small thinly myelinated fibres and unmyelinated fibres (spontaneous pain) [42] . The shortcoming is that this method is time consuming and labor-intensive. Laser evoked potential & contact heat evoked potential Laser evoked potentials (LEP) and contact heat evoked potentials (CHEP) are measures used to specifically locate lesion in Aδ and C fibres without activating mechanoreceptive and Aβ fibres. Both Aδ and C fibres are thermosensitive. Cortical responses are measured during radiant heat stimulation by laser or rapidly delivered adjustable heat pulses temperature. LEP has been suggested in EFNS guideline on neuropathic pain assessment as a versatile and reliable tool to assess function of subcortical nociceptive pathways in all skin territory [43] . Pain-related reflexes Pain-related reflexes are useful to evaluate a specific subgroup of neuropathic pain, the facial pain. The trigeminal reflexes mediated by Aβ fibres are established as helpful for diagnosis of trigeminal pain diagnosis [44] . They are abnormal in structural lesion as in trigeminal neuropathy, symptomatic trigeminal neuralgia and postherpetic neuralgia, and normal in patients with classical trigeminal neuralgia [28] . Recent AAN-EFNS guideline on trigeminal neuralgia confirmed that Aβ mediated trigeminal reflexes (early R1 blink reflex and early SP1 masseter inhibitory reflex) are efficient tools to evaluate symptomatic forms of trigeminal neuralgia with an overall specificity of 94% and sensitivity of 87% [45] . In a study on patients with ophthalmic postherpetic neuralgia, use of pain related reflexes R1 blink reflex has specificity of 100% and sensitivity of 73% [46] . Skin biopsy Immunostaining of standardized 3-mm punch skin biopsy helps to visualize C fibres [47] as they specifically penetrate epidermis and assess the density, morphology and pathology of C fibres together with other skin appendages such
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as blood vessels and sweat glands [48] . In postherpetic neuralgia, the density of intradermal nerve fibres is lower than that in nonaffected skin area [31] . Functional neuroimaging Magnetic Resonance Imaging (MRI) is a very useful tool to delineate lesion in central nervous system [31] , such as anatomy of the concerning nervous structure, any space occupying lesion in vicinity of the nerve and other associating denervation changes in musculoskeletal system [49] . However, any MRI findings should be interpreted in clinical context of the patient as imaging abnormalities may not necessarily explain the pain. Positron emission tomography (PET) and functional MRI (fMRI) are novel techniques of great research value in evaluating neuropathic pain [31] . The rationale behind is to measure regional changes in cerebral blood flow and metabolic rate in response to noxious stimuli [50] . Studies have shown decreased resting regional cerebral blood flow in contralateral thalamus and reversal of this abnormality by analgesic procedures. Hypoperfusion at thalamus could be employed as future marker of neuropathic pain and restoration of thalamic blood flow used for monitoring treatment effect [51] . A grading system for diagnosis of neuropathic pain A grading system has been proposed [33] . If the distribution of pain is neuroanatomically plausible and the history suggests a relevant lesion or disease, the pain is considered ‘possible’ neuropathic pain. Two further confirmatory tests are needed. If there are positive or negative sensory signs confining to the innervation territory of the lesioned nervous structure, and diagnostic tests could confirm a lesion or disease to explain the pain, then it is considered ‘definite’ neuropathic pain. If only one of the above confirmatory tests is positive, it is only considered ‘probable’ neuropathic pain. Management of neuropathic pain Like other chronic pain conditions, neuropathic pain is often managed in a multidisciplinary approach, which is centred around pharmacological treatment and in combination with nonpharmacological treatment regimens such as cognitive-behavioural, physical and occupational therapy. For refractory neuropathic pain,
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Diagnosis & management of neuropathic pain more invasive interventional treatment may be considered. While the primary objective of treatment is reduction of pain, other outcome measures in chronic pain management should be considered, for example, Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials outcome measures [52] . Pharmacological management The implementation of a new definition of neuropathic pain, which involves the need to look for a lesion in the somatosensory nervous system, will have impact on the pharmacological management of neuropathic pain. Without a structural lesion to substantiate the diagnosis of neuropathic pain, use of pharmacological treatment for neuropathic pain may not be justified. As different analgesics have different mechanisms of action, it is sometimes difficult to predict the treatment response to any particular analgesic [53] . Identifying the underlying mechanism of neuropathic pain will allow the use of pharmacological agents targeted at specific pain mechanisms. Different guidelines have been developed by different international institutions for the treatment of neuropathic pain. These include the Neuropathic Pain Special Interest Group
