The Diversity of Neuropathic Pain
Abstract and Keywords
The present chapter presents an update of the current classification, diagnosis, assessment, mechanisms, and treatment of neuropathic pain. Neuropathic pain, which is defined as pain associated with a lesion or disease of the somatosensory nervous system, may be caused by a variety of conditions, such as diabetic neuropathy, herpes zoster, surgical trauma, spinal cord injury, and stroke. The diagnostic criteria for neuropathic pain are a history of a nervous system disease or lesion and pain distribution and sensory signs in a neuroanatomically plausible distribution. The treatment of neuropathic pain is often multidisciplinary and involves specific drugs. Recent progress in the diagnosis, assessment, and understanding of its mechanisms offers the perspective of a more rational therapeutic management, which should result in better therapeutic outcome.
Neuropathic pain is defined as pain associated with a lesion or disease of the somatosensory nervous system (Finnerup et al., 2016) and is caused by various conditions, including diabetes, herpes zoster (HZ), surgery, stroke, spinal cord lesion, and multiple sclerosis (MS) (Colloca et al., 2017). Its prevalence in the general population has been estimated at 3–10% according to several large-scale epidemiological studies (Attal, Bouhassira, & Baron, 2018). Neuropathic pain is a largely unmet medical need with a large number of therapeutic failures in well-conducted, randomized, controlled trials (Finnerup et al., 2015). However, recent progress in the diagnosis, assessment, and understanding of the mechanisms of neuropathic pain offers the perspective of a more rational treatment and hence a better therapeutic outcome. The present chapter presents an update on the classification, diagnosis, assessment, mechanisms, and treatment of neuropathic pain.
Clinical Presentation and Diagnosis of Neuropathic Pain
Patients with neuropathic pain generally exhibit spontaneous and evoked components that often coexist. Spontaneous pain may be continuous (e.g., foot pain in diabetic neuropathy) or intermittent (e.g., pain paroxysms in trigeminal neuralgia [TN]). In addition to temporal variations in pain intensity, subjects with neuropathic pain report varying pain qualities, such as burning, cold, sharp, and squeezing. Intermittent neuropathic pain, often referred to as pain paroxysms, is often described as shooting, stabbing, or electric shock–like. Evoked pains (hyperalgesia or allodynia) may be provoked by brush, pressure, cold, or heat. Importantly, these characteristics are shared by most neuropathic etiologies, which indicates that despite obvious differences in etiology, the clinical entity of neuropathic pain has strong clinical consistency (Attal et al., 2008).
Based on the observation that neuropathic pain has particular clinical characteristics, a number of screening questionnaires have been developed and validated to discriminate neuropathic pain from other types of pain. Frequently used screening questionnaires include the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) and its self-administered version, the Neuropathic Pain Questionnaire, the Douleur Neuropathique en 4 questions (DN4) and its self-administered version, PainDETECT, and ID Pain, and they all use common sensory terms such as burning, electric shocks, tingling, pricking, pins and needles, numbness, itch, or pain evoked by brushing to discriminate between neuropathic and nonneuropathic pain and have good-to-excellent sensitivity (66.6–85%) and specificity (74.4–90%) (Attal et al., 2018) (Table 1). They have also been translated into multiple languages or revalidated and are used worldwide. This has contributed to improve the diagnosis of neuropathic pain in multiple medical settings (e.g., postsurgical settings, spinal cord injury [SCI], and diabetes), leading to improved medical treatment and management. However, screening questionnaires have limitations as they provide no information about the history of the pain, sensory examination is succinct or absent, and these questionnaires can lead to a false diagnosis (i.e., over- or underdiagnosis of neuropathic pain) in 10–20% of cases (Attal et al., 2018).
Table 1. Screening Questionnaires for Neuropathic Pain
Screening Questionnaire for Neuropathic Paina
Sample Size (Original Validation Studies)
Sensitivity (Original Validation Studies)
Specificity (Original Validation Studies)
Leeds Assessment of Neuropathic Symptoms and Signs (LANSS)
5 descriptors (yes or no)
N = 60 (development)
2 exam items (yes or no)
Total score 24
N = 40 (validation)
Score ≥ 12/24: NP likely
Neuropathic Pain Questionnaire (NPQ)
12 descriptors (0 = no to 100 = worst pain imaginable) with variable coefficients
N = 382
Score ≥ 0: NP likely
Self Report Version of the Leeds Assessment of Neuropathic Symptoms and Signs (S LANSS)
7 descriptors (yes or no)
N = 200
Total score 24
Score ≥ 12/24: NP likely
Douleur Neuropathique en 4 Questions (DN4)
7 descriptors (yes or no)
3 exam items (yes or no)
Total score 10
Score ≥ 4/10: NP likely
7 descriptors (yes or no)
N = 160 interview
Total score 7
N = 84 self-reported
Score ≥ 3/7: NP likely
7 descriptors (categorical scales)
N = 392
2 spatiotemporal items + 1 item related to radiating pain
Total score 35 for descriptors
Score ≥ 19: NP likely
Score 12–19: uncertain
5 descriptors (yes or no)
N = 586 (development)
1 negative item (yes or no)
Total score 5
N = 308 (validation)
Score ≥ 3: NP likely
NP, neuropathic pain.
