Introduction
1. Neuropathic pain |
CQ1: How do we define and understand neuropathic pain in clinical medicine? A |
2. Pathology of Neuropathic Pain |
CQ2: How do we understand the pathology of neuropathic pain? A |
3. Diseases which present with neuropathic pain |
CQ3: What diseases are associated with neuropathic pain? A |
4. Neuropathic pain classification and mixed pain condition |
CQ4: What is the neuropathic and nociceptive pain classification and its clinical significance? A |
5. Pain associated with acute peripheral nerve inflammation |
CQ5: Is acute pain that is associated with peripheral nerve inflammation regarded as neuropathic pain? 2C |
6. Chronic pain syndrome and neuropathic pain |
CQ6: What is the chronic pain syndrome in neuropathic pain patients? B |
7. Epidemiology of neuropathic pain |
CQ7: Are there any epidemiological surveys on the prevalence of neuropathic pain? D |
CQ8: Are there any epidemiological surveys on the prevalence of neuropathic pain in cancer patients? C |
8. Diagnosis of neuropathic pain |
CQ9: How do we screen patients who may have neuropathic pain? 1D |
CQ10: How do we diagnose neuropathic pain? 1D |
9. Clinical characteristics of neuropathic pain |
CQ11: What are the clinical characteristics of neuropathic pain? 2D |
10. Neuropathic pain and quality of life (QOL) |
CQ12: What is the impact of neuropathic pain on QOL? 1B |
11. Management plan for neuropathic pain: general remarks |
CQ13: What is the summary of the management plan for neuropathic pain? B |
12. Treatment goal for neuropathic pain |
CQ14: How do we establish the treatment goal for neuropathic pain? 1D |
13. What is neuropathic pain? |
CQ15: What are indexes of the effects of pharmacotherapy for neuropathic pain and the levels of recommendation for the respective drugs? 1B |
13-1 First-line drugs |
• Pregabalin/gabapentin |
• Tricyclic antidepressants (TCAs) |
• Serotonin-noradrenaline reuptake inhibitors (SNRI) |
13-2 Second-line drugs |
• Extract from inflamed cutaneous tissue of rabbits inoculated with vaccinia virus |
• Opioid analgesic [weak]: tramadol |
13-3 Third-line drugs |
• Opioid analgesic |
CQ16: What is the level of recommendation for NSAIDs and acetaminophen for neuropathic pain? 1B |
14. Calcium channel α-2 delta ligand |
CQ17: What is the level of recommendation for pregabalin for neuropathic pain? 1A |
15. Tricyclic antidepressants |
CQ18: Are tricyclic antidepressants useful for neuropathic pain? 1B |
CQ19:What are tricyclic antidepressants (TCAs)? How can we differentiate their uses? 1B |
16. Serotonin-noradrenaline reuptake inhibitor (SNRI) |
CQ20: Are SNRIs effective for neuropathic pain? 1A |
17. Extracts from Inflamed Cutaneous Tissue of Rabbits Inoculated with Vaccinia Virus |
CQ21: What are the features of the extracts from inflamed cutaneous tissue of rabbits inoculated with vaccinia virus? 2B |
18. Pharmacotherapy for neuropathic pain: tramadol |
CQ22: What is the recommendation for tramadol for neuropathic pain? 1A |
19. Opioid analgesics [moderate]: Buprenorphine transdermal patch |
CQ23: What are the features of buprenorphine? (not applicable) |
CQ24: Is buprenorphine effective for neuropathic pain? 2C |
CQ25: What is the efficacy of the buprenorphine patch for neuropathic pain? 2C |
CQ26: What is the safety and tolerability of the buprenorphine patch? 1B |
20. Opioid analgesics [strong]: |
CQ27: Are strong opioid analgesics useful for neuropathic pain? 2C |
21. Pharmacotherapy for Neuropathic pain |
22. Other antidepressants |
CQ28: Are anti-depressants other than TCAs and SNRIs useful for neuropathic pain? 2C |
23. Anti-epileptics |
CQ29: Are anti-epileptics other than pregabalin/gabapentin more effective for neuropathic pain compared to placebo? 2C |
24. N-methyl-D-aspartate (NMDA) receptor antagonists |
CQ30: Are NMDA receptor agonists useful for neuropathic pain? 2C |
25. Anti-arrhythmic drug |
CQ31: Is an anti-arrhythmic drug (mexiletine hydrochloride) effective for neuropathic pain? 2B |
26. Chinese herbal medicine |
CQ32: Is Chinese herbal medicine effective for neuropathic pain? 2D |
27. Post-herpetic neuralgia (chronic phase) |
