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Editorial Toward a definition of pharmacoresistant neuropathic pain 0. Introduction Pharmacological treatment of neuropathic pain relies currently on evidence from large randomised controlled trials. Systematic re- views and recommendations are available, allowing clinicians to adopt a rational based on available scientific evidence when treat- ing neuropathic pain (Attal et al., 2006; Dworkin et al., 2007). De- spite the advances, a considerable number of patients do not get sufficient pain relief and improvement in quality of life (QoL) from available drugs. In evidence-based studies on pain it is customary to consider ‘‘responders” to treatment those patients that report a pain relief amounting to 30–50%. Meta-analysis (Finnerup et al., 2005) as well as experienced clinicians claim that this goal is obtained in only 30–40% of patients across diagnostic entities where all evidence-based pharmacological strategies have been tried. Currently we lack strategies on how to identify responders/ non-responders and treatment approaches can best be character- ised as trial and error. In the optimal scenario pathophysiological mechanisms of the pain should be fitted to drugs with a mecha- nism of action specifically targeting the former. At present we are devoid of detailed information on mechanisms of spontaneous and stimulus-evoked neuropathic pain which offsets a mechanism based treatment approach with available drugs (Baron, 2006; Woolf et al., 1998). Regardless of criteria defining responders, side effects before any or optimal pain relief may disqualify further treatment and may thus be a basis for pharmacoresistancy. 1. Why the need for a definition of pharmacoresistant neuropathic pain? The necessity for defining pharmacoresistant neuropathic pain was derived from the clinical observation that patients exist in whom sustained pharmacological rotation does not produce the desired pain relief or induces intolerable side effects, and hence unaltered low QoL or even worse, a decrease in QoL due to side ef- fects being added to the pain suffering. Such ineffective treatment is also a considerable cost for society. Continued prescription of one drug after another may also add unmet expectancy, anxiety and frustration to the patients’ already difficult situation, thus con- tributing to their psychological derangement and lack of mobilisa- tion of cooping strategies. Moreover, we have only scarce evidence for a combination therapy aiming at different molecular targets (polypharmacy) (e.g., Gilron et al., 2005) and no conclusions can be drawn (Cruccu, 2007), although theoretical implications have been put forth supporting drug combinations in peripheral neuro- pathic pain states (Hansson and Dickenson, 2005). For some neuropathic pain conditions alternative treatment ap- proaches exist, such as electrical neurostimulation (Cruccu et al., 2007) and pharmacological intrathecal therapy with ziconotide (Williams et al., 2008). Furthermore, when pharmacological strat- egies fail and no other procedures are indicated measures such as cognitive-behavioural therapy and physiotherapy may be con- sidered to improve coping strategies and bodily functions. Currently there are no established criteria for what should be considered pharmacoresistance with regard to neuropathic pain. If efforts are to be made toward solving the managing problem of patients who report lack of significant pain relief despite having tried multiple drug monotherapy, a definition of pharmacoresis- tant neuropathic pain is critical. 2. Proposed definition We propose the following definition of pharmacoresistant neu- ropathic pain: ‘‘A neuropathic pain condition is resistant to pharmacotherapy when mono- or a rational combination treatment using drugs pro- ven efficacious in RCTs fails in inducing useful pain relief from the patients/physicians point of view after an appropriate duration of treatment with adequate dosage, or if intolerable side effects occur”. In this context we need to define efficacious drugs, includ- ing polypharmacy, useful pain relief, adequate dosage and treat- ment duration. Unfortunately, data is lacking to support an evidence-based approach to the definition of these terms. In the interest of drawing attention to and promote studies and debate within this area we put forth the following. 2.1. Efficacious drugs and order of precedence We suggest adopting the treatment paradigm recently put forth in European (Attal et al., 2006) and international recommendations (Dworkin et al., 2007) using drug classes that have proven effica- cious in RCTs including tricyclic antidepressants (e.g., amitriptyline and nortriptyline), serotonin noradrenalin reuptake inhibitors (dul- oxetine and venlafaxine), alfa-2-delta ligands (gabapentin and pre- gabalin) and opioids (oxycodone, morphine, methadone and tramadol). Also, topical lidocaine for small areas of pain/mechanical allodynia and sodium channel blockers (carbamazepine and oxcarbazepine) in trigeminal neuralgia should be considered. The treatment paradigm allows for any peripheral neuropathic pain condition to be treated in a monotonous way although the scientific evidence mostly refers to studies on post herpetic neuralgia and painful diabetic polyneuropathy. A rational for monotonous phar- macological treatment of peripheral neuropathic pain conditions based on shared commonalities, i.e., similar pathophysiological mechanisms and overlapping clinical phenomenologies, despite multiple etiologies has recently been published (Hansson and 1090-3801/$36.00 Ó 2009 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpain.2009.02.008 European Journal of Pain 13 (2009) 439–440 Contents lists available at ScienceDirect European Journal of Pain journal homepage: www.EuropeanJournalPain.com

