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

REVIEW

Pharmacological treatment of neuropathic pain: present status and future directionsVincenzo Bonicalzi & Sergio Canavero†

†Author for correspondenceTurin Advanced Neuromodulation Group, Cso Einaudi 2, 10128 Torino, ItalyTel.: +39 349 471 [email protected]

Keywords: central pain, mononeuropathy, neuropathic pain, polyneuropathy

The pharmacological treatment of neuropathic pain remains unsatisfactory. This is partly owing to poor knowledge of available drugs on the part of treating physicians, but equally important is the poor correlation between animal models and clinical effects. In this review, we survey the field and draw several conclusions, particularly that current results are disappointing and that we are not going to see major progress in the near future if current paradigms are not changed. Also, mechanisms of action of drugs must be better explored in view of a drug dissection-based approach.

Peripheral neuropathic pain (NP) can manifestas painful polyneuropathy, mononeuropathy ormultiple mononeuropathy following trauma,inflammation, ischemia, metabolic derange-ments, toxins (including drugs and alcohol),tumors, infections, primary neurological dis-eases, and iatrogenic insults. A few syndromesinvolve both central and peripheral damage,such as brachial plexus avulsion pain and certainstages of postherpetic neuralgia. Uncounted mil-lions suffer painful neuropathies, while no lessthan 7 million people are affected by centralpain (CP) [1].

Where are we?NP/CP is an area of largely unmet therapeuticneed. Despite approximately 100 drugs havingbeen tested (Table 1), drug therapy of NPremains unsatisfactory, as shown in recent meta-analyses and systematic reviews (Tables 2–5).Antidepressants and certain anticonvulsants(i.e., the drugs of choice for most patients) onlyachieve clinically significant (50%) pain relief in30–50% of cases, and 30–40% relief is consid-ered a good response in most studies, with effec-tive dosages of the same drug being highlyvariable from patient to patient. The percentageof patients with NP responsive to any particularregimen is unknown. Even within the same classof medication, some patients fail to respond toone medication but then respond to another.No study has assessed combinations of any ofthese drugs. In general, quality of life has beenimproved less consistently than pain intensity.Treatment duration in clinical trials has beenwithin a few months and the durability of painrelief and the long-term safety and tolerabilityof treatment are unknown. In addition,

cost–effectiveness has been rarely addressed.Most randomized controlled trials of NP haveexamined only diabetic and postherpetic NPand the applicability of the results of clinical tri-als for one NP syndrome to others cannot bedetermined. Few clinical trials have comparedmedication options directly. Systematic evalua-tion of combination treatment is all but lacking.Although many patients are treated with poly-pharmacy, little is known regarding whichpatients are most likely to benefit from combi-nation treatment and whether such treatmenthas additive or synergistic effects. Finally, con-trolled studies combining drugs and other strat-egies, such as neuromodulatory, are lacking. Tocompound the picture, treating physicians areoften ignorant of best available therapies andtheir correct usage (e.g., under-dosing) [2,3]. Thecurrent approach of setting realistic expecta-tions, starting with monotherapy and then add-ing drugs on the basis of trial-and-error andevidence from clinical trials, leaves mostpatients dissatisfied with their treatment [4].

While the area is exploding with new informa-tion, the advance in knowledge has, as yet, notresulted in better clinical treatment. The transi-tion from acute to chronic pain and the reason(s)patients differ in their responses and behaviordespite an apparently similar initial noxiousevent are still unexplained and the generalhypothesis of a genetic predisposition to developchronic pain remains inconsequential.

Present statusThe opinions of many experts – generally withties to drug companies – and their evolution over6 years (2000–2005) are summarized in Table 6.These opinions are, for the most part, discordant

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652 Therapy (2006) 3(5)

and, most importantly, do not appear to hew toevidence-based data available at the time of theircompilation (Table 2). Almost all experts did notdiscriminate CP as a separate nosological entity,thus their recommendations are not pertinent[1,5,6]; it was emphasized that the most effectivedrugs for CP are intravenous or intrathecal andantidepressants appear less effective in cord CPthan brain CP [4,6].

Smorgasbord of mechanismsOver the past 25 years, it has become clear thatnumerous changes occur both in the PNS andCNS after nerve injury. Following nerve injury, acascade of events materializes both peripherallyand centrally, affecting a cornucopia of pep-tide/transmitters, structures and neurophysiologi-cal processes, and a change at one place hasripple-through effects at many others. Hundredsof genes are affected after a single traumatic event.For instance, the γ-aminobutyric acid (GABA)-Areceptor, which is made up of distinct subunitsthat may assemble in a variety of combinations,each with distinct functional characteristics, canpotentially be restructured retrogradely to giverise to different combinations, with disruptive

consequences. Also, impulse traffic, which isknown to regulate metabolism and gene expres-sion, can be altered by injury. The nociceptivesystem is not fixed and static but a dynamic neu-ronal network that continuously alters itsresponse characteristics depending on the priorexposure to noxious activity.

In recent years, all this material has beenreviewed innumerable times both in journals andtextbooks and it has almost grown into a fad;none of these actually broke new ground in ther-apeutic terms. There has also been an unprece-dented number of reviews on drug therapy forNP (Table 2).

Symptom, mechanism & drug dissection-based approachesNP/CP are sometimes difficult to diagnose, evenby experts, since no lesion or other physical findingcan be demonstrated or surpass the limits of cur-rent diagnostic technology: no single symptom orsign is diagnostic. Moreover, symptoms and mech-anisms may be similar in different types of disease,one single mechanism may give rise to differenttypes of pains and more than one mechanism maybe operating in a particular patient.

Table 1. Drugs employed in the treatment of neuropathic pain.

Class Examples

AEDs CBZ, gabapentin, phenitoyn, lamotrigine, pregabalin, tiagabin, topiramate, valproate and vigabatrin

ADs Nortriptyline, lithium, trazodone, amitriptyline, fluvoxamine, chlorimipramine, citalopram, imipramine, paroxetine, clomipramine, desipramine, fluoxetine, mianserin, maprotiline, clomipramine, buspirone, moclobemide, doxepin, topical doxepin, sustained-release bupropion, venlafaxine and zimelidine

GABA-ergic Barbiturates (thiopental, thiopentone, sodium amytal, pentobarbital, thiamylal), propofol, benzodiazepines (chlordiazepoxide, lorazepam, clonazepam, midazolam) and baclofen

Opioids Fentanyl, codeine, morphine, diamorphine, buprenorphine, alfentanil, metadone, oxycodone, transdermal fentanyl, hydrocodone, (tramadol)

Opioid antagonists Naloxone

Neuroleptics (generally with ADs)

Fluphenazine, chlorprothixene, perphenazine, tiapride, chlorpromazine, pimozide, droperidol, haloperidol and levomepromazine

NMDA antagonists Ketamine, dextromethorphan, amantadine, memantine, Mg2+, (methadone, dextropropoxyphene and ketobemidone)

Na+ channel blockers Lidocaine, mexiletine, flecainide, topical lidocaine and EMLA

Ca+ channel blockers Ziconotide and nicardipine

Neurotrophines rhNGF and rhBDNF

Others K+ channel blockers, capsaicin, clonidine, calcitonin, riluzole, cannabinoids, acyclovir, topical aspirin, topical benzydamine, iontophoretic indomethacin, cizorlitine, aldose reductase inhibitors, ketanserin, levodopa, tizanidine, octreotide; topical prostaglandin E1, CCK2 antagonists, glycin antagonist

AD: Antidepressant drug; AED: Antiepileptic drug; CBZ: Carbamazepine; CCK2: Cholecystokinin; EMLA: Eutectic mixture of lidocaine and prilocaine; GABA: γ-aminobutyric acid; NMDA: N-methyl-D-aspartic acid; rhBDNF: Human recombinant brain-derived neurotrophic factor; rhNGF: Recombinant human nerve growth factor.

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Pharmacological treatment of neuropathic pain – REVIEW

Our ability to translate pain complaints andsensory findings into specific pathophysiologi-cal mechanisms that have treatment implica-tions is in its infancy. Even in specializedsettings, it is difficult to identify specific NPmechanisms. Quantitative sensory tests lacksensitivity and specificity in revealing the exactnature of the pathological processes responsiblefor pain. A unifying hypothesis is hard to comeby since NP has several different componentsthat differentially respond to different meas-ures, not to mention an intrinsic differencebetween CP and peripheral NP [5]. In the exem-plificative example of postherpetic neuralgia,several mechanisms may cause the same painfulsymptom, particularly allodynia. Conversely,one mechanism may be responsible for severaldifferent painful symptoms, such as spontane-ous and evoked pain [7–8]. Thus, because they

are not equivalent to mechanisms, symptomsalone are not sufficient tools to define treatmentstrategies. Despite impressive attempted tabula-tions on which drug to use for which mecha-nisms or symptoms (Table 7), results in the clinicremain unimpressive and unpredictable(Tables 2 & 6). Again, in postherpetic neuralgia,the employment of topical agents or Na+ chan-nel blockers has been proposed repeatedly forsymptoms as a result of peripheral sensitizationand proinhibitory drugs (gabapentin and anti-depressants) if sustained by central disinhibi-tion. This kind of targeting is difficult inclinical practice. Thus a mechanism-basedapproach is unreliable in routine management.

A modern concept, for instance, the use ofparenteral drugs with known pharmacody-namic profiles to dissect mechanisms, a veryappealing concept, proves itself difficult to

Table 3. Number needed to treat comparison: antidepressants.

ADs TCAs SSRIs SNRIs Bupropion Ref.

Peripheral neuropathic pain

2 (1.7–2.5) [59]

Same group*

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]

2.3 (2.1–2.7) 5.5 (3.4–13.5) 1.6 (1.3–2.1) [53]

2.6 (2.2–3.3) 6.7 (3.4–435) [70]

Same authors*

1.6 (or 3.2) [61]

1.6 [61]

6.2 [61]

Diabetic neuropathy

1.29 (1.16–1.46) [59]

Same group*

4.1 (2.9–7.2) [52]

6.8 (3.4–441) [53]

Same group*

3.4 (2.6–4.7) [66]

3.4 (2.6–4.7) 3.5 (2.5–5.6) Same as placebo

[69]

Postherpetic neuralgia

2.20 (1.7–3.13) [59]

Same group*

2.1 (1.7–3.0) [66]

2.1 (1.7–3.0) 3.5 (2.5–5.6) [69]

Central pain

Same group*

4.0 (2.6–8.5) [52]

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: Tricyclic antidepressant.


654 Therapy (2006) 3(5)

realize. Presently, all current efforts to pairsymptom, mechanism, optimal drug target andexisting drug appear scarcely useful to guidetherapeutic efforts since the mechanisms ofaction of most drugs are not understood, if nottotally unknown. Distinct exceptions are pro-pofol used at subhypnotic doses to dissectGABAergic mechanisms of CP and baclofen.These provide compelling evidence forderanged GABAergic transmission in CP [5,9].However, lidocaine and fentanyl have central

and peripheral actions, making them less use-ful, while ketamine and thyamylal affect toomany transmitters. However, while antidepres-sants work not only on monoamines but alsoblock adrenergic receptors on regeneratingsprouts, modify endorphins, antagonizeN-methyl-D-aspartic acid (NMDA) receptorsand Na+ channels, the use of more selectivedrugs, such as reboxetine, has robbed norepine-phrine of its starring role in the control ofNP/CP [11], as usually presumed.

Table 4. Number needed to treat comparison: antiepileptic drugs.

Carbamazepine Phenytoin Valproate Lamotrigine Gabapentin/pregabalin

Topiramate Ref.


Same group*

4.3 (3.5–5.7) [55]

2.5 (1.8–3.8) [55]

AEDs: 2.7 (2.2–3.8). Phenytoin/CBZ 2.2 (1.7–3.1)

3.4 (2.1–5.4) [69]

Same group*

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]

4.0 (2.1–4.2) [53]

3.3 (2.0–9.4) 2.1 (1.5–3.6) 4.1 (2.7–8.2) [70]

Gabapentin: 2.2 (or 2.8 or 5.3) Pregabalin: 3.3

[61]

Diabetic neuropathy

Same group*

2.9 (2.2–4.3) [55]

CBZ better than placebo [56]

2.3 (1.5–3.8) [57]

AEDs: 2.7 (2.2–3.8) [66]

Same group*

4.3 (2.8–8.6) [53]

3.3 2.1 3.7 [65]

Postheric neuralgia

Same group*

3.9 (3–5.7) [55]

AEDs: 3.2 (2.4–5.0) [66]

AEDs: 3.2 (2.4–5.0) [69]

Same group*

4.8 (2.6–26.9) 4.3 (3.3–6.1) [53]

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, similar to amitriptyline

[56]

Trigeminal neuralgia

1.9 (1.4–2.8) [56]

*Studies were performed by the same group.AED: Antiepileptic drug; CBZ: Carbamazepine.