CQ33: What is the first drug to be considered for post-herpetic neuralgia? 1A |
CQ34: Are opioids effective for post-herpetic neuralgia? 2B |
CQ35: Is there any other drug that should be considered for post-herpetic neuralgia? 1B |
28. Post-traumatic peripheral neuropathy |
CQ36: Are calcium channel alpha-2-delta ligands useful for post-traumatic peripheral neuropathy? 2B |
CQ37: Are opioids useful for post-traumatic peripheral neuropathic pain? 2C |
CQ38: Are there any other drug therapies that are effective for post-traumatic peripheral neuropathic pain? 2D |
29. Pharmacotherapy for painful diabetic neuropathy |
CQ39: What is the basic management plan and the level of recommendation for drugs for painful diabetic neuropathy? 1B |
30. Trigeminal neuralgia |
CQ40: Is carbamazepine more effective for trigeminal neuralgia compared to placebo? 1B |
CQ41: Are there any drugs other than carbamazepine that are effective for trigeminal neuralgia? 2C |
31. Central neuropathic pain |
CQ42: What drug therapies are useful for central post-stroke pain? 2B |
CQ43: What drug therapies are useful for neuropathic pain associated with multiple sclerosis? 2C |
32. Pain after spinal cord injury |
CQ44: Are TCAs and calcium channel alpha-2-delta ligands useful for pain after spinal cord injury? 1A |
CQ45:Are opioids useful for pain after spinal cord injury? 2B |
CQ46: Are there any drugs that are effective for pain after spinal cord injury other than TCAs, calcium channel alpha-2-delta ligands, and opioids? 2C |
33. Chemotherapy-induced peripheral neuropathy |
CQ47: Is duloxetine useful for chemotherapy-induced peripheral neuropathy? 1C |
CQ48: Are there any drugs other than duloxetine that are useful for chemotherapy-induced peripheral neuropathy? 2D |
34. Neuropathic pain directly caused by cancer |
CQ49: Are strong opioids effective for neuropathic pain directly caused by cancer? 1A |
CQ50: Are neuropathic medications effective for neuropathic pain directly caused by cancer? 2C |
35. Post-operative neuropathic pain (e.g., painful scar) and iatrogenic neuropathy (e.g., post-thoracotomy neuropathic pain, post-mastectomy neuropathic pain) |
CQ51: Does perioperative drug administration reduce post-operative neuropathic pain? 1B |
CQ52: Are there any drugs that are useful for complete chronic post-thoracotomy pain? 1A |
CQ53:Are there any drugs that are useful for complete chronic post-mastectomy pain? 1B |
CQ54: What drug is useful for pain after inguinal hernia repair? 2B |
37. Cervical and lumbar radiculopathy |
CQ55: Are antidepressants useful for cervical and lumbar radiculopathy? 2B |
CQ56: Are calcium channel alpha-2-delta ligands effective for lumbar radiculopathy? 1C |
CQ57: Are opioids effective for cervical and lumbar radiculopathy? 2D |
CQ58: Are there any drugs other than antidepressants, calcium channel alpha-2-delta ligands, and opioids that are effective for cervical and lumbar radiculopathy? 2D |
Task force
Drafting recommendations
Evidence and recommendation levels
Level of evidence |
Level A (strong) Evidence from the results of studies is established. The results will not change even if further studies are conducted |
Level B (moderate) Some clinical investigations moderately support the results but evidence is not enough and confirmed. Further studies might change the results |
Level C (low) Although some clinical investigations suggest the results, the results are still controversial. Further studies would be required and these might change the results |
Level D (very low) There is insufficient evidence for the results. Further studies should be conducted to consider the validity of the results |
Strength of recommendation |
1 (strong): Recommended treatment is certainly of benefit to patients with neuropathic pain, and the benefit exceeds the harm or burden. In the statement, the term “should” is used |
2 (weak): Recommended treatment might be of benefit to patients with neuropathic pain or the benefit may or may not exceed the harm or burden from the recommended treatment. In the statement, the term “might” is use |
Overview of the understanding neuropathic pain
Diseases which present neuropathic pain