Toward a definition of pharmacoresistant neuropathic pain

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Page 1: Toward a definition of pharmacoresistant neuropathic pain

European Journal of Pain 13 (2009) 439–440

Contents lists available at ScienceDirect

European Journal of Pain

journal homepage: www.EuropeanJournalPain.com

Editorial

Toward a definition of pharmacoresistant neuropathic pain

0. Introduction

Pharmacological treatment of neuropathic pain relies currentlyon evidence from large randomised controlled trials. Systematic re-views and recommendations are available, allowing clinicians toadopt a rational based on available scientific evidence when treat-ing neuropathic pain (Attal et al., 2006; Dworkin et al., 2007). De-spite the advances, a considerable number of patients do not getsufficient pain relief and improvement in quality of life (QoL) fromavailable drugs. In evidence-based studies on pain it is customaryto consider ‘‘responders” to treatment those patients that reporta pain relief amounting to 30–50%. Meta-analysis (Finnerupet al., 2005) as well as experienced clinicians claim that this goalis obtained in only 30–40% of patients across diagnostic entitieswhere all evidence-based pharmacological strategies have beentried. Currently we lack strategies on how to identify responders/non-responders and treatment approaches can best be character-ised as trial and error. In the optimal scenario pathophysiologicalmechanisms of the pain should be fitted to drugs with a mecha-nism of action specifically targeting the former. At present weare devoid of detailed information on mechanisms of spontaneousand stimulus-evoked neuropathic pain which offsets a mechanismbased treatment approach with available drugs (Baron, 2006;Woolf et al., 1998). Regardless of criteria defining responders, sideeffects before any or optimal pain relief may disqualify furthertreatment and may thus be a basis for pharmacoresistancy.

1. Why the need for a definition of pharmacoresistantneuropathic pain?

The necessity for defining pharmacoresistant neuropathic painwas derived from the clinical observation that patients exist inwhom sustained pharmacological rotation does not produce thedesired pain relief or induces intolerable side effects, and henceunaltered low QoL or even worse, a decrease in QoL due to side ef-fects being added to the pain suffering. Such ineffective treatmentis also a considerable cost for society. Continued prescription ofone drug after another may also add unmet expectancy, anxietyand frustration to the patients’ already difficult situation, thus con-tributing to their psychological derangement and lack of mobilisa-tion of cooping strategies. Moreover, we have only scarce evidencefor a combination therapy aiming at different molecular targets(polypharmacy) (e.g., Gilron et al., 2005) and no conclusions canbe drawn (Cruccu, 2007), although theoretical implications havebeen put forth supporting drug combinations in peripheral neuro-pathic pain states (Hansson and Dickenson, 2005).

For some neuropathic pain conditions alternative treatment ap-proaches exist, such as electrical neurostimulation (Cruccu et al.,

1090-3801/$36.00 � 2009 European Federation of Chapters of the International Associadoi:10.1016/j.ejpain.2009.02.008

2007) and pharmacological intrathecal therapy with ziconotide(Williams et al., 2008). Furthermore, when pharmacological strat-egies fail and no other procedures are indicated measures suchas cognitive-behavioural therapy and physiotherapy may be con-sidered to improve coping strategies and bodily functions.

Currently there are no established criteria for what should beconsidered pharmacoresistance with regard to neuropathic pain.If efforts are to be made toward solving the managing problem ofpatients who report lack of significant pain relief despite havingtried multiple drug monotherapy, a definition of pharmacoresis-tant neuropathic pain is critical.