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(NeuPSIG) of the IASP, the EFNS and the National Institute for Health and Care Excellence (NICE) in the UK [54–56] . In establishing the guidelines, randomized controlled trials (RCT), systematic reviews and existing guidelines on pharmacological management of neuropathic pain were reviewed and evaluated [57,58] . Medications are recommended in the guidelines, basing on degree of evidence of analgesic efficacy, safety, ease of use and cost-effectiveness. Table 3 summarizes the recommendations for pharmacological treatment of neuropathic pain based on various guidelines. The following is an account of some of the drugs that are commonly used for treatment of neuropathic pain. ●●Tricyclic antidepressants (TCAs)
The efficacy of TCAs is established mainly in painful diabetic neuropathy (PDN) and postherpetic neuralgia (PHN). Their analgesic efficacy is probably mediated by action on descending modulatory inhibitory controls [59] , although a peripheral effect on sodium channels has also been reported [55] . The most common side effects are anticholinergic (e.g., dry mouth, constipation, blurred vision, orthostatic hypotension and urinary retention). Examples include
Table 3. Drugs recommended for treatment of neuropathic pain based on various guidelines (adapted from O’Connar AB & Dworkin RH [57])
NeuPSIG [54]
EFNS [55]
NICE [56]
Tricyclic antidepressants
First line
First line (except TN)
SSNRI Calcium channel α2-δ ligands Lidocaine 5% patch
First line First line
First line for PPN. PHN and CP Second line for PPN First line for PPN, PHN and CP First line for PHN
Not mentioned
Second to third line for PPN and PHN
Consider only if acute rescue therapy is needed
Second to third line for PPN, PHN and CP First line for TN
Should not be used in nonspecialist settings First line for TN
Tramadol
Strong opioids Carbamazepine
First line for localized peripheral NP Second line (exception: First line in acute NP, exacerbation of NP, adjunct during titration with First line drugs, and neuropathic cancer pain) Same as for tramadol Third line (except TN)
First line (except TN) First line (except TN)
CP: Central pain; NP: Neuropathic pain; PHN: Postherpetic neuralgia; PPN: Painful polyneuropathy; SSNRI: Selective serotonin–norepinephrine reuptake inhibitor; TN: Trigeminal neuralgia.
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Review Wong, Hui, Chung & Wong amitriptyline, nortriptyline and imipramine. The average dosage for amitriptyline is 75 mg/day, but effective dosages vary from one patient to another (e.g,. 25–150 mg).
However, on reviewing the evidence for analgesic efficacy of lidocaine patches, the results are conflicting [66] . A meta-ana-lysis shows that its efficacy is modest when compared with placebo [67] .
●●Selective serotonin–norepinephrine
●●Tramadol
reuptake inhibitors (SSNRIs)
The efficacy of tramadol, including the combination with paracetamol, is established predominantly in PDN [55,58,68,69] . Typical dosage starts from 50mg daily to maximum 400 mg daily, with precaution in renal and hepatic dysfunction. Side effects of tramadol include dizziness, dry mouth, nausea, constipation, and somnolence. Serotonin syndrome may occur if tramadol is used in combination with other serotoninergic medications (particularly selective serotonin reuptake inhibitors, but also other antidepressants).
The SSNRIs, duloxetine and venlafaxine, have well documented efficacy in painful polyneuropathy [60–62] . Duloxetine has been shown to be consistently effective in painful diabetic peripheral neuropathy [54] . However, duloxetine has not been thoroughly studied in other types of neuropathic pain, and so its efficacy in such conditions is unclear. Frequent side effects associated with duloxetine are nausea, dry mouth and constipation. Discontinuation rates are approximately 15 to 20% across studies.
●●Strong opioids ●●Calcium channel alpha-2-delta ligands
The efficacy of gabapentin and pregabalin is established in PDN and PHN [63–65] . The analgesic effect is mainly mediated through a decrease in central sensitization and nociceptive transmission through action on the alpha-2delta subunit of calcium channels [55] . Common side effects include dizziness, somnolence, peripheral oedema and weight gain. Effective dosages for neuropathic pain are 1800–3600 mg/day for gabapentin and 150–600 mg/day for pregabalin. ●●Lidocaine 5% topical plasters
Its efficacy is established mainly in PHN. This mediates its analgesic effect, possibly by reducing ectopic discharges through its sodium channel blocking properties. Lidocaine 5% plasters are generally safe and have little systemic absorption.
