Neuropathic pain has a substantial effect on quality of life (QOL). The Japanese Society of Pain Clinicians (JSPC) has developed clinical guidelines of pharmacotherapy for neuropathic pain. These guidelines offer clarity on recommendations based on both the most recent scientific evidence and expert opinions. Understanding the concept, disease entity, and burden of neuropathic pain, as well as its screening and diagnosis are important steps before starting pharmacotherapy. As well as other guidelines, the guidelines propose several lines of pharmacotherapies in a step-wise manner. To name a few different points, our guidelines propose an extract from inflamed cutaneous tissue of rabbits inoculated with vaccinia virus, which has been found to be effective for post-herpetic neuralgia in Japan, as one of the second-line drugs. When prescribing opioid analgesics, proposed as the third-line drugs, for neuropathic pain, the guidelines recommend physicians continue evaluations on either abuse or addiction. The guidelines do not recommend concomitant use of nonsteroidal anti-inflammatory drugs and acetaminophen because of lack of clinical evidence of their efficacy. If patients do not respond well to pharmacotherapy, which is prescribed in a step-wise manner, other treatment strategies should be considered to improve patients’ activities of daily living and QOL. Keywords Neuropathic pain · Pharmacotherapy · Guidelines Introduction The Clinical Guidelines of Pharmacotherapy for Neuropathic Pain: Neuropathic pain has a substantial effect on quality of life Second Edition. Tokyo, Shinko Trading Press, 2016, pp 1–258. (QOL) and is associated with a high economic burden for both individuals and society. It arises from a heterogene- * Masahiko Sumitani ous group disorders that affect the peripheral and central email@example.com somatosensory nervous systems. It is now regarded as a Department of Pain and Palliative Medicine, The distinct clinical entity despite a large variety of causes. University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, People with neuropathic pain may experience altered pain Tokyo 113-0033, Japan sensation, areas of numbness or burning, and continuous Department of Pain Clinic and Anesthesia, Sasebo Kyosai or intermittent evoked or spontaneous pain. Thus, neuro- Hospital, Sasebo, Japan pathic pain is an unpleasant sensory and emotional experi- Department of Anesthesiology and Intensive Care Medicine, ence. Professional organizations, including the Japanese Graduate School of Medicine, Osaka University, Suita, Japan Society of Pain Clinicians (JSPC), and nations have devel- Department of Anesthesiology, School of Medicine, Dokkyo oped guidelines of pharmacotherapy for neuropathic pain. Medical University, Mibu, Japan Existing guidelines share some common elements, includ- Department of Pain Management and Palliative Care ing dosing thresholds, necessity of titration, and risk miti- Medicine, Kyoto Prefectural University of Medicine, Kyoto, gation strategies. However, there is considerable variabil- Japan 6 ity in the specific recommendations (e.g., range of dosing Pain Management Clinic, Shiga University of Medical thresholds), audience (e.g., primary care clinicians versus Science Hospital, Otsu, Japan Vol.:(0123456789) 1 3 464 Journal of Anesthesia (2018) 32:463–478 specialists), use of evidence (e.g., systematic review, grad- Drafting recommendations ing of evidence and recommendations, and role of expert opinion) and rigor of methods for addressing conflicts A draft of clinical questions (CQs) was created by the core of interest. Most guidelines do not reflect the insurance members. Each member in charge of the CQs drafted the system and approved medications in respective countries. recommendations and general background descriptions. In 2011, the JSPC published the Clinical Guidelines of Then, respective members reviewed, modified, and rewrote Pharmacotherapy for Neuropathic Pain, first edition [ 1], each statement on a reciprocal basis. In some fields, only based on evidence from scientific studies available at that outdated articles such as for tricyclic antidepressant were time. According to the most recent scientific evidence, available for references. The entire articles, including the clinical guidelines should be updated after every 5 years. latest ones, were reviewed regardless of the published year. Therefore, the JSPC renewed the guidelines and published The reference articles included those searched under Pub- its second edition in 2016 . These guidelines offered Med, Japan Medical Abstract Society (excluding the min- clarity on recommendations based on the most recent sci- utes) and Cochrane Collaboration. Finally, the external entific evidence in addition to existing evidence and expert expert reviewed the statements in these guidelines, and the opinions. The diversity of scientific viewpoints about neu- final version was established. The document created by each ropathic pain and its pharmacological treatment strategies author was reviewed and revised twice in a cross-checking is still not enough. Therefore, the JSPC based the recom- manner and then finally reviewed and revised again by the mendations after consideration of the clinical evidence, entire committee