Source: Adapted from Attal et al. (2018).
(a) References in Attal et al. (2018).
Screening questionnaires should therefore only be used as a first step in the diagnostic workup for the identification of neuropathic pain. Following a positive questionnaire result, an interview and a neurological examination are recommended to confirm a lesion or disease of the nervous system. The Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain (IASP) has proposed a diagnostic algorithm based mainly on the identification of the neurological lesion or disease (Finnerup et al., 2016). This grading system requires a history of a nervous system lesion or disease with pain onset in temporal relationship to the disorder, a pain distribution, and sensory signs in a neuroanatomically plausible distribution (Finnerup et al., 2016). It allows the characterization of possible, probable, or definite neuropathic pain depending on the number of criteria met.
Assessment of Neuropathic Symptoms and the Neurological Lesion
Several questionnaires based on self-assessment of sensory descriptors (e.g., burning, shooting, electric shocks) have been designed and validated to quantify multiple neuropathic symptoms. They include specific questionnaires for neuropathic pain, particularly the Neuropathic Pain Scale (NPS), the Neuropathic Pain Symptom Inventory (NPSI), and questionnaires applicable to both neuropathic and nonneuropathic pain, for instance, the McGill Short-Form Questionnaire 2 (SF-MPQ 2) derived from the McGill Short-Form Questionnaire (SF-MPQ), and the Pain Quality Assessment Scale (PQAS) derived from the NPS. Using these questionnaires in clinical practice and clinical trials to characterize the nature of patients’ symptoms may help determine which neuropathic symptoms or symptom associations can be alleviated by an individual treatment and to identify profiles of respondents (Bouhassira & Attal, 2016).
The nerve lesion responsible for the patient’s neuropathic pain can be assessed using a variety of psychophysical and objective diagnostic tests that allow investigation of the somatosensory pathway function (Colloca et al., 2017). They include, in particular, bedside evaluation, quantitative sensory testing (QST), neurophysiological techniques, skin biopsy, and corneal confocal microscopy (CCM). QST is used to assess nociceptive and nonnociceptive systems in the periphery and the central nervous system by applying standardized mechanical and thermal stimuli. QST enables the assessment of loss and gain of function of distinct afferent fiber classes, which is a significant advantage over other techniques. Normative values are available based on a standardized protocol proposed by the nationwide German Network on Neuropathic Pain (references in Baron et al., 2017). Standard neurophysiological techniques (e.g., nerve conduction studies, trigeminal reflexes, and somatosensory evoked potentials) are used to identify damage along the large-fiber–mediated somatosensory pathways and are widely used for assessing peripheral and central nervous system diseases causing neuropathic pain, whereas laser-evoked potentials (LEPs) are used to assess nociceptive pathway function (Colloca et al., 2017). In conditions associated with nociceptive pathway damage, LEPs can be absent, reduced in amplitude, or delayed in latency. Skin punch biopsy is used to assess epidermal innervation and is now regarded as the most sensitive tool for diagnosing small-fiber neuropathies. Finally, CCM is under investigation as a possible tool for investigating small nerve fiber damage in patients with small-fiber peripheral neuropathy.
Classification of Neuropathic Pain
The 11th draft revision of the International Classification of Diseases (ICD) of the World Health Organization (WHO) includes a chapter on chronic pain as proposed by the IASP Task Force on ICD11 (Treede et al., 2015). This chapter proposes a classification of chronic neuropathic pain into peripheral and central neuropathic pain and into nine common neuropathic pain diagnostic entities (Table 2) (Scholz et al., 2018).
Table 2. Classification of Chronic Neuropathic Pain
Peripheral Neuropathic Pain
Central Neuropathic Pain
Neuropathic pain associated with spinal cord injury
Neuropathic pain after peripheral nerve injury
Neuropathic pain associated with brain injury
Central poststroke pain
Neuropathic pain associated with multiple sclerosis
Other central neuropathic pain
Other peripheral neuropathic pain
Peripheral Neuropathic Pain
Peripheral neuropathic pain is the most prevalent neuropathic pain condition in the general population and corresponds to a neuropathic pain condition caused by a lesion of disease of the peripheral somatosensory nervous system. The main causes of peripheral neuropathic pain include peripheral diabetic and nondiabetic polyneuropathies, postherpetic neuralgia (PHN), post-traumatic/postsurgical nerve lesions, and radiculopathy such as sciatica.
