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Pharmacotherapy of Neuropathic Pain: Which Drugs, Which Treatment Algorithms? Nadine Attal*, Didier Bouhassira

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Pharmacotherapy of Neuropathic Pain: Which Drugs, Which Treatment Algorithms? Nadine Attal*, Didier Bouhassira Biennial Review of Pain Pharmacotherapy of neuropathic pain: which drugs, which treatment algorithms? Nadine Attal*, Didier Bouhassira Abstract Neuropathic pain (NP) is a significant medical and socioeconomic burden. Epidemiological surveys have indicated that many patients with NP do not receive appropriate treatment for their pain. A number of pharmacological agents have been found to be effective in NP on the basis of randomized controlled trials including, in particular, tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitor antidepressants, pregabalin, gabapentin, opioids, lidocaine patches, and capsaicin high- concentration patches. Evidence-based recommendations for the pharmacotherapy of NP have recently been updated. However, meta-analyses indicate that only a minority of patients with NP have an adequate response to drug therapy. Several reasons may account for these findings, including a modest efficacy of the active drugs, a high placebo response, the heterogeneity of diagnostic criteria for NP, and an inadequate classification of patients in clinical trials. Improving the current way of conducting clinical trials in NP could contribute to reduce therapeutic failures and may have an impact on future therapeutic algorithms. Keywords: Neuropathic pain, Pharmacotherapy, Clinical trials, Therapeutic algorithms, Phenotypic subgrouping 1. Introduction Here, we briefly present the major pharmacological treatments studied in NP and the latest therapeutic recommendations for Neuropathic pain (NP) is estimated to affect as much as 7% of the general population in European countries19,83 and induces their use. We then outline the difficulties associated with a specific disease burden in patients.6,30,83 It is now considered pharmacotherapy of NP in clinical trials and draw prospects for as a clinical entity regardless of the underlying etiology.4 Epidemi- future drug trials and therapeutic algorithms. ological surveys have indicated that many patients with NP do not receive appropriate treatment for their pain.6,33,86 This finding may 2. Which drugs? not only be due to lack of diagnostic accuracy and relatively A number of drug classes alone or in combination have been ineffective drugs but also due to insufficient knowledge about 41,45 65 evaluated in NP based on randomized controlled trials (RCTs). effective drugs and their appropriate use in clinical practice. We will only present the drugs used at repeated dosages or those Evidence-based recommendations for pharmacotherapy of NP are 41 used at single administrations but with long-term efficacy. Practical therefore essential and have recently been updated. recommendations, side effects, and precautions for use for However, meta-analyses and systematic reviews in NP or recommended drugs are indicated in Table 1. of specific NP conditions indicate that only a minority of pa- tients with NP have an adequate response to drug ther- apy.2,3,10,21,31,41,45,67,68,69,84 Furthermore, many recent trials using 2.1. Antidepressants drugs expected to be effective in NP are negative on the primary The analgesic efficacy of antidepressants is independent of their outcome (eg, Ref. 47). Beyond the problem of drug failure or high antidepressant effect. It is probably largely mediated by their action on placebo effect, 1 major reason could be due to trial failure: thus many descending modulatory inhibitory controls, but other mechanisms, negative trials failed to identify responder populations because they such as blockade of sodium channels and glutamate receptors, and did not take into account the heterogeneity of NP syndromes, the effect on b2 adrenergic receptors have been proposed.61,97 Two 1,11,15,17 probably reflecting various mechanisms. antidepressant classes have been found to be beneficial in NP: tricyclic antidepressants (TCAs), particularly amitriptyline (the effects of other TCAs being generally similar in direct comparative trials) Sponsorships or competing interests that may be relevant to content are disclosed and serotonin–norepinephrine reuptake inhibitors (SNRIs) duloxetine at the end of this article. and venlafaxine. In particular, recent studies have indicated that INSERM U-987, Centre d’Evaluation et de Traitement de la Douleur, CHU Ambroise duloxetine, which has been found to be initially beneficial in painful Pare, ´ APHP, F-92100 Boulogne-Billancourt, France and Universite ´ Versailles Saint- 82,91,93 Quentin, Versailles, F-78035, France diabetic neuropathy, is effective in various other NP conditions. *Corresponding author. Address: INSERM U 987 and