members. contextual evidence (including benefits and harms, val- ues and preferences, and resource allocation), and expert Evidence and recommendation levels opinions. The JSPC hopes that not only Japanese, but also international intended end-users are aware of the existence The task force decided to use the evidence and recommenda- of the guidelines and put them into practice. After publica- tion, dissemination of the key messages of the guidelines tion levels (Table 2), based on the recommendations of the Japanese Medical Information Network Distribution Service is of paramount importance. Publication of executive sum- maries as a quick reference guide and the production in (MINDS) for developing clinical practice guidelines, which was published in 2014 by the Japan Council for Quality a format like as a downloadable version, which can be globally read and understood as a stand-alone document, Health Care. Evaluations were made on all crucial outcomes, including hazard, of all important articles. The levels were are helpful. To accomplish this, the present article sum- marizes the recommendations and rationales of the Clini- first suggested by the authors and cross checked twice by the core members and then determined by the entire guidelines cal Guidelines of Pharmacotherapy for Neuropathic Pain, second edition, published in 2016 (Table 1). Interested committee. Finally, the committee discussed the entire evi- dence to decide whether it can be recommended. The final readers would be referred to the full-length version of the guidelines to completely understand the proper context of levels of recommendations for each of the CQs were thus determined. the recommendations. The guidelines are structured by three large categories (i.e., overview of neuropathic pain; diagnosis and treatment Overview of the understanding neuropathic pain of neuropathic pain; and disease with present neuropathic pain) and 37 sub-entries. For these, 58 clinical questions (CQs) are set (details in Table 1). In this executive summary, CQ1: How do we define and understand neuropathic we described headings of the sub-entries and CQs which pain in clinical medicine? indicate numbers in the guidelines (Table 1). CQ2: How do we understand the pathology of neuro- pathic pain? Task force CQ6: What is the chronic pain syndrome in neuropathic The JSPC committee nominated the task force members pain patients? from a pool of specialists with adequate clinical experience Neuropathic pain is defined as “pain caused by a lesion or to cover multidisciplinary areas, and the JSPC Board gave disease of the somatosensory nervous system” . Neuro- the final approval. The task force comprised a total 30 phy - pathic pain should not indicate a single disease, but rather sicians: 3 academic consultants, 1 external expert, 7 core should be recognized as a pathological condition present working members, 8 working members, and 11 collaborators in many patients complaining of pain. Neuropathic pain (“Appendix”). 1 3 Journal of Anesthesia (2018) 32:463–478 465 Table 1 Clinical questions in the clinical guidelines for pharmacotherapy of neuropathic pain by the Japanese Society of Pain Clinicians (second edition) 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 1 3 466 Journal of Anesthesia (2018) 32:463–478 Table 1 (continued) 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 opi- oids? 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 1 3 Journal of Anesthesia (2018) 32:463–478 467 Table 1 (continued) 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 Table 2 Level of evidence and strength of recommendation 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 emerges when there is a lesion or disease in any of the as sleep disorder, lack of energy, depression, anxiety, dry nociceptive pathways from the peripheral nerves to the cer- mouth, and loss of appetite . Although it has not been ebrum. The pathological mechanisms include abnormal sen- clearly understood how these comorbidities are associated sitivity of the somatosensory nervous system and functional with pain, the psychosocial factors for these conditions impairment in the descending pain modulatory system. It is are consistent with those of a vicious cycle known as the noteworthy that clinical criteria, which are based on overall fear-avoidance model, in addition to sleep disorder. These findings of patients with neuropathic pain, are necessary in conditions have not yet been defined, but are referred to as the diagnosis of neuropathic pain because it is often impos- the “chronic pain syndrome” , which is a consequence of sible to demonstrate consistent data from diagnostic tests for complex interactions of bio-psycho-social factors. Therefore, neuropathic pain. In “Guidelines for Pharmacological Treat- we should evaluate their impact on patients’ QOL, and then ment of Neuropathic Pain” published by the JSPC in 2011, determine the management plan. the term “damage” had been used to describe a “lesion.” As this term “lesion” includes a condition that does not involve Diseases which present neuropathic pain an irreversible anatomical change such as compression, it was changed to “lesion” according to the “Taxonomy for Pain Clinics” issued by the JSPC (2011). In addition