Nutrition metabolism | Traumatic | |
Alcoholic polyneuropathy Alcoholic neuropathy Neuropathy due to malnutrition (e.g., beriberi, pellagra) Hypothyroid neuropathy Painful diabetic polyneuropathy Uremic neuropathy Fabry disease Porphyric neuropathy | Iatrogenic neuropathy Post-thoracotomy pain syndrome Post-traumatic sequelae/post-operative sequelae (e.g., persistent post-operative wound pain) Post-ischemic myelopathy Phantom pain Nerve root avulsion Neuropathic myelopathy Nerve injury sequelae Tethered cord syndrome Spinal cord Hemorrhage/infarction Spinal cord injury sequelae Multiple cranial neuropathy | Stump neuralgia Post-mastectomy Stroke sequelae (e.g. thalamic pain, CNS vascular malformation) Complex Regional Pain Syndrome Post-herniorrhaphy pain Radiation-induced plexopathy Radiation-induced encephalopathy/myelopathy Peripheral neurotmesis/injury Brachial plexus avulsion |
Genetic
| ||
Hereditary polyneuropathy with liability to pressure palsy Hereditary sensory and autoimmune neuropathy | ||
Ischemic
|
Toxic
|
Infectious
|
Allergic granulomatous vasculitis Reversible ischemic neuropathy Ischemic neuropathy Connective tissue disease (vasculitis) Polyarteritis nodosa Cryoglobulinemia Mononeuritis multiplex | Chemotherapy-induced neuropathy Gold Mercurial poisoning Toxic neuromyopathy Thinner Lead Arsenic poisoning Drug-induced polyneuropathy Subacute myelo-optico neuropathy (SMON) | Diphtheritic polyneuropathy Neurosyphilis Tabes dorsalis Post-herpetic neuralgia Leprosy neuropathy Lyme disease HIV sensory neuropathy HIV myelopathy HIV neuropathy |
Compression/entrapment
| ||
Crural neuralgia Cervical spondylotic radiculopathy Cubital/antebrachial/wrist/foot/thigh/shoulder Entrapment neuropathy Sciatica Sciatic nerve entrapment Trigeminal neuralgia Cervical/thoracic/lumbosacral spinal cord radiculopathy Neuralgia | Carpal tunnel syndrome Cervical/lumbar spondylolisthesis Myeloradiculopathy Myelopathy Spinal canal stenosis Compressive myelopathy due to spinal canal stenosis Glossopharyngeal neuropathy Hypoglossal neuropathy Multiple sclerosis Polyneuropathy | Intervertebral disc displacement Chronic neuralgia Chronic cauda equine disorder Lumbar sciatic neuralgia Lumbar spondylosis Low back pain Intercostal neuralgia |
Immune
|
Neoplastic
|
Degenerative
|
Carcinomatous neuropathy Guillain–Barre syndrome Sjogren’s syndrome Autoimmune neuropathy Plexitis Inflammatory demyelinating polyneuropathy Idiopathic neuropathy | Malignant tumor Nerve compression by tumor or neuralgia due to tumor invasion Spinal cord tumor Brain tumor Peripheral nerve tumor Neuroma Neurosarcoidosis Neurilemmoma | Amyloidotic autonomic neuropathy Charcot joint Autonomic neuropathy Syringomyelia/syringobulbia Parkinson’s disease Adrenomyeloneuropathy |
Epidemiology of neuropathic pain
Diagnosis and treatment of neuropathic pain
ID Pain | NPQ | painDETECT | LANSS | DN4 | Neuropathic pain screening tool | |
---|---|---|---|---|---|---|
Stinging, prickling pain | + | + | + | + | + | + |
Pain like electric shock or shooting pain | + | + | + | + | + | + |
Smart or burning pain (irritation) | + | + | + | + | + | + |
Tingling pain | + | + | + | + | + | |
Pain induced by light touch | + | + | + | + | + | |
Cold or freezing | + | + | ||||
Pain induced by slight pressure | + | |||||
Pain induced by heat or cold | + | |||||
Pain induced by weather change | + | |||||
Pain limited to joints | − | |||||
Itchiness | + | |||||
Pain pattern | + | |||||
Pain radiating to the other areas (referred pain) | + | |||||
Accompanied by change in the autonomic nerve | + | + | ||||
Hypo/hypersensitivity | + |
Neuropathic pain | Nociceptive (inflammatory) pain | ||
---|---|---|---|
Positive symptoms/signs | Spontaneous pain at the affected site | Present | Present |
Hypersensitive to pain against nociceptive warmth stimulation | Rare | Frequent | |
Allodynia against cold stimulation | Frequent | Rare | |
Increased sensory threshold against pressure stimulation and hypersensitivity to pain | Often | None | |
Persistent feeling of stimulation after somatosensory stimulation | Often | Rare | |
Characteristic subjective symptoms | Sudden pain, burning pain | Throbbing pain | |
