The International Association for the Study of Pain (IASP) has defined pain as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage’.1 Pain is a complex sensory modality, resulting from the physiological activation of nociceptors that trigger a behavioural process to protect the individual from any existing, or further, tissue damage; therefore, it is an essential process for survival.1
Chronic neuropathic pain (NEP) is commonly seen in clinical practice and represents a challenge to patients as well as clinicians. NEP is defined by the IASP as ‘pains resulting from disease or damage of the peripheral or central nervous system and from dysfunction of the nervous system’. NEP can result from damage anywhere along the neuraxis, such as the central nervous system (CNS), peripheral nervous system (PNS), spinal nervous system or supraspinal nervous system, and, to the best of our knowledge, does not serve any protective purpose for the individual.1
Conditions that are frequently associated with NEP can be classified into two main groups: first, conditions that cause damage to the CNS, such as cortical and subcortical strokes, traumatic spinal cord injuries, syringomyelia, trigeminal neuralgia, glossopharyngeal neuralgia and neoplastic as well as other space-occupying lesions; and, secondly, conditions that cause damage to the PNS such as ischaemic neuropathy, peripheral polyneuropathies, nerve root compression, post-amputation stump and phantom pain, post-herpetic neuralgia and cancer-related neuropathies.1
Clinically, NEP can be differentiated from other types of pain by the notable persistence of pain beyond the healing period. It is also characterized by spontaneous shooting pains and evokes amplified pain in response to noxious or non-noxious stimuli. Symptoms consist of both ‘negative’ symptoms such as sensory loss and numbness, and ‘positive’ symptoms such as paraesthesia, spontaneous pain and increased sensation of pain.1
Psychological factors, which include emotional and behavioural responses, are fundamental components in the perception and expression of pain and the patient should be considered in the context of the interactions between biological and psychosocial processes. Attempts to manage pain without considering these interactions will inevitably lead to patient frustration and treatment failure. Management of pain should be tailored to the individual patient on the basis of pain type(s), the causative disease, the relevant psychological factors and the interactions between the biological and psychosocial processes.1
The aim of this article is to review the pathophysiology and treatment modalities of NEP.
There are multiple theories and pathophysiological processes underlying NEP; however, it is crucial to review the physiology of normal pain before exploring that of NEP. The term nociception (from the Latin nocere, meaning ‘to hurt’) refers to the sensory process that is triggered when pain occurs, whereas the term pain refers to the perception of a feeling or the actual sensation of pain.
Nociceptors are unspecialized and unmyelinated nerve endings that transduce a variety of stimuli into nerve impulses, which are interpreted by the brain and lead to the sensation of pain . The nerve cell bodies are located in the dorsal root ganglia, or, in the case the trigeminal nerve, in the trigeminal ganglia, and they send one nerve fibre branch to the periphery of the trigeminal territory and another to the spinal cord or brainstem. There are two types of nociceptors: the C-fibre nociceptors, which respond polymodally to thermal, mechanical and chemical stimuli to produce the sensation of delayed and dull pain, and the A delta (δ)-fibre nociceptors, which respond to mechanical and mechanothermal stimuli to produce the sensation of immediate and sharp pain.2
Normal pain pathways involve activation of nociceptors in response to a painful stimulus. A wave of depolarization is then sent to the first-order neurons, which sodium enters and potassium exits via the sodium–potassium pump. First-order neurons terminate at the brainstem, in the trigeminal nucleus or in the dorsal horn of the spinal cord, and it is here that the electrochemical signals open voltage-gated calcium channels in the presynaptic terminal, allowing calcium to enter and glutamate (an excitatory neurotransmitter) to be released into the synaptic space. Glutamate binds to N-methyld- aspartate (NMDA) receptors on the second-order neurons, causing depolarization. These neurons then cross over in the spinal cord and ascend to enter the thalamus, where they synapse with the third-order neurons. These, in turn, connect to the limbic system and the cerebral cortex.2
Antinociceptive neurons originate in the brainstem and descend the spinal cord, where they synapse with short interneurons in the dorsal horn, releasing serotonin and noradrenaline. The interneurons modulate the synapse between the first-order neurons and the second-order neurons by releasing gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, which results in pain cessation. Suppression of inhibitory synaptic connections can enhance pain sensation.2
Both basic and human research indicates that a lesion of afferent pathways is necessary for development of NEP.2 Furthermore, data clearly indicate that several mechanisms can lead to NEP and that many of these mechanisms do not depend on the cause of the disease, i.e. the same mechanism underlies different diseases. The main mechanisms for the development NEP are as follows.