to these CQ3: What diseases are associated with neuropathic biological factors, it should be mentioned that pain is usually pain? affected by bio-psycho-social factors. Hence, we need clini- cal criteria that not only evaluate the pathological condition CQ4: What is the neuropathic and nociceptive pain clas- of the somatosensory nervous system, but also predict the sification and its clinical significance? presence or absence of psychosocial factors. In fact, neuro- pathic pain is accompanied by various comorbidities such 1 3 468 Journal of Anesthesia (2018) 32:463–478 Table 3 Diseases that can cause neuropathic pain Nutrition metabolism Traumatic Alcoholic polyneuropathy Iatrogenic neuropathy Stump neuralgia Alcoholic neuropathy Post-thoracotomy pain syndrome Post-mastectomy Neuropathy due to malnutrition Post-traumatic sequelae/post-operative sequelae Stroke sequelae (e.g., beriberi, pellagra) (e.g., persistent post-operative wound pain) (e.g. thalamic pain, CNS vascular Hypothyroid neuropathy Post-ischemic myelopathy malformation) Painful diabetic polyneuropathy Phantom pain Complex Regional Pain Syndrome Uremic neuropathy Nerve root avulsion Post-herniorrhaphy pain Fabry disease Neuropathic myelopathy Radiation-induced plexopathy Porphyric neuropathy Nerve injury sequelae Radiation-induced encephalopathy/ Tethered cord syndrome myelopathy Spinal cord Hemorrhage/infarction Peripheral neurotmesis/injury Spinal cord injury sequelae Brachial plexus avulsion Multiple cranial neuropathy Genetic Hereditary polyneuropathy with liability to pressure palsy Hereditary sensory and autoimmune neuropathy Ischemic Toxic Infectious Allergic granulomatous vasculitis Chemotherapy-induced neuropathy Diphtheritic polyneuropathy Reversible ischemic neuropathy Gold Neurosyphilis Ischemic neuropathy Mercurial poisoning Tabes dorsalis Connective tissue disease (vasculitis) Toxic neuromyopathy Post-herpetic neuralgia Polyarteritis nodosa Thinner Leprosy neuropathy Cryoglobulinemia Lead Lyme disease Mononeuritis multiplex Arsenic poisoning HIV sensory neuropathy Drug-induced polyneuropathy HIV myelopathy Subacute myelo-optico neuropathy (SMON) HIV neuropathy Compression/entrapment Crural neuralgia Carpal tunnel syndrome Intervertebral disc displacement Cervical spondylotic radiculopathy Cervical/lumbar spondylolisthesis Chronic neuralgia Cubital/antebrachial/wrist/foot/thigh/shoulder Myeloradiculopathy Chronic cauda equine disorder Entrapment neuropathy Myelopathy Lumbar sciatic neuralgia Sciatica Spinal canal stenosis Lumbar spondylosis Sciatic nerve entrapment Compressive myelopathy due to spinal canal Low back pain Trigeminal neuralgia stenosis Intercostal neuralgia Cervical/thoracic/lumbosacral spinal cord radicu- Glossopharyngeal neuropathy lopathy Hypoglossal neuropathy Neuralgia Multiple sclerosis Polyneuropathy Immune Neoplastic Degenerative Carcinomatous neuropathy Malignant tumor Amyloidotic autonomic neuropathy Guillain–Barre syndrome Nerve compression by tumor or neuralgia due to Charcot joint Sjogren’s syndrome tumor invasion Autonomic neuropathy Autoimmune neuropathy Spinal cord tumor Syringomyelia/syringobulbia Plexitis Brain tumor Parkinson’s disease Inflammatory demyelinating polyneuropathy Peripheral nerve tumor Adrenomyeloneuropathy Idiopathic neuropathy Neuroma Neurosarcoidosis Neurilemmoma CQ5: Is acute pain that is associated with peripheral are more diseases that are not listed in this table . Pain is defined as “an unpleasant sensory and emotional experi- nerve inflammation regarded as neuropathic pain? Nutritional, metabolic, traumatic, ischemic, toxic, genetic, ence associated with actual or potential tissue damage, or described in terms of such damage” . The types of pain infectious, compression/entrapment, immune, neoplastic, or neurodegenerative disorders can cause neuropathic developed by bodily causes are classified into nocicep - tive pain and neuropathic pain. Nociceptive pain is defined pain. Table 3 lists some diseases that can be associated with neuropathic pain. These are just examples, and there as “pain that arises from actual or threatened damage to 1 3 Journal of Anesthesia (2018) 32:463–478 469 non-neural tissues and is due to the activation of nocicep- CQ8: Are there any epidemiological surveys on the prev- tors” . It will be helpful to classify and evaluate noci- alence of neuropathic pain in cancer patients? ceptive pain and neuropathic pain when we plan to treat In surveys conducted in Japan that focused on chronic pain, pain due to these causes. However, pathological conditions an individual with chronic pain was defined as a person who of nociceptive pain and neuropathic pain often overlap had experienced pain with a severity of 4 or above on an clinically, and such a state is called the mixed pain condi- 11-point numeric rating scale (NRS: 0 = no pain; 10 = worst tion. To control the mixed pain condition, pharmacothera- pain imaginable) for at least twice a week for 3–6 months. pies for each pathologic condition would be necessary for As a result, the prevalence was found to be 15.2% for chronic appropriate pain control. pain in the musculoskeletal system and 26.4% for chronic There is a controversy regarding whether acute periph- pain among varied etiologies [8, 9]. Of