Pharmacotherapy for Neuropathic Pain: A Review

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Abstract

Neuropathic pain, comprising a range of heterogeneous conditions, is often severe and difficult to manage, and this may result in a chronic condition that negatively affects the overall functioning and quality of life in patients. The pharmacotherapy of neuropathic pain is challenging and for many patients effective treatment is lacking; therefore, evidence-based recommendations are essential. Currently, there is general agreement on which drugs are appropriate for the first-line treatment of neuropathic pain, whereas debate continues regarding second- and third-line treatments. First-line drugs for neuropathic pain include antidepressants (tricyclic antidepressants and serotonin–noradrenaline reuptake inhibitors) and anticonvulsants acting at calcium channels (pregabalin and gabapentin). Second- and third-line drugs for neuropathic pain include topical lidocaine and opioids. Although efficacious in the treatment of neuropathic pain, opioids are not considered to be a first choice because of adverse drug reactions and, more recently, because of concerns about abuse, diversion, and addiction. A clear understanding of the mechanism of action of currently available drugs is an essential step towards an effective clinical approach that aims to tailor therapies both to the specific neuropathic disease and to the needs of an individual patient. This review provides an overview of current drugs available for the treatment of neuropathic pain with an emphasis on their mechanism of action.

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Pfizer, Italy.

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Most cited references 22

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A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin.

Raymond Miller, S Chapel, Karina P Bürger … (2010)

Pregabalin and gabapentin share a similar mechanism of action, inhibiting calcium influx and subsequent release of excitatory neurotransmitters; however, the compounds differ in their pharmacokinetic and pharmacodynamic characteristics. Gabapentin is absorbed slowly after oral administration, with maximum plasma concentrations attained within 3-4 hours. Orally administered gabapentin exhibits saturable absorption--a nonlinear (zero-order) process--making its pharmacokinetics less predictable. Plasma concentrations of gabapentin do not increase proportionally with increasing dose. In contrast, orally administered pregabalin is absorbed more rapidly, with maximum plasma concentrations attained within 1 hour. Absorption is linear (first order), with plasma concentrations increasing proportionately with increasing dose. The absolute bioavailability of gabapentin drops from 60% to 33% as the dosage increases from 900 to 3600 mg/day, while the absolute bioavailability of pregabalin remains at > or = 90% irrespective of the dosage. Both drugs can be given without regard to meals. Neither drug binds to plasma proteins. Neither drug is metabolized by nor inhibits hepatic enzymes that are responsible for the metabolism of other drugs. Both drugs are excreted renally, with elimination half-lives of approximately 6 hours. Pregabalin and gabapentin both show dose-response relationships in the treatment of postherpetic neuralgia and partial seizures. For neuropathic pain, a pregabalin dosage of 450 mg/day appears to reduce pain comparably to the predicted maximum effect of gabapentin. As an antiepileptic, pregabalin may be more effective than gabapentin, on the basis of the magnitude of the reduction in the seizure frequency. In conclusion, pregabalin appears to have some distinct pharmacokinetic advantages over gabapentin that may translate into an improved pharmacodynamic effect.

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Antidepressants and gabapentinoids in neuropathic pain: Mechanistic insights.

Melanie Kremer, Eric Salvat, André Müller … (2016)

