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Pharmacological treatment of : present status and future directions

Vincenzo Bonicalzi & The pharmacological treatment of neuropathic pain remains unsatisfactory. This is partly Sergio Canavero† owing to poor knowledge of available drugs on the part of treating physicians, but equally †Author for correspondence important is the poor correlation between animal models and clinical effects. In this Turin Advanced Neuromodulation Group, review, we survey the field and draw several conclusions, particularly that current results Cso Einaudi 2, 10128 are disappointing and that we are not going to see major progress in the near future if Torino, Ita ly current paradigms are not changed. Also, mechanisms of action of drugs must be better Tel.: +39 349 471 7819 [email protected] explored in view of a drug dissection-based approach.

Peripheral neuropathic pain (NP) can manifest cost–effectiveness has been rarely addressed. as painful polyneuropathy, mononeuropathy or Most randomized controlled trials of NP have multiple mononeuropathy following trauma, examined only diabetic and postherpetic NP inflammation, ischemia, metabolic derange- and the applicability of the results of clinical tri- ments, toxins (including drugs and ), als for one NP syndrome to others cannot be tumors, infections, primary neurological dis- determined. Few clinical trials have compared eases, and iatrogenic insults. A few syndromes options directly. Systematic evalua- involve both central and peripheral damage, tion of combination treatment is all but lacking. such as brachial plexus avulsion pain and certain Although many patients are treated with poly- stages of postherpetic neuralgia. Uncounted mil- pharmacy, little is known regarding which lions suffer painful neuropathies, while no less patients are most likely to benefit from combi- than 7 million people are affected by central nation treatment and whether such treatment pain (CP) [1]. has additive or synergistic effects. Finally, con- trolled studies combining drugs and other strat- Where are we? egies, such as neuromodulatory, are lacking. To NP/CP is an area of largely unmet therapeutic compound the picture, treating physicians are need. Despite approximately 100 drugs having often ignorant of best available therapies and been tested (Table 1), drug therapy of NP their correct usage (e.g., under-dosing) [2,3]. The remains unsatisfactory, as shown in recent meta- current approach of setting realistic expecta- analyses and systematic reviews (Tables 2–5). tions, starting with monotherapy and then add- Antidepressants and certain ing drugs on the basis of trial-and-error and (i.e., the drugs of choice for most patients) only evidence from clinical trials, leaves most achieve clinically significant (50%) pain relief in patients dissatisfied with their treatment [4]. 30–50% of cases, and 30–40% relief is consid- While the area is exploding with new informa- ered a good response in most studies, with effec- tion, the advance in knowledge has, as yet, not tive dosages of the same drug being highly resulted in better clinical treatment. The transi- variable from patient to patient. The percentage tion from acute to and the reason(s) of patients with NP responsive to any particular patients differ in their responses and behavior regimen is unknown. Even within the same class despite an apparently similar initial noxious of medication, some patients fail to respond to event are still unexplained and the general one medication but then respond to another. hypothesis of a genetic predisposition to develop Keywords: central pain, No study has assessed combinations of any of chronic pain remains inconsequential. mononeuropathy, neuropathic pain, these drugs. In general, quality of life has been polyneuropathy improved less consistently than pain intensity. Present status Treatment duration in clinical trials has been The opinions of many experts – generally with within a few months and the durability of pain ties to drug companies – and their evolution over relief and the long-term safety and tolerability 6 years (2000–2005) are summarized in Table 6. Future Drugs Ltd of treatment are unknown. In addition, These opinions are, for the most part, discordant

10.1586/14750708.3.5.651 © 2006 Future Drugs Ltd ISSN 1475-0708 Therapy (2006) 3(5), 651–677 651 REVIEW – Bonicalzi & Canavero

Table 1. Drugs employed in the treatment of neuropathic pain. Class Examples AEDs CBZ, , phenitoyn, , , tiagabin, , and vigabatrin ADs , lithium, trazodone, , fluvoxamine, chlorimipramine, citalopram, , paroxetine, , , , mianserin, maprotiline, clomipramine, buspirone, moclobemide, , topical doxepin, sustained-release , venlafaxine and zimelidine GABA-ergic (thiopental, thiopentone, sodium amytal, pentobarbital, thiamylal), propofol, (chlordiazepoxide, , clonazepam, midazolam) and , , , diamorphine, , , metadone, , transdermal fentanyl, , () antagonists Naloxone Neuroleptics (generally with Fluphenazine, chlorprothixene, perphenazine, tiapride, , , droperidol, ADs) and levomepromazine NMDA antagonists , , amantadine, memantine, Mg2+, (, and ) Na+ channel blockers , , , topical lidocaine and EMLA Ca+ channel blockers and Neurotrophines rhNGF and rhBDNF Others K+ channel blockers, , , calcitonin, , , acyclovir, topical , topical , iontophoretic indomethacin, cizorlitine, aldose reductase inhibitors, ketanserin, levodopa, , octreotide; topical prostaglandin E1, CCK2 antagonists, glycin antagonist AD: Antidepressant drug; AED: Antiepileptic drug; CBZ: ; CCK2: Cholecystokinin; EMLA: Eutectic mixture of lidocaine and ; GABA: γ-aminobutyric acid; NMDA: N-methyl-D-; rhBDNF: Human recombinant brain-derived neurotrophic factor; rhNGF: Recombinant human nerve growth factor.

and, most importantly, do not appear to hew to consequences. Also, impulse traffic, which is evidence-based data available at the time of their known to regulate and gene expres- compilation (Table 2). Almost all experts did not sion, can be altered by injury. The nociceptive discriminate CP as a separate nosological entity, system is not fixed and static but a dynamic neu- thus their recommendations are not pertinent ronal network that continuously alters its [1,5,6]; it was emphasized that the most effective response characteristics depending on the prior drugs for CP are intravenous or intrathecal and exposure to noxious activity. antidepressants appear less effective in cord CP In recent years, all this material has been than brain CP [4,6]. reviewed innumerable times both in journals and textbooks and it has almost grown into a fad; Smorgasbord of mechanisms none of these actually broke new ground in ther- Over the past 25 years, it has become clear that apeutic terms. There has also been an unprece- numerous changes occur both in the PNS and dented number of reviews on drug therapy for CNS after nerve injury. Following nerve injury, a NP (Table 2). cascade of events materializes both peripherally and centrally, affecting a cornucopia of pep- Symptom, mechanism & drug tide/transmitters, structures and neurophysiologi- dissection-based approaches cal processes, and a change at one place has NP/CP are sometimes difficult to diagnose, even ripple-through effects at many others. Hundreds by experts, since no lesion or other physical finding of genes are affected after a single traumatic event. can be demonstrated or surpass the limits of cur- For instance, the γ-aminobutyric acid (GABA)-A rent diagnostic technology: no single symptom or , which is made up of distinct subunits sign is diagnostic. Moreover, symptoms and mech- that may assemble in a variety of combinations, anisms may be similar in different types of disease, each with distinct functional characteristics, can one single mechanism may give rise to different potentially be restructured retrogradely to give types of pains and more than one mechanism may rise to different combinations, with disruptive be operating in a particular patient.

652 Therapy (2006) 3(5) Pharmacological treatment of neuropathic pain – REVIEW

Table 3. Number needed to treat comparison: antidepressants. ADs TCAs SSRIs SNRIs Bupropion Ref. Peripheral neuropathic pain 2 (1.7–2.5) [59] 3.3 (2.9–3.8) 3.1 (2.7–3.7) 6.8 (3.4–441) 5.5 (3.4–14) 1.6 (1.3–2.1) [52] Same 2.3 (2.1–2.7) 5.5 (3.4–13.5) 1.6 (1.3–2.1) [53] group* 2.6 (2.2–3.3) 6.7 (3.4–435) [70] 1.6 (or 3.2) [61] Same 1.6 [61] authors* 6.2 [61] 1.29 (1.16–1.46) [59] Same 4.1 (2.9–7.2) [52] group* 6.8 (3.4–441) [53] Same 3.4 (2.6–4.7) [66] group* 3.4 (2.6–4.7) 3.5 (2.5–5.6) Same as [69] placebo Postherpetic neuralgia 2.20 (1.7–3.13) [59] Same 2.1 (1.7–3.0) [66] group* 2.1 (1.7–3.0) 3.5 (2.5–5.6) [69] Central pain Same 4.0 (2.6–8.5) [52] group* 4.0 (2.6–8.5) [53] Central post-stroke pain 1.7 (1.2–3.1) [53] Other 3.45 (2.22–7.75) [59] *Studies were performed by the same group. AD: Antidepressant drug; SNRI: Serotonin–norepinephrine reuptake inhibitor; SSRI: Selective serotonin reuptake inhibitor; TCA: .

Our ability to translate pain complaints and are not equivalent to mechanisms, symptoms sensory findings into specific pathophysiologi- alone are not sufficient tools to define treatment cal mechanisms that have treatment implica- strategies. Despite impressive attempted tabula- tions is in its infancy. Even in specialized tions on which drug to use for which mecha- settings, it is difficult to identify specific NP nisms or symptoms (Table 7), results in the clinic mechanisms. Quantitative sensory tests lack remain unimpressive and unpredictable sensitivity and specificity in revealing the exact (Tables 2 & 6). Again, in postherpetic neuralgia, nature of the pathological processes responsible the employment of topical agents or Na+ chan- for pain. A unifying hypothesis is hard to come nel blockers has been proposed repeatedly for by since NP has several different components symptoms as a result of peripheral sensitization that differentially respond to different meas- and proinhibitory drugs (gabapentin and anti- ures, not to mention an intrinsic difference depressants) if sustained by central disinhibi- between CP and peripheral NP [5]. In the exem- tion. This kind of targeting is difficult in plificative example of postherpetic neuralgia, clinical practice. Thus a mechanism-based several mechanisms may cause the same painful approach is unreliable in routine management. symptom, particularly . Conversely, A modern concept, for instance, the use of one mechanism may be responsible for several parenteral drugs with known pharmacody- different painful symptoms, such as spontane- namic profiles to dissect mechanisms, a very ous and evoked pain [7–8]. Thus, because they appealing concept, proves itself difficult to

www.future-drugs.com 653 REVIEW – Bonicalzi & Canavero

Table 4. Number needed to treat comparison: antiepileptic drugs. Carbamazepine Valproate Lamotrigine Gabapentin/ Topiramate Ref. pregabalin Peripheral neuropathic pain 4.3 (3.5–5.7) [55] Same 2.5 (1.8–3.8) [55] group* AEDs: 2.7 (2.2–3.8). Phenytoin/CBZ 3.4 (2.1–5.4) [69] 2.2 (1.7–3.1) 2.0 (1.6–2.5) 2.1 (1.5–3.6) 2.8 (2.1–4.2) 4.9 (3.5–8.1) 4.7 (4.0–5.6) 7.4 (4.3–28) [52] Same 4.0 (2.1–4.2) [53] group* 3.3 (2.0–9.4) 2.1 (1.5–3.6) 4.1 (2.7–8.2) [70] Gabapentin: 2.2 [61] (or 2.8 or 5.3) Pregabalin: 3.3 Diabetic neuropathy 2.9 (2.2–4.3) [55] CBZ better than placebo [56] Same 2.3 (1.5–3.8) [57] group* AEDs: 2.7 (2.2–3.8) [66] Same 4.3 (2.8–8.6) [53] group* 3.3 2.1 3.7 [65] Postheric neuralgia 3.9 (3–5.7) [55] Same AEDs: 3.2 (2.4–5.0) [66] group* AEDs: 3.2 (2.4–5.0) [69] Same 4.8 (2.6–26.9) 4.3 (3.3–6.1) [53] group* 3.4 3.2 [65] Postheric neuralgia + diabetic neuropathy 3.8 (2.6–7.3) [52] AEDs: 2.9 (2.4–3.7) [69] Central pain 3.4 (1.7–105) [52] Central poststroke pain Better than placebo, [56] similar to amitriptyline Trigeminal neuralgia 1.9 (1.4–2.8) [56] *Studies were performed by the same group. AED: Antiepileptic drug; CBZ: Carbamazepine.

realize. Presently, all current efforts to pair and peripheral actions, making them less use- symptom, mechanism, optimal drug target and ful, while ketamine and thyamylal affect too existing drug appear scarcely useful to guide many transmitters. However, while antidepres- therapeutic efforts since the mechanisms of sants work not only on monoamines but also action of most drugs are not understood, if not block adrenergic receptors on regenerating totally unknown. Distinct exceptions are pro- sprouts, modify endorphins, antagonize pofol used at subhypnotic doses to dissect N-methyl-D-aspartic acid (NMDA) receptors GABAergic mechanisms of CP and baclofen. and Na+ channels, the use of more selective These provide compelling evidence for drugs, such as reboxetine, has robbed norepine- deranged GABAergic transmission in CP [5,9]. phrine of its starring role in the control of However, lidocaine and fentanyl have central NP/CP [11], as usually presumed.