these, the prevalence eral nerve inflammation should be included in the neuro- of those who were likely to have neuropathic pain according pathic pain category. The most representative diseases that to the PainDETECT Japanese version  and the “Neu- develop acute pain in association with direct inflammation ropathic Pain Screening Questionnaire (Japanese version)” on the peripheral nerve include shingles in the acute phase was 6.5 and 6.4%, respectively. and radiculopathy due to intervertebral disc displacement. Considering the relationship between neuropathic pain Although nociceptive pain and neuropathic pain may be and the specific disease, cancer pain was systematically present at the same time during a transition phase from reviewed . Among patients with cancer pain, 59.4% had acute to chronic pain in association with peripheral nerve nociceptive pain, 19.0% had only neuropathic pain, 20.1% inflammation, it is currently difficult to figure out how had a mixture of nociceptive pain and neuropathic pain, and much of the acute pain induced by shingles or intervertebral 1.5% had pain of unknown origin or other types of pain. In disc displacement is neuropathic pain. Therefore, in these the European Association for Palliative Care, a study was guidelines, we would not include the acute pain associated conducted using the PainDETECT in 670 patients with pain with terminal nerve inflammation in the neuropathic pain out of 1051 cancer patients; according to the results, 79.7% category. patients had nociceptive pain, 16.9% had neuropathic pain, and 3.4% had pain of unknown origin. Compared to the Epidemiology of neuropathic pain patients with nociceptive pain, those with neuropathic pain required stronger opioid analgesics and adjuvant analgesics, and their performance state remained worse . CQ7: Are there any epidemiological surveys on the prev- alence of neuropathic pain? Table 4 Comparisons among various screening tools 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 + 1 3 470 Journal of Anesthesia (2018) 32:463–478 Table 5 Differences in features between neuropathic pain and nociceptive (inflammatory) pain 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 Often None hypersensitivity to pain 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 should not replace a detailed clinical evaluation” as stated Diagnosis and treatment of neuropathic pain in the guidelines above. Therefore, it is recommended to use a screening tool available, but we should not use the result of the screening tool as a diagnosis of neuropathic CQ9: How do we screen patients who may have neuro- pain by itself. pathic pain? To diagnose neuropathic pain, the International Asso- ciation for the Study of Pain (IASP) developed the flow - CQ10: How do we diagnose neuropathic pain? chart-form diagnostic algorithm (grading system) . The details of this algorithm are described elsewhere. CQ11: What are the clinical characteristics of neuro- Briefly, first identify the present illness and the past medi- pathic pain? cal history that suggest neuropathic pain. Then, perform a Neuropathic pain is distinctive pain that is different from sensory-disturbance evaluation in a neurological examina- nociceptive pain. It is characterized by spontaneous pain tion and a test that confirms the diagnosis of neurological (continuous or intermittent) or pain induced by stimula- lesion or a disease. It is desirable to establish a diagnosis tion (allodynia, hypersensitivity) at the site supplied by following an algorithm by the IASP neuropathic pain spe- the affected nerve, which is complicated by various sen- cific interest group. sory abnormalities caused by the disturbance of a nerve. The characteristic features of neuropathic pain are in the Treatment strategy for neuropathic pain descriptions of the screening tools developed in the EU, US, and Japan (Table 4). The differences in the features of pain characteristic to each disease are presented in Table 5 CQ12: What is the impact of neuropathic pain on [13–17]. Positive and negative findings in the somatosen- QOL? sory system of neuropathic pain and nociceptive pain can be useful when making a diagnosis (Table 5) . CQ13: What is the summary of the management plan Based on these characteristics of neuropathic pain, mul- for neuropathic pain? tiple screening tools have been developed to easily evalu- ate the possibility that a patient has neuropathic pain in CQ14: How do we establish the treatment goal for neu- routine medical practice. There are tools known as the ropathic pain? Japanese neuropathic pain screening questionnaire , The severity of neuropathic pain is relatively higher than PainDETECT Japanese version , and Leeds assess- that of other pain conditions, and neuropathic pain affects ment of neuropathic symptoms and signs (LANSS) Japa- greatly patients’ health-related QOL. Further, patients nese version  developed in Japan. All of these are just with neuropathic pain were more likely to have prolonged screening tools for neuropathic pain in general clinical disease duration and more medical expenses . It was settings, and these demonstrate high sensitivity but mod- found that the higher the pain severity, the lower the QOL erate specificity. There is a systematic review that