Neuropathic Pain
Neuropathic Pain
Various classes of drugs have proven effectiveness in NP in randomised clinical trials; they include tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors antidepressants, antiepilepsy drugs active on sodium channels (carbamazepine, lamotrigine) and calcium channels (α2-δ ligands), opioids, topical lidocaine and capsaicin, and cannabinoids. Some recent meta-analysis and guidelines indicate which drugs should be first, second and third line treatment for NP. Despite this, the treatment of NP is still challenging in the real-life setting. Patients with NP usually require more drugs and report less pain relief than those with nociceptive pain. Common practical reasons for these unsatisfactory outcomes include the prescription of drugs without proven efficacy on NP or use of drugs effective on NP but at insufficient dosage, and side effects, which frequently cause drugs to be stopped. There are other methodological reasons for the gap between guidelines/meta-analysis and real life. The randomised controlled trials enrolled patients mostly with diabetic NP and postherpetic neuralgia, and it is unclear whether their conclusions can be extrapolated to other NP conditions. More recent trials have had more robust designs and explored measures of quality of life, sleep, anxiety and depression in addition to NP intensity (which was the only outcome in older studies). As a result, the evidence for older drugs (eg, tricyclic antidepressants) may be less robust and less complete than for newer ones. There are very few head-to-head randomised controlled trials; comparisons between drugs are based on their respective number needed-to-treat and number needed-to-harm, which may be influenced by different patient populations and differences between placebo effects between trials.
There is a good agreement between guidelines that tricyclic antidepressants, α2-δ ligands, serotonin-norepinephrine reuptake inhibitors, carbamazepine (for trigeminal neuralgia) and topical lidocaine (for localised peripheral NP) are the first line drugs, and tramadol and opioids are second line drugs (figure 5; Table 7). Concerns about side effects, long-term safety, opioids hyperalgesia and addiction have made opioids second line treatment, except in cancer NP, acute or breakthrough (ie, with transitory worsening) NP, or when rapid pain relief is needed while titrating other drugs.
(Enlarge Image)
Figure 5.
Algorithm for the treatment of NP. AEDs, antiepilepsy drugs; BTX, botulinum toxin; CBZ, carbamazepine; CLZ, clonazepam; COPD, chronic obstructive pulmonary disease; CPSP, central poststroke pain; DXM, dextromethorphan; GBP, gabapentin; IVIG, intravenous immunoglobulin; LTG, lamotrigine; MAOIs, monoamine oxidase inhibitors; NP, neuropathic pain; PGB, pregabalin; SNRIs, serotonin-norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants; TN, trigeminal neuralgia.
When first and second line treatments are ineffective or not tolerated, there are other possibilities. They include selective serotonin reuptake inhibitors, other antidepressants (bupropion, citalopram, paroxetine), antiepileptic medications (carbamazepine, oxcarbazepine, lamotrigine, phenytoin, topiramate, valproate), high-concentration capsaicin patches, cannabinoids (for central NP, especially multiple sclerosis), mexiletine, memantine, dextromethorphan, clonazepam, botulinum toxin type A and intravenous immunoglobulin.
Few randomised controlled trials have examined combination therapy in NP, but they converged on there being a more marked pain reduction and fewer side effects when using two drugs together (α2-δ ligands+opioids; α2-δ ligands+tricyclic antidepressants) than each drug alone. The combination of NP drugs may also target different NP mechanisms in the same patient.
Mixed pain (ie, a combination of NP and nociceptive pain) is present in many conditions, including neuropathic low back pain, nerve/root compression and cancer pain. Evidence based medicine does not offer any information for these patients, but combining NP drugs and analgesics for nociceptive pain seems reasonable.
Invasive treatments (neurostimulation, intrathecal infusion of opioids, local anaesthetics, baclofen and ziconotide) are commonly used for patients whose NP is refractory to other therapies. There is only a weak quality of evidence base for these invasive approaches, largely from open case series without a control group. Spinal cord stimulation is a reasonable choice in refractory neuropathic low back pain, and motor cortex stimulation may be the last resort in refractory central poststroke pain.
Despite the availability of several drugs, no more than 30%–50% of NP patients achieve a satisfactory response. Randomised controlled trials recruit patients according to the NP aetiology, and this fails to capture the complex relationship among causes, pathophysiology and clinical manifestations of NP. Furthermore, most trials do not assess pain quality, although some drugs might be effective in subgroups of patients with specific clinical phenotypes or with some NP features. For these reasons, the definition of sensory profiles through symptoms (NP questionnaires) and signs (bedside assessment and quantitative sensory testing) may better stratify patients in randomised controlled trials and personalise treatment of NP. This perspective is tempting but its clinical utility has not yet been demonstrated.
Patients with NP often receive non-pharmacological treatments, including physical exercise, physical therapies (eg, transcutaneous electrical nerve stimulation, graded motor imagery), cognitive behavioural therapy or supportive psychotherapy. There is only limited evidence supporting these treatments, but they play a role in the comprehensive and multidisciplinary management of a complex clinical problem.
The delivery of care for NP may vary between countries, but it is usually performed in an outpatient setting. General practitioners play an important role in first line treatment, given the high prevalence of NP, while consultations with specialised neurology or pain centres are limited to refractory cases. Specialised centres should include medical and paramedical specialties to offer a multidisciplinary approach.