The prevalence of painful polyneuropathy in patients with Type 1 or 2 diabetes has been estimated to be between 14% and 34% in developed countries and up to 65% in the Middle East based on several prospective large-scale studies, many of which used screening questionnaires (references in Attal et al., 2018; Daousi et al., 2004; Davies, Brophy, Williams, & Taylor, 2006). In these studies, the risk factors for developing neuropathic pain were the duration of diabetes and the presence of the metabolic syndrome. Nondiabetic polyneuropathies may be caused by prediabetes and other metabolic dysfunctions, HIV, chemotherapeutic agents, immune system and inflammatory disorders, inherited neuropathies, and channelopathies (Colloca et al., 2017). No definite cause is found in many patients with small-fiber neuropathy, and this condition is referred to as idiopathic small-fiber neuropathy. The topography of the pain in these disorders typically encompasses the distal extremities, often called a “glove-and-stocking” distribution, which characterizes dying-back, length-dependent, distal peripheral neuropathies. Less frequently, the pain has a proximal distribution when the pathology involves the sensory ganglia (Colloca et al., 2017).
Postherpetic neuralgia is the most common complication of HZ and is defined as pain persisting after the resolution of the cutaneous rash. Due to differences in PHN definition (e.g., 1 or 3 months after rash onset) and studied populations, the estimates of the proportion of HZ cases that result in PHN may vary widely between studies. The largest prospective studies provided estimates of 6–10% within the year following HZ (Bouhassira et al., 2012; Helgason, Petursson, Gudmundsson, & Sigurdsson, 2000). Increased age, severe acute pain, higher neuropathic characteristics of pain, and severe or disseminated skin rash have been reported to independently contribute to the risk of PHN (Bouhassira et al., 2012; Jung, Johnson, Griffin, & Dworkin, 2004).
Peripheral neuropathic pain is also common after surgical lesion and is frequently unrecognized (Kehlet, Jensen, & Woolf, 2006). In some cases, the pain is located at the scar site and the surrounding skin area, whereas in others it is located in the neuroanatomical area corresponding to the nerve lesion. Postsurgical neuropathic pain has most commonly been reported following thoracotomy, mastectomy, knee replacement, cholecystectomy, inguinal hernia repair, and varicose vein stripping (Kehlet et al., 2006). The estimated prevalence of chronic postsurgical neuropathic pain varies between 3% and more than 30%, depending on the type of surgery within 3–6 months in large-scale epidemiological studies (references in Attal et al., 2018).
Chronic painful radiculopathy is caused by a lesion or disease involving the cervical, thoracic, lumbar, or sacral nerve roots (e.g., sciatica, cervicobrachial neuralgia). Pain may be spontaneous or provoked by body positions or movements. Negative and positive sensory symptoms or signs must be compatible with the innervation territory of the affected nerve root or roots. Based on large-scale studies using screening questionnaires, chronic painful radiculopathy probably represents the main cause of neuropathic pain in the general population (Bouhassira et al., 2008). The prevalence of neuropathic pain in patients with low back pain has been found to be extremely variable depending on the criteria used to define neuropathic pain (Attal, Perrot et al., 2011). Particular studies using screening questionnaires have found that the prevalence of neuropathic pain in the leg increased depending on how distally the pain radiated; neuropathic pain characteristics were found in 80% of patients with typical pain radiation to the leg, while they were found in less than 20% of cases in patients with a proximal pain area above the knee (Attal, Perrot et al., 2011).
Many patients with central nervous system disorders suffer from chronic pain. Central neuropathic pain (or central pain) is a specific pain condition caused by a lesion or disease of the central somatosensory nervous system. It is distinct from, for example, headache caused by brain trauma, widespread pain conditions associated with post-traumatic stress disorder, and musculoskeletal pain related to spasticity.
Neuropathic pain is one of the most disabling consequences of SCI and is present in about 50% of patients (Burke, Fullen, Stokes, & Lennon, 2017). The onset can be acute but may be delayed several months. Onset after 1 year and facial pain should alert the physician to pain due to syringomyelia (Attal & Bouhassira, 2006). Neuropathic pain following SCI is divided into pain felt at and below the level of lesion (Bryce et al., 2012). At-level pain may be caused by the spinal cord or nerve roots lesions, and it is often not possible to determine whether it is a peripheral neuropathic pain. Below-level pain is considered a central pain caused by the SCI. Neuropathic pain associated with brain injury is less well studied (Ofek & Defrin, 2007; Widerstrom-Noga, Govind, Adcock, Levin, & Maudsley, 2016). The pain distribution is often unilateral, corresponding to the side with the most severe sensory abnormalities and related to decreased thermal sensitivity.