com- of patients [23, 24]. pared and evaluated the quality (e.g., validity, reliability) The treatment goal should be planned based on both of each screening tool . All tools were supported at the severity of pain and their impaired activities of daily the low evidence level; hence, “use of a screening tool 1 3 Journal of Anesthesia (2018) 32:463–478 471 1 3 Table 6 Clinical characteristics of drugs for neuropathic pain Drug name Dosage form Type Specific usage Treatment period Indications Adverse reactions First-line drug Amitriptyline Oral drug Tricyclic antidepressant Initial dose 10 mg/day, 6–8 weeks; the maxi- Depression, peripheral Anti-cholinergic effect, QT (TCA), tertiary amine maximum 150 mg/ mum tolerable dose for neuropathy prolongation, suicide risk day; Once daily, before at least 2 weeks Contraindications: glau- Nortriptyline Oral drug TCA, tertiary amine Depression bedtime; Increase by coma, prostate hypertro- Imipramine Oral drug TCA, secondary amine Depression, enuresis 10–25 mg every 3–7 phy, cardiac diseases days Less adverse events with secondary amine Attention required when used concomitantly with tramadol Gabapentin Oral drug Calcium channel Initial dose 100–300 mg/ In addition to 3–8 weeks Refractory epilepsy Sleepiness, dizziness, α δligand day, maximum of dose-escalation peripheral edema, 3600 mg/day; 1–3 period, 2 more weeks increased body weight times/day; Increase by at the maximum dose A small dose should be 100–300 mg every 1–7 used in patients with days renal dysfunction Pregabalin Oral drug Calcium channel Initial dose 25–150 mg/ 4 weeks Neuropathic pain, pain α δligand day, maximum 600 mg/ associated with fibro- day; 1–3 times/day; myalgia Increase by 25–150 mg every 3–7 days Duloxetine Oral drug Serotonin-noradrenaline Initial dose 20 mg/day 4 weeks Depression, diabetic neu- Nausea reuptake inhibitor maximum 60 mg/ ropathy, fibromyalgia, TCA, attention required (SNRI) day; Once daily, after chronic low back pain when used concomitantly breakfast with tramadol Second-line drug An extract from Oral drug (and injection) Non-proteinogenic 4 tablets (16 unites)/day; 4 weeks Post-herpetic neuralgia, Nausea, sleepiness, inflamed cutaneous physiologically active Twice daily low back pain, cervi- incidence is below 0.1%, tissue of rabbits inocu- substance cobrachial syndrome, high tolerability lated with vaccinia scapulohumeral periar- virus thritis, knee osteoar- thritis Tramadol/acetaminophen Oral drug Opioid + acetaminophen Initial dose 1–4 tablets/ 4 weeks Chronic pain, pain after Nausea/vomiting, constipa- combination day, maximum 8 tab- dental extraction tion, somnolence lets/day; 1–4 times/day Attention required when used concomitantly with SSRI, SNRI, TCA and acetaminophen Tramadol Oral drug (and injection) Opioid Initial dose 25–100/day, 4 weeks Cancer pain, chronic pain Nausea/vomiting, constipa- maximum 400 mg/day; tion, somnolence 1–4 times/day Attention required when used concomitantly with SSRI, SNRI, and TCA 472 Journal of Anesthesia (2018) 32:463–478 living (ADL) and QOL. In a clinical study of chronic pain, it is recommended to evaluate the following six items: intensity of pain, physical functions, mental functions, level of patients’ satisfaction, signs of adverse reactions, and adherence to the treatments [25, 26]. It is considered crucial to evaluate these factors comprehensively in clini- cal practice. The basic treatment strategy is a pharma- cotherapy that can relieve the pain (Table 6). However, if the patients do not respond well to pharmacotherapy, which is prescribed in a stepwise manner, or when their adherence to pharmacotherapy is not adequate, neuro- modulatory treatments or other interventional treatments are considered. Further, to improve the patients’ ADL and QOL, functional exercises such as rehabilitations are pro- vided to patients so that they will be able to recover their self-efficacy. Thus, it is very important to provide inter- or multi-disciplinary treatments for neuropathic pain by combining various treatment approaches according to their bio-psycho-social factors. Pharmacotherapy for neuropathic pain CQ15:What are indexes of the effects of pharmacother - apy for neuropathic pain and the levels of recommenda- tion for the respective drugs? Pathological conditions and diseases associated with neu- ropathic pain vary greatly; it is extremely difficult to conduct a clinical study for each one of the conditions and diseases. Therefore, in these guidelines, we aim to present recom- mendations for neuropathic pain and selected drugs. Some of the drugs listed in these guidelines are not covered by the health insurance when used for neuropathic pain diseases in Japan. Such drugs should be used only after fully informing patients. Different from other published recommendations [e.g., 27], the guidelines presented an algorithm of phar- macotherapies, which is structured by the first to third-line drugs, instead of presenting an evidence list. Drugs that would have a potential to demonstrate analgesic effects on multiple diseases associated with neuropathic pain and have been approved in Japan as analgesics were selected as the first-line drugs. Out of all analgesics approved in Japan, tri- cyclic antidepressant (amitriptyline), pregabalin, and