Pitfalls of animal modelsSince human volunteer models of NP/CP haveyet to be developed (capsaicin injection does notmake the grade), animal models have takencenter stage. These have serious shortcomings:

• It is difficult to know what is actually per-ceived, for example, autotomy may signaldenervation rather than pain;

• Alterations in cutaneous sensory thresholds inresponse to nerve injury rather than an inte-grated pain-related behavior are generallymeasured;

• Animal models are such that animals developNP consistently, while most patients withnerve injury do not go on to develop it;

• Purported signs of pain generally subsidewithin weeks or months, while this is not thecase for human patients;

• Animal models study the pain for weeks ratherthan years, as in the human model;

• Most animal models deal with rats; • There are so many anatomochemical differ-

ences between humans and animals – includ-ing primates – that these models are nearlyirrelevant.

Considerable caution must be exercised inextrapolating hypotheses to clinical pain. Despitemany impressive experimental observations, theultimate proof of concept is in the clinic [11–13].The over-riding importance of the cognitive-affective dimension of pain in man and behavio-ral factors in modifying clinical pain must beconsidered in the treatment strategy: expectationalone is sufficient to increase firing rate in nox-ious-responding neurons. Clinical pain is morecomplex than experimental pain and patients areheterogeneous in terms of their pain.

Sticking to this caveats would have spared thedrug industry huge losses, epitomized by the para-doxical failure of substance P antagonists in view ofthe well-established role of substance P in modulat-ing pain. Also, NMDA antagonists (e.g., oral keta-mine, dextrometorphan and amantadine) haverelieved few patients in the long run, despiteimpressive animal data, and it does not appear todepend entirely on their poor side-effect profile.

Thus, we are left with this humbling notion:much progress is a result of the application to NPof drugs effective in other fields, such as epilepsy(starting from trigeminal neuralgia and extend-ing its use to pain with paroxysmal components)and psychiatry, starting in the 1960s. Drugsstemming from goal-directed efforts are very fewand – up to now – of scarce effectiveness in thevast majority of patients (lidocaine patch andziconotide), despite claims to the contrary [14].

Exploiting descending controlIn the dorsal horn, the locus of entry of sensoryinformation from the periphery, specific centrifu-gal pathways either suppress (descending inhibi-tion) or potentiate (descending facilitation)passage of nociceptive messages to the brain [15].No drug interfering with descending facilitationis currently available for clinical use. Inasmuch asvirtually all transmitters and receptor typesinvolved in descending control display multiplesites and/or mechanisms of action, it is difficult toanticipate the global influence of ligands uponnociception following systemic administration,making direct vectorization of drugs to their sitesof action in the spinal cord, for example, by theintrathecal route, critical. At the same time, mostdrugs are administered parenterally and orally andthe final balance of action should be understood

Table 5. Number needed to treat comparison: opioids.

Morphine (methadone) Oxycodone (Oxycodone CR)

Tramadol Ref.


Not calculated (Table 2) [29]

3.5 (2.4–5.9) [60]

Same group*2.5 (1.9–3.4) 2.6 (1.9–4.1) 3.9 (2.7–6.7) [52]

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.


656 Therapy (2006) 3(5)

for therapeutic purposes. A single transmitter,and even a single receptor class, can exert a diver-gent influence of nociception at both spinal andsupraspinal loci as a function of localization andinfluence upon neuronal excitability. Thus, formany transmitters and receptor classes, a bidirec-tional influence upon nociceptive processing atcerebral and/or segmental loci has been estab-lished. This underlines the difficulty of predict-ing the influence on nociception of even highlyselective ligands, and strongly supports the argu-ment that the assignment of a particular role toindividual classes of descending pathways, oftransmitter and even of receptor, may be mis-leading, if not frankly erroneous [15]. This is par-ticularly true for most neurons that contain andrelease several transmitters modulating nocicep-tive processing. In addition to receptor multi-plicity per se, there is increasing evidence forfunctional interplay among colocalized recep-tors. This is manifested both at the level of sec-ond-messenger systems (e.g., activation of onereceptor may trigger the phosphorylation of adifferent class of colocalized receptor) and interms of their physical association. For example,protein–protein interactions and functional het-erodimers have been demonstrated between vari-ous subtypes of opioid receptors and evenbetween entirely unrelated receptor classes (e.g.,GABA-A and dopamine-5 receptors). Confirma-tion of certain receptors displaying spontaneousactivity would pave the way for the design ofantagonists or reverse agonists at receptors medi-ating descending facilitation. Descending path-ways do not dampen nociceptive transmissionexclusively but also simultaneously enhance itspassage. Excessive activity of descending facilita-tion may contribute to chronic painful states;however, its interruption alone may actuallyinterfere with processes recruiting descendinginhibition [15]. Simultaneous interference withdescending facilitation and reinforcement ofdescending inhibition may prove more rational.Rather than an obsessive and illusory search forhighly selective agents at a single receptor type,multireceptorial (multitarget) agents (e.g., atypi-cal antipychotics for schizophrenia) may permitthe balanced and more efficacious manipulationof mechanisms of descending inhibition andfacilitation. However, mimicking multiplemechanisms of descending inhibition is no easytask. For instance, coactivation of specific sero-tonergic, noradrenergic and other mechanisms inthe dorsal horn may be critical for the mediationof supraspinal opioidergic antinociception.

There is an intricate and reciprocal functionalinter-relationship between the operation ofdescending noradrenergic and serotonergic path-ways, expressed at both segmental and supraspi-nal loci, knowledge of which remainsfragmentary. Most importantly, the same trans-mitter may have both pro- and anti-nociceptiveactions at different sites. This is true for GABA,opioids, glutamatergic agents and others. Clini-cal data support the concept: GABA agonism forCP also increases pain (thiamylal, propofol orbaclofen) [16].

Coadministration of drugs may minimize dosesand side effects: the classic combination is opioidsand clonidine. With the exception of parenteraladministration of µ-opioids (for which a compo-nent of analgesia may be attributed to supraspinalactivation of descending inhibition) and spinalapplication of clonidine (which reproducesnoradrenergic mechanisms of descending inhibi-tion in the dorsal horn), no other approach hasbeen validated extensively in the clinic, howeverpro-opioid cholecystokinin-1 antagonists andadenosine-1 agonists are now under evaluation inclinical trials, although one trial was negative.

Other approachesNonpharmacological approaches are understudy. An open question is whether interven-tions, such as cell implantations [17], neurotoxinsand antisense or gene therapy [18], exert effectsthat are rapid, temporary, controllable andreversible, or whether they initiate, in an unpre-dictable fashion, delayed and possibly irreversiblechanges not necessarily conducive to pain relief(an example are the dyskinesias induced by fetalcell grafts in Parkinson’s disease requiring neuro-modulatory surgery for control). Despite theirinterest, they will likely find applications only inrestricted populations of otherwise refractorypatients. Indeed, it is difficult to imagine thatsuch techniques would supersede more conven-tional strategies of systemic and spinal adminis-tration of drugs interacting rapidly and reversiblywith specific targets. Moreover, they are all moreexpensive than traditional methods.

Although the first animal studies attempted thetransfer of opioid precursor genes and their over-expression mainly at the spinal level, also demon-strating the feasibility and therapeutic effects inmodels of NP, and targeting some proinflamma-tory cytokines involved in the induction and per-petuation of pain raises the possibility of blockingthe development of pain [18], the aforementionedconditions must be borne in mind.



Expert commentary and outlook Several drugs are undergoing Phase I/II/III stud-ies, registration and preregistration: ion channelantagonists, glutamate receptor antagonists(NMDA, glycine and NR2B sites), cannabinoidreceptor agonists/antagonists, growth factor ago-nists, α-adrenoceptor agonists, drugs ofundefined mechanism, GABA agonists, nicotinicagonists, cholecystokinin (CCK) antagonists,adenosine A1 antagonists and IP751 [19,201].Despite these efforts, no revolutionary therapyappears to be in the pipeline.

While the near future will probably see a largeruse of the intrathecal approach with currentlyavailable drugs for all refractory patients [16], it willbe important to develop pre-empting strategies.For instance, carbamazepine may prevent theonset of NP after oxaliplatin exposure [20], whileamitriptyline may have a possible, mild effect inpreventing poststroke CP [21]. Lamotrigine, withits anti-Na+/antiglutamate spectrum, shouldreceive more attention in this regard [22] and genechips may aid in identifying pain-prone patientsin the future.

Pharmacological infusion tests to predict effi-cacy and side effects must be pursued further.Currently, the role of lidocaine in predictingresponse to oral mexiletine is controversial [7],acute administration of opioids has a good neg-ative predictive value but poor positive predic-tive value [19] and phentolamine’s role has beenproved poorly founded [23]. Subhypnotic pro-pofol appears promising in predicting responseto neuromodulation for CP [24].

A major problem is therapy in the elderly, a siz-able portion of those suffering from NP/CP.Drugs with much better pharmacological profilesmust be developed in order to considerably cutside effects [25].

We, and others, strongly believe there is nobasis to such concept as sympathetic pain. Whilethere is ample animal evidence to support itsexistence, the concept collapses on statistical andclinical grounds [26,27]. Pursuing this conceptwill, in our view, end up in further disappointingresults for the vast majority of patients.

While very few CP patients are responsive [28],peripheral NP is now generally accepted to respondto stable doses of opioids, although at higher dosesthan nociceptive pain, with a minimal risk ofaddiction [29]. Since most controlled studies havelasted for less than 8 months, long-term benefit(several years) remains unassessed [29]. Besides toler-ance, long-term use of opioids may also be associ-ated with the development of abnormal sensitivity

to pain, similar to NP itself. Most importantly, opi-oids influence the hypothalamic–pituitary–adre-nal/gonadal axis and immune system, andprolonged opioid use may result in reduced fertil-ity, libido and drive and possibly immunosuppres-sion – particularly at high doses. In summary,prolonged, high-dose opioid therapy may be nei-ther safe nor effective and too high doses should bediscouraged [30]. In a recent controlled study, meth-adone at 20 mg significantly improved several typesof NP, but a third of patients withdrew from thestudy due to side effects [31]. Finally, opioids arepoorly effective for CP [32].

The recent discovery of endocannabinoids aspain modulators has opened a new avenue ofresearch (Tables 2 & 7) [33–34]. Since cannabinoids’loci of action superpose with opioid andmonoaminergic centers, we cannot expect a majorrole in NP therapy [35]. In a recent trial, cannabisextracts moderately (ca. 33%) relieved brachialplexus avulsion (BPA) pain, although maximaldoses in this brief trial had not been reached andall patients continued previous therapy [36].

Studies of neurotrophic factors have not yetdemonstrated significant efficacy (Table 7) [37];their role remains to be assessed.

Microglia may have a role in inducing/sus-taining NP and their targeting possibly repre-sents a novel avenue, although no human studyexists yet.

NMDA receptor antagonists with better effi-cacy and fewer side effects may be found. Mg2+,with its cost–effectiveness, represents an interest-ing approach [38]. However, it should be remem-bered how some NMDA antagonists have shownlittle efficacy in both postherpetic and facial neu-ralgias [39]. Despite optimism, AMPA andmetabotropic blockers may well be provenscarcely effective (Table 7).

Sensory neurons have multiple voltage-dependent Na+ currents, with differential compo-sition in A and C fibers and this may undergo sig-nificant changes upon nerve injury. The Nav1.8isoform is expressed mainly in C-type dorsal rootganglion (DRG) cells and Nav1.8 immunoreac-tivity is evident in peripheral nerve tissues frompatients with chronic NP [40,41]. However, themeasured ectopic activity in injured fibers neednot be an essential characteristic of evoked NPpain and the abnormal activity in uninjured pri-mary afferents may actually be crucial for thehypersensitivity to sensory input. The TTX-resistant Nav1.8 channel-supported Na+ currentis currently believed to play a crucial role in theestablishment of the hyperexcitability state of


658 Therapy (2006) 3(5)

Table 7. Suggested (targeted) pharmacological approaches for neuropathic pain .

Receptor(s) Drug(s) Ref.

Phenytoin, benzodiazepines, valproate, CBZ/OXCBZ, lamotrigine, gabapentin and topiramate

[6]

Phenytoin, benzodiazepines, valproate, CBZ/OXCBZ, lamotrigine, gabapentin, topiramate, zonisamide, tiagabine and levetiracetam

[65]

CBZ, gabapentin, lamotrigine, phenobarbital, clonazepam, valproic acid, topiramate, pregabalin and tiagabine

[74]

CBZ, gabapentin and lamotrigine [73]

Phenytoin, benzodiazepines, valproate, CBZ/OXBC, lamotrigine, gabapentin, topiramate, zonisamide, tiagabine and levetiracetam

[81]

Topiramate [97]

TCAs and newer ADs [98]

Thalidomide [99]

Botulinum toxin 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 receptors activated by ATP)

Receptor-selective antagonists [103]

NMDA Noncompetitive or uncompetitive antagonists [104]

NMDA Conantokin peptides (for neuroprotection) [105]

NMDA Amantadine, dextromethorphan and ketamine [106]

AMPA NMDA

2,3-benzodiazepinesGlycine(B)- and NR2B-selective antagonists, peripheral NMDA receptor antagonists

[107]

AMPA NMDA

TopiramateAmantadine, ketamine, dextromethorphan and TCAs

[96]

AMPA Receptor antagonists [108]

Neuron-specific voltage-gated Ca2+ channels

Selective blockers [109]

Neurone-specific N-type Ca2+ channels Varpi-conotoxin: ziconotide [110]

N-type calcium channels Ziconotide; orally active, selective, small molecule modulators [111]

α2β subunits of voltage-activated Ca2+ channels

Gabapentin, pregabalin [96]

T-type low-voltage Ca2+ channels Zonisamide

Ca channels CBZ, OXCBZ, lamotrigine, levetiracetam, IT ziconotide

N-type voltage-gated Ca2+ channels (Ca(v)2.2)

Peptide blocker Prialt [112]

Voltage-gated Na+ channels Selective blockers [43]

Na+ channels Lidocaine and mexiletine [113]

Voltage-gated Na+ channels µ-conotoxins [114]

Na+ channels CBZ, lamotrigine, lidocaine, bupivacaine, mexiletine, OXCBZ, phenytoin, topiramate, TCAs and zonisamide

[96]

Voltage-gated Na+ channels Use-dependent sodium channel blockers [115]

Voltage-activated K+ channels (K[V]7.2–7.5 [formerlyKCNQ2–5])

Retigabine [116]

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.



sensory neurons that contributes to the abnormalprocessing of nociceptive and/or tactile informa-tion following traumatic injury. These channelsaccumulate in areas of demyelination, neuromasand DRG [42]. The discrete localization of Nav1.8suggests therapeutic potential without the debili-tating side effects observed with the currentlyavailable Na+ channel blockers [43]. However,studies appear to show that ketamine is strongerthan lidocaine in quenching NP and this shouldbe kept in mind when addressing trial options [44].

