Journal of Anesthesia (2018) 32:463–478
https://doi.org/10.1007/s00540-018-2501-0

GUIDELINE

Executive summary of the Clinical Guidelines of Pharmacotherapy
for Neuropathic Pain: second edition by the Japanese Society of Pain
Clinicians
Masahiko Sumitani1 · Tetsuya Sakai2 · Yoichi Matsuda3 · Hiroaki Abe1 · Shigeki Yamaguchi4 · Toyoshi Hosokawa5 ·Sei Fukui6
Received: 16 July 2017 / Accepted: 27 April 2018 / Published online: 8 May 2018
© The Author(s) 2018

Abstract
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 burdenof neuropathic pain, as well as its screening and diagnosis are important steps before starting pharmacotherapy. As well asother 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 ofdaily living and QOL.
Keywords Neuropathic pain · Pharmacotherapy · Guidelines

Introduction
The Clinical Guidelines of Pharmacotherapy for Neuropathic Pain:
Second Edition. Tokyo, Shinko Trading Press, 2016, pp 1–258.
* Masahiko Sumitani
sumitanim‑ane@h.u‑tokyo.ac.jp
1

Department of Pain and Palliative Medicine, The
University of Tokyo Hospital, 7‑3‑1 Hongo, Bunkyo‑ku,
Tokyo 113‑0033, Japan2

Department of Pain Clinic and Anesthesia, Sasebo Kyosai
Hospital, Sasebo, Japan3

Department of Anesthesiology and Intensive Care Medicine,
Graduate School of Medicine, Osaka University, Suita, Japan

4

Department of Anesthesiology, School of Medicine, Dokkyo
Medical University, Mibu, Japan

5

Department of Pain Management and Palliative Care
Medicine, Kyoto Prefectural University of Medicine, Kyoto,
Japan

6

Pain Management Clinic, Shiga University of Medical
Science Hospital, Otsu, Japan

Neuropathic pain has a substantial effect on quality of life
(QOL) and is associated with a high economic burden forboth individuals and society. It arises from a heterogeneous group disorders that affect the peripheral and central
somatosensory nervous systems. It is now regarded as a
distinct clinical entity despite a large variety of causes.
People with neuropathic pain may experience altered pain
sensation, areas of numbness or burning, and continuous
or intermittent evoked or spontaneous pain. Thus, neuropathic pain is an unpleasant sensory and emotional experience. Professional organizations, including the JapaneseSociety of Pain Clinicians (JSPC), and nations have developed guidelines of pharmacotherapy for neuropathic pain.
Existing guidelines share some common elements, including dosing thresholds, necessity of titration, and risk mitigation strategies. However, there is considerable variability in the specific recommendations (e.g., range of dosing
thresholds), audience (e.g., primary care clinicians versus

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specialists), use of evidence (e.g., systematic review, grading of evidence and recommendations, and role of expert
opinion) and rigor of methods for addressing conflictsof interest. Most guidelines do not reflect the insurance
system and approved medications in respective countries.
In 2011, the JSPC published the Clinical Guidelines of
Pharmacotherapy for Neuropathic Pain, first edition [1],based on evidence from scientific studies available at thattime. According to the most recent scientific evidence,clinical guidelines should be updated after every 5 years.
Therefore, the JSPC renewed the guidelines and publishedits second edition in 2016 [2]. These guidelines offeredclarity on recommendations based on the most recent scientific evidence in addition to existing evidence and expert
opinions. The diversity of scientific viewpoints about neuropathic pain and its pharmacological treatment strategies
is still not enough. Therefore, the JSPC based the recommendations after consideration of the clinical evidence,contextual evidence (including benefits and harms, values and preferences, and resource allocation), and expert
opinions. The JSPC hopes that not only Japanese, but alsointernational intended end-users are aware of the existenceof the guidelines and put them into practice. After publication, dissemination of the key messages of the guidelines
is of paramount importance. Publication of executive summaries as a quick reference guide and the production in
a format like as a downloadable version, which can be
globally read and understood as a stand-alone document,
are helpful. To accomplish this, the present article summarizes the recommendations and rationales of the Clinical Guidelines of Pharmacotherapy for Neuropathic Pain,
second edition, published in 2016 (Table 1). Interested
readers would be referred to the full-length version of theguidelines to completely understand the proper context of
the recommendations.
The guidelines are structured by three large categories(i.e., overview of neuropathic pain; diagnosis and treatmentof neuropathic pain; and disease with present neuropathicpain) and 37 sub-entries. For these, 58 clinical questions(CQs) are set (details in Table 1). In this executive summary,
we described headings of the sub-entries and CQs whichindicate numbers in the guidelines (Table 1).