dulox- etine are recommended as the first-line drugs. For the sec- ond-line drugs, we selected analgesic drugs that are effective for only 1 type of disease associated with neuropathic pain (Fig. 1). Opioid analgesics are shown to be ee ff ctive for mul - tiple diseases associated with neuropathic pain. However, we consider them as the third-line drugs because there have been safety concerns for their long-term use. Of all opioid analgesics, only tramadol has been classified as a second- line drug as its improvement effect on QOL is relatively high and its risk for developing addiction is low. It is desirable to 1 3 Table 6 (continued) Drug name Dosage form Type Specific usage Treatment period Indications Adverse reactions Third-line drug Buprenorphine Patch, suppository (and Opioid Initial dose 5 mg/day, 4 weeks Chronic pain difficult to Nausea/vomiting, con- injection) maximum 20 mg/day; treat with non-opioid stipation, somnolence, Once in 7 days analgesic (osteoarthri- respiratory control tis, low back pain) Nausea/vomiting, con- Fentanyl 1-day patch, 3-day patch Opioid Establish the initial dose 4 weeks Chronic pain and cancer pain difficult to treat stipation, somnolence, (and injection) by calculating from the with non-opioid anal- respiratory control opioid dose used before gesic switching to the treat- Can be used just by ment. The maximum switching from other dose is 120 mg/day opioids converted from mor- phine hydrochloride Oxycodone Oral (and injection) Opioid Initial dose 10 mg/day, 4 weeks Cancer pain Nausea/vomiting, con- maximum 120 mg/day stipation, somnolence, respiratory control Morphine Oral, suppository (and Opioid Initial dose 10 mg/day, 4 weeks Cancer pain, chronic pain Nausea/vomiting, con- injection) maximum 120 mg/day stipation, somnolence, respiratory control Journal of Anesthesia (2018) 32:463–478 473 receive a collaborative consultation from a pain management Japan. Therefore, we did not demonstrate topical lidocaine specialist when considering a long-term administration of in the algorithm. opioid analgesics including tramadol. In the original first edition of the guidelines, mexiletine First‑line drugs hydrochloride was recommended as the second-line drug because it has been approved for painful diabetic neuropa- Pregabalin thy. However, because of low efficacy and high incidence of adverse effects, we did not recommend it in the second Pregabalin inhibits the release of excitatory neurotransmit- edition of the guidelines [27, 28]. Topical therapies with ters by combining with alpha-2-delta subunits of voltage- lidocaine have been reported effective [29, 30], and recom- dependent calcium channels in the central nervous system. mended in overseas guidelines, while this is not approved in Similarly, gabapentin and gabapentin enacarbil work by combining with alpha-2-delta subunits of voltage-dependent Fig. 1 Neuropathic pain pharmacotherapy algorithm in the Japanese Society of Pain Clinicians 1 3 474 Journal of Anesthesia (2018) 32:463–478 calcium channels. Pregabalin is the only analgesic drug only amitriptyline is approved for peripheral neuropathic approved for both peripheral and central neuropathic pain pain in Japan. It has been reported that there is no differ - in Japan. Neither gabapentin nor gabapentin enacarbil is ence in analgesic effects between the tertiary amine TCAs approved for pain conditions. Pregabalin has greater anal- (amitriptyline and imipramine), which show well-balanced gesic potential compared to placebo for both Japanese and serotonin–noradrenaline reuptake inhibition, and the sec- other patients with varied peripheral and central neuropathic ondary amine TCA (nortriptyline), which shows relatively pain diseases (e.g., post-herpetic neuralgia , painful dia- selective noradrenaline reuptake inhibition [38, 39]. Hence, betic polyneuropathy , and post-spinal cord injury pain the secondary amine TCA (nortriptyline) is considered more ). Pregabalin also improves sleep disturbance, depres- favorable than the tertiary amine TCAs (amitriptyline and sion, and anxiety associated with neuropathic pain. These imipramine) for being superior in tolerability, but equivalent favorable effects can be clearly observed not only with in analgesic effects. As a majority of clinical studies using respect to pain but also patients’ QOL. TCAs had been conducted before 2000, their effects on QOL The use of gabapentin, as well as pregabalin, for neuro- are still unknown due to lack of appropriate evaluations. pathic pain is supported by evidence from studies world- wide. Gabapentin enacarbil has good evidence for neuro- Second‑line drugs pathic pain. However, these studies have not been confirmed for Japanese neuropathic pain patients yet. Extract from the inflamed cutaneous tissue of rabbits inoculated with vaccinia virus (ERV) Serotonin–noradrenaline reuptake inhibitors (SNRI) In clinical studies conducted only in Japan, the extract from The analgesic effect of serotonin-noradrenaline reuptake inflamed cutaneous tissue of rabbits inoculated with vaccinia inhibitors (SNRIs) is considered to be mediated by activa- virus (ERV) has been found to be effective, particularly for tion of the descending pain inhibitory system. The analgesic post-herpetic neuralgia, and