Ca2+ channels are also under study for theirability to inhibit neurotransmitter release in thedorsal horn, but, to date, intrathecal ziconotide, aconotoxin, has demonstrated limited efficacy witha narrow therapeutic window. Moreover, upregu-lation of subtypes of Ca channels is not observedin all NP types.

Several other targets are under study: VR1blockers, ATP blockers and proton channelblockers [45].

New drugs that activate α-2A or block α-2B/Creceptors may supercede clonidine. However,clonidine is not a major drug. Clonidine patchesare of limited use as they eliminate hyperalgesiaat the relatively small patch site, with limitedbenefits. Contrary to previous trials [46], intrathe-cal clonidine was found to be of limited use, withrelief lasting less than 18 months [47]. Clonidine ispotentiated by neostigmine, an anticholinesterase

agent [48]. However, current cholinergic drugs havedisruptive side effects (notably cardiovascular andmotor) and nicotinic agents also have an addictivepotential. Moreover, they may havepronociceptive and antinociceptive effects [15].

In a recent controlled trial, intravenous adenos-ine proved ineffective for NP; intrathecally, it hada modest effect in the face of common side effects.The role of adenosine and congeners – despitecomforting animal data – does not look good [49].

Current efforts at targeting the mechanismsresponsible for the induction and maintenance ofcentral sensitization is made difficult by the needto avoid interrupting memory formation and cor-tical function – there is a need to be specific. Toachieve this, teasing the differences as well as simi-larities between central sensitization and corticallong-term potentiation will be necessary [50]. Atthis time, ketamine targets both and thus makes itlittle indicated in the clinic.

So-called antiplasticity approaches have, in ouropinion, no future. Plasticity is a basic ubiquitousneural mechanism that takes place – but can alsobe reversed – within minutes and there are cases ofcomplete, immediate abolition of CP afterremoval of the inciting lesion [51], which militateagainst an exclusive role in pain maintenance.

In summary, it is likely that the near future willsee no major progress. We believe that only basicstudies in human patients will forward the field.

CB2 receptors Selective agonists [118]

CB1–CB2 receptorsCB2 receptors

Selective agonists, inhibitors of endocannabinoid uptake or metabolismSelective antagonist/inverse agonist

[119]

CB2-like receptors, vanilloid receptors Anandamide [120]

VR1 receptors VR1 + CB1 receptors

ResiniferatoxinArvanil

[121]

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 + Ca2+ channels)

ORL1 agonists (nociceptin/orphanin FQ) [125]

SP-neurokinin1 receptors Receptor-tagged saporin [96]

Glutamate Many medications, including opioids

Proinflammatory cytokines (IL-1β, IL-6 and TNF)

Antagonists/inhibitors

Table 7. Suggested (targeted) pharmacological approaches for neuropathic pain (Cont.).

Receptor(s) Drug(s) Ref.

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.


660 Therapy (2006) 3(5)

Tab

le 2

. Met

a-an

alys

is a

nd

sys

tem

atic

rev

iew

s.

Pain

typ

eD

rug

(s)/

acti

ve a

gen

tsR

esu

lts

and

au

tho

r co

ncl

usi

on

sR

ef.

NP

105

rand

omiz

ed, d

oubl

e-bl

ind,

pla

cebo

-con

trol

led

stud

ies

Com

bine

d N

NT

(95%

CI)

to o

btai

n on

e pa

tient

with

mor

e th

an 5

0% p

ain

relie

f:

CP

(CPS

P, S

CI,

MS)

PN

P (p

ainf

ul

poly

neur

opat

hy)

PHN

(p

ostm

aste

ctom

y an

d po

stsu

rgic

al,

HIV

-neu

ropa

thy)

phan

tom

lim

b,

brac

hial

ple

xus

avul

sion,

tr

igem

inal

ne

ural

gia,

mix

ed

neur

opat

hic

pain

co

nditi

on)

Ant

idep

ress

ants

TCA

s (a

mitr

ipty

line,

clo

mip

ram

ine,

de

sipra

min

e, im

ipra

min

e, m

apro

tilin

e,

nort

ripty

line)

SSRI

s (c

italo

pram

, flu

oxet

ine,

par

oxet

ine)

SNRI

s (v

enla

faxi

ne)

Oth

er (b

upro

pion

, hyp

eric

um (S

t Joh

n’s

Wor

t)A

ntic

onvu

lsant

s (c

arba

maz

epin

e, g

abap

entin

, la

mot

rigin

e, p

rega

balin

, top

iram

ate,

val

proa

te)

Opi

oids

(met

hado

ne, m

orph

ine,

oxy

codo

ne,

tram

adol

)

NM

DA

ant

agon

ists

(dex

trom

etho

rpha

n,

mem

antin

e, ri

luzo

le)

Na+

cha

nnel

blo

cker

s (li

doca

ine

[topi

cal],

m

exile

tine)

Can

nabi

noid

s (C

T3, d

rona

bino

l, TH

C)

SP d

eple

ters

(cap

saic

in)

Gly

cin

anta

goni

st c

ombi

natio

ns(g

abap

entin

+ m

orph

ine,

gab

apen

tin +

ve

nlaf

axin

e)

3.3

(2.9

–3.8

)

3.1

(2.7

–3.7

) (C

P: 4

.0 [2

.6–8

.5])

6.8

(3.4

–441

)5.

5 (3

.4–1

4)Bu

prop

ion:

1.6

(1.3

–2.1

)C

BZ: 2

.0 (1

.6–2

.5) (

CP:

3.4

[1.7

–105

])G

abap

entin

/pre

gaba

lin: 4

.7 (4

.0–5

.6)

Lam

otrig

ine:

4.9

(3.5

–8.1

)Ph

enyt

oin:

2.1

(1.5

–3.6

)To

pira

mat

e: 7

.4 (4

.3–2

8)Va

lpro

ate:

2.8

(2.1

–4.2

)O

pioi

ds:

Mor

phin

e: 2

.5 (1

.9–3

.4)

Oxy

codo

ne: 2

.6 (1

.9–4

.1)

Tram

adol

: 3.9

(2.7

–6.7

)D

extr

omet

horp

han:

2.5

(1.6

–5.4

) (D

N, l

ack

of e

ffic

acy

in N

PH)

Mem

antin

e: in

effe

ctiv

eM

exile

tine:

7.8

(4.0

–129

)C

anna

bino

ids:

3.4

(1.8

–23)

(MS)

Cap

saic

in: 6

.7 (4

.6–1

2)

Trea

tmen

t alg

orith

m fo

r NP:

base

d on

low

est N

NT

and

pain

relie

f onl

y: T

CA

> o

pioi

ds ≥

tram

adol

≥ g

abap

entin

/pre

gaba

linFo

r CP

ther

e is

limite

d da

ta

base

d on

pai

n re

lief a

nd q

ualit

y of

life

: gab

apen

tin/p

rega

balin

> tr

amad

ol >

opi

oids

> T

CA

s

[52]

AD

: An

tid

epre

ssan

t d

rug

; AED

: An

tiep

ilep

tic

dru

g; C

BZ:

Car

bam

azep

ine;

CI:

Co

nfi

den

ce in

terv

al; C

P: C

hro

nic

pai

n; C

PSP:

Cen

tral

po

stst

roke

pai

n; C

R: C

on

tro

lled

rel

ease

; DN

: Dia

bet

ic n

euro

pat

hy;

i.t

.:In

trat

hec

al; i

.v.:

Intr

aven

ou

s; L

A: L

oca

l an

esth

etic

(s);

MA

OI:

Mo

no

amin

e o

xid

ase

inh

ibit

or;

MS:

Mu

ltip

le s

cler

osi

s; N

aRI:

No

rad

ren

alin

e re

up

take

inh

ibit

or;

NaS

S: N

ora

dre

ner

gic

an

d s

pec

ific

ser

oto

nin

erg

ic

anti

dep

ress

ant;

ND

RI:

No

rep

inep

hri

ne

do

pam

ine

reu

pta

ke in

hib

ito

r; N

NH

: Nu

mb

er n

eed

ed t

o h

arm

; NM

DA

: N-m

eth

yl-d

-asp

arti

c ac

id; N

NT:

Nu

mb

er n

eed

ed t

o t

reat

; NP:

Neu

rop

ath

ic p

ain

; N

SAID

:No

nst

ero

idal

an

ti-i

nfl

amm

ato

ry d

rug

; OX

CB

Z: O

xcar

bam

azep

ine;

PH

N: P

ost

-her

pet

ic n

eura

lgia

; PN

P: P

erip

her

al n

euro

pat

hic

pai

n; R

CT:

Ran

do

miz

ed c

on

tro

lled

tri

al; R

IMA

: Rev

ersi

ble

inh

ibit

ors

of

mo

no

amin

e o

xid

ase

typ

e A

; RSD

: Ref

lex

sym

pat

eth

ic d

ystr

op

hy;

SC

I: Sp

inal

co

rd in

jury

; SN

aRI:

Sero

ton

in a

nd

no

rad

ren

erg

ic r

eup

take

inh

ibit

or;

SN

RI:

Sero

ton

in a

nd

no

rep

inep

hri

ne

reu

pta

ke in

hib

ito

r;

SP:S

ub

stan

ce P

; SSR

I: Se

lect

ive

sero

ton

in r

eup

take

inh

ibit

or;

TC

A: T

ricy

clic

an

tid

epre

ssan

t; T

ENS:

Tra

nsc

uta

neo

us

elec

tric

al n

erve

sti

mu

lati

on

; TH

C: T

etra

hyd

roca

nn

abin

ol;

TN: T

rig

emin

al n

eura

lgia

; V

AS:

Vis

ual

an

alo

g s

cale

.



PNP,

CP

Ant

idep

ress

ants

dru

gs(T

CA

s, S

NRI

s, S

SRIs

, oth

ers)

Re

view

on

the

effe

ct o

f AD

s. N

NT

for p

ain

relie

f >50

%TC

As:

PNP

(exc

ludi

ng H

IV n

euro

path

y): 2

.3 (9

5% C

I: 2.

1–2.

7; n

o m

ajor

diff

eren

ce a

cros

s th

e di

ffer

ent d

iseas

e en

titie

s)C

P (C

PSP

+ S

CI):

4.0

(95%

CI:

2.6–

8.5)

am

itrip

tylin

e in

CPS

P (1

5 pa

tient

s): 1

.7 (9

5% C

I: 1.

2–3.

1; b

ut in

effe

ctiv

e in

SC

I) SS

RIs:

DN

: 6.8

(95%

CI:

3.4–

441)

SN

RI (v

enla

faxi

ne):

PNP:

5.5

(95%

CI:

3.4–

13.5

)Bu

prop

ion:

PNP

(41

patie

nts)

: 1.6

(95%

CI:

1.3–

2.1)

Base

d on

NN

T, T

CA

s te

nd to

wor

k be

tter

than

the

AED

gab

apen

tin (N

NT

in D

N 4

.3 [9

5% C

I: 2.

8–8.

6] in

PH

N 4

.3

[95%

CI:

3.3–

6.1]

) and

lam

otrig

ine

(NTT

in P

NP

4.0

[95%

CI:

2.1–

4.2]

) or o

xyco

done

(NN

T in

PN

P 2.

6 [9

5%C

I:1.

7–6.

0], i

n PH

N 2

.5 [1

.7–5

.1])

or tr

amad

ol (N

TT in

PN

P 3.

5 [9

5% C

I: 2.

4–6.

4], i

n PH

N 4

.8 [9

5% C

I: 2.