Ectopic nerve activity
The sensation of ongoing spontaneous pain, combined with paroxysmal shooting pain, in the absence of an external stimulation, is caused by ectopic impulse generation within nociceptive pathways. After a peripheral nerve lesion, spontaneous activity is evident in both the injured and neighbouring uninjured nociceptive afferents.3–5 Increasing levels of messenger RNA in association with voltage-gated sodium channels seem to correlate with ectopic activity. In addition, increased expression of sodium channels in injured and intact fibres may lower the action potential threshold until ectopic activity occurs. Similar changes in the second-order nociceptive neurons are thought to occur after a central lesion, which leads to central NEP.6
Upregulation of receptor proteins
Nerve injury can induce upregulation of various receptor proteins located in undamaged peripheral nociceptive endings and downregulation of receptor proteins in damaged nerve endings, which may result in spontaneous nerve activity. This spontaneous nerve activity may be induced by normally innocuous tactile stimuli that do not usually induce pain (known as allodynia), or an abnormality such as hyperalgesia (an increased response to normal painful stimuli).2,4,5,7
Central sensitization may develop as a result of ectopic activity in the primary nociceptive afferent fibres without actual structural damage to the CNS. Ongoing discharges of peripheral afferent fibres that release excitatory amino acids and neuropeptides within the dorsal horn of the spinal cord lead to postsynaptic changes in second-order nociceptive neurons, such as the expression of voltage-gated sodium channels. These changes induce neuronal hyperexcitability that enables low-threshold mechanosensitive A beta (β) and Aδ afferent fibres to activate second-order nociceptive neurons, resulting in allodynia. Similar mechanisms may take place at the supraspinal levels.2,4,5,7
Inflammation following a nerve lesion induces activation of macrophages that migrate into the nerve and dorsal root ganglion and release proinflammatory cytokines, including tumour necrosis factor alpha (α), which contributes to pain hypersensitivity. Following peripheral and central nerve lesions, activated microglia within the CNS release several immune modulators that also play a role in NEP.7
After a peripheral nerve lesion, inhibitory GABAergic interneurons in the spinal horn are lost. Prevention of interneuron cell death attenuates the mechanical and thermal hyperalgesia and contributes to NEP. Furthermore, lesions that affect the opioidergic and monoaminergic systems (the inhibitory descending pathways that originate in the brainstem and block pain) contribute to pain exacerbation through disinhibition.2,4,5,7
Pharmacological management of neuropathic pain
The management of a patient with chronic NEP is challenging and the primary goal is to treat the pain and associated comorbidities, such as anxiety and depression. The secondary goals of treatment are to improve sleep, the ability to function normally and the overall quality of life.
Tricyclic antidepressants (TCAs) are the most effective treatment in the management of NEP. These drugs, which were originally thought to block the reuptake of noradrenaline and serotonin, actually block NMDA agonist-induced hyperalgesia and also have sodium channel-blocking properties.8 Although the analgesic effect of TCAs is independent of the antidepressant effect, the analgesic effect could be beneficial to those suffering from depression as depression is commonly associated with NEP.8–11
The anticholinergic effect of TCAs is associated with several adverse effects, such as a dry mouth, constipation, sweating, dizziness, blurred vision, drowsiness, palpitation, orthostatic hypotension, sedation and urinary retention. TCAs can also cause cognitive disorders and disturbance to gait, which may result in falls, particularly in elderly patients.8–11 These adverse effects mean that precautions need to be taken while using TCAs and electrocardiography needs to be conducted before the start of treatment, especially in patients over 40 years of age and/or with a history of ischaemic heart disease, as these patients are at a higher risk of developing adverse effects while taking TCAs. More selective TCAs, such as nortriptyline, cause fewer anticholinergic and sedation effects.8–11
Tricyclic antidepressants should be taken at low dosages initially (10–25 mg in the evening) and then slowly tailored on an individual basis depending on how the patient tolerates the drug. The reported effective dosage of amitriptyline, or its equivalent, ranges from 25 to 150 mg, with the average dosage being 75 mg per day. Owing to the substantial pharmacokinetic variability of TCAs, the monitoring of serum drug concentrations is helpful for guiding treatment.8–11
Serotonin–noradrenaline reuptake inhibitors
