CME

An update on the pharmacologic management

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and treatment of neuropathic pain

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Megan E. Wright, PA-C; Denise Rizzolo, PA-C, PhD

ABSTRACT
Neuropathic pain results directly from a lesion or disease
of the somatosensory nervous system and can be central
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or peripheral in origin. Epidemiologic research suggests

that 7% to 10% of the general population suffers from
neuropathic pain, although the prevalence may be under-
estimated. Patients with neuropathic pain may experience
anxiety, depression, insomnia, disability, and reduced quality
of life. Treatment remains suboptimal because traditional
drugs provide only modest pain relief. This article reviews
the causes of neuropathic pain, patient presentation, diagno-
sis, and management strategies.
Keywords: neuropathic pain, peripheral neuropathy, central
neuropathic pain, pharmacologic management, gabapentin,

DECADE3D / ALAMY STOCK PHOTO

tricyclic antidepressants

Learning objectives

Discuss the common causes of neuropathic pain.

Describe the presenting signs and symptoms in patients
with neuropathic pain.
Review the diagnostic workup for patients with neuro-
pathic pain. agement remains suboptimal because traditional drugs
Compare and contrast the non-pharmacologic and phar- provide only modest pain relief.6 Neuropathic pain remains
macologic treatments in patients with neuropathic pain. difficult to treat, challenging providers across multiple
disciplines. Management strategies address neuropathic
pain as a broad entity without regard for a specific cause.
Ongoing research aims to individualize management of
neuropathic pain by predicting treatment responses in

N
europathic pain affects 7% to 10% of the general
population; however, the prevalence is likely individual pain phenotypes.
underestimated due to limitations of current
epidemiologic research.1-3 Many patients with neuropathic CAUSES
pain also experience anxiety, depression, insomnia, dis- According to the International Association for the Study
ability, and reduced quality of life.4,5 Unfortunately, man- of Pain (IASP), neuropathic pain is the direct result of a
lesion or disease of the central or peripheral somatosensory
nervous system (Figure 1).7 In contrast, nociceptive pain
Megan E. Wright practices in the Department of Physical Medicine
is caused by actual or impending tissue damage outside of
and Rehabilitation at Penn State Milton S. Hershey Medical Center
in Hershey, Pa. Denise Rizzolo is a research coordinator in the PA the somatosensory nervous system. Patients may present
program at Kean University in Union, N.J., and a faculty member of with mixed pain syndromes (coexisting neuropathic and
the Pace Completion Program in New York City. The authors have nociceptive pain), which further complicate diagnosis and
disclosed no potential conflicts of interest, financial or otherwise. treatment. Additionally, some neurologic disorders indi-
DOI:10.1097/01.JAA.0000512228.23432.f7 rectly cause painful complications (such as spasticity and
Copyright © 2017 American Academy of Physician Assistants rigidity) that require different treatment regimens outside

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Copyright © 2017 American Academy of Physician Assistants

 CME

pain syndrome type II. Note that complex regional pain

Key points syndrome type I does not meet the IASP definition of
Neuropathic pain results directly from a lesion or disease neuropathic pain because patients have no identifiable
of the somatosensory nervous system and can be central nerve damage.6
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or peripheral in origin. Some neuropathic pain conditions, such as spinal cord

Patients with neuropathic pain may experience anxiety, injury or phantom limb pain, may be underrepresented
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depression, insomnia, disability, and reduced quality of life. because much of the current research on neuropathic pain
Treatment includes tricyclic antidepressants and gabapen- focuses on painful diabetic peripheral neuropathy and
tin as well as nonpharmacologic interventions. postherpetic neuralgia.