6–26

.9])

whe

reas

ven

lafa

xine

app

ears

to b

e eq

ually

eff

ectiv

e an

d SS

RIs

appa

rent

ly h

ave

low

er e

ffic

acy

Trea

tmen

t opt

ions

oth

er th

an T

CA

s m

ay b

e be

tter

tole

rate

d bu

t, as

AD

s, th

ey w

ill c

ause

sid

e ef

fect

s in

mos

t pa

tient

s (o

vera

ll N

NH

in N

P pa

tient

s fo

r gab

apen

tin 2

6.8,

for o

xyco

done

23.

0, fo

r tra

mad

ol 9

.0).

In c

oncl

usio

n, A

Ds

mus

t stil

l be

cons

ider

ed a

s fir

st-li

ne tr

eatm

ent o

f NP.

With

out h

ead-

to-h

ead

com

paris

ons

betw

een

antid

epre

ssan

ts a

nd o

ther

ana

lges

ics,

it is

not

pos

sible

to p

rovi

de re

al e

vide

nce-

base

d tr

eatm

ent

algo

rithm

s fo

r NP

[53]

CP,

PN

PLo

cal a

nest

hetic

s(li

doca

ine,

mex

iletin

e)M

eta-

anal

ysis

of 1

9 RC

Ts (7

06 p

atie

nts)

com

parin

g LA

with

pla

cebo

or a

ctiv

e dr

ugs

Lido

cain

e (te

n st

udie

s, m

ost c

omm

only

5m

g/kg

i.v.

ove

r 30–

60 m

in) a

nd m

exile

tine

(nin

e st

udie

s, m

edia

n do

se

600

mg

daily

) wer

e su

perio

r to

plac

ebo

(wei

ghte

d m

ean

diff

eren

ce o

n a

0–10

0m

m p

ain

inte

nsity

VA

S: -1

0.60

; 95

% C

I: -1

4.52

to -6

.68)

and

equ

al to

mor

phin

e, g

abap

entin

, am

itrip

tylin

e an

d am

anta

dine

(wei

ghte

d m

ean

diff

eren

ce: -

0.60

; 95%

CI:

-6.9

6–5.

75).

Mor

e co

nsist

ent b

enef

it fo

r per

iphe

ral P

NP

(pos

t-tr

aum

atic

, DN

) and

CP.

Adv

erse

eve

nts

rate

for s

yste

mic

ally

adm

inist

ered

LA

is m

ore

than

pla

cebo

but

equ

ival

ent t

o m

orph

ine,

am

itrip

tylin

e or

gab

apen

tin. N

o m

ajor

adv

erse

eve

nts

was

repo

rted

.

[54]

Tab

le 2

. Met

a-an

alys

is a

nd

sys

tem

atic

rev

iew

s (C

on

t.).

Pain

typ

eD

rug

(s)/

acti

ve a

gen

tsR

esu

lts

and

au

tho

r co

ncl

usi

on

sR

ef.

AD

: An

tid

epre

ssan

t d

rug

; AED

: An

tiep

ilep

tic

dru

g; C

BZ:

Car

bam

azep

ine;

CI:

Co

nfi

den

ce in

terv

al; C

P: C

hro

nic

pai

n; C

PSP:

Cen

tral

po

stst

roke

pai

n; C

R: C

on

tro

lled

rel

ease

; DN

: Dia

bet

ic n

euro

pat

hy;

i.t

.:In

trat

hec

al; i

.v.:

Intr

aven

ou

s; L

A: L

oca

l an

esth

etic

(s);

MA

OI:

Mo

no

amin

e o

xid

ase

inh

ibit

or;

MS:

Mu

ltip

le s

cler

osi

s; N

aRI:

No

rad

ren

alin

e re

up

take

inh

ibit

or;

NaS

S: N

ora

dre

ner

gic

an

d s

pec

ific

ser

oto

nin

erg

ic

anti

dep

ress

ant;

ND

RI:

No

rep

inep

hri

ne

do

pam

ine

reu

pta

ke in

hib

ito

r; N

NH

: Nu

mb

er n

eed

ed t

o h

arm

; NM

DA

: N-m

eth

yl-d

-asp

arti

c ac

id; N

NT:

Nu

mb

er n

eed

ed t

o t

reat

; NP:

Neu

rop

ath

ic p

ain

; N

SAID

:No

nst

ero

idal

an

ti-i

nfl

amm

ato

ry d

rug

; OX

CB

Z: O

xcar

bam

azep

ine;

PH

N: P

ost

-her

pet

ic n

eura

lgia

; PN

P: P

erip

her

al n

euro

pat

hic

pai

n; R

CT:

Ran

do

miz

ed c

on

tro

lled

tri

al; R

IMA

: Rev

ersi

ble

inh

ibit

ors

of

mo

no

amin

e o

xid

ase

typ

e A

; RSD

: Ref

lex

sym

pat

eth

ic d

ystr

op

hy;

SC

I: Sp

inal

co

rd in

jury

; SN

aRI:

Sero

ton

in a

nd

no

rad

ren

erg

ic r

eup

take

inh

ibit

or;

SN

RI:

Sero

ton

in a

nd

no

rep

inep

hri

ne

reu

pta

ke in

hib

ito

r;

SP:S

ub

stan

ce P

; SSR

I: Se

lect

ive

sero

ton

in r

eup

take

inh

ibit

or;

TC

A: T

ricy

clic

an

tid

epre

ssan

t; T

ENS:

Tra

nsc

uta

neo

us

elec

tric

al n

erve

sti

mu

lati

on

; TH

C: T

etra

hyd

roca

nn

abin

ol;

TN: T

rig

emin

al n

eura

lgia

; V

AS:

Vis

ual

an

alo

g s

cale

.


662 Therapy (2006) 3(5)

PNP,

CP

Opi

oids

(m

orph

ine,

alfe

ntan

il, f

enta

nyl,

code

ine,

m

etha

done

, oxy

codo

ne, l

evor

phan

ol)

Resu

lts o

f the

met

a-an

alys

is (m

ean

diff

eren

ces

in la

st m

easu

red

post

-tre

atm

ent p

ain

inte

nsity

[on

a VA

S fr

om

0–10

0] b

etw

een

activ

e tr

eatm

ent a

nd p

lace

bo).

Shor

t-te

rm tr

ial e

ffic

acy:

PN

P (fo

ur s

tudi

es, 6

9 pa

tient

s): -

15.2

2 (9

5% C

I: -2

3.19

to -7

.24;

mea

n po

st-t

reat

men

t pa

in fo

r opi

oids

: 30.

8; fo

r pla

cebo

: 44.

9). C

P (tw

o st

udie

s, 2

1 pa

tient

s): -

17.8

1 (9

5% C

I: 30

.48

to -5

.15;

mea

n po

st-t

reat

men

t pai

n fo

r opi

oids

: 38;

for p

lace

bo: 5

5)In

term

edia

te-t

erm

tria

l eff

icac

y: m

ixed

pop

ulat

ion

(6 st

udie

s, 2

63 p

atie

nts)

: –13

.63

(95%

CI:

17.5

7 to

-9.6

8; m

ean

post

-tre

atm

ent p

ain

for o

pioi

ds: 3

9.8,

for p

lace

bo 5

2.9)

.Sh

ort-

term

stu

dies

pro

vide

onl

y eq

uivo

cal e

vide

nce

rega

rdin

g th

e ef

ficac

y of

opi

oids

in re

duci

ng th

e in

tens

ity o

f N

P. In

term

edia

te-t

erm

stu

dies

dem

onst

rate

sig

nific

ant e

ffic

acy

of o

pioi

ds o

ver p

lace

bo fo

r NP.

Eve

n if

met

a-an

alys

es o

f (lim

ited)

dat

a sh

owed

sim

ilar o

pioi

d re

spon

siven

ess

for C

P an

d PN

P, it

did

not

reso

lve

the

deba

te

rega

rdin

g th

e di

ffer

entia

l eff

icac

y of

opi

oids

for C

P vs

PN

P.A

s th

e du

ratio

n of

stu

dies

was

8 w

eeks

at m

ost,

ther

e ar

e no

dat

a on

the

effic

acy

or a

dver

se e

vent

rate

of o

pioi

ds

over

mon

ths

to y

ears

. Fur

ther

RC

Ts a

re n

eede

d to

est

ablis

h th

eir l

ong-

term

eff

icac

y, s

afet

y an

d ef

fect

s on

qua

lity

oflif

e.

[29]

DN

, PH

N, m

ixed

N

P, S

CI,

othe

rsG

abap

entin

Dat

e of

the

mos

t rec

ent s

earc

hes:

Janu

ary

2004

.D

N: s

even

stu

dies

(fou

r pla

cebo

con

trol

led,

thre

e ac

tive

cont

rolle

d). C

ombi

ned

NN

T fo

r eff

ectiv

enes

s co

mpa

red

with

pla

cebo

: 2.9

(95%

CI:

2.2–

4.3)

.PH

N: t

wo

plac

ebo-

cont

rolle

d st

udie

s. C

ombi

ned

NN

T: 3

.9 (9

5% C

I: 3–

5.7)

.M

ixed

neu

ropa

thic

pai

n: o

ne s

tudy

. No

signi

fican

t diff

eren

ce b

etw

een

gaba

pent

inan

d pl

aceb

o at

wee

ks 7

and

8 (w

eeks

1, 3

, 5, 6

wer

e sig

nific

ant).

Spin

al c

ord

inju

ry p

ain:

one

stu

dy, s

even

pat

ient

s, n

o ev

alua

ble

data

.O

ther

pai

n sy

ndro

mes

: can

cer-r

elat

ed n

euro

path

ic p

ain:

one

10-

day

stud

y; p

hant

om li

mb

pain

: one

stu

dy: o

nly

a sig

nific

ant d

iffer

ence

in p

ain

inte

nsity

in w

eek

6 of

trea

tmen

t; G

uilla

in–B

arrè

syn

drom

e: o

ne s

tudy

, 18

patie

nts,

lim

ited

evid

ence

of g

abap

entin

eff

ectiv

enes

s.N

NT

for a

ll (s

even

) tria

ls: 4

.3 (9

5%C

I: 3.

5–5.

7). 4

2% o

f par

ticip

ants

impr

oved

on

gaba

pent

in c

ompa

red

with

19

% o

n pl

aceb

o.Th

ere

is ev

iden

ce to

sho

w th

at g

abap

entin

is e

ffec

tive

in n

euro

path

ic p

ain.

CBZ

and

TC

A p

rovi

de e

ffec

tive

and

mor

e af

ford

able

alte

rnat

ives

whe

re e

cono

mic

reso

urce

s ar

e sc

arce

.

[55]

Tab

le 2

. Met

a-an

alys

is a

nd

sys

tem

atic

rev

iew

s (C

on

t.).

Pain

typ

eD

rug

(s)/

acti

ve a

gen

tsR

esu

lts

and

au

tho

r co

ncl

usi

on

sR

ef.

AD

: An

tid

epre

ssan

t d

rug

; AED

: An

tiep

ilep

tic

dru

g; C

BZ:

Car

bam

azep

ine;

CI:

Co

nfi

den

ce in

terv

al; C

P: C

hro

nic

pai

n; C

PSP:

Cen

tral

po

stst

roke

pai

n; C

R: C

on

tro

lled

rel

ease

; DN

: Dia

bet

ic n

euro

pat

hy;

i.t

.:In

trat

hec

al; i

.v.:

Intr

aven

ou

s; L

A: L

oca

l an

esth

etic

(s);

MA

OI:

Mo

no

amin

e o

xid

ase

inh

ibit

or;

MS:

Mu

ltip

le s

cler

osi

s; N

aRI:

No

rad

ren

alin

e re

up

take

inh

ibit

or;

NaS

S: N

ora

dre

ner

gic

an

d s

pec

ific

ser

oto

nin

erg

ic

anti

dep

ress

ant;

ND

RI:

No

rep

inep

hri

ne

do

pam

ine

reu

pta

ke in

hib

ito

r; N

NH

: Nu

mb

er n

eed

ed t

o h

arm

; NM

DA

: N-m

eth

yl-d

-asp

arti

c ac

id; N

NT:

Nu

mb

er n

eed

ed t

o t

reat

; NP:

Neu

rop

ath

ic p

ain

; N

SAID

:No

nst

ero

idal

an

ti-i

nfl

amm

ato

ry d

rug

; OX

CB

Z: O

xcar

bam

azep

ine;

PH

N: P

ost

-her

pet

ic n

eura

lgia

; PN

P: P

erip

her

al n

euro

pat

hic

pai

n; R

CT:

Ran

do

miz

ed c

on

tro

lled

tri

al; R

IMA

: Rev

ersi

ble

inh

ibit

ors

of

mo

no

amin

e o

xid

ase

typ

e A

; RSD

: Ref

lex

sym

pat

eth

ic d

ystr

op

hy;

SC

I: Sp

inal

co

rd in

jury

; SN

aRI:

Sero

ton

in a

nd

no

rad

ren

erg

ic r

eup

take

inh

ibit

or;

SN

RI:

Sero

ton

in a

nd

no

rep

inep

hri

ne

reu

pta

ke in

hib

ito

r;

SP:S

ub

stan

ce P

; SSR

I: Se

lect

ive

sero

ton

in r

eup

take

inh

ibit

or;

TC

A: T

ricy

clic

an

tid

epre

ssan

t; T

ENS:

Tra

nsc

uta

neo

us

elec

tric

al n

erve

sti

mu

lati

on

; TH

C: T

etra

hyd

roca

nn

abin

ol;

TN: T

rig

emin

al n

eura

lgia

; V

AS:

Vis

ual

an

alo

g s

cale

.