has been approved for it . potential of duloxetine, an SNRI, has been demonstrated in a It is thought that the extract from the inflamed cutaneous clinical study on pain and numbness associated with diabetic tissue of rabbits inoculated with vaccinia virus activates the neuropathy. Its safety has been confirmed in a 52-week study descending pain inhibitory system, which produces the anal- . Further, it was shown that duloxetine improved cen- gesic effect. In addition to the analgesic effects, this drug tral neuropathic pain compared to placebo in patients with does not induce serious adverse reactions and its tolerabil- multiple sclerosiss . Duloxetine is approved in Japan for ity is very high. It has been used for more than 20 years in not only painful diabetic polyneuropathy and other chronic clinical practice in Japan and has been highly safe. Although pain condition (i.e., osteoarthritis, chronic low back pain, sleep disorder associated with pain improved, efficacy for and fibromyalgia), but also major depression. The clinical other aspects of QOL has not yet been evaluated. studies of duloxetine for painful diabetic polyneuropathy, osteoarthritis, and chronic low back pain did not include Opioid analgesic [weak]: tramadol patients with depressive disorders in Japan. Thus, its anal- gesic property is independent of its anti-depressant mecha- Tramadol acts as both a mu-opioid receptor agonist and nism. In addition, its analgesic effects on cancer chemother - SNRI. It is categorized as an opioid analgesic [weak], apy-induced neuropathy  and low back pain associated which is not designated as a restricted opioid for medical with radiculopathy  have been also observed. On the use. The analgesic effects of tramadol have been demon- basis of these evidences, duloxetine was upgraded as one strated for painful diabetic polyneuropathy [41, 42], post- of the firs-line drugs in the second edition of the guidelines herpetic neuralgia , and cancer-related neuropathic from the second-line drug in the original first edition. Dulox- pain . Improvement in QOL has been also confirmed. etine improves not only pain, but also QOL in patients with Although development of addiction is very unlikely, caution peripheral neuropathy. In addition to duloxetine, two other is required for long-term use. It is best to use this drug for SNRIs, venlafaxine and milnacipran, are available but both a short-term treatment . Adverse effects (e.g., constipa- are not approved for any neuropathic pain diseases in Japan. tion, sleepiness, vomiting) induced by tramadol are gener- ally milder than those of other opioid analgesics. With both Tricyclic antidepressants (TCAs) analgesic effects and QOL improvement, tramadol is given priority over other opioid analgesics. In the second edition of TCAs are significantly effective for a variety of peripheral the guidelines, it is recommended as a second-line drug due and central neuropathic pain compared to placebo. It has to low safety concerns associated with long-term use . been found that the analgesic mechanisms of TCAs are dif- ferent from those of other anti-depressants. Among TCAs, 1 3 Journal of Anesthesia (2018) 32:463–478 475 Third‑line drugs Discussion Opioid analgesics Clinical guidelines represent one strategy for improving pre- scribing practices and health outcomes. Efforts are required Opioid analgesics are effective for a variety of diseases asso- to disseminate the guideline and achieve widespread adop- ciated with peripheral and central neuropathic pain, includ- tion and implementation of the recommendations in clinical ing painful diabetic polyneuropathy and post-herpetic neu- settings. These guidelines provide recommendations that are ralgia . There is abundant evidence for the analgesic based on the best available evidence that was interpreted and efficacy of morphine and oxycodone. Transdermal fentanyl informed by expert opinion. Some of the clinical or scientific (both 1- and 3-day patches) has been approved for moder- evidence for the recommendations are still low in quality. ate-severe cancer pain when switching from other opioid For future guideline development worldwide, more inves- analgesics. Buprenorphine hydrochloride is a partial agonist tigations are necessary to fill in critical evidence gaps. The for mu-opioid receptors, showing equivalent efficacy. Inci- evidence review for these guidelines clearly illustrate that dence of adverse effects (e.g., nausea, constipation, sleepi- there is much to be learn about the effectiveness, safety, and ness) induced by opioid analgesics is relatively high, and economic efficiency of long-term and combined pharmaco- these could persist for a long time throughout the treatment therapies. The JSPC will revisit these guidelines as new evi- period . Moreover, there is no systematic investigation dence becomes available to determine when evidence gaps made on the long-term safety of these opioid analgesics. have been sufficiently closed to warrant an update of the Opioid analgesics might not be safer than other drugs due clinical guidelines. These guidelines are intended to improve to adverse effects, such as development of hypogonadism or communication among clinicians working in varied clinical addiction, though the incidence