Journal of Anesthesia (2018) 32:463–478

Drafting recommendations
A draft of clinical questions (CQs) was created by the core
members. Each member in charge of the CQs drafted therecommendations and general background descriptions.
Then, respective members reviewed, modified, and rewrote
each statement on a reciprocal basis. In some fields, only
outdated articles such as for tricyclic antidepressant wereavailable for references. The entire articles, including thelatest ones, were reviewed regardless of the published year.
The reference articles included those searched under PubMed, Japan Medical Abstract Society (excluding the minutes) and Cochrane Collaboration. Finally, the external
expert reviewed the statements in these guidelines, and thefinal version was established. The document created by eachauthor was reviewed and revised twice in a cross-checking
manner and then finally reviewed and revised again by theentire committee members.

Evidence and recommendation levels
The task force decided to use the evidence and recommendation levels (Table 2), based on the recommendations of theJapanese Medical Information Network Distribution Service(MINDS) for developing clinical practice guidelines, which
was published in 2014 by the Japan Council for Quality
Health Care. Evaluations were made on all crucial outcomes,
including hazard, of all important articles. The levels werefirst suggested by the authors and cross checked twice by thecore members and then determined by the entire guidelines
committee. Finally, the committee discussed the entire evidence to decide whether it can be recommended. The final
levels of recommendations for each of the CQs were thus
determined.

Overview of the understanding neuropathic pain
CQ1: How do we define and understand neuropathic
pain in clinical medicine?

Task force

CQ2: How do we understand the pathology of neuropathic pain?

The JSPC committee nominated the task force members
from a pool of specialists with adequate clinical experience
to cover multidisciplinary areas, and the JSPC Board gave
the final approval. The task force comprised a total 30 physicians: 3 academic consultants, 1 external expert, 7 core
working members, 8 working members, and 11 collaborators(“Appendix”).

CQ6: What is the chronic pain syndrome in neuropathic
pain patients?
Neuropathic pain is defined as “pain caused by a lesion ordisease of the somatosensory nervous system” [3]. Neuropathic pain should not indicate a single disease, but rather
should be recognized as a pathological condition present
in many patients complaining of pain. Neuropathic pain

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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 antidepressantsCQ18: 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

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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 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

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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 andlumbar 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 andthese 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 thestatement, 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 thenociceptive pathways from the peripheral nerves to the cerebrum. The pathological mechanisms include abnormal sensitivity of the somatosensory nervous system and functional
impairment in the descending pain modulatory system. It isnoteworthy that clinical criteria, which are based on overallfindings of patients with neuropathic pain, are necessary inthe diagnosis of neuropathic pain because it is often impossible to demonstrate consistent data from diagnostic tests forneuropathic pain. In “Guidelines for Pharmacological Treatment of Neuropathic Pain” published by the JSPC in 2011,
the term “damage” had been used to describe a “lesion.” As
this term “lesion” includes a condition that does not involve
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 thesebiological factors, it should be mentioned that pain is usuallyaffected by bio-psycho-social factors. Hence, we need clinical criteria that not only evaluate the pathological conditionof the somatosensory nervous system, but also predict thepresence or absence of psychosocial factors. In fact, neuropathic pain is accompanied by various comorbidities suchas sleep disorder, lack of energy, depression, anxiety, drymouth, and loss of appetite [4]. Although it has not beenclearly understood how these comorbidities are associatedwith pain, the psychosocial factors for these conditions
are consistent with those of a vicious cycle known as thefear-avoidance model, in addition to sleep disorder. These
conditions have not yet been defined, but are referred to as
the “chronic pain syndrome” [5], which is a consequence ofcomplex interactions of bio-psycho-social factors. Therefore,
we should evaluate their impact on patients’ QOL, and thendetermine the management plan.

Diseases which present neuropathic pain
CQ3: What diseases are associated with neuropathic
pain?
CQ4: What is the neuropathic and nociceptive pain classification and its clinical significance?

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Table 3  Diseases that can cause neuropathic pain
Nutrition metabolism
Alcoholic polyneuropathy
Alcoholic neuropathy
Neuropathy due to malnutrition(e.g., beriberi, pellagra)
Hypothyroid neuropathy
Painful diabetic polyneuropathy
Uremic neuropathy
Fabry disease
Porphyric neuropathy

Genetic
Hereditary polyneuropathy with liability to pressure
palsy
Hereditary sensory and autoimmune neuropathy
Ischemic
Allergic granulomatous vasculitis
Reversible ischemic neuropathy
Ischemic neuropathy
Connective tissue disease (vasculitis)
Polyarteritis nodosa
Cryoglobulinemia
Mononeuritis multiplex
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
ImmuneCarcinomatous neuropathy
Guillain–Barre syndrome
Sjogren’s syndrome
Autoimmune neuropathy
Plexitis
Inflammatory demyelinating polyneuropathy
Idiopathic neuropathy

Traumatic
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 vascularmalformation)
Complex Regional Pain Syndrome
Post-herniorrhaphy pain
Radiation-induced plexopathy
Radiation-induced encephalopathy/
myelopathy
Peripheral neurotmesis/injury
Brachial plexus avulsion