Pain spreading beyond the affected area | None | None | |
Negative symptoms/signs | Sensory disturbance in the area supplied by the affected nerve | Present | None |
Motor disturbance in the area supplied by the affected nerve | Often | None |
Treatment strategy for neuropathic pain
Drug name | Dosage form | Type | Specific usage | Treatment period | Indications | Adverse reactions |
---|---|---|---|---|---|---|
First-line drug | ||||||
Amitriptyline | Oral drug | Tricyclic antidepressant (TCA), tertiary amine | Initial dose 10 mg/day, maximum 150 mg/day; Once daily, before bedtime; Increase by 10–25 mg every 3–7 days | 6–8 weeks; the maximum tolerable dose for at least 2 weeks | Depression, peripheral neuropathy | Anti-cholinergic effect, QT prolongation, suicide risk Contraindications: glaucoma, prostate hypertrophy, cardiac diseases Less adverse events with secondary amine Attention required when used concomitantly with tramadol |
Nortriptyline | Oral drug | TCA, tertiary amine | Depression | |||
Imipramine | Oral drug | TCA, secondary amine | Depression, enuresis | |||
Gabapentin | Oral drug | Calcium channel α2δligand | Initial dose 100–300 mg/day, maximum 3600 mg/day; 1–3 times/day; Increase by 100–300 mg every 1–7 days | In addition to 3–8 weeks of dose-escalation period, 2 more weeks at the maximum dose | Refractory epilepsy | Sleepiness, dizziness, peripheral edema, increased body weight A small dose should be used in patients with renal dysfunction |
Pregabalin | Oral drug | Calcium channel α2δligand | Initial dose 25–150 mg/day, maximum 600 mg/day; 1–3 times/day; Increase by 25–150 mg every 3–7 days | 4 weeks | Neuropathic pain, pain associated with fibromyalgia | |
Duloxetine | Oral drug | Serotonin-noradrenaline reuptake inhibitor (SNRI) | Initial dose 20 mg/day maximum 60 mg/day; Once daily, after breakfast | 4 weeks | Depression, diabetic neuropathy, fibromyalgia, chronic low back pain | Nausea TCA, attention required when used concomitantly with tramadol |
Second-line drug | ||||||
An extract from inflamed cutaneous tissue of rabbits inoculated with vaccinia virus | Oral drug (and injection) | Non-proteinogenic physiologically active substance | 4 tablets (16 unites)/day; Twice daily | 4 weeks | Post-herpetic neuralgia, low back pain, cervicobrachial syndrome, scapulohumeral periarthritis, knee osteoarthritis | Nausea, sleepiness, incidence is below 0.1%, high tolerability |
Tramadol/acetaminophen combination | Oral drug | Opioid + acetaminophen | Initial dose 1–4 tablets/day, maximum 8 tablets/day; 1–4 times/day | 4 weeks | Chronic pain, pain after dental extraction | Nausea/vomiting, constipation, somnolence Attention required when used concomitantly with SSRI, SNRI, TCA and acetaminophen |
Tramadol | Oral drug (and injection) | Opioid | Initial dose 25–100/day, maximum 400 mg/day; 1–4 times/day | 4 weeks | Cancer pain, chronic pain | Nausea/vomiting, constipation, somnolence Attention required when used concomitantly with SSRI, SNRI, and TCA |
Third-line drug | ||||||
Buprenorphine | Patch, suppository (and injection) | Opioid | Initial dose 5 mg/day, maximum 20 mg/day; Once in 7 days | 4 weeks | Chronic pain difficult to treat with non-opioid analgesic (osteoarthritis, low back pain) | Nausea/vomiting, constipation, somnolence, respiratory control |
Fentanyl | 1-day patch, 3-day patch (and injection) | Opioid | Establish the initial dose by calculating from the opioid dose used before switching to the treatment. The maximum dose is 120 mg/day converted from morphine hydrochloride | 4 weeks | Chronic pain and cancer pain difficult to treat with non-opioid analgesic Can be used just by switching from other opioids | Nausea/vomiting, constipation, somnolence, respiratory control |
Oxycodone | Oral (and injection) | Opioid | Initial dose 10 mg/day, maximum 120 mg/day | 4 weeks | Cancer pain | Nausea/vomiting, constipation, somnolence, respiratory control |
Morphine | Oral, suppository (and injection) | Opioid | Initial dose 10 mg/day, maximum 120 mg/day | 4 weeks | Cancer pain, chronic pain | Nausea/vomiting, constipation, somnolence, respiratory control |