2. Proposed definition

We propose the following definition of pharmacoresistant neu-ropathic pain:

‘‘A neuropathic pain condition is resistant to pharmacotherapywhen mono- or a rational combination treatment using drugs pro-ven efficacious in RCTs fails in inducing useful pain relief from thepatients/physicians point of view after an appropriate duration oftreatment with adequate dosage, or if intolerable side effectsoccur”. In this context we need to define efficacious drugs, includ-ing polypharmacy, useful pain relief, adequate dosage and treat-ment duration. Unfortunately, data is lacking to support anevidence-based approach to the definition of these terms. In theinterest of drawing attention to and promote studies and debatewithin this area we put forth the following.

2.1. Efficacious drugs and order of precedence

We suggest adopting the treatment paradigm recently put forthin European (Attal et al., 2006) and international recommendations(Dworkin et al., 2007) using drug classes that have proven effica-cious in RCTs including tricyclic antidepressants (e.g., amitriptylineand nortriptyline), serotonin noradrenalin reuptake inhibitors (dul-oxetine and venlafaxine), alfa-2-delta ligands (gabapentin and pre-gabalin) and opioids (oxycodone, morphine, methadone andtramadol). Also, topical lidocaine for small areas of pain/mechanicalallodynia and sodium channel blockers (carbamazepine andoxcarbazepine) in trigeminal neuralgia should be considered. Thetreatment paradigm allows for any peripheral neuropathic paincondition to be treated in a monotonous way although the scientificevidence mostly refers to studies on post herpetic neuralgia andpainful diabetic polyneuropathy. A rational for monotonous phar-macological treatment of peripheral neuropathic pain conditionsbased on shared commonalities, i.e., similar pathophysiologicalmechanisms and overlapping clinical phenomenologies, despitemultiple etiologies has recently been published (Hansson and

tion for the Study of Pain. Published by Elsevier Ltd. All rights reserved.

Page 2: Toward a definition of pharmacoresistant neuropathic pain

440 Editorial / European Journal of Pain 13 (2009) 439–440

Dickenson, 2005) and has gained support from a recent study (Attalet al., 2008). The efficacious drugs should be rotated per mechanismof action, i.e., there is no evidence currently to recommend tryingtwo drugs with the same mechanism of action unless impossibleto reach the adequate dosage or treatment duration with one ofthem because of intolerable side effects that the second drug isnot expected to produce.

2.2. Polypharmacy

Available controlled studies have only provided evidence infavour of combining gabapentin with opioids (Gilron et al., 2005;Hanna et al., 2008) or gabapentin and venlafaxine (Simpson,2001). A rational approach would be to combine drugs from thedrug classes that have proved efficacious in relieving neuropathicpain (Hansson and Dickenson, 2005).

2.3. Useful pain relief

In clinical practice the usefulness of a treatment is decided onby the patient and the prescribing physician. A decision to continuemedication is based on summing up the balance between the drugbenefits on pain and comorbidities on one side and the adverseevents on the other, i.e., the patient concludes that the quality oflife is sufficiently improved. Such a decision does not necessarilycorrespond to the 50% or 30% pain relief often referred to in clinicaltrials and is probably better matched by the commonly entertainedPatient Global Impression of Change (PGIC) (Farrar et al., 2001). Inthis context we would like to point out that a drug might act differ-entially on the flora of neuropathic pain symptoms and signs in asingle patient (Baron, 2006). How the patient decides on the over-all efficacy of a drug in such a situation is unknown but should bedetailed in the course of drug evaluation. Alleviation of somesymptoms/signs is not necessarily reflected in the global ratingof the pain. The role of the physician in this process is to supportthe patient in the evaluation process, to carefully weighing prosand cons of continued treatment from a medical perspective and,in addition, to consider health economic aspects. While awaitingfurther studies, evidence-based data suggests that at least a mod-erate improvement using the PGIC-scale may be an indicator ofuseful pain relief (Farrar et al., 2001).

2.4. Dosage

The adequate dosage range is defined by RCT results of effica-cious drugs. If the patient can take the highest recommended dose(i.e., side effects considered tolerable), this should be tried beforeconsidering treatment failure.