Toxic
Chemotherapy-induced neuropathyGold
Mercurial poisoning
Toxic neuromyopathy
Thinner
Lead
Arsenic poisoning
Drug-induced polyneuropathy
Subacute myelo-optico neuropathy (SMON)

Infectious
Diphtheritic polyneuropathy
Neurosyphilis
Tabes dorsalis
Post-herpetic neuralgia
Leprosy neuropathy
Lyme disease
HIV sensory neuropathy
HIV myelopathy
HIV neuropathy

Carpal tunnel syndrome
Cervical/lumbar spondylolisthesis
Myeloradiculopathy
Myelopathy
Spinal canal stenosis
Compressive myelopathy due to spinal canalstenosis
Glossopharyngeal neuropathy
Hypoglossal neuropathy
Multiple sclerosis
Polyneuropathy
Neoplastic
Malignant tumor
Nerve compression by tumor or neuralgia due totumor invasion
Spinal cord tumor
Brain tumor
Peripheral nerve tumor
Neuroma
Neurosarcoidosis
Neurilemmoma

Intervertebral disc displacement
Chronic neuralgia
Chronic cauda equine disorder
Lumbar sciatic neuralgia
Lumbar spondylosis
Low back pain
Intercostal neuralgia

CQ5: Is acute pain that is associated with peripheral
nerve inflammation regarded as neuropathic pain?
Nutritional, metabolic, traumatic, ischemic, toxic, genetic,
infectious, compression/entrapment, immune, neoplastic,or neurodegenerative disorders can cause neuropathic
pain. Table 3 lists some diseases that can be associatedwith neuropathic pain. These are just examples, and there

13

Degenerative
Amyloidotic autonomic neuropathy
Charcot joint
Autonomic neuropathy
Syringomyelia/syringobulbia
Parkinson’s disease
Adrenomyeloneuropathy

are more diseases that are not listed in this table [6]. Painis defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or
described in terms of such damage” [5]. The types of pain
developed by bodily causes are classified into nociceptive pain and neuropathic pain. Nociceptive pain is definedas “pain that arises from actual or threatened damage toJournal of Anesthesia (2018) 32:463–478

469

non-neural tissues and is due to the activation of nociceptors” [7]. It will be helpful to classify and evaluate nociceptive pain and neuropathic pain when we plan to treat
pain due to these causes. However, pathological conditionsof nociceptive pain and neuropathic pain often overlap
clinically, and such a state is called the mixed pain condition. To control the mixed pain condition, pharmacotherapies for each pathologic condition would be necessary for
appropriate pain control.
There is a controversy regarding whether acute peripheral nerve inflammation should be included in the neuropathic pain category. The most representative diseases thatdevelop acute pain in association with direct inflammationon the peripheral nerve include shingles in the acute phaseand radiculopathy due to intervertebral disc displacement.
Although nociceptive pain and neuropathic pain may bepresent at the same time during a transition phase fromacute to chronic pain in association with peripheral nerve
inflammation, it is currently difficult to figure out how
much of the acute pain induced by shingles or intervertebral
disc displacement is neuropathic pain. Therefore, in theseguidelines, we would not include the acute pain associatedwith terminal nerve inflammation in the neuropathic pain
category.

Epidemiology of neuropathic pain
CQ7: Are there any epidemiological surveys on the prevalence of neuropathic pain?

CQ8: Are there any epidemiological surveys on the prevalence of neuropathic pain in cancer patients?
In surveys conducted in Japan that focused on chronic pain,
an individual with chronic pain was defined as a person who
had experienced pain with a severity of 4 or above on an
11-point numeric rating scale (NRS: 0 = no pain; 10 = worst
pain imaginable) for at least twice a week for 3–6 months.
As a result, the prevalence was found to be 15.2% for chronic
pain in the musculoskeletal system and 26.4% for chronic
pain among varied etiologies [8, 9]. Of these, the prevalenceof those who were likely to have neuropathic pain according
to the PainDETECT Japanese version [10] and the “Neuropathic Pain Screening Questionnaire (Japanese version)”
was 6.5 and 6.4%, respectively.
Considering the relationship between neuropathic pain
and the specific disease, cancer pain was systematicallyreviewed [11]. Among patients with cancer pain, 59.4% had
nociceptive pain, 19.0% had only neuropathic pain, 20.1%
had a mixture of nociceptive pain and neuropathic pain, and1.5% had pain of unknown origin or other types of pain. In
the European Association for Palliative Care, a study was
conducted using the PainDETECT in 670 patients with painout of 1051 cancer patients; according to the results, 79.7%
patients had nociceptive pain, 16.9% had neuropathic pain,
and 3.4% had pain of unknown origin. Compared to thepatients with nociceptive pain, those with neuropathic pain
required stronger opioid analgesics and adjuvant analgesics,
and their performance state remained worse [12].