TN, D

N, P

HN

, C

PSP

Car

bam

azep

ine

CBZ

vs

plac

ebo:

NN

T in

TN

: 1.9

(95%

CI:

1.4–

2.8;

two

stud

ies,

47

patie

nts)

. DN

: one

stu

dy, C

BZ b

ette

r tha

n pl

aceb

o. C

PSP:

One

st

udy,

CBZ

bet

ter t

han

plac

ebo,

not

diff

eren

t to

amitr

ipty

line.

CBZ

vs

activ

e co

ntro

l: TN

: thr

ee s

tudi

es, p

imoz

ide

bett

er th

an C

BZ, C

BZ b

ette

r tha

n tiz

anid

ine,

no

deff

eren

ce b

etw

een

CBZ

and

to

cain

ide.

DN

: one

stu

dy, C

BZ =

nor

trip

tylin

e +

fluf

enaz

ine.

PH

N: o

ne s

tudy

, CBZ

+ c

lom

ipra

min

e be

tter

th

anTE

NS.

NN

T fo

r mod

erat

e re

lief i

n an

y N

P: 2

.5 (9

5% C

I: 1.

8–3.

8).

Ther

e is

evid

ence

to s

how

that

CBZ

is e

ffec

tive

but t

rials

are

smal

l.

[56]

DN

A

EDs

(Phe

nyto

in)

Dat

e of

the

mos

t rec

ent s

earc

hes:

Sep

tem

ber 1

999.

Plac

ebo-

cont

rolle

d tr

ial (

one

stud

y):

Phen

ytoi

n. D

N, N

NT:

2.3

(95%

CI:

1.5–

3.8)

.

[57]

DN

Am

itrip

tylin

eFl

uoxe

tine

Des

ipra

min

eC

lom

ipra

min

eC

italo

pram

Pa

roxe

tine

Imip

ram

ine

Nor

trip

tylin

e +

flu

phen

azin

eTr

amad

ol

Oxy

codo

ne C

RC

arba

maz

epin

eLa

mot

rigin

e So

dium

val

proa

teG

abap

entin

Dex

trom

etho

rpha

nM

exile

tine

Ace

tyl-L

-car

nitin

e

Sear

ch re

stric

ted

to fu

lly p

ublis

hed

RCTs

from

199

0 to

Nov

. 200

3 on

ora

l tre

atm

ents

for p

ainf

ul D

N (l

imits

: Eng

lish

lang

uage

, adu

lt hu

man

s).

Resu

lts: 1

9 pl

aceb

o-co

ntro

lled

RCTs

, fiv

e co

mpa

rativ

e RC

Ts. T

reat

men

t dur

atio

n: m

inim

um 6

wee

ks, m

axim

um

1ye

ar.

Stat

istic

ally

sig

nific

ant i

mpr

ovem

ent i

n pa

in in

tens

ity fr

om b

asel

ine

to e

ndpo

int v

s pl

aceb

o fo

r: de

sipra

min

e, tr

amad

ol, o

xyco

done

, lam

otrig

ine

(onl

y w

ith h

igh

dose

s), s

odiu

m v

alpr

oate

, gab

apen

tin, m

exile

tine

(in o

ne o

f thr

ee s

tudi

es),

acet

yl-L

-car

nitin

e.C

ompa

rativ

e RC

Ts (a

mitr

ipty

line

vs d

esip

ram

ine,

am

itrip

tylin

e vs

gab

apen

tin, n

ortr

ipty

line

+flu

phen

azin

e vs

ca

rbam

azep

ine)

: no

stat

istic

ally

sig

nific

ant d

iffer

ence

s in

eff

icac

y be

twee

n th

e in

vest

igat

ed tr

eatm

ents

.A

dver

se e

ffec

ts: d

esip

ram

ine

(one

stu

dy),

tram

adol

, oxy

codo

ne a

nd a

cety

l-L-c

arni

tine

gave

hig

her d

iscon

tinua

tion

rate

s th

an p

lace

bo.

Gab

apen

tin, l

amot

rigin

e an

d so

dium

val

proa

te (a

nd d

esip

ram

ine

[one

stu

dy] g

ave

simila

r disc

ontin

uatio

n ra

tes

to

the

plac

ebo)

. In

com

para

tive

RCTs

, the

disc

ontin

uatio

n ra

tes

wer

e qu

ite s

imila

r exc

ept f

or im

ipra

min

e (h

ighe

r rat

es

than

par

oxet

ine)

.

[58]

Tab

le 2

. Met

a-an

alys

is a

nd

sys

tem

atic

rev

iew

s (C

on

t.).

Pain

typ

eD

rug

(s)/

acti

ve a

gen

tsR

esu

lts

and

au

tho

r co

ncl

usi

on

sR

ef.

AD

: An

tid

epre

ssan

t d

rug

; AED

: An

tiep

ilep

tic

dru

g; C

BZ:

Car

bam

azep

ine;

CI:

Co

nfi

den

ce in

terv

al; C

P: C

hro

nic

pai

n; C

PSP:

Cen

tral

po

stst

roke

pai

n; C

R: C

on

tro

lled

rel

ease

; DN

: Dia

bet

ic n

euro

pat

hy;

i.t

.:In

trat

hec

al; i

.v.:

Intr

aven

ou

s; L

A: L

oca

l an

esth

etic

(s);

MA

OI:

Mo

no

amin

e o

xid

ase

inh

ibit

or;

MS:

Mu

ltip

le s

cler

osi

s; N

aRI:

No

rad

ren

alin

e re

up

take

inh

ibit

or;

NaS

S: N

ora

dre

ner

gic

an

d s

pec

ific

ser

oto

nin

erg

ic

anti

dep

ress

ant;

ND

RI:

No

rep

inep

hri

ne

do

pam

ine

reu

pta

ke in

hib

ito

r; N

NH

: Nu

mb

er n

eed

ed t

o h

arm

; NM

DA

: N-m

eth

yl-d

-asp

arti

c ac

id; N

NT:

Nu

mb

er n

eed

ed t

o t

reat

; NP:

Neu

rop

ath

ic p

ain

; N

SAID

:No

nst

ero

idal

an

ti-i

nfl

amm

ato

ry d

rug

; OX

CB

Z: O

xcar

bam

azep

ine;

PH

N: P

ost

-her

pet

ic n

eura

lgia

; PN

P: P

erip

her

al n

euro

pat

hic

pai

n; R

CT:

Ran

do

miz

ed c

on

tro

lled

tri

al; R

IMA

: Rev

ersi

ble

inh

ibit

ors

of

mo

no

amin

e o

xid

ase

typ

e A

; RSD

: Ref

lex

sym

pat

eth

ic d

ystr

op

hy;

SC

I: Sp

inal

co

rd in

jury

; SN

aRI:

Sero

ton

in a

nd

no

rad

ren

erg

ic r

eup

take

inh

ibit

or;

SN

RI:

Sero

ton

in a

nd

no

rep

inep

hri

ne

reu

pta

ke in

hib

ito

r;

SP:S

ub

stan

ce P

; SSR

I: Se

lect

ive

sero

ton

in r

eup

take

inh

ibit

or;

TC

A: T

ricy

clic

an

tid

epre

ssan

t; T

ENS:

Tra

nsc

uta

neo

us

elec

tric

al n

erve

sti

mu

lati

on

; TH

C: T

etra

hyd

roca

nn

abin

ol;

TN: T

rig

emin

al n

eura

lgia

; V

AS:

Vis

ual

an

alo

g s

cale

.


664 Therapy (2006) 3(5)

DN

, PH

N, C

PA

ntid

epre

ssan

t m

edic

ines

TCA

s (a

mitr

ipty

line,

clo

mip

ram

ine,

de

sipr

amin

e, im

ipra

min

e, m

apro

tilin

e,

nort

ripty

line)

MA

OIs

SS

RIs

(cita

lopr

am, f

luox

etin

e, p

arox

etin

e)SN

RIs

(reb

oxet

ine,

sib

utra

min

e, v

enla

faxi

ne)

RIM

As

New

er a

ntid

epre

ssan

ts

Oth

er (b

upro

pion

, flu

pent

hixo

l, flu

phen

azin

e,

hype

ricum

(St

John

's W

ort)

, reb

oxet

ine,

tia

nept

ine,

tra

zodo

ne, t

rypt

opha

n)

RCTs

from

196

6 to

Dec

embe

r 200

3.50

stu

dies

(55

repo

rts,

251

5 pa

rtic

ipan

ts, 1

725

patie

nts

on a

ntid

epre

ssan

t med

icin

es) i

nclu

ded

in th

e re

view

.D

N: 1

2 pl

aceb

o-co

ntro

lled

stud

ies.

Ove

rall

NN

T fo

r eff

ectiv

enes

s: 1

.29

(95%

CI:

1.16

–1.4

6).

PHN

: fou

r pla

cebo

-con

trol

led

stud

ies.

Ove

rall

NN

T fo

r eff

ectiv

enes

s: 2

.20

(95%

CI:

1.70

–3.1

3).

Aty

pica

l fac

ial p

ain:

thre

e pl

aceb

o-co

ntro

lled

stud

ies,

NN

T fo

r eff

ectiv

enes

s co

mpa

red

with

pla

cebo

(tw

o st

udie

s):

3.45

(95%

CI:

2.22

–7.7

5).

Oth

er p

lace

bo-c

ontr

olle

d st

udie

s (N

NT

not r

epor

ted)

: CP:

four

; HIV

-rel

ated

neu

ropa

thy:

two;

Bur

ning

mou

th

synd

rom

e: o

ne s

tudy

; Pos

tope

rativ

e ne

urop

athi

c pa

in a

fter

bre

ast c

ance

r tre

atm

ents

: tw

o st

udie

s.Th

e re

view

pro

vide

s ro

bust

evi

denc

e fo

r the

eff

ectiv

enes

s of

AD

s in

trea

ting

a va

riety

of N

P. T

he b

est e

vide

nce

avai

labl

e is

for a

mitr

ipty

line,

whi

ch, i

n do

ses

of u

p to

150

mg/

day,

has

an

NN

T of

2 (9

5% C

I: 1.

7–2.

5). T

here

are

on

ly li

mite

d da

ta fo

r the

eff

ectiv

enes

s of

SSR

Is. N

o co

nclu

sion

can

be m

ade

for S

t Joh

n’s

Wor

t, ve

nlaf

axin

e an

d L-

tryp

toph

an (s

tudi

es to

o sm

all).

It is

not p

ossib

le to

iden

tify

the

mos

t eff

ectiv

e A

Ds.

Ther

e is

evid

ence

that

TC

As

are

effe

ctiv

e in

DN

and

PH

N b

ut a

re in

effe

ctiv

e in

HIV

-rel

ated

neu

ropa

thie

s. T

here

is

som

e (li

mite

d) in

dica

tion

of e

ffec

tiven

ess

in C

P an

d at

ypic

al fa

cial

pai

n (fe

w tr

ials

and

smal

l par

ticip

ant n

umbe

rs).

Ther

e is

a la

ck o

f evi

denc

e fo

r any

eff

ect i

n bu

rnin

g m

outh

syn

drom

e.A

dver

se e

ffec

ts w

ith T

CA

can

lead

to w

ithdr

awal

from

trea

tmen

t in

at le

ast 2

0% o

f sub

ject

s.

[59]

PNP

Tram

adol

From

196

6 to

July

200

2, s

earc

h fo

r RC

Ts a

nd q

uasi-

RCTs

.El

igib

le tr

ials:

Tram

adol

vs

plac

ebo

(thre

e st

udie

s): N

NT

to re

ach

at le

ast 5

0% p

ain

relie

f: 3.

5 (9

5% C

I: 2.

4–5.

9, m

eta-

anal

ysis

of

two

out o

f the

thre

e tr

ials,

161

par

ticip

ants

).Tr

amad

ol v

s cl

omip

ram

ine

(one

stu

dy, n

ot b

linde

d an

d no

t ana

lyse

d on

an

ITT

basis

, des

pite

a 4

0% tr

ial d

ropo

ut

rate

ove

r 21

patie

nts)

.Tr

amad

ol v

s m

orph

ine

(one

stu

dy, n

ot b

linde

d, 4

0 ca

ncer

pai

n pa

tient

s, s

ome

of w

hom

had

NP)

: tra

mad

ol w

as

mor

e ef

fect

ive

in re

lievi

ng N

P in

the

first

trea

tmen

t wee

k on

ly. N

o di

ffer

ence

in e

ffec

tiven

ess

betw

een

mor

phin

e an

d tr

amad

ol a

t 2, 3

and

4 w

eeks

.In

suff

icie

nt d

ata

to d

raw

con

clus

ions

rega

rdin

g th

e ef

fect

iven

ess

of tr

amad

ol c

ompa

red

with

eith

er c

lom

ipra

min

e or

mor

phin

e.A

utho

rs’ c

oncl

usio

ns: T

ram

adol

is a

n ef

fect

ive

trea

tmen

t for

NP.