HISTORY AND PHYSICAL EXAMINATION

the realm of neuropathic pain management.8 This article Patients with neuropathic pain may have positive and/or
focuses on managing patients with neuropathic pain, negative signs and symptoms (Table 1). Positive signs and
although some of the treatment approaches also may be symptoms reflect nervous system hyperactivity; negative
beneficial for patients with mixed pain. signs and symptoms reflect loss of nervous system function.
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The presence of both positive and negative signs and

PERIPHERAL VS. CENTRAL symptoms is highly suggestive of an underlying neuropathic
Peripheral neuropathic pain is more commonly encountered pain condition. This is a nonspecific finding, however, as
in the primary care setting than central neuropathic pain. patients with nociceptive pain may experience both posi-
This type of neuropathic pain may develop as a result of tive and negative symptoms.5
mononeuropathy (carpal tunnel syndrome or sciatica), Positive signs and symptoms include burning, shooting,
polyneuropathy (diabetes), varicella zoster virus (posther- stabbing, coldness, tightness, paresthesias, or electric shock-
petic neuralgia), trauma, surgically induced nerve injury, like sensations. The pain may be characterized as continu-
Guillain-Barré syndrome, chemotherapy, or radiculopathy. ous or intermittent, and spontaneous or evoked.4
Central neuropathic pain is associated with spinal cord Negative signs and symptoms are nonpainful and are
injury, multiple sclerosis, stroke, tumor compression, often discovered during physical examination.5 Findings
amputation (phantom limb pain), and complex regional may include muscle weakness; loss of deep tendon reflexes;
absent or impaired sensation to
light, touch, pinprick, vibration,
and temperature.4,5
Establishing the patient’s pain
distribution is perhaps the most
important part of clinical evalu-
ation. Neuropathic pain is local-
ized to a peripheral nerve region
or to neuroanatomical correlates
MEDICAL IMAGES RM / ROBERT MARGULIES

of the central nervous system,

such as dermatomes, myotomes,
and afferent spinal pathways,
raising suspicion for an underly-
ing lesion or disease of the
somatosensory nervous system.8

DIAGNOSIS
History and physical examina-
tion remain the gold standard
of the neuropathic pain diagno-
sis. Despite screening tools such
as the Douleur Neuropathique
en 4, Leeds Assessment of Neu-
ropathic Symptoms and Signs,
and PainDETECT, no consensus
exists on which tool is superior.
FIGURE 1. High serum glucose causes thickening of the capillary basement membrane, They all miss 10% to 20% of
resulting in neuronal hypoxia and necrosis and interruption of nerve pathways. patients who are later diagnosed

14 www.JAAPA.com Volume 30 • Number 3 • March 2017

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 An update on pharmacologic management and treatment of neuropathic pain

with neuropathic pain syndromes.9,10 Keeping these limi- TABLE 1. Signs and symptoms of neuropathic pain9
tations in mind, primary care providers may use the tools
Negative
along with clinical judgment to help establish a diagnosis • Hypoesthesia—reduced sensation to nonpainful stimuli
of neuropathic pain. As mentioned above, the combination
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• Hypoalgesia—decreased sensation to painful stimuli

of negative and positive signs and symptoms is highly
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suggestive of a neuropathic pain syndrome, especially Positive

when localized to a neuroanatomic region of the body. Spontaneous
In 2008, Treede and colleagues proposed a grading • Paresthesia—abnormal, nonpainful somatic sensation,
system that incorporates a focused approach to clinical such as tingling or skin-crawling
• Paroxysmal pain—shooting electrical sensations, usually
evaluation with additional diagnostic testing to determine
lasting for seconds at a time
the likelihood of neuropathic pain.8 Useful diagnostic tests • Superficial pain—painful ongoing sensation, usually burn-
may include plain radiographs, CT, MRI, electromyogra- ing in nature
phy (EMG), somatosensory-evoked potentials, laser-evoked
potentials, skin biopsy, or reflex responses.8 An underlying Evoked
• Allodynia—pain in response to nonpainful stimuli
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cause should be identified when possible. In the primary