Table 4  Comparisons among various screening tools

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

ID Pain

NPQ

painDETECT

LANSS

DN4

Neuropathic
pain screening
tool

+
+
+
+
+

+
+
+
+
+
+

+
+
+
+
+

+
+
+

+
+
+
+

+
+
+
+
+

−

+

+

+

+
+

+
+

+

+

+
+

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Table 5  Differences in features between neuropathic pain and nociceptive (inflammatory) pain

Positive symptoms/signs

Negative symptoms/signs

Spontaneous pain at the affected site
Hypersensitive to pain against nociceptive warmth stimulation
Allodynia against cold stimulation
Increased sensory threshold against pressure stimulation andhypersensitivity to pain
Persistent feeling of stimulation after somatosensory stimulation
Characteristic subjective symptoms
Pain spreading beyond the affected area
Sensory disturbance in the area supplied by the affected nerve
Motor disturbance in the area supplied by the affected nerve

Diagnosis and treatment of neuropathic pain
CQ9: How do we screen patients who may have neuropathic pain?
CQ10: How do we diagnose neuropathic pain?
CQ11: What are the clinical characteristics of neuropathic pain?
Neuropathic pain is distinctive pain that is different from
nociceptive pain. It is characterized by spontaneous pain(continuous or intermittent) or pain induced by stimulation (allodynia, hypersensitivity) at the site supplied by
the affected nerve, which is complicated by various sensory abnormalities caused by the disturbance of a nerve.
The characteristic features of neuropathic pain are in thedescriptions of the screening tools developed in the EU,
US, and Japan (Table 4). The differences in the features ofpain characteristic to each disease are presented in Table 5[13–17]. Positive and negative findings in the somatosensory system of neuropathic pain and nociceptive pain canbe useful when making a diagnosis (Table 5) [15].
Based on these characteristics of neuropathic pain, multiple screening tools have been developed to easily evaluate the possibility that a patient has neuropathic pain inroutine medical practice. There are tools known as theJapanese neuropathic pain screening questionnaire [18],PainDETECT Japanese version [10], and Leeds assessment of neuropathic symptoms and signs (LANSS) Japanese version [19] developed in Japan. All of these are justscreening tools for neuropathic pain in general clinicalsettings, and these demonstrate high sensitivity but moderate specificity. There is a systematic review that compared and evaluated the quality (e.g., validity, reliability)of each screening tool [20]. All tools were supported at
the low evidence level; hence, “use of a screening tool

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Neuropathic pain

Nociceptive(inflammatory)
pain

Present
Rare
Frequent
Often

Present
Frequent
Rare
None

Often
Sudden pain, burning pain
None
Present
Often

Rare
Throbbing pain
None
None
None

should not replace a detailed clinical evaluation” as statedin the guidelines above. Therefore, it is recommended touse a screening tool available, but we should not use theresult of the screening tool as a diagnosis of neuropathic
pain by itself.
To diagnose neuropathic pain, the International Association for the Study of Pain (IASP) developed the flowchart-form diagnostic algorithm (grading system) [21].
The details of this algorithm are described elsewhere.
Briefly, first identify the present illness and the past medical history that suggest neuropathic pain. Then, perform asensory-disturbance evaluation in a neurological examination and a test that confirms the diagnosis of neurologicallesion or a disease. It is desirable to establish a diagnosis
following an algorithm by the IASP neuropathic pain specific interest group.

Treatment strategy for neuropathic pain
CQ12: What is the impact of neuropathic pain on
QOL?
CQ13: What is the summary of the management planfor neuropathic pain?
CQ14: How do we establish the treatment goal for neuropathic pain?
The severity of neuropathic pain is relatively higher thanthat of other pain conditions, and neuropathic pain affects
greatly patients’ health-related QOL. Further, patientswith neuropathic pain were more likely to have prolonged
disease duration and more medical expenses [22]. It was
found that the higher the pain severity, the lower the QOLof patients [23, 24].
The treatment goal should be planned based on boththe severity of pain and their impaired activities of daily

Oral drug

Oral drug

Pregabalin

Duloxetine

Serotonin-noradrenaline
reuptake inhibitor(SNRI)

Calcium channel
α2δligandCalcium channel
α2δligandTramadol

Oral drug (and injection)

OpioidOpioid + acetaminophen

Oral drug

Gabapentin

Tramadol/acetaminophen Oral drug
combination

Oral drug
Oral drug

Nortriptyline
Imipramine

Tricyclic antidepressant(TCA), tertiary amine
TCA, tertiary amine
TCA, secondary amine

Non-proteinogenic
physiologically active
substance

Oral drugFirst-line drug
Amitriptyline

Type

Second-line drug
Oral drug (and injection)
An extract frominflamed cutaneous
tissue of rabbits inoculated with vaccinia
virus