654 Therapy (2006) 3(5) Pharmacological treatment of neuropathic pain – REVIEW

Table 5. Number needed to treat comparison: opioids. Morphine (methadone) Oxycodone Tramadol Ref. (Oxycodone CR) Peripheral neuropathic pain Not calculated (Table 2) [29] 3.5 (2.4–5.9) [60] 2.5 (1.9–3.4) 2.6 (1.9–4.1) 3.9 (2.7–6.7) [52] Same group* 2.6 (1.7–6.0) 3.5 (2.4–6.4) [53] 3.4 (2.3–6.4) [70] Postherpetic neuralgia 4.8 (2.6–26.9) [53] 3 2.5 4.7 [61] *Studies were performed by the same group. CR: Controlled release.

Pitfalls of animal models Sticking to this caveats would have spared the Since human volunteer models of NP/CP have drug industry huge losses, epitomized by the para- yet to be developed (capsaicin injection does not doxical failure of antagonists in view of make the grade), animal models have taken the well-established role of substance P in modulat- center stage. These have serious shortcomings: ing pain. Also, NMDA antagonists (e.g., oral keta- • It is difficult to know what is actually per- mine, dextrometorphan and amantadine) have ceived, for example, autotomy may signal relieved few patients in the long run, despite denervation rather than pain; impressive animal data, and it does not appear to • Alterations in cutaneous sensory thresholds in depend entirely on their poor side-effect profile. response to nerve injury rather than an inte- Thus, we are left with this humbling notion: grated pain-related behavior are generally much progress is a result of the application to NP measured; of drugs effective in other fields, such as epilepsy (starting from trigeminal neuralgia and extend- • Animal models are such that animals develop ing its use to pain with paroxysmal components) NP consistently, while most patients with and psychiatry, starting in the 1960s. Drugs nerve injury do not go on to develop it; stemming from goal-directed efforts are very few • Purported signs of pain generally subside and – up to now – of scarce effectiveness in the within weeks or months, while this is not the vast majority of patients (lidocaine patch and case for human patients; ziconotide), despite claims to the contrary [14]. • Animal models study the pain for weeks rather than years, as in the human model; Exploiting descending control • Most animal models deal with rats; In the dorsal horn, the locus of entry of sensory • There are so many anatomochemical differ- information from the periphery, specific centrifu- ences between humans and animals – includ- gal pathways either suppress (descending inhibi- ing primates – that these models are nearly tion) or potentiate (descending facilitation) irrelevant. passage of nociceptive messages to the brain [15]. Considerable caution must be exercised in No drug interfering with descending facilitation extrapolating hypotheses to clinical pain. Despite is currently available for clinical use. Inasmuch as many impressive experimental observations, the virtually all transmitters and receptor types ultimate proof of concept is in the clinic [11–13]. involved in descending control display multiple The over-riding importance of the cognitive- sites and/or mechanisms of action, it is difficult to affective dimension of pain in man and behavio- anticipate the global influence of ligands upon ral factors in modifying clinical pain must be following systemic administration, considered in the treatment strategy: expectation making direct vectorization of drugs to their sites alone is sufficient to increase firing rate in nox- of action in the spinal cord, for example, by the ious-responding neurons. Clinical pain is more intrathecal route, critical. At the same time, most complex than experimental pain and patients are drugs are administered parenterally and orally and heterogeneous in terms of their pain. the final balance of action should be understood www.future-drugs.com 655 REVIEW – Bonicalzi & Canavero

for therapeutic purposes. A single transmitter, There is an intricate and reciprocal functional and even a single receptor class, can exert a diver- inter-relationship between the operation of gent influence of nociception at both spinal and descending noradrenergic and serotonergic path- supraspinal loci as a function of localization and ways, expressed at both segmental and supraspi- influence upon neuronal excitability. Thus, for nal loci, knowledge of which remains many transmitters and receptor classes, a bidirec- fragmentary. Most importantly, the same trans- tional influence upon nociceptive processing at mitter may have both pro- and anti-nociceptive cerebral and/or segmental loci has been estab- actions at different sites. This is true for GABA, lished. This underlines the difficulty of predict- opioids, glutamatergic agents and others. Clini- ing the influence on nociception of even highly cal data support the concept: GABA agonism for selective ligands, and strongly supports the argu- CP also increases pain (thiamylal, propofol or ment that the assignment of a particular role to baclofen) [16]. individual classes of descending pathways, of Coadministration of drugs may minimize doses transmitter and even of receptor, may be mis- and side effects: the classic combination is opioids leading, if not frankly erroneous [15]. This is par- and clonidine. With the exception of parenteral ticularly true for most neurons that contain and administration of µ-opioids (for which a compo- release several transmitters modulating nocicep- nent of analgesia may be attributed to supraspinal tive processing. In addition to receptor multi- activation of descending inhibition) and spinal plicity per se, there is increasing evidence for application of clonidine (which reproduces functional interplay among colocalized recep- noradrenergic mechanisms of descending inhibi- tors. This is manifested both at the level of sec- tion in the dorsal horn), no other approach has ond-messenger systems (e.g., activation of one been validated extensively in the clinic, however receptor may trigger the phosphorylation of a pro-opioid cholecystokinin-1 antagonists and different class of colocalized receptor) and in -1 are now under evaluation in terms of their physical association. For example, clinical trials, although one trial was negative. protein–protein interactions and functional het- erodimers have been demonstrated between vari- Other approaches ous subtypes of opioid receptors and even Nonpharmacological approaches are under between entirely unrelated receptor classes (e.g., study. An open question is whether interven- GABA-A and dopamine-5 receptors). Confirma- tions, such as cell implantations [17], neurotoxins tion of certain receptors displaying spontaneous and antisense or gene therapy [18], exert effects activity would pave the way for the design of that are rapid, temporary, controllable and antagonists or reverse agonists at receptors medi- reversible, or whether they initiate, in an unpre- ating descending facilitation. Descending path- dictable fashion, delayed and possibly irreversible ways do not dampen nociceptive transmission changes not necessarily conducive to pain relief exclusively but also simultaneously enhance its (an example are the dyskinesias induced by fetal passage. Excessive activity of descending facilita- cell grafts in Parkinson’s disease requiring neuro- tion may contribute to chronic painful states; modulatory surgery for control). Despite their however, its interruption alone may actually interest, they will likely find applications only in interfere with processes recruiting descending restricted populations of otherwise refractory inhibition [15]. Simultaneous interference with patients. Indeed, it is difficult to imagine that descending facilitation and reinforcement of such techniques would supersede more conven- descending inhibition may prove more rational. tional strategies of systemic and spinal adminis- Rather than an obsessive and illusory search for tration of drugs interacting rapidly and reversibly highly selective agents at a single receptor type, with specific targets. Moreover, they are all more multireceptorial (multitarget) agents (e.g., atypi- expensive than traditional methods. cal antipychotics for ) may permit Although the first animal studies attempted the the balanced and more efficacious manipulation transfer of opioid precursor genes and their over- of mechanisms of descending inhibition and expression mainly at the spinal level, also demon- facilitation. However, mimicking multiple strating the feasibility and therapeutic effects in mechanisms of descending inhibition is no easy models of NP, and targeting some proinflamma- task. For instance, coactivation of specific sero- tory cytokines involved in the induction and per- tonergic, noradrenergic and other mechanisms in petuation of pain raises the possibility of blocking the dorsal horn may be critical for the mediation the development of pain [18], the aforementioned of supraspinal opioidergic antinociception. conditions must be borne in mind.

656 Therapy (2006) 3(5) Pharmacological treatment of neuropathic pain – REVIEW

Expert commentary and outlook to pain, similar to NP itself. Most importantly, opi- Several drugs are undergoing Phase I/II/III stud- oids influence the hypothalamic–pituitary–adre- ies, registration and preregistration: nal/gonadal axis and immune system, and antagonists, glutamate receptor antagonists prolonged opioid use may result in reduced fertil- (NMDA, and NR2B sites), ity, libido and drive and possibly immunosuppres- receptor agonists/antagonists, growth factor ago- sion – particularly at high doses. In summary, nists, α-adrenoceptor agonists, drugs of prolonged, high-dose opioid therapy may be nei- undefined mechanism, GABA agonists, nicotinic ther safe nor effective and too high doses should be agonists, cholecystokinin (CCK) antagonists, discouraged [30]. In a recent controlled study, meth- adenosine A1 antagonists and IP751 [19,201]. adone at 20 mg significantly improved several types Despite these efforts, no revolutionary therapy of NP, but a third of patients withdrew from the appears to be in the pipeline. study due to side effects [31]. Finally, opioids are While the near future will probably see a larger poorly effective for CP [32]. use of the intrathecal approach with currently The recent discovery of endocannabinoids as available drugs for all refractory patients [16], it will pain modulators has opened a new avenue of be important to develop pre-empting strategies. research (Tables 2 & 7) [33–34]. Since cannabinoids’ For instance, carbamazepine may prevent the loci of action superpose with opioid and onset of NP after oxaliplatin exposure [20], while centers, we cannot expect a major amitriptyline may have a possible, mild effect in role in NP therapy [35]. In a recent trial, preventing poststroke CP [21]. Lamotrigine, with extracts moderately (ca. 33%) relieved brachial its anti-Na+/antiglutamate spectrum, should plexus avulsion (BPA) pain, although maximal receive more attention in this regard [22] and gene doses in this brief trial had not been reached and chips may aid in identifying pain-prone patients all patients continued previous therapy [36]. in the future. Studies of neurotrophic factors have not yet Pharmacological infusion tests to predict effi- demonstrated significant efficacy (Table 7) [37]; cacy and side effects must be pursued further. their role remains to be assessed. Currently, the role of lidocaine in predicting Microglia may have a role in inducing/sus- response to oral mexiletine is controversial [7], taining NP and their targeting possibly repre- acute administration of opioids has a good neg- sents a novel avenue, although no human study ative predictive value but poor positive predic- exists yet. tive value [19] and phentolamine’s role has been NMDA receptor antagonists with better effi- proved poorly founded [23]. Subhypnotic pro- cacy and fewer side effects may be found. Mg2+, pofol appears promising in predicting response with its cost–effectiveness, represents an interest- to neuromodulation for CP [24]. ing approach [38]. However, it should be remem- A major problem is therapy in the elderly, a siz- bered how some NMDA antagonists have shown able portion of those suffering from NP/CP. little efficacy in both postherpetic and facial neu- Drugs with much better pharmacological profiles ralgias [39]. Despite optimism, AMPA and must be developed in order to considerably cut metabotropic blockers may well be proven side effects [25]. scarcely effective (Table 7). We, and others, strongly believe there is no Sensory neurons have multiple voltage- basis to such concept as sympathetic pain. While dependent Na+ currents, with differential compo- there is ample animal evidence to support its sition in A and C fibers and this may undergo sig- existence, the concept collapses on statistical and nificant changes upon nerve injury. The Nav1.8 clinical grounds [26,27]. Pursuing this concept isoform is expressed mainly in C-type dorsal root will, in our view, end up in further disappointing ganglion (DRG) cells and Nav1.8 immunoreac- results for the vast majority of patients. tivity is evident in peripheral nerve tissues from While very few CP patients are responsive [28], patients with chronic NP [40,41]. However, the peripheral NP is now generally accepted to respond measured ectopic activity in injured fibers need to stable doses of opioids, although at higher doses not be an essential characteristic of evoked NP than nociceptive pain, with a minimal risk of pain and the abnormal activity in uninjured pri- addiction [29]. Since most controlled studies have mary afferents may actually be crucial for the lasted for less than 8 months, long-term benefit hypersensitivity to sensory input. The TTX- (several years) remains unassessed [29]. Besides toler- resistant Nav1.8 channel-supported Na+ current ance, long-term use of opioids may also be associ- is currently believed to play a crucial role in the ated with the development of abnormal sensitivity establishment of the hyperexcitability state of www.future-drugs.com 657 REVIEW – Bonicalzi & Canavero

Table 7. Suggested (targeted) pharmacological approaches for neuropathic pain . Receptor(s) Drug(s) Ref.