2.5. Treatment duration

Here the pharmacokinetics of the drug in combination with rec-ommended titration time serves as a basis. To what extent thepharmacodynamics of a drug at maximally tolerated dose requiresa certain time to optimally come into effect is not known. A main-tenance period of 3 weeks before evaluation is proposed, and long-er if suggested by available RCTs. Furthermore, at regular intervals(e.g., 6 months) it should be assessed by drug tapering whether atherapy is still efficacious.

The required scientific evidence to put forth a non-disputabledefinition of pharmacoresistant neuropathic pain is not available.To improve this, a major workload is foreseen with, e.g., head-to-head studies of available drugs in different clinical diagnosticentities. In the interest of the patients we believe that the issueof pharmacoresistance in neuropathic pain is important and henceconsider it useful to propose this preliminary definition and

arguments to attract further discussion and development. Also,we desperately need more efficacious drugs and accumulatinginformation about the usefulness of polypharmacy and effective-ness of non-pharmacological measures.

References

Attal N, Cruccu G, Haanpaa M, Hansson P, Jensen TS, Nurmikko T, et al. EFNSguidelines on pharmacological treatment of neuropathic pain. Eur J Neurol2006;13:1153–69.

Attal N, Fermanian C, Fermanian J, Lanteri-Minet M, Alchaar H, Bouhassira D.Neuropathic pain: are there distinct subtypes depending on the aetiology oranatomical lesion?. Pain 2008;138:343–53.

Baron R. Mechanisms of disease: neuropathic pain – a clinical perspective. Nat ClinPract Neurol 2006;2:95–106.

Cruccu G. Treatment of painful neuropathy. Curr Opin Neurol 2007;20:531–5.Cruccu G, Aziz TZ, Garcia-Larrea L, Hansson P, Jensen TS, Lefaucheur JP, et al. EFNS

guidelines on neurostimulation therapy for neuropathic pain. Eur J Neurol2007;14:952–70.

Dworkin RH, O’Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, et al.Pharmacologic management of neuropathic pain: evidence-basedrecommendations. Pain 2007;132:237–51.

Farrar JT, Young Jr JP, LaMoreaux L, Werth JL, Poole RM. Clinical importance ofchanges in chronic pain intensity measured on an 11-point numerical painrating scale. Pain 2001;94:149–58.

Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathicpain treatment: an evidence based proposal. Pain 2005;118:289–305.

Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, gabapentin,or their combination for neuropathic pain. N Engl J Med 2005;352:1324–34.

Hanna M, O’Brien C, Wilson MC. Prolonged-release oxycodone enhances the effectsof existing gabapentin therapy in painful diabetic neuropathy patients. Eur JPain 2008;12:804–13.

Hansson PT, Dickenson AH. Pharmacological treatment of peripheral neuropathicpain conditions based on shared commonalities despite multiple etiologies.Pain 2005;113:251–4.

Simpson DA. Gabapentin and venlafaxine for the treatment of painful diabeticneuropathy. J Clin Neuromuscul Dis 2001;3(2):53–62.

Williams JA, Day M, Heavner JE. Ziconotide: an update and a review. Expert OpinPharmacother 2008;9(9):1575–83.

Woolf CJ, Bennett GJ, Doherty M, Dubner R, Kidd B, Koltzenburg M, et al. Towards amechanism-based classification of pain?. Pain 1998;77:227–9.

Per T. HanssonPain Center,

Department of Neurosurgery,Section of Clinical Pain Research,

Department of Molecular Medicine and Surgery,Karolinska University Hospital/Institutet,

171 76 Stockholm, Sweden.Tel.: +46 8 51 77 54 35; fax: +46 8 51 77 56 25

E-mail address: [email protected]

Nadine AttalINSERM U-792,

Boulogne-Billancourt F-92100,France

CHU Ambroise Pare,APHP, Boulogne-Billancourt F-92100,

FranceUniversité Versailles-Saint-Quentin,

Versailles F-78035,France

Ralf BaronDivision of Neurological Pain Research and Therapy,

Department of Neurology,Universitatsklinikum Schleswig-Holstein,

24105 Kiel, Germany

Giorgio CruccuDepartment of Neurological Sciences,

La Sapienza University,I-00185 Rome, Italy

Available online 25 March 2009