Dosage form

Drug name

Table 6  Clinical characteristics of drugs for neuropathic pain

6–8 weeks; the maximum tolerable dose forat least 2 weeks

Treatment period

Initial dose 25–100/day,
maximum 400 mg/day;
1–4 times/day

Initial dose 1–4 tablets/day, maximum 8 tablets/day; 1–4 times/day

4 tablets (16 unites)/day;Twice daily

4 weeks

4 weeks

4 weeks

Initial dose 100–300 mg/ In addition to 3–8 weeks
of dose-escalation
day, maximum
period, 2 more weeks
3600 mg/day; 1–3
at the maximum dosetimes/day; Increase by
100–300 mg every 1–7
days
4 weeks
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
Initial dose 20 mg/day
maximum 60 mg/
day; Once daily, after
breakfast

Initial dose 10 mg/day,
maximum 150 mg/
day; Once daily, before
bedtime; Increase by
10–25 mg every 3–7
daysSpecific usage

Anti-cholinergic effect, QT
prolongation, suicide risk
Contraindications: glaucoma, prostate hypertrophy, cardiac diseases
Less adverse events withsecondary amine
Attention required whenused concomitantly withtramadolSleepiness, dizziness,
peripheral edema,increased body weight
A small dose should be
used in patients withrenal dysfunction

Adverse reactions

Nausea, sleepiness,incidence is below 0.1%,
high tolerability

Nausea/vomiting, constipation, somnolence
Attention required whenused concomitantly with
SSRI, SNRI, TCA andacetaminophen
Cancer pain, chronic pain Nausea/vomiting, constipation, somnolence
Attention required whenused concomitantly with
SSRI, SNRI, and TCA​

Post-herpetic neuralgia,
low back pain, cervicobrachial syndrome,
scapulohumeral periarthritis, knee osteoarthritis
Chronic pain, pain after
dental extraction

Depression, diabetic neu- Nausea
TCA, attention required
ropathy, fibromyalgia,
when used concomitantly
chronic low back painwith tramadol

Neuropathic pain, pain
associated with fibromyalgia

Refractory epilepsy

Depression, peripheral
neuropathy
Depression
Depression, enuresis

Indications

Journal of Anesthesia (2018) 32:463–478
471

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Nausea/vomiting, constipation, somnolence,
respiratory control
Cancer pain, chronic pain Nausea/vomiting, constipation, somnolence,
respiratory control
Oral, suppository (andinjection)
Morphine

OpioidInitial dose 10 mg/day,
maximum 120 mg/day

4 weeks

Cancer pain
Oral (and injection)
Oxycodone

Opioid1-day patch, 3-day patch(and injection)
Fentanyl

OpioidEstablish the initial dose 4 weeks
by calculating from theopioid dose used before
switching to the treatment. The maximum
dose is 120 mg/day
converted from morphine hydrochloride
Initial dose 10 mg/day,
4 weeks
maximum 120 mg/day

Nausea/vomiting, constipation, somnolence,
respiratory control

Nausea/vomiting, constipation, somnolence,
respiratory control

Chronic pain difficult totreat with non-opioid
analgesic (osteoarthritis, low back pain)
Chronic pain and cancer
pain difficult to treat
with non-opioid analgesic
Can be used just by
switching from otheropioids
Third-line drug
Buprenorphine

Drug name

Table 6  (continued)

Dosage form

Patch, suppository (andinjection)

Type

OpioidSpecific usage

Initial dose 5 mg/day,
maximum 20 mg/day;Once in 7 days

4 weeks

Treatment period

Adverse reactions

Journal of Anesthesia (2018) 32:463–478

Indications

472

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 consideredcrucial to evaluate these factors comprehensively in clinical practice. The basic treatment strategy is a pharmacotherapy 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 theiradherence to pharmacotherapy is not adequate, neuromodulatory treatments or other interventional treatments
are considered. Further, to improve the patients’ ADL and
QOL, functional exercises such as rehabilitations are provided to patients so that they will be able to recover theirself-efficacy. Thus, it is very important to provide interor multi-disciplinary treatments for neuropathic pain bycombining various treatment approaches according to their
bio-psycho-social factors.

Pharmacotherapy for neuropathic pain
CQ15:What are indexes of the effects of pharmacotherapy for neuropathic pain and the levels of recommendation for the respective drugs?
Pathological conditions and diseases associated with neuropathic 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 recommendations for neuropathic pain and selected drugs. Someof the drugs listed in these guidelines are not covered by thehealth insurance when used for neuropathic pain diseases inJapan. Such drugs should be used only after fully informing
patients. Different from other published recommendations[e.g., 27], the guidelines presented an algorithm of pharmacotherapies, which is structured by the first to third-line
drugs, instead of presenting an evidence list. Drugs thatwould have a potential to demonstrate analgesic effects on
multiple diseases associated with neuropathic pain and havebeen approved in Japan as analgesics were selected as thefirst-line drugs. Out of all analgesics approved in Japan, tricyclic antidepressant (amitriptyline), pregabalin, and duloxetine are recommended as the first-line drugs. For the second-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 effective for multiple diseases associated with neuropathic pain. However,
we consider them as the third-line drugs because there havebeen safety concerns for their long-term use. Of all opioid
analgesics, only tramadol has been classified as a secondline drug as its improvement effect on QOL is relatively highand its risk for developing addiction is low. It is desirable toJournal of Anesthesia (2018) 32:463–478

