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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.
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.
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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