care setting, this may involve laboratory testing, radio- • Hyperalgesia—exaggerated pain response to painful stimuli
• Temporal summation (“wind-up pain”)—increasing pain
graphs, CT, MRI, and referral to a specialist service.
sensation from repetitive application of an identical single
noxious stimulus
NONPHARMACOLOGIC MANAGEMENT
No concrete evidence demonstrates the effectiveness of
nonpharmacologic interventions such as exercise, biofeed- their efficacy.6,12-15 According to a NICE meta-analysis,
back, cognitive behavioral therapy (CBT), transcutaneous patients taking tricyclic antidepressants were more likely to
electrical nerve stimulation (TENS), and repetitive tran- report at least 30% pain relief.12 For patients who achieve
scranial magnetic stimulation (rTMS) in treating neuropathic adequate pain relief with amitriptyline but are unable to
pain.11 Potential benefits of treatment may outweigh the tolerate the adverse reactions, consider switching to nor-
risks; providers may consider one or more of these therapies triptyline or imipramine. Anticholinergic adverse reactions
in addition to traditional pharmacologic management. to tricyclic antidepressants are common, and include seda-
tion, dry mouth and constipation. When tricyclic antidepres-
PHARMACOLOGIC MANAGEMENT sants are taken at bedtime, their sedating properties may be
Pharmacologic management focuses on neuropathic pain as used strategically for treating neuropathic pain and associ-
a broad clinical entity, and regardless of cause, similar treat- ated insomnia.
ment strategies often are used.11,12 An exception is trigeminal SNRIs include duloxetine and venlafaxine. Both drugs,
neuralgia. Multiple research studies analyze the condition especially duloxetine, are recommended as first-line treat-
as a separate entity because of its distinct treatment approach. ment for painful diabetic peripheral neuropathy.6,12,13,15
Guidelines and consensus statements for the pharmaco- They also may be used as first-line treatments for neuro-
logic management of neuropathic pain have been published pathic pain from other causes.6,12,13,15 NICE reports that
by the IASP’s special interest group on neuropathic pain, patients taking duloxetine were more likely to report at
the Canadian Pain Society, the European Federation of least 30% pain relief from all causes.12 Duloxetine also
Neurological Societies, and the United Kingdom’s National significantly reduced pain intensity in a study of patients
Institute for Health and Clinical Excellence (NICE). These with chemotherapy-induced painful peripheral neuropa-
statements apply to neuropathic pain in general and do thy.13 In general, duloxetine is preferred over venlafaxine
not take underlying causes into account. Disease-specific due to its greater evidence of efficacy.6,12
recommendations are provided only for painful diabetic Pregabalin is strongly recommended for first-line treatment
peripheral neuropathy. The findings from these reports are of neuropathic pain by each of the organizations mentioned
summarized below. above. This drug has dose-dependent effects and is given
First-line treatment options include tricyclic antidepres- twice daily.6,15 According to NICE, patients taking prega-
sants, serotonin-norepinephrine reuptake inhibitors balin were more likely to report at least 30% pain reduction.12
(SNRIs), gabapentin, and pregabalin (Table 2).6,12,13 When Efficacy for pain relief has been established in patients with
deciding which medication to prescribe first, consider postherpetic neuralgia and chronic pain resulting from
patient preferences, lifestyles, risk factors, comorbidities, spinal cord injury.13,15 Common adverse reactions to prega-
insurance coverage, and the patient’s financial situation. balin include dizziness, somnolence, and weight gain.
Tricyclic antidepressants, especially amitriptyline, have Gabapentin is an anticonvulsant that may be used to
historically been used as first-line treatment for neuropathic treat neuropathic pain and may be dosed several times a
pain, despite a lack of high-quality evidence demonstrating day. NICE reports that patients taking gabapentin were

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Copyright © 2017 American Academy of Physician Assistants