receive a collaborative consultation from a pain management
specialist when considering a long-term administration of
opioid analgesics including tramadol.
In the original first edition of the guidelines, mexiletinehydrochloride was recommended as the second-line drug
because it has been approved for painful diabetic neuropathy. However, because of low efficacy and high incidenceof adverse effects, we did not recommend it in the second
edition of the guidelines [27, 28]. Topical therapies withlidocaine have been reported effective [29, 30], and recommended in overseas guidelines, while this is not approved in

473

Japan. Therefore, we did not demonstrate topical lidocaine
in the algorithm.

First‑line drugs
Pregabalin
Pregabalin inhibits the release of excitatory neurotransmitters by combining with alpha-2-delta subunits of voltagedependent calcium channels in the central nervous system.
Similarly, gabapentin and gabapentin enacarbil work by
combining with alpha-2-delta subunits of voltage-dependentFig. 1  Neuropathic pain
pharmacotherapy algorithm in
the Japanese Society of Pain
Clinicians

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calcium channels. Pregabalin is the only analgesic drug
approved for both peripheral and central neuropathic pain
in Japan. Neither gabapentin nor gabapentin enacarbil isapproved for pain conditions. Pregabalin has greater analgesic potential compared to placebo for both Japanese andother patients with varied peripheral and central neuropathic
pain diseases (e.g., post-herpetic neuralgia [31], painful diabetic polyneuropathy [32], and post-spinal cord injury pain[33]). Pregabalin also improves sleep disturbance, depression, and anxiety associated with neuropathic pain. Thesefavorable effects can be clearly observed not only withrespect to pain but also patients’ QOL.
The use of gabapentin, as well as pregabalin, for neuropathic pain is supported by evidence from studies worldwide. Gabapentin enacarbil has good evidence for neuropathic pain. However, these studies have not been confirmed
for Japanese neuropathic pain patients yet.
Serotonin–noradrenaline reuptake inhibitors (SNRI)
The analgesic effect of serotonin-noradrenaline reuptake
inhibitors (SNRIs) is considered to be mediated by activation of the descending pain inhibitory system. The analgesic
potential of duloxetine, an SNRI, has been demonstrated in aclinical study on pain and numbness associated with diabetic
neuropathy. Its safety has been confirmed in a 52-week study[34]. Further, it was shown that duloxetine improved central neuropathic pain compared to placebo in patients withmultiple sclerosiss [35]. Duloxetine is approved in Japan for
not only painful diabetic polyneuropathy and other chronic
pain condition (i.e., osteoarthritis, chronic low back pain,
and fibromyalgia), but also major depression. The clinicalstudies of duloxetine for painful diabetic polyneuropathy,
osteoarthritis, and chronic low back pain did not include
patients with depressive disorders in Japan. Thus, its analgesic property is independent of its anti-depressant mechanism. In addition, its analgesic effects on cancer chemotherapy-induced neuropathy [36] and low back pain associatedwith radiculopathy [37] have been also observed. On thebasis of these evidences, duloxetine was upgraded as oneof the firs-line drugs in the second edition of the guidelines
from the second-line drug in the original first edition. Duloxetine improves not only pain, but also QOL in patients with
peripheral neuropathy. In addition to duloxetine, two other
SNRIs, venlafaxine and milnacipran, are available but bothare not approved for any neuropathic pain diseases in Japan.
Tricyclic antidepressants (TCAs)
TCAs are significantly effective for a variety of peripheral
and central neuropathic pain compared to placebo. It has
been found that the analgesic mechanisms of TCAs are different from those of other anti-depressants. Among TCAs,

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Journal of Anesthesia (2018) 32:463–478

only amitriptyline is approved for peripheral neuropathic
pain in Japan. It has been reported that there is no difference in analgesic effects between the tertiary amine TCAs
(amitriptyline and imipramine), which show well-balanced
serotonin–noradrenaline reuptake inhibition, and the secondary amine TCA (nortriptyline), which shows relatively
selective noradrenaline reuptake inhibition [38, 39]. Hence,the secondary amine TCA (nortriptyline) is considered morefavorable than the tertiary amine TCAs (amitriptyline andimipramine) for being superior in tolerability, but equivalent
in analgesic effects. As a majority of clinical studies using
TCAs had been conducted before 2000, their effects on QOL
are still unknown due to lack of appropriate evaluations.