Phenytoin, benzodiazepines, valproate, CBZ/OXCBZ, lamotrigine, gabapentin and [6] topiramate Phenytoin, benzodiazepines, valproate, CBZ/OXCBZ, lamotrigine, gabapentin, [65] topiramate, , tiagabine and CBZ, gabapentin, lamotrigine, phenobarbital, clonazepam, valproic acid, [74] topiramate, pregabalin and tiagabine CBZ, gabapentin and lamotrigine [73] Phenytoin, benzodiazepines, valproate, CBZ/OXBC, lamotrigine, gabapentin, [81] topiramate, zonisamide, tiagabine and levetiracetam Topiramate [97] TCAs and newer ADs [98] Thalidomide [99] types A and B [100] Virally mediated delivery of enkephalin and other neuropeptide transgenes [101] Adenosine (A1) Adenosine, theophylline and caffeine [102] Peripheral p2x receptors (ionotropic Receptor-selective antagonists [103] receptors activated by ATP) NMDA Noncompetitive or uncompetitive antagonists [104] NMDA Conantokin (for neuroprotection) [105] NMDA Amantadine, dextromethorphan and ketamine [106] AMPA 2,3-benzodiazepines [107] NMDA Glycine(B)- and NR2B-selective antagonists, peripheral NMDA receptor antagonists AMPA Topiramate [96] NMDA Amantadine, ketamine, dextromethorphan and TCAs AMPA Receptor antagonists [108] Neuron-specific voltage-gated Ca2+ Selective blockers [109] channels Neurone-specific N-type Ca2+ channels Varpi-: ziconotide [110] N-type calcium channels Ziconotide; orally active, selective, small molecule modulators [111] α2β subunits of voltage-activated Ca2+ Gabapentin, pregabalin [96] channels T-type low-voltage Ca2+ channels Zonisamide Ca channels CBZ, OXCBZ, lamotrigine, levetiracetam, IT ziconotide N-type voltage-gated Ca2+ channels blocker Prialt [112] (Ca(v)2.2) Voltage-gated Na+ channels Selective blockers [43] Na+ channels Lidocaine and mexiletine [113] Voltage-gated Na+ channels µ- [114] Na+ channels CBZ, lamotrigine, lidocaine, , mexiletine, OXCBZ, phenytoin, [96] topiramate, TCAs and zonisamide Voltage-gated Na+ channels Use-dependent blockers [115] Voltage-activated K+ channels [116] (K[V]7.2–7.5 [formerlyKCNQ2–5]) CB receptors Cannabinoids [117] AMPA: 1-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; CB: Cannabinoid; CBZ: Carbamazepine; IL: Interleukin; IT: Intrathecal; NMDA: N-methyl-D-aspartic acid; ORL: Opioid receptor-like; OXCBZ: Oxcarbamazepine; SP: Substance P; TCA: Tricyclic antidepressant; TNF: Tumor necrosis factor; VR: Vanilloid receptor.

658 Therapy (2006) 3(5) Pharmacological treatment of neuropathic pain – REVIEW

Table 7. Suggested (targeted) pharmacological approaches for neuropathic pain (Cont.). Receptor(s) Drug(s) Ref.

CB2 receptors Selective agonists [118] CB1–CB2 receptors Selective agonists, inhibitors of endocannabinoid uptake or metabolism [119] CB2 receptors Selective antagonist/inverse CB2-like receptors, vanilloid receptors Anandamide [120] VR1 receptors Resiniferatoxin [121] VR1 + CB1 receptors Arvanil VR1 receptor Modulators [122] VR receptors Capsaicin [123] VR1 receptor VR1 antagonists [94] Receptors for neurotrophic factors Neurotrophic factors: NGF, BDNF, NT3, GDNF (neurturin, persephin, artemin) [84] Opioids receptors + ? Tramadol [124] ORL1 receptors (+ glutamate receptors ORL1 agonists (nociceptin/orphanin FQ) [125] + Ca2+ channels) SP-neurokinin1 receptors Receptor-tagged saporin [96] Glutamate Many , including opioids Proinflammatory cytokines (IL-1β, IL-6 Antagonists/inhibitors and TNF) AMPA: 1-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; CB: Cannabinoid; CBZ: Carbamazepine; IL: Interleukin; IT: Intrathecal; NMDA: N-methyl-D-aspartic acid; ORL: Opioid receptor-like; OXCBZ: Oxcarbamazepine; SP: Substance P; TCA: Tricyclic antidepressant; TNF: Tumor necrosis factor; VR: Vanilloid receptor.

sensory neurons that contributes to the abnormal agent [48]. However, current cholinergic drugs have processing of nociceptive and/or tactile informa- disruptive side effects (notably cardiovascular and tion following traumatic injury. These channels motor) and nicotinic agents also have an addictive accumulate in areas of demyelination, neuromas potential. Moreover, they may have and DRG [42]. The discrete localization of Nav1.8 pronociceptive and antinociceptive effects [15]. suggests therapeutic potential without the debili- In a recent controlled trial, intravenous adenos- tating side effects observed with the currently ine proved ineffective for NP; intrathecally, it had available Na+ channel blockers [43]. However, a modest effect in the face of common side effects. studies appear to show that ketamine is stronger The role of adenosine and congeners – despite than lidocaine in quenching NP and this should comforting animal data – does not look good [49]. be kept in mind when addressing trial options [44]. Current efforts at targeting the mechanisms Ca2+ channels are also under study for their responsible for the induction and maintenance of ability to inhibit neurotransmitter release in the central sensitization is made difficult by the need dorsal horn, but, to date, intrathecal ziconotide, a to avoid interrupting memory formation and cor- conotoxin, has demonstrated limited efficacy with tical function – there is a need to be specific. To a narrow therapeutic window. Moreover, upregu- achieve this, teasing the differences as well as simi- lation of subtypes of Ca channels is not observed larities between central sensitization and cortical in all NP types. long-term potentiation will be necessary [50]. At Several other targets are under study: VR1 this time, ketamine targets both and thus makes it blockers, ATP blockers and proton channel little indicated in the clinic. blockers [45]. So-called antiplasticity approaches have, in our New drugs that activate α-2A or block α-2B/C opinion, no future. Plasticity is a basic ubiquitous receptors may supercede clonidine. However, neural mechanism that takes place – but can also clonidine is not a major drug. Clonidine patches be reversed – within minutes and there are cases of are of limited use as they eliminate hyperalgesia complete, immediate abolition of CP after at the relatively small patch site, with limited removal of the inciting lesion [51], which militate benefits. Contrary to previous trials [46], intrathe- against an exclusive role in pain maintenance. cal clonidine was found to be of limited use, with In summary, it is likely that the near future will relief lasting less than 18 months [47]. Clonidine is see no major progress. We believe that only basic potentiated by neostigmine, an anticholinesterase studies in human patients will forward the field. www.future-drugs.com 659 REVIEW – Bonicalzi & Canavero [52] Ref. RIMA: Reversible inhibitors of nnabinol; TN: Trigeminal neuralgia; nnabinol;Trigeminal TN: gabapentin/pregabalin ≥ tramadol ≥ NT: Number needed to treat; NP: Neuropathic pain; NT: in; RCT: Randomized controlled trial; in; RCT: ke ke inhibitor; SNRI: Serotonin and norepinephrine reuptake inhibitor; poststrokepain; CR: ControlledDN: Diabetic neuropathy;release; rve stimulation; THC: Tetrahydroca pentin/pregabalin > tramadol > opioids > TCAs > > opioids tramadol > pentin/pregabalin Noradrenaline reuptake inhibitor; NaSS: Noradrenergic and specific serotoninergic serotoninergic and specific Noradrenergic NaSS: inhibitor; reuptake Noradrenaline : Chronic pain; CPSP: Central rotonin and noradrenergic reupta harm; NMDA: N-methyl-d-aspartic acid; N harm; acid; NMDA: N-methyl-d-aspartic MS: Multiple sclerosis; NaRI: For CP there data is limited For CP there gaba of life: and quality relief pain on based 105 randomized, double-blind, placebo-controlled studies placebo-controlled double-blind, 105 randomized, pain relief: 50% than more with one patient to obtain CI) NNT (95% Combined 3.3 (2.9–3.8) [2.6–8.5]) 4.0 (CP: (2.7–3.7) 3.1 6.8 (3.4–441) 5.5 (3.4–14) 1.6 (1.3–2.1) Bupropion: [1.7–105]) 3.4 (CP: (1.6–2.5) 2.0 CBZ: Gabapentin/pregabalin : 4.7 (4.0–5.6) 4.9 (3.5–8.1) Lamotrigine: 2.1 (1.5–3.6) Phenytoin: (4.3–28) 7.4 Topiramate: 2.8 (2.1–4.2) Valproate: Opioids: 2.5 (1.9–3.4) Morphine: (1.9–4.1) 2.6 Oxycodone: 3.9 (2.7–6.7) Tramadol: in NPH) (DN, lack of efficacy 2.5 (1.6–5.4) Dextromethorphan: Memantine: ineffective (4.0–129) 7.8 Mexiletine: (MS) 3.4 (1.8–23) Cannabinoids: (4.6–12) 6.7 Capsaicin: algorithm for NP: Treatment TCA > only: opioids based on lowest NNT and pain relief Results and author conclusions author and Results PHN: Post-herpetic neuralgia; PNP: Peripheral neuropathic pa Spinal cord injury; SNaRI: Se epine; CI: Confidence interval; CP Tricyclic antidepressant; TENS: Transcutaneous electrical ne electrical Transcutaneous TENS: antidepressant; Tricyclic : Monoamine oxidase inhibitor; reuptake inhibitor; NNH: Number needed to channel blockers (lidocaine [topical], [topical], (lidocaine channel blockers + Antidepressants Antidepressants clomipramine, TCAs (amitriptyline, maprotiline, imipramine, desipramine, nortriptyline) fluoxetine, paroxetine) (citalopram, SSRIs (venlafaxine) SNRIs Wort) John’s hypericum (St Other (bupropion, (carbamazepine, gabapentin, Anticonvulsants valproate) topiramate, lamotrigine, pregabalin, oxycodone, (methadone, morphine, Opioids tramadol) (dextromethorphan, NMDA antagonists riluzole) memantine, Na mexiletine) THC) , (CT3, Cannabinoids (capsaicin) SP depleters combinations Glycin antagonist + morphine, gabapentin (gabapentin + venlafaxine) Drug(s)/active agents VAS: Visual analog scale. CP (CPSP, SCI, SCI, CP (CPSP, MS) PNP (painful polyneuropathy) PHN (postmastectomy and postsurgical, HIV-neuropathy) phantom limb, plexus brachial avulsion, trigeminal mixed neuralgia, pain neuropathic condition) Table 2. Meta-analysis and systematic reviews 2. Meta-analysis Table . type Pain NP SP: TCA: inhibitor; reuptake serotonin Selective P; SSRI: Substance antidepressant; NDRI: Norepinephrine dopamine NSAID: Nonsteroidal anti-inflammatory drug; OXCBZ: Oxcarbamazepine; monoamine oxidase type A; RSD:monoamineA;oxidase sympatethic Reflex type dystrophy;SCI: AD: Antidepressant drug; AED: Antiepileptic drug; CBZ: Carbamaz i.t.: Intravenous;LA: (s); MAOI Intrathecal; i.v.:

660 Therapy (2006) 3(5) Pharmacological treatment of neuropathic pain – REVIEW [53] [54] Ref. 1; but ineffective in 1; but ineffective RIMA: Reversible inhibitors of head-to-head comparisons head-to-head nnabinol; TN: Trigeminal neuralgia; nnabinol;Trigeminal TN: ): 1.7 (95% CI: 1.2–3. bapentin (NNT in DN 4.3 [95% CI: 2.8–8.6] in PHN 4.3 PHN 4.3 in DN [95% in bapentin (NNT 4.3 CI: 2.8–8.6] NT: Number needed to treat; NP: Neuropathic pain; NT: 30–60 min) and mexiletine (nine studies, median dose in; RCT: Randomized controlled trial; in; RCT: pentin, amitriptyline and amantadine (weighted mean amantadine and amitriptyline pentin, possible to provide real evidence-based treatment evidence-based treatment real to provide possible ke ke inhibitor; SNRI: Serotonin and norepinephrine reuptake inhibitor; [95%CI: 2.1–4.2]) or oxycodone (NNT in PNP 2.6 PNP 2.6 (NNT in or oxycodone 2.1–4.2]) [95%CI: line treatment of NP. Without of NP. treatment line poststrokepain; CR: ControlledDN: Diabetic neuropathy;release; rve stimulation; THC: Tetrahydroca Noradrenaline reuptake inhibitor; NaSS: Noradrenergic and specific serotoninergic serotoninergic and specific Noradrenergic NaSS: inhibitor; reuptake Noradrenaline mparing LA with placebo or active placebo or active drugs mparing LA with be better tolerated but, as ADs, they will cause side effects in most in effects cause side will they as ADs, but, better tolerated be administered LA is more to than placebo but equivalent morphine, LA more is administered CI: 2.6–8.5) amitriptyline in CPSP (15 patients 2.6–8.5) amitriptyline CI: : Chronic pain; CPSP: Central rotonin and noradrenergic reupta harm; NMDA: N-methyl-d-aspartic acid; N harm; acid; NMDA: N-methyl-d-aspartic MS: Multiple sclerosis; NaRI: between antidepressants and other , it is not it analgesics, other and antidepressants between SCI) SSRIs: 3.4–441) CI: (95% 6.8 DN: SNRI (venlafaxine): 3.4–13.5) CI: (95% 5.5 PNP: Bupropion: 1.3–2.1) CI: (95% 1.6 patients): PNP (41 AED ga than the better work to tend TCAs on NNT, Based PNP 4.0 in (NTT and lamotrigine 3.3–6.1]) [95%CI: [95% CI: CI: [95% 4.8 PHN in 2.4–6.4], CI: [95% PNP 3.5 in (NTT or tramadol [1.7–5.1]) PHN 2.5 in 1.7–6.0], have lower efficacy apparently and SSRIs effective equally appears to be venlafaxine 2.6–26.9]) whereas other than TCAs may options Treatment for tramadol 9.0). 23.0, for oxycodone 26.8, in NP patients for gabapentin NNH (overall patients as first- be considered still ADs must conclusion, In NP algorithms for Review on the effect of ADs. NNT for pain relief >50% relief NNT for pain of ADs. effect the Review on TCAs: entities) disease different the across major difference no 2.1–2.7; CI: (95% 2.3 neuropathy): HIV PNP (excluding CP (CPSP + SCI): 4.0 (95% Results and author conclusions author and Results (706 patients) co Meta-analysis of 19 RCTs Lidocaine (ten studies, most commonly 5 most studies, (ten Lidocaine over i.v. mg/kg on a 0–100 mean to placebo (weighted difference superior 600 mg daily) were -10.60; mm pain intensity VAS: gaba to morphine, equal and to -6.68) -14.52 95% CI: -6.96–5.75). 95% CI: -0.60; difference: CP. and DN) (post-traumatic, PNP consistent benefit for peripheral More Adverse events rate for systemically reported. major adverse events was No gabapentin. or amitriptyline PHN: Post-herpetic neuralgia; PNP: Peripheral neuropathic pa Spinal cord injury; SNaRI: Se epine; CI: Confidence interval; CP Tricyclic antidepressant; TENS: Transcutaneous electrical ne electrical Transcutaneous TENS: antidepressant; Tricyclic : Monoamine oxidase inhibitor; reuptake inhibitor; NNH: Number needed to (TCAs, SNRIs, SSRIs, others) others) SSRIs, SNRIs, (TCAs, Drug(s)/active agents anesthetics Local mexiletine) (lidocaine, VAS: Visual analog scale. SP: TCA: inhibitor; reuptake serotonin Selective P; SSRI: Substance antidepressant; NDRI: Norepinephrine dopamine NSAID: Nonsteroidal anti-inflammatory drug; OXCBZ: Oxcarbamazepine; monoamine oxidase type A; RSD:monoamineA;oxidase sympatethic Reflex type dystrophy;SCI: Table 2. Meta-analysis and systematic reviews (Cont.). and systematic reviews 2. Meta-analysis Table type Pain CPPNP, drugs Antidepressants PNP CP, AD: Antidepressant drug; AED: Antiepileptic drug; CBZ: Carbamaz i.t.: Intravenous;LA: Local anesthetic(s); MAOI Intrathecal; i.v.:

www.future-drugs.com 661 REVIEW – Bonicalzi & Canavero [29] [55] Ref. RIMA: Reversible inhibitors of ome: one study, 18 patients, 18 study, ome: one nnabinol; TN: Trigeminal neuralgia; nnabinol;Trigeminal TN: efficacy, safety and effects on quality on quality effects safety and efficacy, CI: -23.19 to -7.24; mean post-treatment to -7.24; mean CI: -23.19 post-treatment ng the efficacy of opioids in reducing the intensity of the reducing in of opioids ng the efficacy NT: Number needed to treat; NP: Neuropathic pain; NT: es, 263 patients): –13.63 (95% CI: 17.57 to -9.68; –13.63 (95% 17.57 to -9.68; mean es, 263 patients): CI: ponsiveness for CP and PNP, it did not resolve the the debate it did not resolve for ponsiveness CP and PNP, in; RCT: Randomized controlled trial; in; RCT: participants improved on gabapentin compared with compared gabapentin on improved participants controlled). Combined NNT for effectiveness compared compared Combined NNT for effectiveness controlled). measured post-treatment pain intensity [on a VAS from from VAS a intensity [on pain post-treatment measured ke ke inhibitor; SNRI: Serotonin and norepinephrine reuptake inhibitor; treatment; Guillain–Barrè syndr Guillain–Barrè treatment; poststrokepain; CR: ControlledDN: Diabetic neuropathy;release; rve stimulation; THC: Tetrahydroca Noradrenaline reuptake inhibitor; NaSS: Noradrenergic and specific serotoninergic serotoninergic and specific Noradrenergic NaSS: inhibitor; reuptake Noradrenaline at most, there are no data on the efficacy or adverse event rate of opioids rate of opioids adverse event or on the efficacy data no are at most, there 1, 3, 5, 6 were significant). were 1, 3, 5, 6 Combined NNT: 3.9 (95% 3–5.7). CI: NNT: Combined e needed to establish their long-term their long-term needed to establish e PNP (four studies, 69 patients): -15.22 (95% -15.22 69 patients): (four studies, PNP : Chronic pain; CPSP: Central rotonin and noradrenergic reupta harm; NMDA: N-methyl-d-aspartic acid; N harm; acid; NMDA: N-methyl-d-aspartic MS: Multiple sclerosis; NaRI: Results of the meta-analysis (mean differences in last last in differences (mean the meta-analysis of Results and placebo). 0–100] between active treatment Short-termefficacy: trial 19% on placebo. 19% on pain. neuropathic in is effective gabapentin that show to evidence is There scarce. are alternatives economic resources where affordable and more effective CBZ and TCA provide limited evidence of gabapentin effectiveness. limited 4.3 (95% all (seven) trials: NNT for 42% of 3.5–5.7). CI: with placebo: 2.9 (95% CI: 2.2–4.3). CI: (95% 2.9 placebo: with studies. two placebo-controlled PHN: gabapentin between difference significant No one study. pain: Mixed neuropathic (weeks and 8 at weeks 7 and placebo data. no evaluable seven patients, study, one pain: injury cord Spinal limb pain: one study; study: only a phantom pain: 10-day neuropathic cancer-related Other pain syndromes: 6 of week in intensity pain in difference significant Results and author conclusions author and Results January 2004. searches: Date of the most recent active three DN: seven studies (four placebo controlled, of life. pain for opioids: 30.8; for placebo: 44.9). CP (two studies, 21 patients): -17.81 (95% CI: 30.48 to -5.15; mean to -5.15; 30.48 CI: (95% -17.81 21 patients): (two studies, CP 44.9). placebo: for 30.8; for opioids: pain 55) placebo: for 38; for opioids: pain post-treatment mixed population (6 studi trial efficacy: Intermediate-term 52.9). for placebo 39.8, for opioids: pain post-treatment only equivocal evidence regardi Short-term studies provide Even if of over placebo for NP. opioids efficacy demonstrate significant studies Intermediate-term NP. opioid res meta-analyses data showed similar of (limited) CP for vs PNP. of opioids efficacy the differential regarding weekswas 8 studies As the duration of ar over months to years. Further RCTs PHN: Post-herpetic neuralgia; PNP: Peripheral neuropathic pa Spinal cord injury; SNaRI: Se epine; CI: Confidence interval; CP Tricyclic antidepressant; TENS: Transcutaneous electrical ne electrical Transcutaneous TENS: antidepressant; Tricyclic : Monoamine oxidase inhibitor; reuptake inhibitor; NNH: Number needed to (morphine, alfentanil, fentanyl, codeine, codeine, fentanyl, alfentanil, (morphine, oxycodone, ) methadone, Drug(s)/active agents Gabapentin VAS: Visual analog scale. SP: TCA: inhibitor; reuptake serotonin Selective P; SSRI: Substance antidepressant; NDRI: Norepinephrine dopamine NSAID: Nonsteroidal anti-inflammatory drug; OXCBZ: Oxcarbamazepine; monoamine oxidase type A; RSD:monoamineA;oxidase sympatethic Reflex type dystrophy;SCI: Table 2. Meta-analysis and systematic reviews (Cont.). and systematic reviews 2. Meta-analysis Table type Pain CPPNP, Opioids mixed PHN, DN, others SCI, NP, AD: Antidepressant drug; AED: Antiepileptic drug; CBZ: Carbamaz i.t.: Intravenous;LA: Local anesthetic(s); MAOI Intrathecal; i.v.:

662 Therapy (2006) 3(5) Pharmacological treatment of neuropathic pain – REVIEW [56] [57] [58] Ref. RIMA: Reversible inhibitors of nnabinol; TN: Trigeminal neuralgia; nnabinol;Trigeminal TN: -carnitine gave higher discontinuation -carnitine discontinuation gave higher CBZ better than placebo. CPSP: One CPSP: placebo. than CBZ better L nt duration: minimum 6 weeks, maximum 6 weeks, nt duration: minimum gh doses), sodium valproate, gabapentin, mexiletine mexiletine gabapentin, valproate, sodium gh doses), 2003 on oral treatments for painful DN (limits: English English DN (limits: painful for treatments oral on 2003 NT: Number needed to treat; NP: Neuropathic pain; NT: in; RCT: Randomized controlled trial; in; RCT: azine. PHN: one study, CBZ + clomipramine better clomipramine CBZ + study, PHN: one azine. riptyline vs gabapentin, vs gabapentin, nortriptylineriptyline + vs fluphenazine tter than tizanidine, no defference between CBZ and no defference tter than tizanidine, ke ke inhibitor; SNRI: Serotonin and norepinephrine reuptake inhibitor; poststrokepain; CR: ControlledDN: Diabetic neuropathy;release; rve stimulation; THC: Tetrahydroca Noradrenaline reuptake inhibitor; NaSS: Noradrenergic and specific serotoninergic serotoninergic and specific Noradrenergic NaSS: inhibitor; reuptake Noradrenaline o studies, o studies, 47 patients). DN: one study, udy), tramadol, oxycodone and acetyl- and oxycodone tramadol, udy), -carnitine. L ed RCTs, five comparative RCTs. Treatme comparativeRCTs. five ed RCTs, : Chronic pain; CPSP: Central rotonin and noradrenergic reupta harm; NMDA: N-methyl-d-aspartic acid; N harm; acid; NMDA: N-methyl-d-aspartic MS: Multiple sclerosis; NaRI: than TENS. 1.8–3.8). CI: (95% 2.5 NP: in any relief moderate for NNT small. are trials but is effective CBZ that show to evidence is There study, CBZ better than placebo, not different to amitriptyline. not different placebo, better than CBZ study, CBZ vs active control: studies, pimozide better than CBZ, CBZ be TN: three CBZ = nortriptyline + flufen DN: one . study, NNT in TN: tw 1.9 (95% CI: 1.4–2.8; Search restricted to fully published RCTs from 1990 to Nov. from published RCTs to fully restricted Search humans). adult language, placebo-controll 19 Results: 1 year. for: vs placebo to endpoint baseline from intensity in pain improvement significant Statistically (only with hi oxycodone, lamotrigine tramadol, desipramine, (in one of three studies), acetyl- studies), three of one (in Results and author conclusions author and Results 1999. September searches: Date of the most recent (one study): trial Placebo-controlled 2.3 (95% 1.5–3.8). CI: DN, Phenytoin. NNT: rates than placebo. rates to gave discontinuation study] similar [one desipramine (and and sodium valproate lamotrigine Gabapentin, rates (higher quite imipramine exceptsimilar for the discontinuation rates were In comparative RCTs, the placebo). than paroxetine). Comparative RCTs (amitriptyline vs desipramine, amit desipramine, vs (amitriptyline RCTs Comparative carbamazepine): no statistically significant differences in efficacy between the investigated treatments. in efficacy differences significant carbamazepine): no statistically desipramine (one st Adverse effects: PHN: Post-herpetic neuralgia; PNP: Peripheral neuropathic pa Spinal cord injury; SNaRI: Se epine; CI: Confidence interval; CP Tricyclic antidepressant; TENS: Transcutaneous electrical ne electrical Transcutaneous TENS: antidepressant; Tricyclic : Monoamine oxidase inhibitor; reuptake inhibitor; NNH: Number needed to -carnitine L Carbamazepine CBZ vs placebo: Fluoxetine Desipramine Clomipramine Citalopram Paroxetine Imipramine + fluphenazine Nortriptyline Tramadol CR Oxycodone Carbamazepine Lamotrigine valproate Sodium Gabapentin Dextromethorphan Mexiletine Acetyl- Drug(s)/active agents (Phenytoin) AEDs VAS: Visual analog scale. SP: TCA: inhibitor; reuptake serotonin Selective P; SSRI: Substance antidepressant; NDRI: Norepinephrine dopamine NSAID: Nonsteroidal anti-inflammatory drug; OXCBZ: Oxcarbamazepine; monoamine oxidase type A; RSD:monoamineA;oxidase sympatethic Reflex type dystrophy;SCI: Table 2. Meta-analysis and systematic reviews (Cont.). and systematic reviews 2. Meta-analysis Table type Pain TN, DN, PHN, CPSP DN DN Amitriptyline AD: Antidepressant drug; AED: Antiepileptic drug; CBZ: Carbamaz i.t.: Intravenous;LA: Local anesthetic(s); MAOI Intrathecal; i.v.:

www.future-drugs.com 663 REVIEW – Bonicalzi & Canavero [59] [60] Ref. RIMA: Reversible inhibitors of nnabinol; TN: Trigeminal neuralgia; nnabinol;Trigeminal TN: mpared with placebo (two studies): studies): (two with placebo mpared tidepressant medicines) included in the review. in included medicines) tidepressant facial pain (few trials and small participant numbers). numbers). participant and small trials (few pain facial s use may be limited by side effects, although these are these although are s use by side effects, may be limited analysed on an ITT basis, despite a 40% trial dropout dropout 40% trial despite a basis, an ITT on analysed of ADs in treating a variety of NP. The best evidence of NP. a variety of ADs in treating 50% pain relief: 3.5 (95% CI: 2.4–5.9, meta-analysis of 2.4–5.9, CI: (95% 3.5 relief: 50% pain NT: Number needed to treat; NP: Neuropathic pain; NT: pain patients, some of whom had NP): tramadol was but are ineffective in HIV-related neuropathies. There is There neuropathies. HIV-related in ineffective but are in; RCT: Randomized controlled trial; in; RCT: lusion can be made for St John’s Wort, venlafaxine and and venlafaxine Wort, made for St John’s can be lusion 150 mg/day, has an NNT of 2 (95% CI: 1.7–2.5). There are are has There an NNT of 2 CI: 1.7–2.5). (95% 150 mg/day, ke ke inhibitor; SNRI: Serotonin and norepinephrine reuptake inhibitor; in after breast cancer treatments: two studies. cancer treatments: in after breast poststrokepain; CR: ControlledDN: Diabetic neuropathy;release; from treatment in at least 20% of subjects. at least in treatment from rve stimulation; THC: Tetrahydroca Noradrenaline reuptake inhibitor; NaSS: Noradrenergic and specific serotoninergic serotoninergic and specific Noradrenergic NaSS: inhibitor; reuptake Noradrenaline fective treatment for NP. Its efficacy is similar to Itsfor that efficacy ADs reported and fective treatment for NP. ntrolled studies, NNT for effectiveness co studies, NNT for effectiveness ntrolled NT not reported): CP: four; HIV-related neuropathy: two; Burning mouth neuropathy: CP: four; HIV-related NT not reported): es. Overall NNT for effectiveness: 1.29 (95% CI: 1.16–1.46). CI: (95% 1.29 NNT for effectiveness: Overall es. studies. Overall NNT for effectiveness: 2.20 (95% 1.70–3.13). 2.20 (95% CI: NNT for effectiveness: Overall studies. : Chronic pain; CPSP: Central rotonin and noradrenergic reupta harm; NMDA: N-methyl-d-aspartic acid; N harm; acid; NMDA: N-methyl-d-aspartic MS: Multiple sclerosis; NaRI: -tryptophan (studies too small). RCTs from 1966 to December 2003. 1966 from RCTs on an patients 1725 2515 participants, reports, 50 studies (55 studi placebo-controlled 12 DN: four placebo-controlled PHN: placebo-co three pain: facial Atypical Results and author conclusions author and Results L quasi-RCTs. and for RCTs search 2002, to July 1966 From trials: Eligible least at studies): NNT to reach (three vs placebo Tramadol participants). 161 trials, the three of two out and not not blinded study, (one vs clomipramine Tramadol rate over21 patients). vs morphineTramadol 40 cancer blinded, not study, (one between morphine in effectiveness difference No week only. treatment the first NP in relieving in effective more 4 weeks. and 2, 3 and tramadol at either clomipramine with compared of tramadol the effectiveness regarding data to draw conclusions Insufficient or morphine. ef is an Tramadol conclusions: Authors’ It not available. comparisons are AEDs, but adequate direct threatening. and not life reversible It is not possible to identify the most effective ADs. effective the most to identify not It possible is PHN DN and in effective are TCAs that evidence is There atypical CP and in of effectiveness indication (limited) some syndrome. burning in mouth effect for any of evidence a lack is There with TCA can lead to withdrawalAdverse effects The review provides robust evidence for the effectiveness the effectiveness evidence for robust provides The review to doses of up in which, amitriptyline, for is available of SSRIs. No conc data for the effectiveness only limited 3.45 (95% 2.22–7.75). CI: studies (N Other placebo-controlled pa neuropathic Postoperative study; one syndrome: PHN: Post-herpetic neuralgia; PNP: Peripheral neuropathic pa Spinal cord injury; SNaRI: Se epine; CI: Confidence interval; CP Tricyclic antidepressant; TENS: Transcutaneous electrical ne electrical Transcutaneous TENS: antidepressant; Tricyclic : Monoamine oxidase inhibitor; reuptake inhibitor; NNH: Number needed to Wort), reboxetine, reboxetine, Wort), TCAs (amitriptyline, clomipramine, maprotiline, imipramine, desipramine, nortriptyline) MAOIs SSRIs paroxetine) fluoxetine, (citalopram, venlafaxine) sibutramine, SNRIs (reboxetine, RIMAs Newer antidepressants fluphenazine, flupenthixol, Other (bupropion, hypericum (St John's tryptophan) trazodone, tianeptine, Drug(s)/active agents Tramadol VAS: Visual analog scale. SP: TCA: inhibitor; reuptake serotonin Selective P; SSRI: Substance antidepressant; NDRI: Norepinephrine dopamine NSAID: Nonsteroidal anti-inflammatory drug; OXCBZ: Oxcarbamazepine; monoamine oxidase type A; RSD:monoamineA;oxidase sympatethic Reflex type dystrophy;SCI: Table 2. Meta-analysis and systematic reviews (Cont.). and systematic reviews 2. Meta-analysis Table type Pain DN, PHN, CP medicines Antidepressant PNP AD: Antidepressant drug; AED: Antiepileptic drug; CBZ: Carbamaz i.t.: Intravenous;LA: Local anesthetic(s); MAOI Intrathecal; i.v.:

664 Therapy (2006) 3(5) Pharmacological treatment of neuropathic pain – REVIEW ) [61] Ref. RIMA: ReversibleRIMA: inhibitors of ease; DN: Diabetic neuropathy; nnabinol; TN: Trigeminal neuralgia; nnabinol;Trigeminal TN: , pregabalin, TCAs. , pregabalin, rength of evidence, and low level of side effects: effects: of side level low and of evidence, rength pidural), nicardipine, (topical), stellate stellate (topical), piroxicam nicardipine, pidural), He: Ne laser irradiation, ketamine, ketamine, irradiation, He: Ne laser NT: Number needed to treat; NP: NeuropathicNT: pain; in; RCT: Randomized controlled trial; in; RCT: ke inhibitor;ke SNRI: Serotonin and norepinephrine reuptake inhibitor; poststrokepain; CR: Controlled rel rve stimulation; THC: Tetrahydroca morphine sulfate (CR) sulfate morphine Noradrenaline reuptake inhibitor; NaSS: Noradrenergic and specific serotoninergic serotoninergic and specific Noradrenergic NaSS: inhibitor; reuptake Noradrenaline TCAs); oxycodone CR: 2.5; tramadol: 4.7. CR: 2.5; tramadol: oxycodone TCAs); Ganoderma lucidu, Ganoderma Peripheral neuropathicPNP: pa rotonin and noradrenergic reupta MS: Multiple sclerosis; NaRI: interval; CP: Chronic pain; CPSP: Central NNT: opioids). 6.2 (vs or nortriptyline: desipramine 1.6; desipramine: (or 3.2); 1.6 TCAs: Amitriptyline: 3 (vs or methadone: Morphine Opioids: 3.3. pregabalin: or (or 2.8 5.3); 2.2 AEDs: Gabapentin: 3.2. capsaicin: 3; aspirin/diethylether: study); enrolment 2 (enriched patch: Lidocaine agents: Topical 1.3 (IT): Methylprednisolone st good efficacy, high to medium with Treatments 1: Group or patch, oxycodone lidocaine gabapentin, side- or evidence of strength limited 1, group in listed those than efficacy lower with Treatments 2: Group (i.t.). methylprednisolone topical, capsaicin, ointment, or cream in concerns: aspirin effect benzydamine acupuncture, with placebo: compared efficacy no treatment indicating 3: Evidence Group vincristine (epidural), methylprednisolone lorazepam, indomethacin, dextromethorphan, cream, E, zimelidine. vitamin (iontophoresis), chlorprothixene, carbamazepine, biperidin, IV studies: to Class limited benefit Reports of 4: treatment Group of lesion, extract DREZ cryocautery, methylprednisolone (iontophoresis), morphine sulfate (e morphine (iontophoresis), methylprednisolone ganglion block, triamcinolone (intralesional). triamcinolone block, ganglion Results and author conclusions author and Results PHN: Post-herpetic neuralgia; Post-herpetic PHN: NNH: Number needed to harm; NMDA: N-methyl-d-aspartic acid; N Spinal cord injury; SNaRI: Se A: Tricyclic antidepressant; TENS: Transcutaneous electrical ne electrical Transcutaneous TENS: antidepressant; Tricyclic A: :oxidase Monoamine inhibitor; ic drug;CI: CBZ: Carbamazepine;ic Confidence Gabapentin Pregabalin patch Lidocaine Opioids Others Drug(s)/active agents VAS: Visual analogscale. SP: Substance P; SSRI: Selective serotonin reuptake inhibitor; TC antidepressant; NDRI: Norepinephrine dopamine reuptake inhibitor; monoamine oxidase type A; RSD: Reflex sympatethic dystrophy; SCI: NSAID: Nonsteroidal anti-inflammatory drug; OXCBZ: Oxcarbamazepine; i.t.:Intravenous; LA: Local anesthetic(s);MAOI Intrathecal; i.v.: Table 2. Meta-analysis and systematic reviews (Cont.). 2. Meta-analysis and systematic reviews Table Pain type PHN TCAs AD: Antidepressant drug; AED: Antiepilept

