The levels of evidence (class I-IV) supporting the recommendations and ratings of recommendations (A-C) are defined at the end of the "Major Recommendations" field.
Definitions
Testing the validity of a narrow versus a broad definition of neuropathic pain (see the original guideline document for pain definitions) should be a major goal for future studies. In the meanwhile, however, the guideline developers suggest the narrow definition and classification is retained, because of risk of overestimating neuropathic pain and because it is easy to understand (grade C recommendation).
Clinical Examination and Psychophysiological Measures
Bedside Examination
Although there are no validated studies on bedside examination, the guideline developers emphasize that in pain patients a thorough neurological examination is invaluable—the sensory testing being the most important part of it—and is preliminary to any quantitative assessment (grade C recommendation).
Quantitative Sensory Testing
Because also found in non-neuropathic pains, quantitative sensory testing (QST) abnormalities cannot be taken as a conclusive demonstration of neuropathic pain; furthermore, QST depends on expensive equipment, it is time consuming and thus difficult to use in clinical practice (grade B recommendation). QST is helpful to quantify the effects of treatments on allodynia and hyperalgesia and may reveal a differential efficacy of treatments on different pain components (grade A recommendation). To evaluate mechanical allodynia/hyperalgesia, the guideline developers recommend the use of simple tools such as a brush and at least one high-threshold von Frey filament. The evaluation of pain in response to thermal stimuli is best performed using the thermotest, but the systematic measure of thermal stimuli is not recommended except for pathophysiological research or treatment trials. A simple and sensitive tool to quantify pain induced by thermal stimuli in clinical practice should be developed.
Pain Quality and Intensity Scales
It is recommended to rate the intensity and the unpleasantness of pain separately. The intensity of the different pain components that the patient may report (spontaneous ongoing pain, spontaneous paroxysmal pain, dysesthesiae, and paresthesiae) or the evoked pains (allodynia and hyperalgesia), and pain worsening with movement, should be rated separately, but using the same scale. If different pain components involve different territories, these can be documented on a template body map. The simplest scales are probably the best. Whereas verbal rating scale (VRS) is found easier by many patients, visual analogue scale (VAS) is more apt to treatment trials because it permits parametric statistics. The 11-point Likert numerical rating scale (NRS) is a good compromise (grade C recommendation).
Methods Specifically Designed to Assess Treatment Efficacy
All the psychometric instruments assessing treatment in neuropathic pain have been shown sensitive in several randomized controlled trials (level Ib). The guideline developers recommend the use of unidimensional pain scales, particularly the VAS and pain relief scales and the evaluation of specific pain symptoms (such as burning pain, pain paroxysms, or allodynia) as this may reveal preferential effects of treatments. The guideline developers do not favour the systematic use of nonspecific multidimensional scales (e.g., McGill Pain Questionnaire [MPQ]). Although interesting, the multidimensional scales specific for neuropathic pain still lack extensive validation.
Other Outcome Measures
In clinical studies, quality of life (QoL) should be assessed with a validated and comprehensive scale such as SF-36 Health Survey (SF-36) or Nottingham Health Profile (NHP). Mood, sleep, anxiety, and depression, if not included in the chosen QoL measure, should be assessed separately (grade C recommendation).
Laboratory Tests
Standard Electrodiagnostic Studies
Standard neurophysiological responses to electrical stimuli, such as nerve conduction studies and somatosensory-evoked potentials, are useful to demonstrate, locate, and quantify damage along the peripheral or central sensory pathways. But they do not assess function of nociceptive pathways (grade A recommendation).
Nociceptive Reflexes
The electrically elicited trigeminal reflexes (blink reflex and masseter inhibitory reflex) are diagnostically useful to differentiate essential trigeminal neuralgia from symptomatic trigeminal pains (grade A recommendation). The other nociceptive reflexes have little diagnostic value (grade C statement). The nociceptive reflex that is most used and appears to be most reliable in assessing treatment efficacy is the RIII flexion reflex (grade B recommendation).
Laser-Evoked Potentials
The laser-evoked potentials (LEPs) are the easiest and most reliable neurophysiological method of assessing function of nociceptive pathways; in clinical practice their main limit is that they are currently available in too few centres. Late LEPs (which assess A-delta pathways) are diagnostically useful in peripheral and central neuropathic pains (grade B recommendation). The experience as a tool for assessing treatments is so far insufficient. More studies on ultralate LEPs in patients with neuropathic pain are encouraged.
Functional Neuroimaging
There is converging evidence that chronic spontaneous neuropathic pain is associated with decreased activity in contralateral thalamus, whereas provoked neuropathic pain is associated with increased activity in the thalamic, insular, and somatosensory regions (grade B statement).
In view of the potential relevance of these data, the guideline developers encourage functional neuroimaging studies in patients with neuropathic pain.
Biopsy
Often a cause for underlying neuropathy may not be found despite extensive investigations, and careful evaluation is needed before such cases are considered as idiopathic or "psychogenic." Punch skin biopsy, which can detect changes when sural nerve biopsy is still normal, is emerging as a minimally invasive tool for detecting small fibre involvement; in pain patients it should be preferred to nerve biopsy (grade B recommendation).
Definitions:
Evidence Classification Scheme for a Diagnostic Measure
Class I: A prospective study in a broad spectrum of persons with the suspected condition, using a "gold standard" for case definition, where the test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy
Class II: A prospective study of a narrow spectrum of persons with the suspected condition, or a well-designed retrospective study of a broad spectrum of persons with an established condition (by "gold standard") compared to a broad spectrum of controls, where test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy
Class III: Evidence provided by a retrospective study where either persons with the established condition or controls are of a narrow spectrum, and where test is applied in a blinded evaluation
Class IV: Any design where test is not applied in blinded evaluation OR evidence provided by expert opinion alone or in descriptive case series (without controls)
Rating of Recommendations
Level A rating (established as useful/predictive or not useful/predictive) requires at least one convincing class I study or at least two consistent, convincing class II studies.
Level B rating (established as probably useful/predictive or not useful/predictive) requires at least one convincing class II study or overwhelming class III evidence.
Level C rating (established as possibly useful/predictive or not useful/predictive) requires at least two convincing class III studies.