Its

effic

acy

is sim

ilar t

o th

at re

port

ed fo

r AD

s an

d A

EDs,

but

ade

quat

e di

rect

com

paris

ons

are

not a

vaila

ble.

Its

use

may

be

limite

d by

sid

e ef

fect

s, a

lthou

gh th

ese

are

reve

rsib

le a

nd n

ot li

fe th

reat

enin

g.

[60]

Tab

le 2

. Met

a-an

alys

is a

nd

sys

tem

atic

rev

iew

s (C

on

t.).

Pain

typ

eD

rug

(s)/

acti

ve a

gen

tsR

esu

lts

and

au

tho

r co

ncl

usi

on

sR

ef.

AD

: An

tid

epre

ssan

t d

rug

; AED

: An

tiep

ilep

tic

dru

g; C

BZ:

Car

bam

azep

ine;

CI:

Co

nfi

den

ce in

terv

al; C

P: C

hro

nic

pai

n; C

PSP:

Cen

tral

po

stst

roke

pai

n; C

R: C

on

tro

lled

rel

ease

; DN

: Dia

bet

ic n

euro

pat

hy;

i.t

.:In

trat

hec

al; i

.v.:

Intr

aven

ou

s; L

A: L

oca

l an

esth

etic

(s);

MA

OI:

Mo

no

amin

e o

xid

ase

inh

ibit

or;

MS:

Mu

ltip

le s

cler

osi

s; N

aRI:

No

rad

ren

alin

e re

up

take

inh

ibit

or;

NaS

S: N

ora

dre

ner

gic

an

d s

pec

ific

ser

oto

nin

erg

ic

anti

dep

ress

ant;

ND

RI:

No

rep

inep

hri

ne

do

pam

ine

reu

pta

ke in

hib

ito

r; N

NH

: Nu

mb

er n

eed

ed t

o h

arm

; NM

DA

: N-m

eth

yl-d

-asp

arti

c ac

id; N

NT:

Nu

mb

er n

eed

ed t

o t

reat

; NP:

Neu

rop

ath

ic p

ain

; N

SAID

:No

nst

ero

idal

an

ti-i

nfl

amm

ato

ry d

rug

; OX

CB

Z: O

xcar

bam

azep

ine;

PH

N: P

ost

-her

pet

ic n

eura

lgia

; PN

P: P

erip

her

al n

euro

pat

hic

pai

n; R

CT:

Ran

do

miz

ed c

on

tro

lled

tri

al; R

IMA

: Rev

ersi

ble

inh

ibit

ors

of

mo

no

amin

e o

xid

ase

typ

e A

; RSD

: Ref

lex

sym

pat

eth

ic d

ystr

op

hy;

SC

I: Sp

inal

co

rd in

jury

; SN

aRI:

Sero

ton

in a

nd

no

rad

ren

erg

ic r

eup

take

inh

ibit

or;

SN

RI:

Sero

ton

in a

nd

no

rep

inep

hri

ne

reu

pta

ke in

hib

ito

r;

SP:S

ub

stan

ce P

; SSR

I: Se

lect

ive

sero

ton

in r

eup

take

inh

ibit

or;

TC

A: T

ricy

clic

an

tid

epre

ssan

t; T

ENS:

Tra

nsc

uta

neo

us

elec

tric

al n

erve

sti

mu

lati

on

; TH

C: T

etra

hyd

roca

nn

abin

ol;

TN: T

rig

emin

al n

eura

lgia

; V

AS:

Vis

ual

an

alo

g s

cale

.



PHN

TCA

sG

abap

entin

Preg

abal

inLi

doca

ine

patc

hO

pioi

dsO

ther

s

NN

T:TC

As:

Am

itrip

tylin

e: 1

.6 (o

r 3.

2); d

esip

ram

ine:

1.6

; des

ipra

min

e or

nor

trip

tylin

e: 6

.2 (v

s op

ioid

s).

Opi

oids

: Mor

phin

e or

met

hado

ne: 3

(vs

TCA

s); o

xyco

done

CR:

2.5

; tra

mad

ol: 4

.7.

AED

s: G

abap

entin

: 2.2

(or

2.8

or 5

.3);

preg

abal

in: 3

.3.

Topi

cal a

gent

s: L

idoc

aine

pat

ch: 2

(enr

iche

d en

rolm

ent

stud

y); a

spiri

n/di

ethy

leth

er: 3

; cap

saic

in: 3

.2.

Met

hylp

redn

isol

one

(IT):

1.3

Gro

up 1

: Tre

atm

ents

with

med

ium

to

high

eff

icac

y, g

ood

stre

ngth

of

evid

ence

, and

low

leve

l of

side

eff

ects

: ga

bape

ntin

, lid

ocai

ne p

atch

, oxy

codo

ne o

r m

orph

ine

sulfa

te (C

R), p

rega

balin

, TC

As.

Gro

up 2

: Tre

atm

ents

with

low

er e

ffic

acy

than

tho

se li

sted

in g

roup

1, l

imite

d st

reng

th o

f ev

iden

ce o

r si

de-

effe

ct c

once

rns:

asp

irin

in c

ream

or

oint

men

t, c

apsa

icin

, top

ical

, met

hylp

redn

isol

one

(i.t.

).G

roup

3: E

vide

nce

indi

catin

g no

tre

atm

ent

effic

acy

com

pare

d w

ith p

lace

bo: a

cupu

nctu

re, b

enzy

dam

ine

crea

m, d

extr

omet

horp

han,

indo

met

haci

n, lo

raze

pam

, met

hylp

redn

isol

one

(epi

dura

l), v

incr

istin

e (io

ntop

hore

sis)

, vita

min

E, z

imel

idin

e.G

roup

4: R

epor

ts o

f tr

eatm

ent

bene

fit li

mite

d to

Cla

ss IV

stu

dies

: bip

erid

in, c

arba

maz

epin

e, c

hlor

prot

hixe

ne,

cryo

caut

ery,

DRE

Z le

sion

, ext

ract

of

Gan

oder

ma

luci

du, H

e: N

e la

ser

irrad

iatio

n, k

etam

ine,

m

ethy

lpre

dnis

olon

e (io

ntop

hore

sis)

, mor

phin

e su

lfate

(epi

dura

l), n

icar

dipi

ne, p

iroxi

cam

(top

ical

), st

ella

te

gang

lion

bloc

k, t

riam

cino

lone

(int

rale

sion

al).

[61]

)

Tab

le 2

. Met

a-an

alys

is a

nd

sys

tem

atic

rev

iew

s (C

on

t.).

Pain

typ

eD

rug

(s)/

acti

ve a

gen

tsR

esu

lts

and

au

tho

r co

ncl

usi

on

sR

ef.

AD

: An

tid

epre

ssan

t d

rug

; AED

: An

tiep

ilep

tic

dru

g; C

BZ:

Car

bam

azep

ine;

CI:

Co

nfi

den

ce in

terv

al; C

P: C

hro

nic

pai

n; C

PSP:

Cen

tral

po

stst

roke

pai

n; C

R: C

on

tro

lled

rel

ease

; DN

: Dia

bet

ic n

euro

pat

hy;

i.t

.:In

trat

hec

al; i

.v.:

Intr

aven

ou

s; L

A: L

oca

l an

esth

etic

(s);

MA

OI:

Mo

no

amin

e o

xid

ase

inh

ibit

or;

MS:

Mu

ltip

le s

cler

osi

s; N

aRI:

No

rad

ren

alin

e re

up

take

inh

ibit

or;

NaS

S: N

ora

dre

ner

gic

an

d s

pec

ific

ser

oto

nin

erg

ic

anti

dep

ress

ant;

ND

RI:

No

rep

inep

hri

ne

do

pam

ine

reu

pta

ke in

hib

ito

r; N

NH

: Nu

mb

er n

eed

ed t

o h

arm

; NM

DA

: N-m

eth

yl-d

-asp

arti

c ac

id; N

NT:

Nu

mb

er n

eed

ed t

o t

reat

; NP:

Neu

rop

ath

ic p

ain

; N

SAID

:No

nst

ero

idal

an

ti-i

nfl

amm

ato

ry d

rug

; OX

CB

Z: O

xcar

bam

azep

ine;

PH

N: P

ost

-her

pet

ic n

eura

lgia

; PN

P: P

erip

her

al n

euro

pat

hic

pai

n; R

CT:

Ran

do

miz

ed c

on

tro

lled

tri

al; R

IMA

: Rev

ersi

ble

inh

ibit

ors

of

mo

no

amin

e o

xid

ase

typ

e A

; RSD

: Ref

lex

sym

pat

eth

ic d

ystr

op

hy;

SC

I: Sp

inal

co

rd in

jury

; SN

aRI:

Sero

ton

in a

nd

no

rad

ren

erg

ic r

eup

take

inh

ibit

or;

SN

RI:

Sero

ton

in a

nd

no

rep

inep

hri

ne

reu

pta

ke in

hib

ito

r;

SP:S

ub

stan

ce P

; SSR

I: Se

lect

ive

sero

ton

in r

eup

take

inh

ibit

or;

TC

A: T

ricy

clic

an

tid

epre

ssan

t; T

ENS:

Tra

nsc

uta

neo

us

elec

tric

al n

erve

sti

mu

lati

on

; TH

C: T

etra

hyd

roca

nn

abin

ol;

TN: T

rig

emin

al n

eura

lgia

; V

AS:

Vis

ual

an

alo

g s

cale

.


666 Therapy (2006) 3(5)

NP

Ant

idep

ress

ants

Ant

icon

vuls

ants

Topi

cal a

gent

sN

arco

tics

Ana

lges

ics

Oth

er

Com

preh

ensiv

e lit

erat

ure

revi

ew e

xten

ding

bac

k ov

er 1

0ye

ars

Sear

ch s

trat

egie

s:

Leve

l 1: R

CTs

of l

arge

sam

ple

size

(n >

100

) and

met

a-an

alys

es; l

evel

2: a

dditi

onal

tria

ls w

ith m

any

but n

ot a

ll of

th

e de

sirab

le tr

aits

of e

vide

nce-

base

d tr

ials;

leve

l 3: c

ompa

rison

of k

ey fi

ndin

gs s

tate

d in

ane

cdot

al re

port

s of

ver

y sm

all (

n <

15)

, poo

rly d

esig

ned

tria

ls w

ith th

e le

vel 1

or 2

resu

lts.

NP

trea

tmen

t is

larg

ely

empi

rical

, oft

en re

lyin

g he

avily

on

data

from

sm

all a

nd g

ener

ally

poo

rly d

esig

ned

clin

ical

tr

ials

or a

necd

otal

evi

denc

e.Pr

opos

ed tr

eatm

ent a

lgor

ithm

:Fi

rst-

line:

(any

one

of t

he p

ropo

sed

drug

cla

sses

cou

ld b

e co

nsid

ered

as

a po

tent

ial s

tart

ing

poin

t): A

Ds

(am

itrip

tylin

e, n

ortr

ipty

line,

imip

ram

ine,

des

ipra

min

e, v

enla

faxi

ne, f

luox

etin

e, p

arox

etin

e, s

ertr

alin

e) >

failu

re o

f am

itrip

tylin

e an

d at

leas

t tw

o ot

her A

Ds:

AED

s (g

abap

entin

, car

bam

azep

ine,

lam

otrig

ine,

topi

ram

ate,

phe

nyto

in)

> fa

ilure

of g

abap

entin

and

at l

east

two

othe

r AED

s: to

pica

l ant

ineu

ralg

ics

(cap

saic

in,k

etam

ine,

lidoc

aine

) > fa

ilure

of

gab

apen

tin a

nd a

t lea

st tw

o ot

her A

EDs

or o

f top

ical

trea

tmen

ts.

Seco

nd-li

ne: N

arco

tics

(mor

phin

e, c

odei

ne, m

etha

done

, tra

mad

ol, o

xyco

done

, alfe

ntan

il) >

failu

re o

f nar

cotic

s:

Refr

acto

ry tr

eatm

ents

(tiz

anid

ine,

ket

amin

e, b

aclo

fen,

clo

nidi

ne, d

extr

omet

horp

han,

mex

iletin

e, a

man

tadi

ne,

lithi

um) >

failu

re o

f ref

ract

ory

trea

tmen

ts o

r nar

cotic

s.Th

ird-li

ne: C

ombi

natio

n th

erap

y an

d co

nsul

t pai

n se

rvic

e.Fo

urth

-line

: Sur

gica

l int

erve

ntio

n.A

djun

ctiv

e th

erap

y: ib

upro

fen,

nap

roxe

n, in

dom

etha

cin,

cel

ecox

ib, r

ofec

oxib

, ace

tam

inop

hen,

asp

irin,

ac

etam

inop

hen/

code

ine.

[62]

Chr

onic

pai

n fr

om

neur

opat

hic

or

mus

culo

skel

etal

di

sord

ers

Topi

cally

app

lied

caps

aici

nSy

stem

atic

revi

ew o

f RC

Ts c

ompa

ring

topi

cally

app

lied

caps

aici

n w

ith p

lace

bo o

r ano

ther

trea

tmen

t. Pr

imar

y ou

tcom

e: d

icho

tom

ous

info

rmat

ion

for t

he n

umbe

r of p

atie

nts

with

app

roxi

mat

ely

a 50

% re

duct

ion

in p

ain.