Central poststroke pain occurs in 3–8% of stroke patients (Andersen, Vestergaard, Ingeman, & Jensen, 1995; Klit, Finnerup, Andersen, & Jensen, 2011) with the highest prevalence in lateral medullary infarctions and thalamic lesions (Bogousslavsky, Regli, & Uske, 1988; Lampl, Yazdi, & Roper, 2002; MacGowan et al., 1997). Central poststroke pain is experienced contralateral to the side of the stroke in the whole hemibody or in smaller body areas.
Neuropathic pain associated with MS is present in about 25% of cases (Osterberg, Boivie, & Thuomas, 2005). The distribution of central pain is compatible with spinal or brain lesions of the somatosensory nervous system (Okuda, Melmed, Matsuwaki, Blomqvist, & Craig, 2014; Svendsen, Sorensen, Jensen, Hansen, & Bach, 2011). In addition to “classical” central pain, patients with MS may also suffer from secondary TN and Lhermitte phenomenon (O’Connor, Schwid, Herrmann, Markman, & Dworkin, 2008; Truini, Barbanti, Pozzilli, & Cruccu, 2013). Trigeminal neuralgia in MS is similar to classical TN with brief, severe, paroxysmal pain attacks restricted to one or more divisions of the trigeminal nerve. It is often unilateral but may be bilateral (Cruccu Finnerup et al., 2016; Truini, Barbanti, et al., 2013). Lhermitte phenomenon is transient and short-lasting electric shock-like sensations spreading down the back, often provoked by neck movement (O’Connor et al., 2008; Truini, Barbanti, et al., 2013).
Other central pain conditions include pain following nerve root avulsion. This often involves the brachial plexus and is common after motorcycle accidents. It is a preganglionic lesion, where the nerve roots are disconnected from the spinal cord (Teixeira et al., 2015). It is often associated with severe neuropathic pain, typically with pain attacks shooting down the arm and hand, sometimes associated with ongoing pain. It is sometimes considered a peripheral neuropathic pain because of the mixed peripheral and central mechanisms as there may be a concomitant lesion of the nerve plexus, and it is not always possible to identify the lesion site. Central pain may also occur in brain tumors and epilepsy (Amancio, Peluso, Santos, Pena-Dias, & Debs, 2002; Gates, Nayernouri, & Sengupta, 1984; Silbergeld, Hebb, & Loeser, 2011). In Parkinson disease, some pain types are considered to be neuropathic (Blanchet & Brefel-Courbon, 2017; Truini, Frontoni, & Cruccu, 2013), but the pain does not have the typical distribution of pain explained by a lesion of the somatosensory nervous system, and potential sensory changes are not necessarily related to the pain (Blanchet & Brefel-Courbon, 2017; Tinazzi et al., 2008; Zambito et al., 2011). Sensory disturbances are also suggested to precede Parkinson disease in the absence of pain (Strobel et al., 2018). It is discussed if altered sensation is related to altered pain modulation due to involvement of striatal dopamine receptors in inhibitory pathways (Pertovaara & Wei, 2008) or due to dysfunction of peripheral small nerve fibers due to alpha-synuclein deposits in dermal fibers (Doppler et al., 2014).
The mechanisms underlying neuropathic pain involve ectopic activity in the pain pathways and peripheral and central sensitization (Colloca et al., 2017; Vardeh, Mannion, & Woolf, 2016). In peripheral neuropathic pain, ectopic activity in lesioned nerves, neighboring nerves, neuromas, or dorsal root ganglia is thought to be responsible for the ongoing and paroxysmal spontaneous pain (Kleggetveit et al., 2012; Koplovitch & Devor, 2018; Serra, 2012). In patients with peripheral nerve injury and polyneuropathy, a peripheral nerve block caused complete relief of spontaneous and evoked pain (Haroutounian et al., 2014), and blockade of the dorsal root ganglion relieved phantom limb pain (Vaso et al., 2014). Damage to the peripheral nerve may also cause a peripheral and central sensitization that may give rise to evoked pain with allodynia and hyperalgesia. Often, evoked pain extends the area of sensory loss and spontaneous pain and affects neighboring dermatomes.