The use of strong opioids in chronic neuropathic pain is debatable. However, several randomized controlled trials (RCTs) have now established that strong opioids (oxycodone, methadone, and morphine) have efficacy in PDN and PHN at dosages ranging from 10–120 mg for oxycodone, the most studied drug in neuropathic pain [55,58,69] . However, the analgesic effect achieved for neuropathic pain is not necessarily associated with improvement in aspects such as quality of life, psychological comorbidities and sleep. Problems with prolonged used of opioids include immunological changes, hypogonadism [58] and risk of addiction [70] . Opioid induced hyperalgesia, was found in animal models, and it is worried that it might also occur in humans [71] . Owing to the above reasons, opioids are considered to be second-line treatment for noncancer neuropathic pain in all current recommendations [55,58,72] .
Table 4. Step-by-step approach to the management of neuropathic pain† Step 1
Step 2
Step 3
Step 4
a. Establish diagnosis of neuropathic pain. If uncertain of diagnosis, refer to pain specialist b. Treat the cause of neuropathic pain a. Start therapy for the disease causing neuropathic pain b. Start symptom treatment with one or more of the first line drugs c. Consider nonpharmacological treatments a. Reassess pain b. If pain responsive to treatment, continue treatment c. If partial pain response, add one other first line drugs d. If minimal pain response at target dosage after an adequate trial, switch to an alternative first line drug a. If trials of first line drugs and in combination fail, consider second and third line drugs or referral to pain specialist
Adapted from [54].
†
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Diagnosis & management of neuropathic pain ●●Other drugs
Certain antidepressant medications (e.g., citalopram and paroxetine), certain antiepileptic medications (e.g., carbamazepine, lamotrigine, topiramate and valproic acid) and topical low concentration capsaicin have shown efficacy for treatment of neuropathic pain, either in a single RCT or inconsistently across multiple RCTs. Most of the guidelines recommend that these drugs should be reserved for patients who cannot tolerate or who do not respond adequately to first and second line drugs [54–56] . ●●Combination therapy
A few placebo-controlled trials found the efficacy of combining different analgesic agents over single agent. Examples include gabapentin combined with nortriptyline or morphine compared with gabapentin monotherapy in a mixed group of patients with PDN and PHN [73,74] . It was demonstrated that the combination therapy using lower dosages of individual agents had lower side effects compared with using higher dosage of a single agent. Another example is gabapentin in combination with oxycodone, being superior to gabapentin alone, in diabetic neuropathic pain [75] . This was further supported by another study using combination of duloxetine and pregabalin for the treatment of PDN [76] . Nonpharmacological treatment Psychological and physical interventions are effective means for rehabilitation of patients with chronic pain. Cognitive-behavioural therapy has been shown to have a positive impact on shortterm psychological outcomes following spinal cord injury [77] . Physical and occupational therapies are often recommended for patients with chronic pain disorders but evidence of their effectiveness in neuropathic pain is lacking. Interventional treatment Interventional treatment refers to invasive procedures to deliver drugs to the targeted body areas, as well as ablation or modulation of targeted nerves. A lot of these procedures have been performed for References
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patients with refractory neuropathic pain. These include epidural block with local anaesthetics and steroids for herpes zoster and spinal radiculopathy; sympathetic blockade, intrathecal methylprednisolone and pulsed radiofrequency treatment for PHN; spinal cord stimulation (SCS) and deep brain stimulation (DBS) for neuropathic pain due to spinal cord injury and central post-stroke pain; adhesiolysis and SCS for failed back surgery syndrome (FBSS); microvascular depression, radiosurgery and radiofrequency rhizotomy for trigeminal neuralgia. However, most evidences of efficacy were mainly from anecdotal reports or poor quality studies. A recent recommendation concluded weak recommendations could only be made on the use of steroid injections for acute neuropathic pain associated with herpes zoster and radiculopathy, and SCS for FBSS [78] . ●●Step-by-step approach to management of
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Table 4
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