Treatment of Neuropathic Pain: An Overview of Recent Guidelines

doi:10.1016/j.amjmed.2009.04.007

The American Journal of Medicine

Volume 122, Issue 10, Supplement, October 2009, Pages S22-S32

https://doi.org/10.1016/j.amjmed.2009.04.007 Get rights and content

Abstract

A number of different treatments for neuropathic pain have been studied, but the literature is sizable, rapidly evolving, and lacks important information about practical aspects of patient management. Under the auspices of the International Association for the Study of Pain (IASP) Neuropathic Pain Special Interest Group (NeuPSIG), a consensus process was used to develop evidence-based guidelines for the pharmacologic management of neuropathic pain that take into account clinical efficacy, adverse effects, impact on health-related quality of life, convenience, and costs. On the basis of randomized clinical trials, medications recommended as first-line treatments for neuropathic pain included certain antidepressants (i.e., tricyclic antidepressants and dual reuptake inhibitors of both serotonin and norepinephrine), calcium channel α₂-δ ligands (i.e., gabapentin and pregabalin), and topical lidocaine. Opioid analgesics and tramadol were recommended as second-line treatments that can be considered for first-line use in selected clinical circumstances. Other medications that generally would be used as third-line treatments include certain other antidepressant and antiepileptic medications, topical capsaicin, mexiletine, and N-methyl-d-aspartate receptor antagonists. Two other national and international associations recently published pharmacologic treatment guidelines for neuropathic pain, which are summarized and contrasted with the NeuPSIG recommendations. Recent guidelines for the use of neurostimulation for the treatment of neuropathic pain also are summarized. For all treatments for neuropathic pain, long-term studies, head-to-head comparisons, and studies of treatment combinations are a priority for future research.

Section snippets

General Considerations Regarding Guidelines for the Treatment of Neuropathic Pain

Although consensus guidelines for the treatment of neuropathic pain are based on synthesizing results from RCTs, a large number of gaps in the literature exist. For example, most of the pharmacotherapy trials have investigated patients with postherpetic neuralgia or painful diabetic peripheral neuropathy, yet there are many patients with neuropathic pain who have a different lesion or disease as the cause of their pain. This raises an important concern: to what extent is it reasonable to

International Association for the Study of Pain Neuropathic Pain Special Interest Group Guidelines for the Treatment of Neuropathic Pain

The NeuPSIG guidelines recommend medications as first-line treatment if multiple RCTs have demonstrated consistent efficacy in Neuropathic Pain (Oxford Centre for Evidence-based Medicine grade A recommendation¹⁶) and the authors believed them to be good first choices for patients with neuropathic pain; as second-line if multiple RCTs demonstrated consistent efficacy in neuropathic pain (grade A recommendation) but the authors had reservations about their use relative to the first-line

Antidepressants with Both Norepinephrine and Serotonin Reuptake Inhibition (TCAs and SSNRIs)

Numerous placebo-controlled RCTs have established the efficacy of TCAs for treating a variety of types of neuropathic pain (Table 2). However, RCTs in some neuropathic pain conditions, such as painful HIV and chemotherapy peripheral neuropathies, have been negative.13, 18

The biggest advantages of TCAs are their low cost, once-daily dosing, and beneficial effects on depression, which is a common comorbidity with neuropathic pain. Importantly, TCAs appear to have equivalent analgesic benefits in

Second-Line Medications Appropriate for First-Line Use in Certain Circumstances

Opioid analgesics and tramadol have been found to be efficious in several high-quality RCTs in patients with various types of neuropathic pain (grade A recommendation). However, owing to concerns over their long-term safety (relative to first-line medications), they are recommended principally for patients who have not responded to the first-line medications, except in certain clinical circumstances (i.e., for the treatment of acute neuropathic pain, episodic exacerbations of severe neuropathic

Third-Line Medications

A number of other medications have shown efficacy in neuropathic pain in a single RCT or inconsistent results in different RCTs (grade B recommendation). In general, these medications should be reserved for patients who do not tolerate or respond to the first- and second-line medications, or for whom the first- and second-line medications are contraindicated.

Several additional antidepressant medications have been studied for treatment of neuropathic pain.¹⁸ Single RCTs have shown efficacy for

Central Neuropathic Pain

The NeuPSIG guidelines note that few medications have been found to be efficacious in neuropathic pain originating from a lesion in the central nervous system. RCTs have demonstrated efficacy for TCAs in central poststroke pain, and for calcium channel α₂-δ ligands in spinal cord injury and poststroke central neuropathic pain (Table 2).13, 35

Cannabinoids have demonstrated efficacy in pain associated with multiple sclerosis, but their use is limited by availability and concerns over long-term

Canadian Pain Society Guidelines

The Canadian Pain Society created 4 levels of recommendation, with first- and second-line medications differentiated by “the quality of evidence and the evidence of efficacy” based on NNTs.¹⁵ Medications were classified as third-line treatments if they have good evidence of efficacy, but require specialized monitoring and follow-up not required of drugs at the other levels. Fourth-line medications were described as having “at least 1 positive RCT, but required further study”.¹⁵

The authors

European Federation of Neurological Societies Pharmacological Treatment Guidelines

As with the NeuPSIG and Canadian Pain Society guidelines, the EFNS guidelines grade the level of evidence for different available treatments. However, unlike the other 2 sets of guidelines, separate recommendations were made for the treatment of patients with painful polyneuropathies (including painful diabetic peripheral neuropathy), postherpetic neuralgia, trigeminal neuralgia, and central neuropathic pain.¹⁴

Consistent with the NeuPSIG and Canadian Pain Society guidelines, the EFNS guidelines

European Federation of Neurological Societies Guidelines for Neurostimulation Therapy in Patients with Neuropathic Pain