www.future-drugs.com 665 REVIEW – Bonicalzi & Canavero [62] [63] [64] Ref. RIMA: Reversible inhibitors of rse events with capsaicin rse events with capsaicin in anecdotal reports of very anecdotal reports in nnabinol; TN: Trigeminal neuralgia; nnabinol;Trigeminal TN: adol, oxycodone, alfentanil) > failure of narcotics: of narcotics: > failure adol, oxycodone, alfentanil) ses; level 2: additional trials with many but not all of not all but with many trials additional 2: level ses; 1 (95% CI: 4.6–34) local adve local 4.6–34) (95% CI: 1 afaxine, fluoxetine, paroxetine, sertraline) > failure of failure > sertraline) paroxetine, fluoxetine, afaxine, tients with approximately a 50% reduction in pain. a 50% reduction tients with approximately NT: Number needed to treat; NP: Neuropathic pain; NT: arison of key findings stated of key findings arison tin, carbamazepine, lamotrigine, topiramate, phenytoin) phenytoin) topiramate, lamotrigine, carbamazepine, tin, cal antineuralgics (capsaicin,ketamine,lidocaine) > failure > failure cal antineuralgics (capsaicin,ketamine,lidocaine) poor efficacy in the treatment of chronic musculoskeletal musculoskeletal of chronic in the treatment poor efficacy in; RCT: Randomized controlled trial; in; RCT: on data from small and generally poorly designed clinical clinical designed poorly generally and small on data from d capsaicin with placebo or another treatment. Primary placebo or another treatment. with d capsaicin d be considered as a potential starting point): ADs point): starting as a potential considered d be ke ke inhibitor; SNRI: Serotonin and norepinephrine reuptake inhibitor; eak. erapy for a small number of patients who are unresponsive to, unresponsive who are erapy for a small number of patients poststrokepain; CR: ControlledDN: Diabetic neuropathy;release; 56 5.7 0.075%: capsaicin topical NNT: patients). rve stimulation; THC: Tetrahydroca acute on chronic NP: IV; phantom: II–IV. PHN; II–IV PHN; II–IV. phantom: IV; NP: chronic acute on Noradrenaline reuptake inhibitor; NaSS: Noradrenergic and specific serotoninergic serotoninergic and specific Noradrenergic NaSS: inhibitor; reuptake Noradrenaline ADs: AEDs (gabapen ketamine, baclofen, clonidine, dextromethorphan, mexiletine, amantadine, mexiletine, dextromethorphan, clonidine, ketamine, baclofen, her AEDs or of topical treatments. topical her AEDs or of : Chronic pain; CPSP: Central rotonin and noradrenergic reupta harm; NMDA: N-methyl-d-aspartic acid; N harm; acid; NMDA: N-methyl-d-aspartic MS: Multiple sclerosis; NaRI: small (n < 15), poorly designed trials with the level 1 or 2 results. or 2 1 with the level trials designed poorly 15), < (n small heavily relying often largely empirical, is NP treatment trials or anecdotal evidence. algorithm: treatment Proposed coul drug classes of the proposed one (any First-line: venl desipramine, imipramine, nortriptyline, (amitriptyline, and at least two other amitriptyline topi of gabapentin and at least two other AEDs: > failure of gabapentin and at two least ot tram methadone, codeine, (morphine, Second-line: Narcotics (tizanidine, Refractory treatments or narcotics. of treatments refractory lithium) > failure service. pain consult therapy and Combination Third-line: Surgical intervention. Fourth-line: aspirin, acetaminophen, , , indomethacin, , , therapy: Adjunctive acetaminophen/codeine. Comprehensive literature review extending back over 10 review literature Comprehensive years strategies: Search and meta-analy 100) > size (n large sample of RCTs Level 1: the desirable traits 3: comp level of trials; evidence-based in approximately 33% of patients. in approximately applied capsaicin has topically moderate to Conclusions: th but may be useful as an adjunct or sole it or NP, or intolerant of, other treatments. Results and author conclusions author and Results applie topically comparing of RCTs review Systematic number of pa the for information dichotomous outcome: Results: (6 trials NP: six placebo-controlled double-blind (95% CI: 8. or plaster: 0.025% capsaicin topical 4.0–10.0); Levels: SCI: II–IV; CP: IV; nonspecific NP: II–IV; nonspecific NP: II–IV; CP: IV; Levels:SCI: II–IV; are Further RCTs needed. NP. episodes of severe in acute on ’ chronic Ketamine may be a ‘third-line PHN: Post-herpetic neuralgia; PNP: Peripheral neuropathic pa Spinal cord injury; SNaRI: Se epine; CI: Confidence interval; CP Tricyclic antidepressant; TENS: Transcutaneous electrical ne electrical Transcutaneous TENS: antidepressant; Tricyclic : Monoamine oxidase inhibitor; reuptake inhibitor; NNH: Number needed to Anticonvulsants agents Topical Narcotics Analgesics Other NMDA antagonist (ketamine) w to moderate is ketamine of efficacy for Evidence Drug(s)/active agents capsaicin applied Topically VAS: Visual analog scale. SP: TCA: inhibitor; reuptake serotonin Selective P; SSRI: Substance antidepressant; NDRI: Norepinephrine dopamine NSAID: Nonsteroidal anti-inflammatory drug; OXCBZ: Oxcarbamazepine; monoamine oxidase type A; RSD:monoamineA;oxidase sympatethic Reflex type dystrophy;SCI: Table 2. Meta-analysis and systematic reviews (Cont.). and systematic reviews 2. Meta-analysis Table type Pain NP Antidepressants pain Chronic from or neuropathic musculoskeletal disorders phantom, CP, nonspecific PHN, NP AD: Antidepressant drug; AED: Antiepileptic drug; CBZ: Carbamaz i.t.: Intravenous;LA: Local anesthetic(s); MAOI Intrathecal; i.v.:

666 Therapy (2006) 3(5) Pharmacological treatment of neuropathic pain – REVIEW [65] [66] [35] [67] [68] Ref. RIMA: Reversible inhibitors of nnabinol; TN: Trigeminal neuralgia; nnabinol;Trigeminal TN: an codeine in controlling pain and have depressant pain and have depressant in controlling an codeine e-escalation may be associated with increased CNS side be associated with increased may e-escalation ct for TN or any other NP condition. Valproic acid is ct for TN or any other NP condition. Valproic NT: Number needed to treat; NP: Neuropathic pain; NT: bo, but SSRIs are not more effective than placebo. No effective not more bo, but are SSRIs Is and TCAs, the analgesia obtained with TCAs was obtained the analgesia TCAs, Is and in; RCT: Randomized controlled trial; in; RCT: ears ineffective in DN. Gabapentin is the AED with the with AED the is Gabapentin DN. in ears ineffective Ds. Incidence of major adverse effects higher with ADs. higher with major adverse effects of Incidence Ds. for breaking acute attacks of NP. OXCBZ is now the drug of OXCBZ is acute attacks of NP. for breaking widespread Their in NP. and spasticity in efficacy ke ke inhibitor; SNRI: Serotonin and norepinephrine reuptake inhibitor; poststrokepain; CR: ControlledDN: Diabetic neuropathy;release; rve stimulation; THC: Tetrahydroca support an analgesic effect of trazodone. effect an analgesic support Noradrenaline reuptake inhibitor; NaSS: Noradrenergic and specific serotoninergic serotoninergic and specific Noradrenergic NaSS: inhibitor; reuptake Noradrenaline fect of gabapentin in DN and PHN. TCAs are analgesic in painful DN and PHN. They analgesic have exhibited TCAs are between venlafaxine and tramadol are striking. There are no published are There striking. between venlafaxine and tramadol are : Chronic pain; CPSP: Central rotonin and noradrenergic reupta harm; NMDA: N-methyl-d-aspartic acid; N harm; acid; NMDA: N-methyl-d-aspartic MS: Multiple sclerosis; NaRI: NNT: NNT: 3.4 CBZ: CP: 3.2; gabapentin: PHN: 3.7; gabapentin: 3.3; CBZ: 2.1; phenytoin: DN: suitable makes it infusion for i.v. availability Phenytoin effe an documenting RCTs no are for TN but there choice app Topiramate DN. probably and CP (SCI) in ineffective in NP. for efficacy best evidence, at present, testing. undergoing clinical currently clonazepam, felbamate, and are tiagabine vigabatrin Pregabalin, spasticity. THC reduced than placebo. effective both THC (codeine) more th effective no more are Authors conclusion: cannabinoids Suggestions of their use. the CNS that limit on effects for cannabinoids can be considered Before practice for is undesirable. clinical into introduction needed. are RCTs further valid NP, treating the that TCAs: Consistent evidence and CPSP. CP in efficacy not superior of the They have SSRIs are been disappointing. effects analgesic regarding SSRIs: The results SSR both examining studies In hoped. as was analgesics, in every case. superior not do general trials in Controlled Trazodone: SSNRIs: The structural similarities controlled trials. Results and author conclusions author and Results NNTDN: 2.2–3.8). CI: (95% 2.7 AEDs: 2.6–4.7); CI: (95% 3.4 ADs: 2.4–5.0). CI: (95% AEDs: 3.2 1.7–3.0); (95% CI: 2.1 NNT ADs: PHN: place vs effect analgesic have and AEDs clearly ADs Both AE and older gabapentin between efficacy in difference ef positive quality): high (two Six RCTs 26 not RCTs: positive effect on different types of NP. on different effect positive RCTs: 26 not dos rapid effectiveness; low doses may have reduced Very effects. side less severe fewer and reported studies Uncontrolled effects. PHN: Post-herpetic neuralgia; PNP: Peripheral neuropathic pa Spinal cord injury; SNaRI: Se epine; CI: Confidence interval; CP Tricyclic antidepressant; TENS: Transcutaneous electrical ne electrical Transcutaneous TENS: antidepressant; Tricyclic : Monoamine oxidase inhibitor; reuptake inhibitor; NNH: Number needed to AEDs (phenytoin, carbamazepine, OXCBZ, OXCBZ, carbamazepine, (phenytoin, AEDs gapapentin, acid, valproic lamotrigine, clonazepam, pregabalin, topiramate, vigabatrin) tiagabine, felbamate, THC, of analog nitrogen (THC, Cannabinoids benzopyranoperidine) levonantradol, Antidepressants clomipramine, imipramine, (amitriptyline, TCAs desipramine) nortriptyline, citalopram, SSRIs (fluoxetine, paroxetine, zimelidine) (trazodone) Triazolopyridines Selective serotonin–norepinephrine (venlafaxine) inhibitors reuptake Drug(s)/active agents (TCAs, SSRIs) Antidepressants carbamazepine, (phenytoin, Anticonvulsants gabapentin) Gabapentin VAS: Visual analog scale. SP: TCA: inhibitor; reuptake serotonin Selective P; SSRI: Substance antidepressant; NDRI: Norepinephrine dopamine NSAID: Nonsteroidal anti-inflammatory drug; OXCBZ: Oxcarbamazepine; monoamine oxidase type A; RSD:monoamineA;oxidase sympatethic Reflex type dystrophy;SCI: Table 2. Meta-analysis and systematic reviews (Cont.). and systematic reviews 2. Meta-analysis Table type Pain CP, PHN, DN, NP, peripheral PHN DN, Acute, chronic or nonmalignant, . SCI: (one patient) CP, PHN, DN, TN, mixed NP, painful neuropathies, others CP DN, PHN, SCI) (CPSP, Mixed NP, deafferentation pain AD: Antidepressant drug; AED: Antiepileptic drug; CBZ: Carbamaz i.t.: Intravenous;LA: Local anesthetic(s); MAOI Intrathecal; i.v.:

www.future-drugs.com 667 REVIEW – Bonicalzi & Canavero [69] [70] [71] [72] Ref. RIMA: Reversible inhibitors of nnabinol; TN: Trigeminal neuralgia; nnabinol;Trigeminal TN: No evidence that SSRIs are better than older ADs. better than older are that SSRIs evidence No ve minor adverse reactions and four will have to stop to stop have and four will minor adverse reactions ve NT: Number needed to treat; NP: Neuropathic pain; NT: ly more effective than benzodiazepines; paroxetine and paroxetine benzodiazepines; than effective more ly in; RCT: Randomized controlled trial; in; RCT: 2–3.8); TCAs: 3.5 (95% CI: 2.5–5.6); SSRIs showed no 2.5–5.6); CI: (95% 3.5 TCAs: 2–3.8); th placebo, of 100placebo, th given patients with NP who are results for AEDs; still unclear which drug class should be drug class should unclear which still for AEDs; results . Patients were more to stop taking ADs likely than AEDs more . Patients were 95% CI: 2.7–8.2); dextromethorphan: ? 1.9 (95% CI: CI: (95% ? 1.9 dextromethorphan: 95% CI: 2.7–8.2); ke ke inhibitor; SNRI: Serotonin and norepinephrine reuptake inhibitor; poststrokepain; CR: ControlledDN: Diabetic neuropathy;release; rve stimulation; THC: Tetrahydroca -Dopa: ? 3.4 (95% CI: 1.5–infinity); topical capsaicin: 5.9 (95% (95% 5.9 capsaicin: topical 1.5–infinity); ? (95% CI: -Dopa: 3.4 L Noradrenaline reuptake inhibitor; NaSS: Noradrenergic and specific serotoninergic serotoninergic and specific Noradrenergic NaSS: inhibitor; reuptake Noradrenaline by gabapentin, tramadol and CBZ and tramadol by gabapentin, effective or ineffective effective lorazepam, acyclovir, topical benzydamine. acyclovir, lorazepam, : : Chronic pain; CPSP: Central rotonin and noradrenergic reupta harm; NMDA: N-methyl-d-aspartic acid; N harm; acid; NMDA: N-methyl-d-aspartic MS: Multiple sclerosis; NaRI: -: 5.6 (95% CI: 3.2–24) CI: 5.6 (95% acid: -lipoic α fective. Others ADs less less ADs Others fective. NNT: NNT: 2. CI: (95% 2.7 AEDs: 2.6–4.7); CI: (95% 3.4 ADs: DN: placebo. with difference significant 2.5–5.6). CI: (95% 3.5 TCAs: 2.4–5.0); CI: (95% 3.2 AEDs: 1.7–3.0); CI: (95% 2.1 ADs: PHN: 2.4–3.7). CI: (95% AEDs 2.9 2.4–3.7); CI: (95% 2.9 ADs: + PHN: DN CBZ 2.2 NNT phenytoin/ 2.1–5.4) CI: (95% 3.4 NNT gabapentin vs CBZ/phenytoin: Gabapentin (95% CI: 1.7–3.1). adverse. of minor incidence and and AEDs: same efficacy ADs AEDs better than older is evidence that gabapentin No adverse effects. owing to wi Compared than imipramine. effective mianserin less ha 30 will relief, obtain >50% pain will 30 antidepressants, similar Very effects. to major adverse owing treatment choice. first No significant difference between TCAs; TCAs significant between TCAs; difference significant No Results and author conclusions author and Results NNT: 3.4–435) CI: (95% 6.7 SSRIs 2.2–3.3); CI: (95% TCAs: 2.6 mexiletine: 3 (95% CI: 1.5–10); Lidocaine: 2.0–9.4); CI: (95% 3.3 CBZ: 3.0–infinity); CI: (95% ? 38 ( 4.1 gabapentin: 1.5–3.6); CI: 2.1 (95% phenytoin: 2.3–6.4); CI: (95% 3.4 tramadol: 1.1–3.7); treatments: Effective vincristine. TCAs, iontoforetic with blinding). problems (heterogeneity, capsaicin effect: Uncertain treatments Uneffective Based on evidence from randomized trials, TCAs appear to be the only agents of proven for benefit of TCAs appear to be the only agents proven trials, randomized from Based on evidence PHN. established CI: 3.8–13); 3.8–13); CI: Drugs of first choice: TCA, followed PHN: Post-herpetic neuralgia; PNP: Peripheral neuropathic pa Spinal cord injury; SNaRI: Se epine; CI: Confidence interval; CP Tricyclic antidepressant; TENS: Transcutaneous electrical ne electrical Transcutaneous TENS: antidepressant; Tricyclic : Monoamine oxidase inhibitor; reuptake inhibitor; NNH: Number needed to channel blockers (AEDs) blockers channel channel blockers (antiarythmic, (antiarythmic, blockers channel + 2+ -lipoic acid anticonvulsants) Ca clomipramine, maprotiline, citalopram, citalopram, maprotiline, clomipramine, amitriptyline mianserin, fluoxetine, paroxetine, fluphenazine + nortriptyline + fluphenazine, carbamazepine, gabapentin) AEDs (phenytoin, Drug(s)/active agents (TCAs, SSRIs) Antidepressants Na α therapies: Different acyclovir, lorazepam, TCAs, capsaicin, (ionto). vincristine (topical), benzydamine NMDA-antagonist (dextromethorphan) NMDA-antagonist (tramadol) Opioids (L-Dopa) precursors Dopamine (capsaicin) SP depleters VAS: Visual analog scale. SP: TCA: inhibitor; reuptake serotonin Selective P; SSRI: Substance antidepressant; NDRI: Norepinephrine dopamine NSAID: Nonsteroidal anti-inflammatory drug; OXCBZ: Oxcarbamazepine; monoamine oxidase type A; RSD:monoamineA;oxidase sympatethic Reflex type dystrophy;SCI: Table 2. Meta-analysis and systematic reviews (Cont.). and systematic reviews 2. Meta-analysis Table type Pain DN, PHN desipramine, amitriptyline, ADs (imipramine, Polyneuropathy DN) (including CP PHN, DN, ADs) other (TCAs, Antidepressants PHN ef TCAs AD: Antidepressant drug; AED: Antiepileptic drug; CBZ: Carbamaz i.t.: Intravenous;LA: Local anesthetic(s); MAOI Intrathecal; i.v.:

668 Therapy (2006) 3(5) Pharmacological treatment of neuropathic pain – REVIEW [73] [74] [75] [76] [77] [78] Ref. of some ed on the : Local NaRI:anesthetic; Noradrenaline -aspartic acid NSAID: Nonsteroidal anti- D but not performed routinely. but not performed -methyl- traditional pain therapies. pain traditional N as good as ADs (including amitriptyline) and amitriptyline) (including as ADs as good RSD: Reflex sympatethic dystrophy;Resiniferatoxin; RTX: SCI: Spinal .t.: Intrathecal; i.v.: Intravenous; LA .t.: Intrathecal; i.v.: c pain; NMDA: ic antidepressant; TN: Trigeminal neuralgia; VR: Vanilloid receptor. neuralgia; VR:ic Vanilloid antidepressant; TN: Trigeminal e clinically available; they may be effective in in the treatment they may be effective available; e clinically gy for NP, despite an increasing number of clinical trials number of trials clinical an despite increasing NP, gy for nd PHN. Gabapentin has a favorable side-effect profile and, bas profile has a favorable side-effect nd PHN. Gabapentin eness of long-term treatments eness long-term treatments of nce it does not respond well to well it not nce does respond as first-line treatment for neuropathic pain. for neuropathic treatment first-line as nagement of NP over the past 5nagement of NP years. (CBZ or phenytoin). (CBZ Gabapentin at least or phenytoin). for neuropathic pain (2000–2005)for neuropathic . ststroke pain; DN: DiabeticststrokeDN: pain;neuropathy; i fractory to the above agents. fractory to the above controlled trial; rhNGF: Recombinant human nerve growth factor; rgic antidepressants;rgicgrowth factor; NGF: NerveNP: Neuropathi rs; SSRI: Selective serotonin reuptake inhibitor; TCA: Tricycl types of chronic pain. types of chronic results of these studies, it should be considered it should of these studies, results in TN. pain control Improved Used in the treatment of TN, painful DN and PHN. DN of TN, painful the treatment Used in NP. relieving in efficacy evidence for its No DN a of painful for the treatment effective Clearly specifically NMDA antagonists ar of only a handful effects; side Dose-limiting Effective. evidence for efficacy. Less effectiv the for predicting proposed tests: Pharmacological Authors’ comments PHN. DN and TN, painful in Effective choice therapy for NP. First and PHN. DN painful in effective Specifically if any. effect Weak pain. neuropathic to modulate Good potential and control trials. not yet in clinical fully determined Efficacy and antinociceptive activities. antihyperalgesic Potential si clinicians to challenge therapeutic formidable is a NP Better alternatives to older medications much safer. alternativeReasonable to AEDs or antidepressants. May be useful in patients re agent. Revolutionary new has been madema in the Much progress satisfactory. Often less than Controversial. New drug classes. the clinician. to a challenge to be continues of NP The treatment There is no consensus is concerningThere the optimal therapeutic strate drugs. with several relief pain successful demonstrating rmacological treatment options rmacological treatment drug; CBZ: Carbamazepine; CPSP:po Central Table 6. Experts’ opinion on pha Table Drug(s) CBZ Phenytoin Gabapentin Lamotrigine CBZ Gabapentin Phenytoin Lamotrigine clonazepam, valproic Others (phenobarbital, tiagabine) and acid, topiramate, pregabalin (ketamine, antagonists NMDA receptor amantadine memantine, dextromethorphan, [methadone, dextropropoxyphene, ketobemidone]) Newer AEDs (notably gabapentin) Mexiletine Long-acting opioids patch lidocaine Topical antiepileptics, newer and TCAs, standard local and topical systemic tramadol, opioids, anesthetics, some NMDA receptor antagonists SSRIs, antiarrhythmics (mexiletine), capsaicin of infusions tests (short-term Pharmacological ketamine, opioids, propofol, barbiturates, lidocain) ADs antiarrhythmics, Anticonvulsants, Cannabinoids Conotoxins, cord injury; SNaRI: Serotonin and noradrenergic reuptake inhibito inflammatory drug; PHN: Postherpetic neuralgia; RCT: Randomized inflammatory drug; neuralgia; RCT: Postherpetic PHN: reuptake inhibitors; NaSSA: Noradrenergic and specific serotonine AD: Antidepressant drug; AED: Antiepileptic

www.future-drugs.com 669 REVIEW – Bonicalzi & Canavero [79] [80] [81] [82] [83] Ref. d ile. ractice. s in e of adverse : Local NaRI:anesthetic; Noradrenaline -aspartic acid NSAID: Nonsteroidal anti- D -methyl- N RSD: Reflex sympatethic dystrophy;Resiniferatoxin; RTX: SCI: Spinal .t.: Intrathecal; i.v.: Intravenous; LA .t.: Intrathecal; i.v.: c pain; NMDA: ic antidepressant; TN: Trigeminal neuralgia; VR: Vanilloid receptor. neuralgia; VR:ic Vanilloid antidepressant; TN: Trigeminal in other painful neuropathic disorders, such as CPSP, SCI an SCI such as CPSP, disorders, neuropathic other painful in udy methodology; CBZ has been very difficult to use p in clinical to use udy been CBZ methodology; very has difficult SSRIs over TCAs, although there was an improved side-effect prof side-effect an improved was although there SSRIs over TCAs, neuropathic pain (2000–2005) (Cont.). neuropathic associated neuropathy and CPSP. Adverse events could be a significant limiting Adverse factor limiting events could be a significant and CPSP. neuropathy associated m the earlier indications of efficacy. of efficacy. indications m the earlier ststroke pain; DN: DiabeticststrokeDN: pain;neuropathy; i tter side-effect profile than TCAs. profile tter side-effect -adrenoceptor agonists: used at present. agonists: -adrenoceptor α controlled trial; rhNGF: Recombinant human nerve growth factor; rgic antidepressants;rgicgrowth factor; NGF: NerveNP: Neuropathi rs; SSRI: Selective serotonin reuptake inhibitor; TCA: Tricycl Available literature did not show an effective superiority for superiority did not show an effective literature Available overshadowed in st by limitations are in RCTs Positive results forFirst-line medications NP. Second-line medications. RCTs. of results Awaiting circumstances. in individual be effective They may occasionally RCTs provide some evidence for the efficacy of phenytoin in NP, but data on its utility are still lacking. are data on its utility but some of phenytoin in NP, evidence for the provide efficacy RCTs occurrenc to overall pain in painful DN well tolerated and is to and PHN, is similar placebo with regard in relieving Effective use of gabapentin the warranted to investigate events. Studies are ADs, glutamate receptor antagonists: some clinical data on some clinical their use. antagonists: ADs, glutamate receptor its use. Authors’ comments to confir failed trail clinical Phase III of rhNGF. with further development not to proceed decided has Genentech LA, opioids, capsaicin, NSAIDs, phantom limb pain. TN, HIV- refractory relieving in Effective Venlafaxine is effective, with a be with a is effective, Venlafaxine works reported. and experimental Only anecdotal therapeutic results acological treatment options for acological treatment drug; CBZ: Carbamazepine; CPSP:po Central -adrenoceptor agonists, antidepressants, agonists, antidepressants, -adrenoceptor reuptake inhibitors; NaSSA: Noradrenergic and specific serotonine Table 6. Experts’ opinion on pharm Table Drug(s) SSRIs, TCAs nefazodone and venlafaxine SNaRI: NaSSA: mirtazapine reboxetine NaRI: NGF rhNGF CBZ Phenytoin Gabapentin Lamotrigine and other forms of peripheral Topical of: administration local anesthetics, opioids, capsaicin, NSAIDs, α patch, 5% lidocaine (AED), Gabapentin hydrochloride, tramadol analgesics, opioid antidepressants tryciclic (nortriptyline/desipramine) (lamotrigine, Anticonvulsants (SSRI: antidepressants carbamazepine), citalopram, paroxetine, bupropion, venlafaxine) (levetiracetam, Anticonvulsants tiagabin, pregabalin, oxcarbamazepin, zonisamide) topiramate, clonidine, capsaicin, Other medications: mexiletine dextromethorphan, AD: Antidepressant drug; AED: Antiepileptic glutamate receptor antagonists glutamate receptor cord injury; SNaRI: Serotonin and noradrenergic reuptake inhibito inflammatory drug; PHN: Postherpetic neuralgia; RCT: Randomized inflammatory drug; neuralgia; RCT: Postherpetic PHN:

670 Therapy (2006) 3(5) Pharmacological treatment of neuropathic pain – REVIEW [84] [85] [86] [87] [88] [89] [90] Ref. rs, ent and int, d h CP cacy ffective led ical need ness arly eatments. s have shown s have shown e or poorly tolerated. poorly e or therapy for the therapy for : Local NaRI:anesthetic; Noradrenaline ed. However, owing to logistic owing ed. However, -aspartic acid NSAID: Nonsteroidal anti- D y used as adjuncts to other tr -methyl- N pain; not efficacious against PHN. Useful efficacious pain; not large (over 200 (over large placebo-control patients), RSD: Reflex sympatethic dystrophy;Resiniferatoxin; RTX: SCI: Spinal .t.: Intrathecal; i.v.: Intravenous; LA .t.: Intrathecal; i.v.: c pain; NMDA: ic antidepressant; TN: Trigeminal neuralgia; VR: Vanilloid receptor. neuralgia; VR:ic Vanilloid antidepressant; TN: Trigeminal tolerable side effects. Primaril tolerable side effects. ment of CP has been demonstrat been ment of CP has rse events and incidence of adverse events. Small patient numbe patient Small events. of adverse incidence and events rse syndromes: i.v. lidocaine, opioids, amitriptyline, gabapentin an gabapentin amitriptyline, opioids, lidocaine, i.v. syndromes: rts their efficacy in the treatment of NP. Among 15 patients wit of NP. in the treatment rts their efficacy only partially to available therapies. There is a high unmet med to therapies. There only partially available dules and study design and between differ flaws made comparison of CP in patients with spasticity. To date, only three studie three date, only To of CP in patients with spasticity. of the improvement in pain intensity between baseline and in pain intensity end po of the improvement PSP, two SCI) had discontinued oral morphine due to minimal effi due to minimal morphine oral discontinued had two SCI) PSP, . Combinations of baclofen and morphine or clonidine are more e more are or clonidine . Combinations of baclofen and morphine for CP symptoms, although its oral analog mexiletine is not simil on of patients find this drug ineffective, partially effectiv drug ineffective, find this on of patients on; modest pain relief; limited by side effects. side by limited relief; modest pain on; rtially efficacious against deafferentation deafferentation against efficacious rtially conclusion: only gabapentin is in studied conclusion: neuropathic pain (2000–2005) (Cont.). neuropathic ststroke pain; DN: DiabeticststrokeDN: pain;neuropathy; i controlled trial; rhNGF: Recombinant human nerve growth factor; rgic antidepressants;rgicgrowth factor; NGF: NerveNP: Neuropathi rs; SSRI: Selective serotonin reuptake inhibitor; TCA: Tricycl differences in patient populations, variabiliy in treatment sche treatment in variabiliy populations, patient in differences Authors’ scientifically impossible. studies studies showing good efficacy and safety. efficacy good showing studies treatment of the neuropathic pain of PHN. of the neuropathic treatment tolerability by number of study discontinuations because of adve of because study discontinuations by number of tolerability Limited efficacy in NP. Limited efficacy nerve lesions or DN; Eficacious against pa limited by adverse effects. limited side effects. by Usefulness limited and DN. injury nerve PHN, in pain Alleviate pain. and lancinating TN activity against Clinical and PHN, DN, peripheral nerve injury RSD. against Efficacy by limited in against DN, PHN and RSD. Efficacy Moderate activity for therapies that treat NP effectively. that treat therapies for Critical selection of RCTs. Efficacy evaluated as a percentage evaluated as a percentage Efficacy Critical selection of RCTs. Modest, probably artefactual effects; can exacerbate NP in HIV. in can exacerbate NP effects; artefactual probably Modest, or poorly and responds to treatment refractory generally NP is (CPSP six, SCI nine) at the end of 1 year, all but three (one C all but three (CPSP at the end six, SCI nine) of 1 year, lamotrigine. agent available the most effective is lidocaine probably i.v. effective. evidence suppo but evolving is controversial opioids The use of Authors’ comments effects. side unacceptable by tolerance and limited Some relief, half populati the patient in approximately Effective relief provides that baclofen studies have indicated i.t. Several and efficacy. number in limited are CP for options treatment Effective CP in efficacy with demonstrated interventions Pharmacological Current therapies Current offor limited benefit. NP are it to be effective in patients with peripheral nociceptive or NP peripheral nociceptive in patients with it to be effective and/or poor tolerability. and/or poor treat for the morphine and of lidocaine efficacy the In conclusion, side-effect issues, these therapies are not optimal for long-term management of CP. these therapies are issues, side-effect than each drug alone. each drug than acological treatment options for acological treatment drug; CBZ: Carbamazepine; CPSP:po Central channels blockers (lidocaine, mexiletine) blockers (lidocaine, channels + reuptake inhibitors; NaSSA: Noradrenergic and specific serotonine Anticonvulsants (carbamazepine, Na (carbamazepine, Anticonvulsants lamotrigine) valproate, Gabapentin TCAs capsaicin Topical Table 6. Experts’ opinion on pharm Table Drug(s) NSAIDs Opioids Na Opioids Gabapentin Gabapentin baclofen i.t. 5% lidocaine patchLidocaine Mexiletine Opioids Amitriptyline a substantial proporti NP; however, Often used to treat Gabapentin Lamotrigine a first-line as recommended patch has been lidocaine the 5% profile, and safety efficacy to its proven Owing Gabapentin Others AD: Antidepressant drug; AED: Antiepileptic cord injury; SNaRI: Serotonin and noradrenergic reuptake inhibito inflammatory drug; PHN: Postherpetic neuralgia; RCT: Randomized inflammatory drug; neuralgia; RCT: Postherpetic PHN:

www.future-drugs.com 671 REVIEW – Bonicalzi & Canavero [91] [92] [93] [94] [95] Ref. is nt agents, agents, ar m this. : Local NaRI:anesthetic; Noradrenaline e, ), first-generation AEDs first-generation duloxetine), e, -aspartic acid NSAID: Nonsteroidal anti- D -methyl- N RSD: Reflex sympatethic dystrophy;Resiniferatoxin; RTX: SCI: Spinal .t.: Intrathecal; i.v.: Intravenous; LA .t.: Intrathecal; i.v.: c pain; NMDA: alin) are effective in the treatment of NP. The efficacy and The efficacy of NP. in the treatment effective are alin) r, RCTs have demonstrated that effective pain relief with TCA pain relief have demonstrated that effective RCTs r, onvulsant gabapentin and the LA lidocaine (adhesive patch) for patch) (adhesive lidocaine LA the and onvulsant gabapentin shown promise in controlled clinical trials for PHN trials manageme clinical in controlled shown promise ic antidepressant; TN: Trigeminal neuralgia; VR: Vanilloid receptor. neuralgia; VR:ic Vanilloid antidepressant; TN: Trigeminal As present risks of numerous side effects that are of particul of are that effects side risks of numerous present As nd side-effect profiles differ. TCAs are the most cost–effective the most cost–effective TCAs are differ. profiles nd side-effect well tolerated and present little risk of drug–drug interaction. risk of drug–drug little present tolerated and well rtain novel ADs (i.e., bupropion, venlafaxin bupropion, rtain novel ADs (i.e., the treatment of NP. However, further RCTs are needed to confir to needed are RCTs further However, of NP. treatment the fewer safety concerns in elderly patients. neuropathic pain (2000–2005) (Cont.). neuropathic ststroke pain; DN: DiabeticststrokeDN: pain;neuropathy; i triptyline, nortriptyline, desipramine), ce desipramine), nortriptyline, triptyline, controlled trial; rhNGF: Recombinant human nerve growth factor; rgic antidepressants;rgicgrowth factor; NGF: NerveNP: Neuropathi rs; SSRI: Selective serotonin reuptake inhibitor; TCA: Tricycl concern among the elderly, who comprise the majority of PHN patients. majority of PHN the comprise who concernthe elderly, among in PHN the antic patients, the US FDA has approved Based on RCTs pain in PHN. Unlike TCAs, both these agents appear to be of have also treatment, opioid long-acting including Other therapies, Until recently, TCAs were the treatment of choice for PHN; howeve for of choice the treatment TCAs were recently, Until pregab AEDs (gabapentin, and second-generation (CBZ, phenytoin) tolerability of ADs and AEDs are comparable, although safety a although comparable, of ADs and AEDs are tolerability reported in only approximately half of all patients. Moreover, TC half Moreover, of patients. all in only approximately reported Authors’ comments evaluation and of development a management strategy for each patient. thorough individual PHN requires gabapentin. or the AED nortriptyline) (e.g., TCAs with therapy is Initial frequently. Reduces allodynia required. sometimes are opioids Strong tolerated. is poorly but of patients, proportion a small for beneficial is cream Topical of ketamine. the exception with beneficial, Not proved including syndromes, a number of clinical for used currently RTX, are and capsaicin including agonists of VR1, molecule Small intractable NP. but second-generation AEDs are associated with AEDs are but second-generation acological treatment options for acological treatment drug; CBZ: Carbamazepine; CPSP:po Central reuptake inhibitors; NaSSA: Noradrenergic and specific serotonine Table 6. Experts’ opinion on pharm Table Drug(s) TCAs lidocaine patch Gabapentin, others and Opioids TCAs and gabapentin lidocaine Topical Opioids Capsaicin NMDA antagonists Topiramate agonists VR1 and AEDs Antidepressants AD: Antidepressant drug; AED: Antiepileptic ami (e.g., TCAs in is effective topiramate that now evidence is There cord injury; SNaRI: Serotonin and noradrenergic reuptake inhibito inflammatory drug; PHN: Postherpetic neuralgia; RCT: Randomized inflammatory drug; neuralgia; RCT: Postherpetic PHN:

672 Therapy (2006) 3(5) Pharmacological treatment of neuropathic pain – REVIEW [96] Ref. se of ve to to ve : Local NaRI:anesthetic; Noradrenaline ded positive results in a number ded positive results -aspartic acid NSAID: Nonsteroidal anti- D AED for NP in patients unresponsi for NP in AED ncerns: long-term use of opioids raises raises opioids use of ncerns: long-term -methyl- N RSD: Reflex sympatethic dystrophy;Resiniferatoxin; RTX: SCI: Spinal .t.: Intrathecal; i.v.: Intravenous; LA .t.: Intrathecal; i.v.: c pain; NMDA: discussions on side effects and functional improvement with u with and functional improvement on discussions side effects ic antidepressant; TN: Trigeminal neuralgia; VR: Vanilloid receptor. neuralgia; VR:ic Vanilloid antidepressant; TN: Trigeminal A-approved for PHN. It has yiel It has for PHN. A-approved a RCT in patients with painful DN. Effective vs placebo at painful DN. with Effective a RCT in patients is suggested as a second-line ndations were made before the FDA approval of duloxetine the FDA approval made before ndations were ho prescribes opioids opioids should obtain a signed opioid agreement ho prescribes th different NP states. NB: major safety concerns. major NB: NP states. different th ne AED for NP in patients unresponsive to gabapentin unresponsive patients NP in for AED ne should should be used as medication for NP a first-line of only 8–12 weeks duration). NB: safety co NB: weeks duration). 8–12 of only pain, Guillain–Barré syndrome, SCI, CRPS 1). CRPS SCI, syndrome, pain, Guillain–Barré first-line treatments for NP should be the 5% first-line treatments patch, opioids, gabapentin, lidocaine neuropathic pain (2000–2005) (Cont.). neuropathic ststroke pain; DN: DiabeticststrokeDN: pain;neuropathy; i s that increase the activity of both norepinephrine and serotonin. the activity of norepinephrine both s that increase controlled trial; rhNGF: Recombinant human nerve growth factor; rgic antidepressants;rgicgrowth factor; NGF: NerveNP: Neuropathi rs; SSRI: Selective serotonin reuptake inhibitor; TCA: Tricycl RCTs in NP (painful limb DN, PHN, in NP (painful phantom RCTs gabapentin Dworkin and colleagues suggest that It HIV. SCI, CPSP, DN, due to against NP in RCTs efficacy Shown Authors’ comments PHN. in Effective RCTs). (six effect overall significant No second-li Suggested as a TN. for FDA-approved US CBZ: Gabapentin has the broadest evidence for efficacy against NP. FD against NP. for efficacy evidence has the broadest Gabapentin concerns about increasing hyperalgesia. The practitioner w The practitioner hyperalgesia. concerns about increasing to check Follow-up and for compliance. use random urine screening of the opioid should of the should be documented. opioid Dworkin and colleagues suggested that the be noted that these recomme should TCAs. It tramadol, and and pregabalin. gabapentin. studies on NP. controlled No published DN. in RCT one benefit in Shown DN. PHN and for painful FDA-approved usefulness for its indicating NP No RCTs in one. positive results in DN, RCTs in three Negative results DN. in one studypainful for Positive results of NP.. be useful for the treatment to RCTs many small shown in Have been against NP than AD effective Less between the TCA imipramine and in venlafaxine No difference higher dosage. painful DN. of for the treatment FDA-approved wi than placebo in patients effective more SR bupropion pain conditions. of chronic the treatment for Not recommended PHN. NP states, different DN, painful in RCTs from Positive results and DN (studies PHN in effective Oxycodone: acological treatment options for acological treatment drug; CBZ: Carbamazepine; CPSP:po Central reuptake inhibitors; NaSSA: Noradrenergic and specific serotonine Table 6. Experts’ opinion on pharm Table Drug(s) medications: 5% patch, lidocaine Topical Capsaicin AEDs: CBZ Gabapentin Lamotrigine Levetiracetam OXCBZ Pregabalin Tiagabine Topiramate Valproate Antidepressants: TCAs SSRIs SNRIs Duloxetine NDRIs Benzodiazepines Analgesics: Tramadol Opioids AD: Antidepressant drug; AED: Antiepileptic cord injury; SNaRI: Serotonin and noradrenergic reuptake inhibito inflammatory drug; PHN: Postherpetic neuralgia; RCT: Randomized inflammatory drug; neuralgia; RCT: Postherpetic PHN:

www.future-drugs.com 673 REVIEW – Bonicalzi & Canavero

Highlights

• Pain following peripheral and central neuropathic pain remains a challenge. • All available drug therapies remain only partially satisfactory, with several compounds having considerable side effects or only limited efficacy. • Despite a huge amount of animal data, few, if any, have paved the way to effective drugs for human patients, given the ample diversity in terms of anatomy and neurochemistry. • Only basic studies (e.g., microdyalisis during neurosurgical procedures and in vivo chemical neuroimaging) in human patients will forward the field.

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