Duloxetine and venlafaxine are serotonin–noradrenaline reuptake inhibitors (SNRIs) that are efficacious in the treatment of painful polyneuropathies. The most common adverse effects associated with duloxetine are nausea, somnolence, a dry mouth, constipation, reduced appetite, diarrhoea, hyperhidrosis and dizziness. Additional rare adverse effects that have been reported are the elevation of plasma glucose, hepatic enzymes or blood pressure. The reported adequate dosage of duloxetine ranges from 60 to 120 mg per day. Treatment should be prescribed at 30 mg per day initially to avoid nausea and increased to 60 mg per day after 1 week. In comparison, only high doses of venlafaxine (150–225 mg per day) are effective. Patients have been reported to tolerate venlafaxine better than duloxetine and the main side-effect is gastrointestinal disturbance.8–11
Gabapentin and pregabalin bind to presynaptic voltage-gated calcium channels in the dorsal horn, resulting in a decrease in the release of excitatory neurotransmitters such as glutamate and substance P. Studies reporting on diabetic neuropathy12 and post-herpetic neuralgia13 concluded that gabapentin treatment produced significant pain relief and significant improvement in quality of life and patient mood. Pregabalin is an analogue of gabapentin with the same mechanism of action, but demonstrates linear pharmacokinetics and has a higher affinity for the presynaptic calcium channel. It has been shown that pregabalin provides significant pain relief and improved quality of sleep in post-herpetic neuralgia and painful diabetic neuropathy. Pregabalin also produces significant pain relief for chronic central NEP following injury to the spinal cord.9–13
The most common side-effects of gabapentin and pregabalin are dizziness, somnolence, peripheral oedema, weight gain, asthenia, headache and a dry mouth. The reported effective dosage is 1800–3600 mg per day for gabapentin and 150–600 mg per day for pregabalin; however, inconsistent effects have been reported with a dose of 150 mg of pregabalin per day. Both drugs need to be tailored to the individual patient, but the period for tailoring is generally shorter for pregabalin (the dose should be increased by 75 mg every 3 days) than for gabapentin (the dose should be increased by 600–900 mg over 3 days in three divided doses). Gabapentin is generally administered three times a day, with the exception of the extended-release formulation, which releases drug over an extended period of time; pregabalin is generally administered twice a day.
Carbamazepine remains the treatment of choice for cases of idiopathic trigeminal neuralgia; however, this drug is not recommended for the management of NEP.
Lidocaine relieves pain through the non-specific block of sodium channels on the ectopic peripheral afferent fibres without causing numbness of the treated skin. Lidocaine patches are generally safe and give low systemic absorption, which offers the benefit of local side-effects only, such as a mild skin reaction. Up to four patches per day may be used to cover the painful area and alteration of the dosage is not necessary. Lidocaine patches are most appropriate for localized peripheral NEP such as post-herpetic neuralgia.14
Tramadol shows direct agonist activity at both presynaptic and postsynaptic opioid receptors. Furthermore, it has additional analgesic properties through the inhibition of serotonin and noradrenaline reuptake. Tramadol can induce dizziness, a dry mouth, nausea, constipation and somnolence and can aggravate existing cognitive impairment, particularly in elderly patients. Patients with history of epilepsy, or who are receiving drugs to reduce the seizure threshold, such as TCAs, are at an increased risk of seizures while taking tramadol. Serotonergic syndrome may occur if tramadol is used in combination with serotonergic medication, particularly SNRIs. The effective dose of tramadol ranges from 200 to 400 mg per day, but it should be prescribed at low dosage initially (50 mg per day), and continuous low dosage is recommended for elderly patients and patients with renal impairment and cirrhosis.10,11,15
Opioid analgesics such as oxycodone, methadone, fentanyl and morphine are presynaptic and postsynaptic opioid receptor agonists. Randomized controlled trials have reported the efficacy of opioids for different peripheral and central neuropathic disorders.10,11,15,16 Opioids have a comparable analgesic efficacy to TCAs;17 however, concerns about long-term side-effects, such as immunological changes, physical dependency and drug abuse, may limit the use of strong opioids in patients with chronic neuropathic non-cancerous pain. Oxycodone is the most commonly studied drug for the treatment of NEP and the recommended dose ranges from 10 to 200 mg per day.
Using opioids for the treatment of NEP is not necessarily associated with a significant improvement in quality of life, psychological comorbidities or sleep disorders.15 The most common side-effects are constipation, sedation, nausea, dizziness and vomiting; however, these effects generally decrease after long-term treatment. Opioid-induced hyperalgesia, which consists of an increase in pain sensitivity and potential aggravation of existing pain, may also be observed in patients receiving long-term opioid treatment.