In central pain, spontaneous discharges in damaged pain pathways or deafferented rostral neurons are thought to be responsible for spontaneous pain (Vardeh et al., 2016). However, a seemingly spontaneous pain may also be caused by a decreased threshold and temporal summation, by which stimuli occurring at physiological levels from, for example, breathing, movement, and ambient temperature may cause an ongoing activity in pain pathways, resulting in ongoing or intermittent pain (Bennett, 2012). This may explain why a peripheral nerve block resulted in complete abolition of pain in seven patients with chronic postsurgical pain, who all had both spontaneous and evoked pain in the area affected by the nerve block (Haroutounian et al., 2018). Spontaneous central pain is in other cases more likely to be generated by neurons in the central nervous system, which may explain why below-level SCI pain may persist after cordotomy (Melzack & Loeser, 1978). Electrophysiological recordings in the dorsal root entry zone (DREZ) of the spinal cord in patients with SCI pain and pain from root avulsion have documented areas of abnormal focal spontaneous and evoked hyperactivity in up to seven segments rostral to the level of injury, with ablation resulting in relief of pain (Edgar, Best, Quail, & Obert, 1993; Falci, Best, Bayles, Lammertse, & Starnes, 2002). Abnormal bursting activity has also been documented in the thalamus in patients with SCI pain, but the relationship to pain is unclear (Hirayama, Dostrovsky, Gorecki, Tasker, & Lenz, 1989; Tasker, Gorecki, Lenz, Hirayama, & Dostrovsky, 1987). Central sensitization in the spinal cord, thalamus, and other brain areas is thought to be responsible for evoked pain, aftersensations, and temporal summation (Woolf, 2011). Recent studies have found that sensory hypersensitivity (mechanical and cold allodynia, hyperalgesia, and temporal summation of pain) precedes and predicts later development of central pain (chronic poststroke pain and below-level SCI pain), supporting a role of neuronal hyperexcitability also for ongoing central pain (Finnerup et al. 2014; Klit, Hansen, Marcussen, Finnerup, & Jensen, 2014; Zeilig, Enosh, Rubin-Asher, Lehr, & Defrin, 2012).
Several neurochemical, excitotoxic, anatomical, and inflammatory neuropathic pain mechanisms have been identified from basic research (Brown & Weaver, 2012; Colloca et al., 2017). These include modulation of sodium and calcium channels, downregulation of potassium channels, and phosphorylation of glutamate receptors, causing neuronal hyperexcitability. The peripheral and central immune systems are also involved with altered state of microglia, astrocytes, and macrophages and release of pro-inflammatory cytokines and chemokines. Disinhibition by decreased glycine or γ-aminobutyric acid (GABA-)-ergic and glycinergic tone and imbalance between descending inhibitory and facilitatory pathways also contributes to central sensitization.
Before initiating treatment, a comprehensive pain assessment is required, and the pain type should be identified. Red flag conditions that may cause, aggravate, or mimic neuropathic pain should be considered (Mehta et al., 2016). For patients with central nervous system lesions, these include fractures, spasticity, and other musculoskeletal disorders; urinary tract infections and other visceral disorders; cardiovascular and gastrointestinal diseases; and malignancy. In patients with polyneuropathy, they can include pain in the legs from ischemia or osteoarthritis, and in postsurgical pain, inflammation or instability in fractures. Psychosocial factors that may contribute to disability and exacerbate pain-related distress have been termed yellow flags (Mehta et al., 2016). Addressing these aspects is important for choosing the optimal treatment and treatment success. Therefore, symptoms related to depression and anxiety; altered sleep, physical activities, and motivation; social function; fear-avoidance behavior; pain beliefs; social support; and dependence on drugs, alcohol, or illicit substances should be assessed. Age is another important factor to consider as there are limited studies and treatment guidelines for children and the elderly, and concurrent medical problems can influence the treatment plan and success.
Whenever possible, the focus is to treat the cause of pain, but often the treatment is symptomatic. As for many chronic pain conditions, only partial pain relief can be expected, and it is beneficial to ensure that the patient has realistic expectations for a treatment.
Self-Management and Behavioral and Psychological Interventions
Patients often request knowledge of how to live with their pain and information on mental strategies, exercise, and physical therapy and report that they experience pain relief after exercising (Lofgren & Norrbrink, 2012). Physical activity is an important aspect of pain treatment (Kaiser, Mooreville, & Kannan, 2015). Several mechanistic studies in humans and animal studies provided mechanistic insights into the effect of exercise in pain. Regular exercise seems to promote pain relief by increasing inhibitory pathways by acting on serotonin and opioid systems, decreasing facilitation by reduced N-methyl-d-aspartate (NMDA) receptor phosphorylation, and by modulation of maladaptive plasticity, for example, by decreasing microglia activity and normalizing levels of neurotrophic factors (Lima, Abner, & Sluka, 2017; Nees, Finnerup, Blesch, & Weidner, 2017).