Resu

lts:

NP:

six

dou

ble-

blin

d pl

aceb

o-co

ntro

lled

tria

ls (6

56pa

tient

s). N

NT:

topi

cal c

apsa

icin

0.0

75%

: 5.7

(9

5%C

I:4.

0–10

.0);

topi

cal c

apsa

icin

0.0

25%

or p

last

er: 8

.1 (9

5% C

I: 4.

6–34

) loc

al a

dver

se e

vent

s w

ith c

apsa

icin

in

app

roxi

mat

ely

33%

of p

atie

nts.

Con

clus

ions

: top

ical

ly a

pplie

d ca

psai

cin

has

mod

erat

e to

poo

r eff

icac

y in

the

trea

tmen

t of c

hron

ic m

uscu

losk

elet

al

or N

P, b

ut it

may

be

usef

ul a

s an

adj

unct

or s

ole

ther

apy

for a

sm

all n

umbe

r of p

atie

nts

who

are

unr

espo

nsiv

e to

, or

into

lera

nt o

f, ot

her t

reat

men

ts.

[63]

CP,

pha

ntom

, PH

N, n

onsp

ecifi

c N

P

NM

DA

ant

agon

ist

(ket

amin

e)Ev

iden

ce fo

r eff

icac

y of

ket

amin

e is

mod

erat

e to

wea

k.Le

vels:

SC

I: II–

IV; C

P: IV

; non

spec

ific

NP:

II–I

V; a

cute

on

chro

nic

NP:

IV; p

hant

om: I

I–IV

. PH

N; I

I–IV

Ket

amin

e m

ay b

e a

‘third

-line

ana

lges

ic’ i

n ac

ute

on c

hron

ic e

piso

des

of s

ever

e N

P. F

urth

er R

CTs

are

need

ed.

[64]

Tab

le 2

. Met

a-an

alys

is a

nd

sys

tem

atic

rev

iew

s (C

on

t.).

Pain

typ

eD

rug

(s)/

acti

ve a

gen

tsR

esu

lts

and

au

tho

r co

ncl

usi

on

sR

ef.

AD

: An

tid

epre

ssan

t d

rug

; AED

: An

tiep

ilep

tic

dru

g; C

BZ:

Car

bam

azep

ine;

CI:

Co

nfi

den

ce in

terv

al; C

P: C

hro

nic

pai

n; C

PSP:

Cen

tral

po

stst

roke

pai

n; C

R: C

on

tro

lled

rel

ease

; DN

: Dia

bet

ic n

euro

pat

hy;

i.t

.:In

trat

hec

al; i

.v.:

Intr

aven

ou

s; L

A: L

oca

l an

esth

etic

(s);

MA

OI:

Mo

no

amin

e o

xid

ase

inh

ibit

or;

MS:

Mu

ltip

le s

cler

osi

s; N

aRI:

No

rad

ren

alin

e re

up

take

inh

ibit

or;

NaS

S: N

ora

dre

ner

gic

an

d s

pec

ific

ser

oto

nin

erg

ic

anti

dep

ress

ant;

ND

RI:

No

rep

inep

hri

ne

do

pam

ine

reu

pta

ke in

hib

ito

r; N

NH

: Nu

mb

er n

eed

ed t

o h

arm

; NM

DA

: N-m

eth

yl-d

-asp

arti

c ac

id; N

NT:

Nu

mb

er n

eed

ed t

o t

reat

; NP:

Neu

rop

ath

ic p

ain

; N

SAID

:No

nst

ero

idal

an

ti-i

nfl

amm

ato

ry d

rug

; OX

CB

Z: O

xcar

bam

azep

ine;

PH

N: P

ost

-her

pet

ic n

eura

lgia

; PN

P: P

erip

her

al n

euro

pat

hic

pai

n; R

CT:

Ran

do

miz

ed c

on

tro

lled

tri

al; R

IMA

: Rev

ersi

ble

inh

ibit

ors

of

mo

no

amin

e o

xid

ase

typ

e A

; RSD

: Ref

lex

sym

pat

eth

ic d

ystr

op

hy;

SC

I: Sp

inal

co

rd in

jury

; SN

aRI:

Sero

ton

in a

nd

no

rad

ren

erg

ic r

eup

take

inh

ibit

or;

SN

RI:

Sero

ton

in a

nd

no

rep

inep

hri

ne

reu

pta

ke in

hib

ito

r;

SP:S

ub

stan

ce P

; SSR

I: Se

lect

ive

sero

ton

in r

eup

take

inh

ibit

or;

TC

A: T

ricy

clic

an

tid

epre

ssan

t; T

ENS:

Tra

nsc

uta

neo

us

elec

tric

al n

erve

sti

mu

lati

on

; TH

C: T

etra

hyd

roca

nn

abin

ol;

TN: T

rig

emin

al n

eura

lgia

; V

AS:

Vis

ual

an

alo

g s

cale

.



DN

, PH

N, C

P,

perip

hera

l NP,

AED

s (p

heny

toin

, car

bam

azep

ine,

OX

CBZ

, la

mot

rigin

e, v

alpr

oic

acid

, gap

apen

tin,

topi

ram

ate,

pre

gaba

lin, c

lona

zepa

m,

felb

amat

e, t

iaga

bine

, vig

abat

rin)

NN

T:

DN

: phe

nyto

in: 2

.1; C

BZ: 3

.3; g

abap

entin

: 3.7

; PH

N: g

abap

entin

: 3.2

; CP:

CBZ

: 3.4

Phen

ytoi

n av

aila

bilit

y fo

r i.v

. inf

usio

n m

akes

it s

uita

ble

for b

reak

ing

acut

e at

tack

s of

NP.

OX

CBZ

is n

ow th

e dr

ug o

f ch

oice

for T

N b

ut th

ere

are

no R

CTs

doc

umen

ting

an e

ffec

t for

TN

or a

ny o

ther

NP

cond

ition

. Val

proi

c ac

id is

in

effe

ctiv

e in

CP

(SC

I) an

d pr

obab

ly D

N. T

opira

mat

e ap

pear

s in

effe

ctiv

e in

DN

. Gab

apen

tin is

the

AED

with

the

best

evi

denc

e, a

t pre

sent

, for

eff

icac

y in

NP.

Preg

abal

in, c

lona

zepa

m, f

elba

mat

e, ti

agab

ine

and

viga

batr

in a

re c

urre

ntly

und

ergo

ing

clin

ical

test

ing.

[65]

DN

, PH

NA

ntid

epre

ssan

ts (T

CA

s, S

SRIs

)A

ntic

onvu

lsan

ts (p

heny

toin

, car

bam

azep

ine,

ga

bape

ntin

)

DN

: NN

TA

Ds:

3.4

(95%

CI:

2.6–

4.7)

; AED

s: 2

.7 (9

5% C

I: 2.

2–3.

8).

PHN

: NN

T A

Ds:

2.1

(95%

CI:

1.7–

3.0)

; AED

s: 3

.2 (9

5% C

I: 2.

4–5.

0).

Both

AD

s an

d A

EDs

clea

rly h

ave

anal

gesic

eff

ect v

s pl

aceb

o, b

ut S

SRIs

are

not m

ore

effe

ctiv

e th

an p

lace

bo. N

o di

ffer

ence

in e

ffic

acy

betw

een

gaba

pent

in a

nd o

lder

AED

s. In

cide

nce

of m

ajor

adv

erse

eff

ects

hig

her w

ith A

Ds.

[66]

Acu

te, c

hron

ic

nonm

alig

nant

, or

canc

er p

ain.

SC

I: (o

ne p

atie

nt)

Can

nabi

noid

s (T

HC

, nitr

ogen

ana

log

of T

HC

, le

vona

ntra

dol,

benz

opyr

anop

erid

ine)

THC

(cod

eine

) bot

h m

ore

effe

ctiv

e th

an p

lace

bo. T

HC

redu

ced

spas

ticity

.A

utho

rs c

oncl

usio

n: c

anna

bino

ids

are

no m

ore

effe

ctiv

e th

an c

odei

ne in

con

trol

ling

pain

and

hav

e de

pres

sant

ef

fect

s on

the

CN

S th

at li

mit

thei

r use

. Sug

gest

ions

of e

ffic

acy

in s

past

icity

and

in N

P. T

heir

wid

espr

ead

intr

oduc

tion

into

clin

ical

pra

ctic

e fo

r pai

n m

anag

emen

t is

unde

sirab

le. B

efor

e ca

nnab

inoi

ds c

an b

e co

nsid

ered

for

trea

ting

NP,

furt

her v

alid

RC

Ts a

re n

eede

d.

[35]

DN

, PH

N, C

P,

mix

ed N

P, T

N,

pain

ful

neur

opat

hies

, ot

hers

Gab

apen

tinSi

x RC

Ts (t

wo

high

qua

lity)

: pos

itive

eff

ect o

f gab

apen

tin in

DN

and

PH

N.

26 n

ot R

CTs

: pos

itive

eff

ect o

n di

ffer

ent t

ypes

of N

P.Ve

ry lo

w d

oses

may

hav

e re

duce

d ef

fect

iven

ess;

rapi

d do

se-e

scal

atio

n m

ay b

e as

soci

ated

with

incr

ease

d C

NS

side

effe

cts.

Unc

ontr

olle

d st

udie

s re

port

ed fe

wer

and

less

sev

ere

side

effe

cts.

[67]

PHN

, DN

, CP

(CPS

P, S

CI)

Mix

ed N

P,

deaf

fere

ntat

ion

pain

Ant

idep

ress

ants

TCA

s (a

mitr

ipty

line,

imip

ram

ine,

clo

mip

ram

ine,

no

rtrip

tylin

e, d

esip

ram

ine)

SS

RIs

(fluo

xetin

e, p

arox

etin

e, c

italo

pram

, zi

mel

idin

e)Tr

iazo

lopy

ridin

es (t

razo

done

)Se

lect

ive

sero

toni

n–no

repi

neph

rine

reup

take

inhi

bito

rs (v

enla

faxi

ne)

TCA

s: C

onsis

tent

evi

denc

e th

at th

e TC

As

are

anal

gesic

in p

ainf

ul D

N a

nd P

HN

. The

y ha

ve e

xhib

ited

anal

gesic

ef

ficac

y in

CP

and

CPS

P.SS

RIs:

The

resu

lts re

gard

ing

anal

gesic

eff

ects

of t

he S

SRIs

have

bee

n di

sapp

oint

ing.

The

y ar

e no

t sup

erio

r an

alge

sics,

as

was

hop

ed. I

n st

udie

s ex

amin

ing

both

SSR

Is an

d TC

As,

the

anal

gesia

obt

aine

d w

ith T

CA

s w

as

supe

rior i

n ev

ery

case

.Tr

azod

one:

Con

trol

led

tria

ls in

gen

eral

do

not s

uppo

rt a

n an

alge

sic e

ffec

t of t

razo

done

.SS

NRI

s: T

he s

truc

tura

l sim

ilarit

ies

betw

een

venl

afax

ine

and

tram

adol

are

str

ikin

g. T

here

are

no

publ

ished

co

ntro

lled

tria

ls.

[68]

Tab

le 2

. Met

a-an

alys

is a

nd

sys

tem

atic

rev

iew

s (C

on

t.).

Pain

typ

eD

rug

(s)/

acti

ve a

gen

tsR

esu

lts

and

au

tho

r co

ncl

usi

on

sR

ef.

AD

: An

tid

epre

ssan

t d

rug

; AED

: An

tiep

ilep

tic

dru

g; C

BZ:

Car

bam

azep

ine;

CI:

Co

nfi

den

ce in

terv

al; C

P: C

hro

nic

pai

n; C

PSP:

Cen

tral

po

stst

roke

pai

n; C

R: C

on

tro

lled

rel

ease

; DN

: Dia

bet

ic n

euro

pat

hy;

i.t

.:In

trat

hec

al; i

.v.:

Intr

aven

ou

s; L

A: L

oca

l an

esth

etic

(s);

MA

OI:

Mo

no

amin

e o

xid

ase

inh

ibit

or;

MS:

Mu

ltip

le s

cler

osi

s; N

aRI:

No

rad

ren

alin

e re

up

take

inh

ibit

or;

NaS

S: N

ora

dre

ner

gic

an

d s

pec

ific

ser

oto

nin

erg

ic

anti

dep

ress

ant;

ND

RI:

No

rep

inep

hri

ne

do

pam

ine

reu

pta

ke in

hib

ito

r; N

NH

: Nu

mb

er n

eed

ed t

o h

arm

; NM

DA

: N-m

eth

yl-d

-asp

arti

c ac

id; N

NT:

Nu

mb

er n

eed

ed t

o t

reat

; NP:

Neu

rop

ath

ic p

ain

; N

SAID

:No

nst

ero

idal

an

ti-i

nfl

amm

ato

ry d

rug

; OX

CB

Z: O

xcar

bam

azep

ine;

PH

N: P

ost

-her

pet

ic n

eura

lgia

; PN

P: P

erip

her

al n

euro

pat

hic

pai

n; R

CT:

Ran

do

miz

ed c

on

tro

lled

tri

al; R

IMA

: Rev

ersi

ble

inh

ibit

ors

of

mo

no

amin

e o

xid

ase

typ

e A

; RSD

: Ref

lex

sym

pat

eth

ic d

ystr

op

hy;

SC

I: Sp

inal

co

rd in

jury

; SN

aRI:

Sero

ton

in a

nd

no

rad

ren

erg

ic r

eup

take

inh

ibit

or;

SN

RI:

Sero

ton

in a

nd

no

rep

inep

hri

ne

reu

pta

ke in

hib

ito

r;

SP:S

ub

stan

ce P

; SSR

I: Se

lect

ive

sero

ton

in r

eup

take

inh

ibit

or;

TC

A: T

ricy

clic

an

tid

epre

ssan

t; T

ENS:

Tra

nsc

uta

neo

us

elec

tric

al n

erve

sti

mu

lati

on

; TH

C: T

etra

hyd

roca

nn

abin

ol;

TN: T

rig

emin

al n

eura

lgia

; V

AS:

Vis

ual

an

alo

g s

cale

.