Centre d’Evaluation et de Somnolence and constipation are the most common side effects of Traitement De La Douleur, 9 Avenue Charles De Gaulle, Boulogne-Billancourt antidepressants in clinical trials, whereas dry mouth is more common 92104, France. Tel.: 133149094434;fax:133149094435. with TCA and nausea is more common with duloxetine. However, E-mail address: [email protected] (N. Attal). tertiary amine TCAs (imipramine, amitriptyline, and clomipramine) PAIN 156 (2015) S104–S114 have a poorer side effect profile with major anticholinergic effects © 2015 International Association for the Study of Pain including postural hypotension and cardiac conduction slowing, http://dx.doi.org/10.1097/01.j.pain.0000460358.01998.15 sedative side effects, and consequently risk of falls. S104 N. Attal, D. Bouhassira·156 (2015) S104–S114 PAIN® Copyright Ó 2015 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited. April 2015· Volume 156· Number 4· Supplement 1 www.painjournalonline.com S105 Table 1 Summary of evidence-based recommendations for pharmacotherapy of neuropathic pain. Drug Main Common major Precautions for Other benefits Initial/maximum Titration Level of GRADE mechanisms of side effects use beyond NP dosage/effective recommendation action dosages for NP* Tricyclic antidepressants Inhibition of Somnolence, Cardiac disease, Improvement of 10-25 mg at Increase by 10-25 Strong for; Nortriptyline reuptake of anticholinergic glaucoma, depression, bedtime/150 mg mg every 3-7 d up recommended as Desipramine monoamines, effects, weight prostatic although at daily. Effective to efficacy and side first line Amitriptyline† blockade of gain adenoma, seizure, generally higher doses vary from effects Clomipramine† sodium channels, use of tramadol. dosages than pain one patient to Imipramine† anticholinergic Tertiary amines (75 mg/h) and another effects should be avoided sleep at dosages .75 (amitriptyline) mg in older adults Serotonin–norepinephrine Strong for; reuptake inhibitors recommended as first line Duloxetine Inhibition of Nausea Hepatic disorder, Improvement of 30 mg once daily/ May start at 30 mg serotonin and use of tramadol, depression and 60 mg twice daily. once daily and norepinephrine hypertension generalized Effective doses: then increase by reuptake anxiety, 60-120 mg daily 30 mg after 1 wk improvement of as tolerated up to sleep 120 mg daily Venlafaxine Inhibition of Nausea, Cardiac disease, Improvement of 37.5 mg once or Increase by 37.5- serotonin and hypertension at hypertension, use depression and twice daily/225 75 mg each week norepinephrine high dosages of tramadol generalized mg daily. Effective as tolerated reuptake anxiety, doses 150-225 improvement of mg daily sleep Calcium channel alpha-2- Strong for; delta ligands recommended as first line Gabapentin Acts on alpha-2- Sedation, Reduce dosages in No significant drug 100-300 mg once Increase by 100- Gabapentin ER/ delta subunit of dizziness, renal insufficiency interactions, to 3 times daily/ 300 mg 3 times enacarbil voltage-gated peripheral edema, improvement of 1200 mg 3 times daily every 3-7 calcium channels, weight gain generalized daily. Effective d as tolerated which decreases anxiety and sleep doses 1200-3600 central mg daily sensitization Pregabalin Acts on alpha-2- Sedation, Reduce dosages in No significant drug 25-75 mg once Increase by 75 mg delta subunit of dizziness, renal insufficiency interactions, daily/300 mg daily after 3-7 voltage-gated peripheral edema, improvement of twice daily. d and then by 150 calcium channels, weight gain generalized Effective doses mg every 3 to 7 which decreases anxiety and sleep 150-600 mg daily d as tolerated central sensitization Topical lidocaine Lidocaine 5% plasters Block of sodium Local erythema, None No systemic side 1-3 patches/3 None Weak for in channels itch rash effects patches for 12 h to peripheral NP; cover the painful recommended as area second line; first line in frail and ederly patients Capsaicin high- TRPV1 agonist Pain, erythema, No overall No systemic side 1-4 patches to None Weak for in concentration patches itching. Rare cases impairment of effects cover the painful peripheral NP: (8%) of high blood sensory evaluation area, repeat every recommended as pressure (initial after repeated 3 mo; 30-minute second line increase in pain) applications, application to the caution in feet; 60 minutes progressive for the rest of the neuropathy body; avoid the face; hospital use in several countries (continued on next page) Copyright Ó 2015 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited. S106 N. Attal, D. Bouhassira·156 (2015) S104–S114 PAIN® Table 1 (continued) Drug Main Common major Precautions for Other benefits Initial/maximum Titration Level of GRADE mechanisms of side effects use beyond NP dosage/effective recommendation action dosages for NP* Opioids
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