Neuropathic pain arises as a consequence of a lesion or disease affecting the somatosensory system. It is generally chronic and challenging to treat. The recommended pharmacotherapy for neuropathic pain includes the use of some antidepressants, such as tricyclic antidepressants (TCAs) (amitriptyline…) or serotonin and noradrenaline re-uptake inhibitors (duloxetine…), and/or anticonvulsants such as the gabapentinoids gabapentin or pregabalin. Antidepressant drugs are not acute analgesics but require a chronic treatment to relieve neuropathic pain, which suggests the recruitment of secondary downstream mechanisms as well as long-term molecular and neuronal plasticity. Noradrenaline is a major actor for the action of antidepressant drugs in a neuropathic pain context. Mechanistic hypotheses have implied the recruitment of noradrenergic descending pathways as well as the peripheral recruitment of noradrenaline from sympathetic fibers sprouting into dorsal root ganglia; and importance of both α2 and β2 adrenoceptors have been reported. These monoamine re-uptake inhibitors may also indirectly act as anti-proinflammatory cytokine drugs; and their therapeutic action requires the opioid system, particularly the mu (MOP) and/or delta (DOP) opioid receptors. Gabapentinoids, which target the voltage-dependent calcium channels α2δ-1 subunit, inhibit calcium currents, thus decreasing the excitatory transmitter release and spinal sensitization. Gabapentinoids also activate the descending noradrenergic pain inhibitory system coupled to spinal α2 adrenoceptors. Gabapentinoid treatment may also indirectly impact on neuroimmune actors, like proinflammatory cytokines. These drugs are effective against neuropathic pain both with acute administration at high dose and with repeated administration. This review focuses on mechanistic knowledge concerning chronic antidepressant treatment and gabapentinoid treatment in a neuropathic pain context.

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Prevalence of opioid adverse events in chronic non-malignant pain: systematic review of randomised trials of oral opioids

R Moore, Henry J McQuay (2005)

Adverse events of opioids may restrict their use in non-cancer pain. Analysis of the incidence of common adverse events in trials conducted in non-cancer pain has usually been limited to opioids used to treat severe pain according to the WHO three-step ladder. To examine the incidence of common adverse events of opioids in non-cancer pain, a systematic review and meta-analysis of information from randomised trials of all opioids in non-cancer pain was undertaken. Studies used were published randomised trials of oral opioid in non-cancer pain, with placebo or active comparator. Thirty-four trials with 5,546 patients were included with 4,212 patients contributing some information on opioid adverse events. Most opioids used (accounting for 90% of patients) were for treating moderate rather than severe pain. Including trials without a placebo increased the amount of information available by 1.4 times. Because of clinical heterogeneity in condition, opioid, opioid dose, duration, and use of titration, only broad results could be calculated. Use of any oral opioid produced higher rates of adverse events than did placebo. Dry mouth (affecting 25% of patients), nausea (21%), and constipation (15%) were the most common adverse events. A substantial proportion of patients on opioids (22%) withdrew because of adverse events. Because most trials were short, less than four weeks, and because few titrated the dose, these results have limited applicability to longer-term use of opioids in clinical practice. Suggestions for improved studies are made.

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Author and article information

Contributors

Diego Fornasari: diego.fornasari@unimi.it

Journal

Journal ID (nlm-ta): Pain Ther

Journal ID (iso-abbrev): Pain Ther

Title: Pain and Therapy

Publisher: Springer Healthcare (Cheshire )

ISSN (Print): 2193-8237

ISSN (Electronic): 2193-651X

Publication date (Electronic): 24 November 2017

Publication date PMC-release: 24 November 2017

Publication date (Print): December 2017

Volume: 6

Issue: Suppl 1

Pages: 25-33

Affiliations

ISNI 0000 0004 1757 2822, GRID grid.4708.b, Department of Medical Biotechnology and Translational Medicine, , Università degli Studi di Milano, ; Milan, Italy

Article

Publisher ID: 91

DOI: 10.1007/s40122-017-0091-4

PMC ID: 5701897

PubMed ID: 29178034

SO-VID: a1f9c996-10ef-44d8-a161-3b349cb5a673

History

Date received : 19 September 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100004319, Pfizer;

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Keywords: anticonvulsants,antidepressants,gabapentin,mechanism of action,neuropathic pain,opioids,pregabalin,serotonin–noradrenaline reuptake inhibitors,tricyclic antidepressants

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Keywords: anticonvulsants, antidepressants, gabapentin, mechanism of action, neuropathic pain, opioids, pregabalin, serotonin–noradrenaline reuptake inhibitors, tricyclic antidepressants

Pharmacotherapy for Neuropathic Pain: A Review

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Most cited references 22

A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin.

Antidepressants and gabapentinoids in neuropathic pain: Mechanistic insights.

Prevalence of opioid adverse events in chronic non-malignant pain: systematic review of randomised trials of oral opioids

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