is low. We consider them as settings and patients about concept of neuropathic pain, its the third-line drugs because opioid analgesics have safety specific disease burden, the goals of treatment, and the risks concerns for long-term use. Hence, it is desirable to receive and benefits of pharmacotherapies. These are also intended a collaborative consultation from a pain management spe- to improve the safety and effectiveness of pain treatment. cialist when using opioid analgesics [moderate and strong] The JSPC is committed to evaluating the guidelines to iden- listed in this chapter. When prescribing opioids for chronic tify the impact of the recommendations on clinician and pain conditions including neuropathic pain, we always need patient outcomes, both intended and unintended, and revis- to continue evaluations on either abuse or addiction. The ing the recommendations in the future when warranted. recommended maintenance dose of an opioid analgesic is 15–120 mg/day when converted to oral morphine hydro- Compliance with ethical standards chloride. The JSPC has been continuously considering the Conflict of interest Members of the task force have conflicts of inter - risk–benefit of pharmacotherapy for neuropathic pain from a est with respect to this work, but none of them received any finan- long-term perspective. We are now debating the necessity of cial support to develop these guidelines. Astellas, Abott Japan, Eisai, lowering the upper limit of maintenance doses (e.g., 60 mg/ MSD Japan, Elliquence, Otsuka Pharmacetical, Ono Pharmacetical, day) of opioid analgesics following a US report . Kyowa Hakko Kirin Co., LTD., Sato Healthcare Innovation, Shiono- gi & Co., LTD., Showa Yakuhin Kako Co., LTD., St. Jude Medical Japan, Daiichi-Sankyo, Daiken Medical Co. LTD., Taisho Toyama CQ16: What is the level of recommendation of NSAIDs Pharmacetical, Sumitomo Dainippon Pharma, Taiho Pharma, Takeda and acetaminophen for neuropathic pain? Pharmacetical, Mitsubishi Tanabe Pharma, Tsumura & Co., Teikoku There is no high-quality study that has demonstrated the Seiyaku, Terumo, Torii Pharmaceutical, Toray, Drager Medical Japan, Nipro, Eli Lilly Japan, Nippon Kayaku, Nippon Shinyaku Co., LTD., efficacy of both NSAIDs, including selective cyclooxyge- Nippon Zoki, Boehringer Ingelheim Japan, Hisamitsu Pharmaceutical, nase (COX)-2 inhibitors, and acetaminophen for neuropathic Bitakain Seiyaku KK., B. Braun Aesculap Japan, Pfizer Japan, Fuji- pain. Concomitant use of NSAIDs in addition to pharma- film sonosite Japan, Boston Scientific Japan, Maruishi Pharmaceuti- cotherapy can be effective in the treatment of a mixed pain cal, Maruho, Mundipharma, Mochida Pharmaceutical, Janssen Phar- macetical KK. condition where neuropathic pain is complicated by noci- ceptive inflammatory pain [ 48]. It is not recommended for Open Access This article is distributed under the terms of the Crea- mixed pain condition as there is hardly any anti-inflamma- tive Commons Attribution 4.0 International License (http://creat iveco tory effects with acetaminophen. mmons.or g/licenses/b y/4.0/), which permits unrestricted use, distribu- tion, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 1 3 476 Journal of Anesthesia (2018) 32:463–478 Collaborators Appendix Keisuke Yamaguchi, Associate Professor, Department of Members of the task force for the clinical guidelines Anesthesiology and Pain Medicine, Juntendo University of pharmacotherapy for neuropathic pain School of Medicine; Yoshika Takahashi, Assistant Profes- sor, Department of Anesthesiology and Pain Medicine, Jun- Academic consultants tendo University School of Medicine; Makito Oji, Assistant Professor, Pain Clinic, NTT East Medical Center; Kumiko Toyoshi Hosokawa, Professor, Department of Pain Man- Hida, Assistant Professor Department of Anesthesiology, agement and Palliative Care Medicine, Kyoto Prefectural Nagasaki University School of Medicine; Koji Ishii, Assis- University of Medicine; Yasuhisa Okuda, Professor, Anes- tant Professor Department of Anesthesiology, Nagasaki thesiology, Dokkyo Medical University Koshigaya Hospital; University School of Medicine; Keisuke Watanabe, Lec- Kiyoshige Oseto, Professor, Department of Anesthesiology, turer, Department of Anesthesiology and Pain Center, Nara Tokyo Medical University. Medical University; Hidekazu Watanabe, Sendai Pain Clinic External expert. Center; Noriko Taguchi, Sendai Pain Clinic Center; Tomoko Naoki Nogo, Director, Musashi Kokubunji Park Clinic. Kitamura, Sendai Pain Clinic Center; Nanase Watabiki, Sen- dai Pain Clinic Center; Akira Yamashiro, Sendai Pain Clinic Core working members Center. Sei Fukui, Clinical Professor and Chair of these guidelines, Pain Management Clinic, Shiga University of Medical Sci- ence Hospital; Hisashi Date, Director, Sendai Pain Clinic References Center; Masahiko Iseki, Professor, Department of Anesthe- siology and Pain Medicine, Juntendo University School of 1. The committee for the Guidelines for the Pharmacologic Man- Medicine; Shigeki Yamaguchi, Professor, Department of agement of Neuropathic Pain. Guidelines for the Pharmacologic Anesthesiology, Dokkyo Medical University School of Med- Management of Neuropathic Pain, 1st edn. 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