Treatment
Various classes of drugs have proven effectiveness in NP in randomised clinical trials; they include tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors antidepressants, antiepilepsy drugs active on sodium channels (carbamazepine, lamotrigine) and calcium channels (α2-δ ligands), opioids, topical lidocaine and capsaicin, and cannabinoids. Some recent meta-analysis and guidelines indicate which drugs should be first, second and third line treatment for NP. Despite this, the treatment of NP is still challenging in the real-life setting. Patients with NP usually require more drugs and report less pain relief than those with nociceptive pain. Common practical reasons for these unsatisfactory outcomes include the prescription of drugs without proven efficacy on NP or use of drugs effective on NP but at insufficient dosage, and side effects, which frequently cause drugs to be stopped. There are other methodological reasons for the gap between guidelines/meta-analysis and real life. The randomised controlled trials enrolled patients mostly with diabetic NP and postherpetic neuralgia, and it is unclear whether their conclusions can be extrapolated to other NP conditions. More recent trials have had more robust designs and explored measures of quality of life, sleep, anxiety and depression in addition to NP intensity (which was the only outcome in older studies). As a result, the evidence for older drugs (eg, tricyclic antidepressants) may be less robust and less complete than for newer ones. There are very few head-to-head randomised controlled trials; comparisons between drugs are based on their respective number needed-to-treat and number needed-to-harm, which may be influenced by different patient populations and differences between placebo effects between trials.
There is a good agreement between guidelines that tricyclic antidepressants, α2-δ ligands, serotonin-norepinephrine reuptake inhibitors, carbamazepine (for trigeminal neuralgia) and topical lidocaine (for localised peripheral NP) are the first line drugs, and tramadol and opioids are second line drugs (figure 5; Table 7). Concerns about side effects, long-term safety, opioids hyperalgesia and addiction have made opioids second line treatment, except in cancer NP, acute or breakthrough (ie, with transitory worsening) NP, or when rapid pain relief is needed while titrating other drugs.
(Enlarge Image)
Figure 5.
Algorithm for the treatment of NP. AEDs, antiepilepsy drugs; BTX, botulinum toxin; CBZ, carbamazepine; CLZ, clonazepam; COPD, chronic obstructive pulmonary disease; CPSP, central poststroke pain; DXM, dextromethorphan; GBP, gabapentin; IVIG, intravenous immunoglobulin; LTG, lamotrigine; MAOIs, monoamine oxidase inhibitors; NP, neuropathic pain; PGB, pregabalin; SNRIs, serotonin-norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants; TN, trigeminal neuralgia.
When first and second line treatments are ineffective or not tolerated, there are other possibilities. They include selective serotonin reuptake inhibitors, other antidepressants (bupropion, citalopram, paroxetine), antiepileptic medications (carbamazepine, oxcarbazepine, lamotrigine, phenytoin, topiramate, valproate), high-concentration capsaicin patches, cannabinoids (for central NP, especially multiple sclerosis), mexiletine, memantine, dextromethorphan, clonazepam, botulinum toxin type A and intravenous immunoglobulin.
Few randomised controlled trials have examined combination therapy in NP, but they converged on there being a more marked pain reduction and fewer side effects when using two drugs together (α2-δ ligands+opioids; α2-δ ligands+tricyclic antidepressants) than each drug alone. The combination of NP drugs may also target different NP mechanisms in the same patient.
Mixed pain (ie, a combination of NP and nociceptive pain) is present in many conditions, including neuropathic low back pain, nerve/root compression and cancer pain. Evidence based medicine does not offer any information for these patients, but combining NP drugs and analgesics for nociceptive pain seems reasonable.
Invasive treatments (neurostimulation, intrathecal infusion of opioids, local anaesthetics, baclofen and ziconotide) are commonly used for patients whose NP is refractory to other therapies. There is only a weak quality of evidence base for these invasive approaches, largely from open case series without a control group. Spinal cord stimulation is a reasonable choice in refractory neuropathic low back pain, and motor cortex stimulation may be the last resort in refractory central poststroke pain.
Despite the availability of several drugs, no more than 30%–50% of NP patients achieve a satisfactory response. Randomised controlled trials recruit patients according to the NP aetiology, and this fails to capture the complex relationship among causes, pathophysiology and clinical manifestations of NP. Furthermore, most trials do not assess pain quality, although some drugs might be effective in subgroups of patients with specific clinical phenotypes or with some NP features. For these reasons, the definition of sensory profiles through symptoms (NP questionnaires) and signs (bedside assessment and quantitative sensory testing) may better stratify patients in randomised controlled trials and personalise treatment of NP. This perspective is tempting but its clinical utility has not yet been demonstrated.
Patients with NP often receive non-pharmacological treatments, including physical exercise, physical therapies (eg, transcutaneous electrical nerve stimulation, graded motor imagery), cognitive behavioural therapy or supportive psychotherapy. There is only limited evidence supporting these treatments, but they play a role in the comprehensive and multidisciplinary management of a complex clinical problem.
The delivery of care for NP may vary between countries, but it is usually performed in an outpatient setting. General practitioners play an important role in first line treatment, given the high prevalence of NP, while consultations with specialised neurology or pain centres are limited to refractory cases. Specialised centres should include medical and paramedical specialties to offer a multidisciplinary approach.
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