Mexiletine is a class 1B local anaesthetic and antiarrhythmic agent that functions by blocking sodium channels. Mexiletine regulates an ectopic neural pacemaker by slowing its conduction and therefore may have a prolonged duration of action. However, mexiletine has produced positive results in only two of seven NEP trials.18
Clonidine is an α2-agonist sympathetic blocker which has proved to have benefits for a subset of patients with painful diabetic neuropathy in an enriched enrolment trial.16
Capsaicin is an agonist of the transient receptor potential vanilloid receptors (TRPV1s) on nociceptive fibres. After several days of capsaicin treatment, TRPV1-containing sensory axons become desensitized, thereby inhibiting the transmission of pain. Standard capsaicin-containing creams have been found to be moderately effective in postherpetic neuralgia; however, these creams need to be applied several times a day and cause a burning sensation before the analgesic effect begins. Recently, a single highly concentrated (8%) capsaicin patch, applied to the painful area for 30, 60 or 120 minutes, has been demonstrated to be effective during weeks 2–12 of post-herpetic neuropathy.15
Adverse effects while using capsaicin are primarily due to local capsaicin-related reactions at the application site (pain, erythema and sometimes oedema and itching). Furthermore, the patient's blood pressure should be monitored because of the risk of high blood pressure during treatment.15
The therapeutic potential of cannabinoids for the remedy of chronic pain has been extensively investigated. Oromucosal cannabinoids (2.7 mg δ-9-tetrahydrocannabinol plus 2.5 mg cannabidiol) have been found to be effective for multiple sclerosis-associated pain and allodynia associated with refractory peripheral NEP.15 Adverse effects include dizziness, a dry mouth, sedation, fatigue, gastrointestinal problems and oral discomfort, and cannabinoids may aggravate existing mental conditions. Oromucosal cannabinoids are currently available for the treatment of NEP only in Canada.
Botulinum toxin A
Several investigations have suggested that botulinum toxin A (BTX-A), a potent neurotoxin commonly used for the treatment of focal muscle hyperactivity, may have analgesic effects that are independent of its action on muscle tone, possibly by acting on neurogenic inflammation.19 In patients with mononeuropathy, 100–200 units of BTX-A is injected into the painful area, which is usually the area associated with mechanical allodynia; the onset of action of BTX-A is about 1 week and duration of effect 3 months. BTX-A has an excellent safety profile with no systemic side-effects.
Summary of current recommendations for medical treatment of neuropathic pain
Management of NEP should be tailored to the individual patient on the basis of pain type(s), the causative disease, the relevant psychological factors and the interactions between the biological and psychosocial processes. Classification of evidence for drug treatments in commonly studied NEP conditions, and recommendations for their use, can be seen in Table 1.
|Aetiology||Level Aa rating for efficacy||Level Bb rating for efficacy||Level Cc rating for efficacy||Level A/B rating for inefficacy or discrepant results||Recommendations as first-line treatment||Recommendations as second- or third-line treatment|
Tramadol alone or with acetaminophen
Venlafaxine extended release
Selective serotonin reuptake inhibitors
Venlafaxine extended release
Capsaicin 8% patch
|Capsaicin cream Valproate*||
Cannabinoids (oromucosal or oral) (multiple sclerosis)
Pregabalin (spinal cord injury)
Lamotrigine (central post-stroke pain)
TCAs (spinal cord injury, central post-stroke pain)
Tramadol (spinal cord injury)*
Duloxetine (found efective in allodynia in one study)
Lamotrigine in spinal cord injury (except in patient with allodynia in one study)
|Gabapentin Pregabalin TCAs||
Cannabinoids (multiple sclerosis)
Tramadol (spinal cord injury)
a Good scientific evidence suggests that the benefits of treatment substantially outweigh the potential risks.
c At least fair scientific evidence suggests that there are benefits provided by the clinical service, but the balance between benefits and risks are too close for making general recommendations.
Clinicians need not offer it unless there are individual considerations.
f Tramadol is recommended as a first-line treatment in patients with acute exacerbations of pain, in particular the tramadol–acetaminophen combination.
Tricyclic antidepressants, gabapentin, pregabalin and SNRI antidepressants are recommended as first-line treatments for NEP by the Neuropathic Pain Special Interest Group of the IASP10,11,15 and the European Federation of the Neurological Society.10 It is reasonable to initiate treatment with either TCAs or anticonvulsants and, if TCAs fail, then switch to anticonvulsants, or vice versa. If TCAs provide only partial relief, then an anticonvulsant can be added to the treatment plan.
Topical lidocaine is recommended as a first-line treatment in for post-herpetic neuralgia, especially in elderly patients. If first-line medications fail, tramadol or conventional opioid analgesics may be useful as second-line treatment; however, these are also recommended as first-line treatments in patients with episodic pain exacerbations10 and for breakthrough pain during the first-line medication-tailoring period.
Third-line treatment for management of NEP includes prescription of cannabinoids, mexiletine, clonidine, methadone, lamotrigine, topramate and valproic acid. These should be considered when other options have failed or are not possible and they can be considered as adjunctive therapies if there is no concern regarding polypharmacy or drug interactions. Intractable pain may require treatment with a combination of antidepressants, anticonvulsants and opioids.