Second‑line drugs
Extract from the inflamed cutaneous tissue of rabbits
inoculated with vaccinia virus (ERV)In clinical studies conducted only in Japan, the extract frominflamed cutaneous tissue of rabbits inoculated with vaccinia
virus (ERV) has been found to be effective, particularly forpost-herpetic neuralgia, and has been approved for it [40].
It is thought that the extract from the inflamed cutaneous
tissue of rabbits inoculated with vaccinia virus activates thedescending pain inhibitory system, which produces the analgesic effect. In addition to the analgesic effects, this drug
does not induce serious adverse reactions and its tolerability is very high. It has been used for more than 20 years inclinical practice in Japan and has been highly safe. Although
sleep disorder associated with pain improved, efficacy forother aspects of QOL has not yet been evaluated.
Opioid analgesic [weak]: tramadol
Tramadol acts as both a mu-opioid receptor agonist andSNRI. It is categorized as an opioid analgesic [weak],which is not designated as a restricted opioid for medical
use. The analgesic effects of tramadol have been demonstrated for painful diabetic polyneuropathy [41, 42], postherpetic neuralgia [43], and cancer-related neuropathic
pain [44]. Improvement in QOL has been also confirmed.
Although development of addiction is very unlikely, caution
is required for long-term use. It is best to use this drug fora short-term treatment [27]. Adverse effects (e.g., constipation, sleepiness, vomiting) induced by tramadol are generally milder than those of other opioid analgesics. With both
analgesic effects and QOL improvement, tramadol is given
priority over other opioid analgesics. In the second edition of
the guidelines, it is recommended as a second-line drug due
to low safety concerns associated with long-term use [45].

Journal of Anesthesia (2018) 32:463–478

475

Third‑line drugs

Discussion

Opioid analgesics

Clinical guidelines represent one strategy for improving prescribing practices and health outcomes. Efforts are required
to disseminate the guideline and achieve widespread adoption and implementation of the recommendations in clinicalsettings. These guidelines provide recommendations that are
based on the best available evidence that was interpreted andinformed by expert opinion. Some of the clinical or scientificevidence for the recommendations are still low in quality.
For future guideline development worldwide, more investigations are necessary to fill in critical evidence gaps. The
evidence review for these guidelines clearly illustrate that
there is much to be learn about the effectiveness, safety, andeconomic efficiency of long-term and combined pharmacotherapies. The JSPC will revisit these guidelines as new evidence becomes available to determine when evidence gaps
have been sufficiently closed to warrant an update of theclinical guidelines. These guidelines are intended to improve
communication among clinicians working in varied clinicalsettings and patients about concept of neuropathic pain, its
specific disease burden, the goals of treatment, and the risks
and benefits of pharmacotherapies. These are also intended
to improve the safety and effectiveness of pain treatment.
The JSPC is committed to evaluating the guidelines to identify the impact of the recommendations on clinician andpatient outcomes, both intended and unintended, and revising the recommendations in the future when warranted.

Opioid analgesics are effective for a variety of diseases associated with peripheral and central neuropathic pain, including painful diabetic polyneuropathy and post-herpetic neuralgia [27]. There is abundant evidence for the analgesic
efficacy of morphine and oxycodone. Transdermal fentanyl(both 1- and 3-day patches) has been approved for moderate-severe cancer pain when switching from other opioid
analgesics. Buprenorphine hydrochloride is a partial agonist
for mu-opioid receptors, showing equivalent efficacy. Incidence of adverse effects (e.g., nausea, constipation, sleepiness) induced by opioid analgesics is relatively high, andthese could persist for a long time throughout the treatment
period [46]. Moreover, there is no systematic investigation
made on the long-term safety of these opioid analgesics.
Opioid analgesics might not be safer than other drugs due
to adverse effects, such as development of hypogonadism or
addiction, though the incidence is low. We consider them as
the third-line drugs because opioid analgesics have safetyconcerns for long-term use. Hence, it is desirable to receive
a collaborative consultation from a pain management specialist when using opioid analgesics [moderate and strong]
listed in this chapter. When prescribing opioids for chronic
pain conditions including neuropathic pain, we always needto continue evaluations on either abuse or addiction. The
recommended maintenance dose of an opioid analgesic is
15–120 mg/day when converted to oral morphine hydrochloride. The JSPC has been continuously considering therisk–benefit of pharmacotherapy for neuropathic pain from along-term perspective. We are now debating the necessity oflowering the upper limit of maintenance doses (e.g., 60 mg/day) of opioid analgesics following a US report [47].
CQ16: What is the level of recommendation of NSAIDs
and acetaminophen for neuropathic pain?
There is no high-quality study that has demonstrated theefficacy of both NSAIDs, including selective cyclooxygenase (COX)-2 inhibitors, and acetaminophen for neuropathic
pain. Concomitant use of NSAIDs in addition to pharmacotherapy can be effective in the treatment of a mixed pain
condition where neuropathic pain is complicated by nociceptive inflammatory pain [48]. It is not recommended formixed pain condition as there is hardly any anti-inflammatory effects with acetaminophen.