Multidisciplinary treatment and active self-care are important components of chronic pain treatment (Kaiser et al., 2015). Pain management programs can reduce the impact and perceived powerlessness to pain, and patients may continue to use self-management of chronic pain with acquired cognitive behavioral treatment strategies (Egan, Lennon, Power, & Fullen, 2017). Cognitive behavioral therapy is a group of techniques that focus on developing coping strategies and changing unhelpful pain behaviors, thoughts, and beliefs about pain (Daniel & Van der Merwe, 2006). A newer form is acceptance and commitment therapy, which emphasizes acknowledgment and acceptance of thoughts and emotions (Kaiser et al., 2015). Other psychological interventions used to affect the brain processes that contribute to distress and disability include hypnosis, relaxation, mindfulness, meditation, and neurofeedback (Hasan, Fraser, Conway, Allan, & Vuckovic, 2016; Jensen, Day, & Miro, 2014). There is generally a need for more studies of psychological interventions for patients with neuropathic pain (Colloca et al., 2017; Eccleston, Hearn, & Williams, 2015).
Neuropathic pain drugs act by either targeting pathophysiological mechanisms maintaining the pain or modulating pain pathways without targeting the underlying mechanisms (Hansson & Dickenson, 2005). Many centrally acting drugs used in neuropathic pain also have efficacy in the treatment of other pain and nonpain conditions, and it is likely that they act by having a neuronal depressant effect that is not specific to underlying pain mechanisms.
Pharmacological treatment often provides only partial pain relief and no pain relief at all in some patients. The NNT, which is the number of patients needed to treat with a certain drug to obtain one patient with at least 50% pain reduction and is calculated as the reciprocal of the absolute risk reduction, is around four to ten for drugs recommended for neuropathic pain (Finnerup et al., 2015). In comparison, the NNT for nonsteroidal anti-inflammatory drugs (NSAIDs) for acute postoperative pain is on the order of 1.6–2.1 (Moore, Derry, Aldington, & Wiffen, 2015).
The Neuropathic Pain Special Interest group of the IASP published guidelines for the pharmacological treatment of neuropathic pain in 2015 (Finnerup et al., 2015). The guidelines are based on a systematic review and meta-analysis of published and unpublished trials. Only randomized, placebo-controlled, double-blind studies were included. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used to rate the quality of evidence and strength of recommendations (Guyatt et al., 2008). The recommendations are summarized in Table 3. The recommendations are general to neuropathic pain conditions except for TN, for which there is limited evidence from randomized, placebo-controlled trials. Carbamazepine and oxcarbazepine are first-line treatments for TN (Cruccu et al., 2008).
Table 3. Recommendations for the Pharmacological Treatment of Neuropathic Pain
Daily Dosages and Mode of Administration
1,200–3,600 mg in 3 divided doses
1,200–3,600 mg in 2 divided doses
300–600 mg in 2 divided doses
60–120 mg once daily
SNRI venlafaxine ER
150–225 mg once daily
25–150 mg once or twice a day
Capsaicin 8% patches
1–4 patches every 3 months
Second line (PNP)
1–3 patches for up to 12 hours
Second line (PNP)
200–400 mg in 2 or 3 divided doses
Botulinum toxin type A
50–200 units sc every 3 months
Third line (PNP)c
Combination therapy, carbamazepine, lacosamide, lamotrigine, oxcarbazepine, topiramate, zonisamide, SSRI antidepressants, tapentadol, NMDA antagonists, capsaicin cream, topical clonidine
ER = extended release; PNP = peripheral neuropathic pain; sc = subcutaneous; SNRIs = serotonin noradrenaline reuptake inhibitors; TCAs = tricyclic antidepressant.
(a) Tertiary amine TCAs (amitriptyline, imipramine, clomipramine) are not recommended at dosages greater than 75 mg/day in older adults.
(b) IASP recommends caution when prescribing opioids for chronic pain because of tolerance, dependence, and other neuroadaptations that compromise both efficacy and safety (IASP, 2018).
(c) Specialist use. Adapted from Finnerup et al. (2015).