An EFNS task force recently reviewed the literature on neurostimulation therapy and developed guidelines for its use in neuropathic pain. In general, the quality of evidence was inadequate to make specific recommendations for many types of neuropathic pain. One noteworthy problem in many studies assessing neurostimulation interventions, which are typically only applied to patients who are refractory to pharmacologic treatment, is the absence of a good control or comparator (e.g., a placebo or

Summary

Three evidence-based consensus guidelines for the pharmacologic treatment of neuropathic have been published recently. These guidelines all recommend TCAs, gabapentin, and pregabalin as first-line treatment options for patients with neuropathic pain (excluding trigeminal neuralgia). They also recommend reserving opioid analgesics and tramadol as second- or third-line options in most cases, despite evidence of efficacy in neuropathic pain. In 2 of the guidelines, topical lidocaine is recommended

Author Disclosures

The authors who contributed to this article have disclosed the following industry relationships:

Alec B. O'Connor, MD, MPH, has no disclosures to report.
Robert H. Dworkin, PhD, In the past 12 months, has worked as a consultant to Allergan, Inc., Astellas Pharma US, Inc., Avigen, Inc., Balboa Biosciences Inc., Bristol-Myers Squibb Company, Cara Therapeutics, Inc., Cervelo Pharmaceuticals Inc., Eli Lilly and Company, Endo Pharmaceuticals, EpiCept Corporation, Fralex Therapeutics Inc.,

References (37)

G. Oster et al.
Pain, medication use, and health-related quality of life in older persons with postherpetic neuralgia: results from a population-based survey
J Pain
(2005)
M. Gore et al.
Burden of illness in painful diabetic peripheral neuropathy: the patients' perspectives
J Pain
(2006)
A.M. McDermott et al.
The burden of neuropathic pain: results of a cross-sectional survey
Eur J Pain
(2006)
A. Berger et al.
Clinical characteristics and economic costs of patients with painful neuropathic disorders
J Pain
(2004)
R.H. Dworkin et al.
Pharmacologic management of neuropathic pain: evidence-based recommendations
Pain
(2007)
N.B. Finnerup et al.
Algorithm for neuropathic pain treatment: an evidence based proposal
Pain
(2005)
H.W. Cohen et al.
Excess risk of myocardial infarction in patients treated with antidepressant medications: association with use of tricyclic agents
Am J Med
(2000)
M.C. Rowbotham et al.
Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study
Pain
(2004)
J. Højsted et al.
Addiction to opioids in chronic pain patients: a literature review
Eur J Pain
(2007)
J.H. Vranken et al.
Pregabalin in patients with central neuropathic pain: a randomized, double-blind, placebo-controlled trial of a flexible-dose regimen
Pain
(2008)

A.B. O'Connor et al.

Pain associated with multiple sclerosis: systematic review and proposed classification

Pain

(2008)

R.D. Treede et al.

Neuropathic pain: redefinition and a grading system for clinical research purposes

Neurology

(2008)

M.P. Jensen et al.

The impact of neuropathic pain on health-related quality of life: review and implications

Neurology

(2007)

A.B. O'Connor

Neuropathic pain: a review of the quality of life impact, costs, and cost-effectiveness of therapy

Pharmacoeconomics

(2009)

R.H. Dworkin et al.

Healthcare costs of acute and chronic pain associated with a diagnosis of herpes zoster

J Am Geriatr Soc

(2007)

J. Lachaine et al.

Painful neuropathic disorders: an analysis of the Régie de l'Assurance Maladie du Québec database

Pain Res Manag

(2007)

R.H. Dworkin et al.

Healthcare expenditure burden of persisting herpes zoster pain

Pain Med

(2008)

N. Torrance et al.

Medication and treatment use in primary care patients with chronic pain of predominantly neuropathic origin

Fam Pract

(2007)

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: Dr. O'Connor has received support from the Mayday Fund, and the US National Institutes of Health (NIH). Dr. Dworkin has received support from the NIH and the US Veterans Administration (VA). He is a Special Government Employee of the US Food and Drug Administration Center for Drug Evaluation and Research (FDA CDER).

: Statement of author disclosure: Please see the Author Disclosures section at the end of this article.

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Treatment of Neuropathic Pain: An Overview of Recent Guidelines

Abstract

Section snippets

General Considerations Regarding Guidelines for the Treatment of Neuropathic Pain

International Association for the Study of Pain Neuropathic Pain Special Interest Group Guidelines for the Treatment of Neuropathic Pain

Antidepressants with Both Norepinephrine and Serotonin Reuptake Inhibition (TCAs and SSNRIs)

Second-Line Medications Appropriate for First-Line Use in Certain Circumstances

Third-Line Medications

Central Neuropathic Pain

Canadian Pain Society Guidelines

European Federation of Neurological Societies Pharmacological Treatment Guidelines

European Federation of Neurological Societies Guidelines for Neurostimulation Therapy in Patients with Neuropathic Pain

Summary

Author Disclosures

J Pain

J Pain

Eur J Pain

J Pain

Pain

Pain

Am J Med

Pain

Eur J Pain

Pain

Pain

Neuropathic pain: redefinition and a grading system for clinical research purposes

Neurology

The impact of neuropathic pain on health-related quality of life: review and implications

Neurology

Neuropathic pain: a review of the quality of life impact, costs, and cost-effectiveness of therapy

Pharmacoeconomics

Healthcare costs of acute and chronic pain associated with a diagnosis of herpes zoster

J Am Geriatr Soc

Painful neuropathic disorders: an analysis of the Régie de l'Assurance Maladie du Québec database

Pain Res Manag

Healthcare expenditure burden of persisting herpes zoster pain

Pain Med

Medication and treatment use in primary care patients with chronic pain of predominantly neuropathic origin

Fam Pract