 CME

more likely to report at least 50% pain relief.12 Unfortu- interested in prescribing and/or administering high-
nately, there is less consensus on when gabapentin should concentrate capsaicin patches. The long-term effects of
be prescribed. The IASP Special Interest Group on Neu- these patches have not been thoroughly investigated.11
ropathic Pain and the Canadian Pain Society endorse Cannabinoids and opioids for neuropathic pain are con-
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first-line use of gabapentin for patients with neuropathic troversial. Finnerup and colleagues recommend opioids as
pain, regardless of underlying cause.6,13 However, the third-line treatment due to concerns for potential abuse,
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European Federation of Neurological Sciences recommends diversion, misuse, and overdose.6 Opioids may be used
first-line use of gabapentin only for painful diabetic periph- most appropriately on a short-term basis, perhaps for acute
eral neuropathy, postherpetic neuralgia, and central pain.15 pain control during titration of other agents. Cannabinoids
Common adverse reactions to gabapentin include dizziness, also remain controversial. They are available in several
somnolence, and fatigue. routes of administration, including oral and intramucosal,
Second-line treatment options include tramadol, lidocaine and may play a role in treating central neuropathic pain,
patches, and high-concentration capsaicin patches.11 Con- though additional research is needed.13 In many states,
sider using tramadol before opioids such as morphine and legislation continues to limit the free prescription of can-
oxycodone because it generally has a less significant effect nabinoids. Similar to opioids, cannabinoids raise concerns
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on cognition and a decreased risk of misuse and abuse.6 for abuse, misuse, and psychosis, especially in patients with
Lidocaine patches and high-concentration capsaicin patches a premorbid psychiatric history.
lack high-quality evidence of efficacy but have more favor- Research to date fails to show significant efficacy of one
able safety profiles and usually are well tolerated.11-13 drug over another for specific neuropathic pain conditions,
Topical lidocaine may be a prudent treatment option for with the exception of duloxetine for painful diabetic
older adults who may not be able to tolerate the adverse peripheral neuropathy and carbamazepine for trigeminal
reactions to more aggressive pharmacologic treatments. neuralgia.11-13 Promising research suggests that patients
Special training is encouraged for healthcare providers with certain sensory phenotypes may be more likely to

TABLE 2. Pharmacologic treatment options for adults with neuropathic pain12,18

Drug Starting Maximum Common adverse Off-label use Comments
dose dose reactions
Amitriptyline 10 mg daily 150 mg daily Dry mouth, Yes • If patients achieve adequate pain
Imipramine 50 mg daily 150 mg daily sedation relief with amitriptyline but are
or 25 mg unable to tolerate the adverse
twice daily reactions, consider switching to
imipramine or nortriptyline
Nortriptyline 10 mg daily 150 mg daily • May also treat concurrent depression
• Dose at bedtime to treat concur-
rent insomnia or if patient is expe-
riencing daytime somnolence
• Allow 6 to 8 weeks for an adequate
trial
Gabapentin 300 mg daily 3,600 mg daily Dizziness, Yes • Gabapentin may be administered
Pregabalin 75 mg daily 600 mg daily somnolence, Yes, except for multiple times per day, commonly
or 50 mg weight gain patients with posther- three times daily
three times petic neuralgia, pain- • Allow 4 weeks for an adequate trial
per day ful diabetic peripheral of gabapentin or pregabalin
neuropathy, or neuro-
pathic pain associated
with spinal cord injury
Duloxetine 60 mg daily 120 mg daily Dry mouth, Yes, except for • Recommended for first-line treat-
constipation, patients with painful ment of painful diabetic peripheral
gastrointestinal diabetic peripheral neuropathy
upset neuropathy • May also treat concurrent depression
• Allow 4 weeks for an adequate trial
Tramadol 50 to 100 400 mg daily Dizziness, fatigue, No • May reduce the seizure threshold
mg no more gastrointestinal • Allow 4 weeks for an adequate trial
than every upset
4 hours