Compliance with ethical standards
Conflict of interest Members of the task force have conflicts of interest with respect to this work, but none of them received any financial support to develop these guidelines. Astellas, Abott Japan, Eisai,
MSD Japan, Elliquence, Otsuka Pharmacetical, Ono Pharmacetical,
Kyowa Hakko Kirin Co., LTD., Sato Healthcare Innovation, Shionogi & Co., LTD., Showa Yakuhin Kako Co., LTD., St. Jude Medical
Japan, Daiichi-Sankyo, Daiken Medical Co. LTD., Taisho Toyama
Pharmacetical, Sumitomo Dainippon Pharma, Taiho Pharma, Takeda
Pharmacetical, Mitsubishi Tanabe Pharma, Tsumura & Co., Teikoku
Seiyaku, Terumo, Torii Pharmaceutical, Toray, Drager Medical Japan,
Nipro, Eli Lilly Japan, Nippon Kayaku, Nippon Shinyaku Co., LTD.,
Nippon Zoki, Boehringer Ingelheim Japan, Hisamitsu Pharmaceutical,
Bitakain Seiyaku KK., B. Braun Aesculap Japan, Pfizer Japan, Fujifilm sonosite Japan, Boston Scientific Japan, Maruishi Pharmaceutical, Maruho, Mundipharma, Mochida Pharmaceutical, Janssen Pharmacetical KK.
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​
mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate
credit to the original author(s) and the source, provide a link to theCreative Commons license, and indicate if changes were made.

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Journal of Anesthesia (2018) 32:463–478

Appendix

Collaborators

Members of the task force for the clinical guidelinesof pharmacotherapy for neuropathic pain

Keisuke Yamaguchi, Associate Professor, Department ofAnesthesiology and Pain Medicine, Juntendo University
School of Medicine; Yoshika Takahashi, Assistant Professor, Department of Anesthesiology and Pain Medicine, Juntendo University School of Medicine; Makito Oji, AssistantProfessor, Pain Clinic, NTT East Medical Center; KumikoHida, Assistant Professor Department of Anesthesiology,
Nagasaki University School of Medicine; Koji Ishii, Assistant Professor Department of Anesthesiology, Nagasaki
University School of Medicine; Keisuke Watanabe, Lecturer, Department of Anesthesiology and Pain Center, Nara
Medical University; Hidekazu Watanabe, Sendai Pain Clinic
Center; Noriko Taguchi, Sendai Pain Clinic Center; Tomoko
Kitamura, Sendai Pain Clinic Center; Nanase Watabiki, Sendai Pain Clinic Center; Akira Yamashiro, Sendai Pain Clinic
Center.

Academic consultants
Toyoshi Hosokawa, Professor, Department of Pain Management and Palliative Care Medicine, Kyoto Prefectural
University of Medicine; Yasuhisa Okuda, Professor, Anesthesiology, Dokkyo Medical University Koshigaya Hospital;
Kiyoshige Oseto, Professor, Department of Anesthesiology,
Tokyo Medical University.
External expert.
Naoki Nogo, Director, Musashi Kokubunji Park Clinic.
Core working members
Sei Fukui, Clinical Professor and Chair of these guidelines,
Pain Management Clinic, Shiga University of Medical Science Hospital; Hisashi Date, Director, Sendai Pain Clinic
Center; Masahiko Iseki, Professor, Department of Anesthesiology and Pain Medicine, Juntendo University School of
Medicine; Shigeki Yamaguchi, Professor, Department ofAnesthesiology, Dokkyo Medical University School of Medicine; Masahiko Sumitani, Department Director, Departmentof Pain and Palliative Medicine, The University of Tokyo
Hospital; Tetsuya Sakai, Associate Professor, Departmentof Anesthesiology, Nagasaki University Hospital; Narihito
Iwashita, Lecturer, Pain Management Clinic, Shiga Medical
University Hospital.
Working members
Jitsu Kato, Professor, Department of Anesthesiology,
Division of Anesthesiology, Nihon University Schoolof Medicine; Yoshiyuki Kimura, Associate Professor,
Department of Anesthesiology, Dokkyo Medical University School of Medicine; Shizuko Kosugi, AssistantProfessor, Department of Anesthesiology, Keio University
School of Medicine; Munetaka Hirose, Professor, Department of Anesthesiology and Pain Medicine, Hyogo College of Medicine; Keita Fukazawa, Lecturer, Departmentof Pain Management and Palliative Care Medicine, Kyoto
Prefectural University of Medicine; Hidekimi Fukui,
Lecturer, Department of Anesthesiology, Tokyo Medical
University; Yoichi Matsuda, Assistant Professor, Department of Anesthesiology and Intensive Care Medicine,
Osaka University Graduate School of Medicine; Masanori Yamauchi, Professor, Department of Anesthesiology
and Perioperative Medicine, Tohoku University Schoolof Medicine.

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