First-line drugs have high-quality evidence and strong GRADE recommendations for use. These are gabapentin (including gabapentin extended release [ER] and gabapentin enacarbil), pregabalin, serotonin–noradrenaline reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs) for both peripheral and central neuropathic pain. Gabapentin and pregabalin bind to α2δ subunits of voltage-gated calcium channels and may act by reducing release of neurotransmitters. Dizziness and drowsiness are the most common side effects. The dose should be reduced in patients with renal insufficiency. TCAs and SNRIs act by inhibiting the reuptake of serotonin and noradrenaline, thereby increasing inhibitory control. TCAs also act on sodium channels and opioid receptors and have NMDA antagonist-like and anticholinergic and antihistamine effects (Sindrup, Otto, Finnerup, & Jensen, 2005). Side effects include drowsiness, dizziness, dry mouth, and orthostatic hypotension. TCAs may cause QT prolongation, and an electrocardiogram should be taken before initiating treatment. Although amitriptyline is the TCA most often examined, TCAs have similar effectiveness on neuropathic pain, and secondary amines (nortriptyline, desipramine) or imipramine may be preferred because of their less sedative side effects (Sindrup et al., 2005). Tertiary amine TCAs (amitriptyline, imipramine, clomipramine) are not recommended at dosages greater than 75 mg/day in patients above 65 years because of their sedative and anticholinergic effects and associated risk of falls (American Geriatrics Society 2012 Beers Criteria Update Expert Panel, 2012).
Drugs with weak recommendation for use are recommended as second- or third-line drugs. Localized treatments include lidocaine 5% and capsaicin 8% patches as second-line treatments and botulinum toxin type A as a third-line treatment for peripheral neuropathic pain. The lidocaine patch contains 5% lidocaine. Up to three to four patches can be applied to intact skin for 12 hours per day. The side effects are local, with skin irritation, and often are mild; use produces minimal systemic exposure of lidocaine. Capsaicin 8% patches have to be applied by a healthcare provider. Up to four patches can be used at the same time and remain applied for 30–60 minutes. There is minimal systemic absorption, and the side effects during application are mainly transient skin reactions with redness, pain, and itching. The treatment may provide up to 3 months of pain reduction, after which the treatment can be repeated. Capsaicin causes degeneration of epidermal nerve fibers. The rate of regeneration is slower in patients with diabetes and HIV (Hahn, Triolo, Hauer, McArthur, & Polydefkis, 2007; Polydefkis et al., 2004), and the long-term safety with repeated applications is not firmly established.
Botulinum toxin type A is administered subcutaneously or intradermally in doses of 100–300 IU divided over the area of pain in a specialist setting. The application is painful, and local anesthetics and inhalation of 50% nitrous oxide and oxygen can be used before and throughout the treatment to minimize the pain (Attal et al., 2016). Besides the pain on application, the treatment is generally considered safe, although there is limited evidence from long-term studies. Tramadol and opioids also have some effect in neuropathic pain, but because of concerns with dependence, addiction, abuse, tolerance, and other harms, IASP recommends caution when prescribing opioids for chronic pain (IASP, 2018).
A number of drugs have inconclusive GRADE recommendations (Table 3). The reason is that the results from clinical trials are inconsistent. It is possible that this is due to poor study designs or high placebo responses or that the drugs are only effective in some patients. Because monotherapy often does not result in sufficient pain relief, combination treatments are often used. This is particularly advantageous if the treatments are complementary with synergistic or additive effects or if the side effects are less additive than the analgesic effects.
Targeted drug delivery, often with the use of intrathecal medication delivery through an implanted pump, can be used in refractory cases. Morphine, for example in combination with clonidine and ziconotide (a selective N-type calcium channel blocker), is used, but there is no high-quality evidence for its use in neuropathic pain, and the treatment is associated with an increased risk for morbidity and mortality (Deer et al., 2012). Given the high placebo responses (Kupers, Maeyaert, Boly, Faymonville, & Laureys, 2007), further placebo-controlled studies are needed.
New drug classes that are under development for the treatment of neuropathic pain include transient receptor potential cation channel subfamily V member 1 (TRPV1) antagonist, subtype-selective sodium channel blockers such as NaV1.7 blockers, angiotensin II type 2 receptor antagonists, and nerve growth factor antagonists (Bouhassira & Attal, 2018).
Neuromodulation using electrical stimulation is increasingly used for chronic pain. Some of the neuromodulation procedures are associated with significant potential risks and costs and can be associated with high placebo effects (Marchand, Kupers, Bushnell, & Duncan, 2003). In general, there is a need for large multicenter placebo-controlled trials in neuropathic pain.