16 www.JAAPA.com Volume 30 • Number 3 • March 2017

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 An update on pharmacologic management and treatment of neuropathic pain

respond to specific medications (for example, patients with 4. Gilron I, Baron R, Jensen T. Neuropathic pain: principles of
pinprick hyperalgesia had a positive response to pregaba- diagnosis and treatment. Mayo Clin Proc. 2015;90(4):532-545.
5. Magrinelli F, Zanette G, Tamburin S. Neuropathic pain:
lin), but this is still under investigation.16 diagnosis and treatment. Pract Neurol. 2013;13(5):292-307.
6. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy
B50jWdZvh13wjwbqP5pfvEyMMb9zA5070xXroi8vI1iieH60wAqUMfANsgmsL0cx1fSojzE/AqtnASHmcD2Xoth141ynJBhLsb00

CONCLUSION for neuropathic pain in adults: a systematic review and meta-

Neuropathic pain is an important clinical issue that often analysis. Lancet Neurol. 2015;14(2):162-173.
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7. International Association for the Study of Pain. Taxonomy.

is accompanied by anxiety, depression, sleep disturbance, www.iasp-pain.org/Taxonomy#Neuropathicpain. Accessed
functional impairment, and reduced quality of life. Due to November 21, 2016.
the refractory nature of neuropathic pain, clinicians should 8. Treede RD, Jensen TS, Campbell JN, et al. Neuropathic pain:
consider using pharmacologic and nonpharmacologic redefinition and a grading system for clinical and research
purposes. Neurology. 2008;70(18):1630-1635.
intervention in patient management. A multidisciplinary 9. Baron R, Binder A, Wasner G. Neuropathic pain: diagnosis,
approach that involves the patient and includes the primary pathophysiological mechanisms, and treatment. Lancet Neurol.
care provider, pain specialist, physical and occupational 2010;9(8):807-819.
therapists, psychologist, neurologist, and/or physiatrist is 10. Haanpää M, Attal N, Backonja M, et al. NeuPSIG guidelines on
neuropathic pain assessment. Pain. 2011;152(1):14-27.
recommended. JAAPA
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11. Dworkin RH, O’Connor AB, Kent J, et al. Interventional

Earn Category I CME Credit by reading both CME articles in this issue, management of neuropathic pain: NeuPSIG recommendations.
Pain. 2013;154(11):2249-2261.
reviewing the post-test, then taking the online test at http://cme.aapa.
12. Centre for Clinical Practice at NICE (UK). Neuropathic Pain:
org. Successful completion is defined as a cumulative score of at least
The Pharmacological Management of Neuropathic Pain in
70% correct. This material has been reviewed and is approved for 1 hour Adults in Non-Specialist Settings. London: National Institute for
of clinical Category I (Preapproved) CME credit by the AAPA. The term of Health and Clinical Excellence (UK); 2010.
approval is for 1 year from the publication date of March 2017. 13. Moulin D, Boulanger A, Clark AJ, et al. Pharmacological manage-
ment of chronic neuropathic pain: revised consensus statement from
REFERENCES the Canadian Pain Society. Pain Res Manag. 2014;19(6):328-335.
1. Torrance N, Smith BH, Bennett MI, Lee AJ. The epidemiology of 14. Moore RA, Derry S, Aldington D, et al. Amitriptyline for
chronic pain of predominantly neuropathic origin. Results from neuropathic pain in adults. Cochrane Database Syst Rev. 2015;
a general population survey. J Pain. 2006;7(4):281-289. (7):CD008242.
2. Bouhassira D, Lantéri-Minet M, Attal N, et al. Prevalence of 15. Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the
chronic pain with neuropathic characteristics in the general pharmacological treatment of neuropathic pain: 2010 revision.
population. Pain. 2008;136(3):380-387. Eur J Neurol. 2010;17(9):1113-e88.
3. van Hecke O, Austin SK, Khan RA, et al. Neuropathic pain in 16. Simpson DM, Schifitto G, Clifford DB, et al. Pregabalin for
the general population: a systematic review of epidemiological painful HIV neuropathy: a randomized, double-blind, placebo-
studies. Pain. 2014;155(4):654-662. controlled trial. Neurology. 2010;74(5):413-420.

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