Spinal cord stimulation involves implanted electrodes that deliver an electrical field to the dorsal epidural space. Multiple neurotransmitters are involved in the pain-relieving effects, but we still lack an exact understanding of the neuronal pathways and circuits involved (Sdrulla, Guan, Y., & Raja, 2018). There is low quality of evidence for the effect of spinal cord stimulation in neuropathic pain (Cruccu, Garcia-Larrea, et al., 2016; Dworkin et al., 2013), with best evidence for spinal cord stimulation in failed back surgery and complex regional pain syndrome (Sdrulla et al., 2018). Two randomized trials found the superiority of spinal cord stimulation added to conventional medical treatment compared to conventional medical treatment in painful diabetic neuropathy (de Vos et al., 2014; Slangen et al., 2014). Several new techniques have been developed, including high-frequency technology, dorsal root ganglion stimulation, and burst stimulation (Sdrulla et al., 2018). These are suggested to provide similar or better pain relief; importantly, they make it easier to do placebo-controlled, double-blind randomized trials, as they do not give paresthesia (Wolter, Kiemen, Porzelius, & Kaube, 2012). Peripheral nerve stimulation and peripheral nerve–field stimulation involve implantation of an electrode over the target nerve and subcutaneously in the pain area, respectively (Petersen & Slavin, 2014). There is so far only preliminary evidence for effects in chronic neuropathic pain (Colloca et al., 2017; Petersen & Slavin, 2014).
Noninvasive transcranial brain stimulation techniques include repeated transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). They are thought to act on central modulatory systems (Bouhassira & Attal, 2018). The clinical use is limited because of a low or very low level of quality (Cruccu, Garcia-Larrea, et al., 2016), but multicenter, double-blind, randomized trials are currently under way (Bouhassira & Attal, 2018).
Given the low quality of evidence, the recommendation for deep brain stimulation in neuropathic pain is inconclusive (Cruccu, Garcia-Larrea, et al., 2016), while there is a weak or inconclusive recommendation for the use of epidural motor cortex stimulation for refractory neuropathic pain (Cruccu, Garcia-Larrea, et al., 2016; Dworkin et al., 2013).
Neurosurgical treatments are indicated when they can treat the underlying cause, such as with surgical release of the transverse carpal ligament in carpal tunnel syndrome or removal of a tumor or a herniated disk that presses on a nerve or nerve root or spinal cord. In patients with TN and with a neurovascular conflict, decompression of the trigeminal nerve is the first choice in medically refractory patients (Maarbjerg, Di, Bendtsen, & Cruccu, 2017). The second choice of neurosurgical treatment in TN is lesioning of the trigeminal ganglion by radiofrequency thermocoagulation, although there is no good evidence (Maarbjerg et al., 2017). There is inconclusive evidence for radio-frequency denervation or pulsed radio-frequency for PHN and cervical radiculopathy and weak evidence against radio-frequency lesioning for lumbar radiculopathy (Dworkin et al., 2013). DREZ lesions are sometimes used for brachial or lumbosacral plexus nerve root avulsions, although there is limited evidence (Dworkin et al., 2013). Surgical treatments of neuroma include excision, either alone or with transposition, cap, or repair, and neurolysis and coverage, with no clear difference between techniques (Poppler et al., 2017). As the studies are not controlled, often of low quality, and the follow-up time variable, there is little information on reoccurrence of pain and limited evidence for the long-term effect (Poppler et al., 2017).
Treatment of neuropathic pain is currently a “trial-and-error” process. It has been suggested for many years that a mechanism-based classification of pain will improve the treatment of the individual patient (Max, 1990). One approach is to classify patients based on pain phenotypes (specific symptoms and signs or clusters of such) with the assumption that these reflect specific underlying pain mechanisms (Attal et al., 2008; Baron et al., 2017; Bouhassira & Attal, 2016). There is, however, still limited evidence for this approach. A phenotype-stratified study used QST to divide patients into those with and without the irritable nociceptor phenotype; the primary outcome was to examine whether there was a better effect of the sodium channel blocker oxcarbazepine on the irritable nociceptor phenotype (Demant et al., 2014). This phenotype was defined by hypersensitivity to thermal or mechanical stimuli and preserved small-fiber function (normal cold and warm sensory thresholds). The study found that oxcarbazepine was more effective in patients with than without the irritable nociceptor phenotype. Another trial tested whether the presence or severity of allodynia and sensory deficits as secondary outcomes were predictive of the treatment response to botulinum toxin A (Attal et al., 2016). This study found that patients with allodynia had better effect of the treatment, and that less thermal deficits were associated with greater efficacy of botulinum toxin A. To obtain further knowledge of predictors of drug response, future clinical trials should obtain a detailed description of the individual patient’s pain, including pain descriptors, sensory signs, and psychosocial factors, and report whether any of these are related to the effect, so that it could generate hypotheses to be tested in future trials and analyzed systematically in systematic reviews and meta-analyses.
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