668 Therapy (2006) 3(5)

DN

, PH

NA

Ds

(imip

ram

ine,

des

ipra

min

e, a

mitr

ipty

line,

cl

omip

ram

ine,

map

rotil

ine,

cita

lopr

am,

fluox

etin

e, p

arox

etin

e, m

ians

erin

, am

itrip

tylin

e +

flup

hena

zine

, nor

trip

tylin

e +

flup

hena

zine

A

EDs

(phe

nyto

in, c

arba

maz

epin

e, g

abap

entin

)

NN

T:

DN

: AD

s: 3

.4 (9

5% C

I: 2.

6–4.

7); A

EDs:

2.7

(95%

CI:

2.2–

3.8)

; TC

As:

3.5

(95%

CI:

2.5–

5.6)

; SSR

Is sh

owed

no

signi

fican

t diff

eren

ce w

ith p

lace

bo.

PHN

: AD

s: 2

.1 (9

5% C

I: 1.

7–3.

0); A

EDs:

3.2

(95%

CI:

2.4–

5.0)

; TC

As:

3.5

(95%

CI:

2.5–

5.6)

.D

N +

PH

N: A

Ds:

2.9

(95%

CI:

2.4–

3.7)

; AED

s 2.

9 (9

5% C

I: 2.

4–3.

7).

Gab

apen

tin v

s C

BZ/p

heny

toin

: NN

T ga

bape

ntin

3.4

(95%

CI:

2.1–

5.4)

NN

T ph

enyt

oin/

CBZ

2.2

(9

5%C

I:1.

7–3.

1).

AD

s an

d A

EDs:

sam

e ef

ficac

y an

d in

cide

nce

of m

inor

adv

erse

. No

evid

ence

that

SSR

Is ar

e be

tter

than

old

er A

Ds.

N

o ev

iden

ce th

at g

abap

entin

is b

ette

r tha

n ol

der A

EDs.

Pat

ient

s w

ere

mor

e lik

ely

to s

top

taki

ng A

Ds

than

AED

s ow

ing

to a

dver

se e

ffec

ts.

[69]

Poly

neur

opat

hy

(incl

udin

g D

N)

Ant

idep

ress

ants

(TC

As,

SSR

Is)

Na+

cha

nnel

blo

cker

s (a

ntia

ryth

mic

, an

ticon

vuls

ants

)C

a2+

cha

nnel

blo

cker

s (A

EDs)

NM

DA

-ant

agon

ist

(dex

trom

etho

rpha

n)O

pioi

ds (t

ram

adol

)D

opam

ine

prec

urso

rs (L

-Dop

a)SP

dep

lete

rs (c

apsa

icin

)α

-lipo

ic a

cid

NN

T:

TCA

s: 2

.6 (9

5% C

I: 2.

2–3.

3); S

SRIs

6.7

(95%

CI:

3.4–

435)

Lido

cain

e: 3

(95%

CI:

1.5–

10);

mex

iletin

e:?

38 (9

5% C

I: 3.

0–in

finity

); C

BZ: 3

.3 (9

5% C

I: 2.

0–9.

4);

phen

ytoi

n: 2

.1 (9

5% C

I: 1.

5–3.

6); g

abap

entin

: 4.1

(95%

CI:

2.7–

8.2)

; dex

trom

etho

rpha

n: ?

1.9

(95%

CI:

1.1–

3.7)

; tra

mad

ol: 3

.4 (9

5% C

I: 2.

3–6.

4); L

-Dop

a: ?

3.4

(95%

CI:

1.5–

infin

ity);

topi

cal c

apsa

icin

: 5.9

(95%

C

I: 3.

8–13

); α

-lipo

ic a

cid:

5.6

(95%

CI:

3.2–

24)

Dru

gs o

f fir

st c

hoic

e: T

CA

, fol

low

ed b

y ga

bape

ntin

, tra

mad

ol a

nd C

BZ

[70]

DN

, PH

N, C

PA

ntid

epre

ssan

ts (T

CA

s, o

ther

AD

s)TC

As

effe

ctiv

e. O

ther

s A

Ds

less

eff

ectiv

e or

inef

fect

ive

No

signi

fican

t diff

eren

ce b

etw

een

TCA

s; T

CA

s sig

nific

antly

mor

e ef

fect

ive

than

ben

zodi

azep

ines

; par

oxet

ine

and

mia

nser

in le

ss e

ffec

tive

than

imip

ram

ine.

Com

pare

d w

ith p

lace

bo, o

f 100

patie

nts

with

NP

who

are

giv

en

antid

epre

ssan

ts, 3

0 w

ill o

btai

n >

50%

pai

n re

lief,

30 w

ill h

ave

min

or a

dver

se re

actio

ns a

nd fo

ur w

ill h

ave

to s

top

trea

tmen

t ow

ing

to m

ajor

adv

erse

eff

ects

. Ver

y sim

ilar r

esul

ts fo

r AED

s; s

till u

ncle

ar w

hich

dru

g cl

ass

shou

ld b

e fir

st c

hoic

e.

[71]

PHN

Diff

eren

t th

erap

ies:

TCA

s, c

apsa

icin

, lor

azep

am, a

cycl

ovir,

be

nzyd

amin

e (t

opic

al),

vinc

ristin

e (io

nto)

.

Effe

ctiv

e tr

eatm

ents

:TC

As,

iont

ofor

etic

vin

cris

tine.

Unc

erta

in e

ffec

t: c

apsa

icin

(het

erog

enei

ty, p

robl

ems

with

blin

ding

).U

neff

ectiv

e tr

eatm

ents

: lor

azep

am, a

cycl

ovir,

top

ical

ben

zyda

min

e.Ba

sed

on e

vide

nce

from

ran

dom

ized

tria

ls, T

CA

s ap

pear

to

be t

he o

nly

agen

ts o

f pr

oven

ben

efit

for

esta

blis

hed

PHN

.

[72]

Tab

le 2

. Met

a-an

alys

is a

nd

sys

tem

atic

rev

iew

s (C

on

t.).

Pain

typ

eD

rug

(s)/

acti

ve a

gen

tsR

esu

lts

and

au

tho

r co

ncl

usi

on

sR

ef.

AD

: An

tid

epre

ssan

t d

rug

; AED

: An

tiep

ilep

tic

dru

g; C

BZ:

Car

bam

azep

ine;

CI:

Co

nfi

den

ce in

terv

al; C

P: C

hro

nic

pai

n; C

PSP:

Cen

tral

po

stst

roke

pai

n; C

R: C

on

tro

lled

rel

ease

; DN

: Dia

bet

ic n

euro

pat

hy;

i.t

.:In

trat

hec

al; i

.v.:

Intr

aven

ou

s; L

A: L

oca

l an

esth

etic

(s);

MA

OI:

Mo

no

amin

e o

xid

ase

inh

ibit

or;

MS:

Mu

ltip

le s

cler

osi

s; N

aRI:

No

rad

ren

alin

e re

up

take

inh

ibit

or;

NaS

S: N

ora

dre

ner

gic

an

d s

pec

ific

ser

oto

nin

erg

ic

anti

dep

ress

ant;

ND

RI:

No

rep

inep

hri

ne

do

pam

ine

reu

pta

ke in

hib

ito

r; N

NH

: Nu

mb

er n

eed

ed t

o h

arm

; NM

DA

: N-m

eth

yl-d

-asp

arti

c ac

id; N

NT:

Nu

mb

er n

eed

ed t

o t

reat

; NP:

Neu

rop

ath

ic p

ain

; N

SAID

:No

nst

ero

idal

an

ti-i

nfl

amm

ato

ry d

rug

; OX

CB

Z: O

xcar

bam

azep

ine;

PH

N: P

ost

-her

pet

ic n

eura

lgia

; PN

P: P

erip

her

al n

euro

pat

hic

pai

n; R

CT:

Ran

do

miz

ed c

on

tro

lled

tri

al; R

IMA

: Rev

ersi

ble

inh

ibit

ors

of

mo

no

amin

e o

xid

ase

typ

e A

; RSD

: Ref

lex

sym

pat

eth

ic d

ystr

op

hy;

SC

I: Sp

inal

co

rd in

jury

; SN

aRI:

Sero

ton

in a

nd

no

rad

ren

erg

ic r

eup

take

inh

ibit

or;

SN

RI:

Sero

ton

in a

nd

no

rep

inep

hri

ne

reu

pta

ke in

hib

ito

r;

SP:S

ub

stan

ce P

; SSR

I: Se

lect

ive

sero

ton

in r

eup

take

inh

ibit

or;

TC

A: T

ricy

clic

an

tid

epre

ssan

t; T

ENS:

Tra

nsc

uta

neo

us

elec

tric

al n

erve

sti

mu

lati

on

; TH

C: T

etra

hyd

roca

nn

abin

ol;

TN: T

rig

emin

al n

eura

lgia

; V

AS:

Vis

ual

an

alo

g s

cale

.



Tab

le 6

. Exp

erts

’ op

inio

n o

n p

har

mac

olo

gic

al t

reat

men

t o

pti

on

s fo

r n

euro

pat

hic

pai

n (

2000

–200

5).

Dru

g(s

)A

uth

ors

’ co

mm

ents

Ref

.

CBZ

Phen

ytoi

nG

abap

entin

Lam

otrig

ine

Use

d in

the

trea

tmen

t of T

N, p

ainf

ul D

N a

nd P

HN

.N

o ev

iden

ce fo

r its

eff

icac

y in

relie

ving

NP.

Cle

arly

spe

cific

ally

eff

ectiv

e fo

r the

trea

tmen

t of p

ainf

ul D

N a

nd P

HN

. Gab

apen

tin h

as a

favo

rabl

e sid

e-ef

fect

pro

file

and,

bas

ed o

n th

e re

sults

of t

hese

stu

dies

, it s

houl

d be

con

sider

ed a

s fir

st-li

ne tr

eatm

ent f

or n

euro

path

ic p

ain.

Impr

oved

pai

n co

ntro

l in

TN.

[73]

CBZ

Gab

apen

tinPh

enyt

oin

Lam

otrig

ine

Oth

ers

(phe

noba

rbita

l, cl

onaz

epam

, val

proi

c ac

id, t

opira

mat

e, p

rega

balin

and

tiag

abin

e)

Effe

ctiv

e in

TN

, pai

nful

DN

and

PH

N.

Spec

ifica

lly e

ffec

tive

in p

ainf

ul D

N a

nd P

HN

. Firs

t cho

ice

ther

apy

for N

P.W

eak

effe

ct if

any

.G

ood

pote

ntia

l to

mod

ulat

e an

d co

ntro

l neu

ropa

thic

pai

n.Po

tent

ial a

ntih

yper

alge

sic a

nd a

ntin

ocic

eptiv

e ac

tiviti

es. E

ffic

acy

not y

et fu

lly d

eter

min

ed in

clin

ical

tria

ls.N

P is

a fo

rmid

able

ther

apeu

tic c

halle

nge

to c

linic

ians

sin

ce it

doe

s no

t res

pond

wel

l to

trad

ition

al p

ain

ther

apie

s.

[74]

NM

DA

rece

ptor

ant

agon

ists

(ket

amin

e,

dext

rom

etho

rpha

n, m

eman

tine,

am

anta

dine

[m

etha

done

, dex

trop

ropo

xyph

ene,

ke

tobe

mid

one]

)

Dos

e-lim

iting

sid

e ef

fect

s; o

nly

a ha

ndfu

l of N

MD

A a

ntag

onist

s ar

e cl

inic

ally

ava

ilabl

e; th

ey m

ay b

e ef

fect

ive

in th

e tr

eatm

ent o

f som

e ty

pes

of c

hron

ic p

ain.

[75]

New

er A

EDs

(not

ably

gab

apen

tin)

Mex

iletin

eLo

ng-a

ctin

g op

ioid

sTo

pica

l lid

ocai

ne p

atch

Bett

er a

ltern

ativ

es to

old

er m

edic

atio

ns (C

BZ o

r phe

nyto

in).

Gab

apen

tin a

t lea

st a

s go

od a

s A

Ds

(incl

udin

g am

itrip

tylin

e) a

nd

muc

hsa

fer.

Reas

onab

le a

ltern

ativ

e to

AED

s or

ant

idep

ress

ants

.M

ay b

e us

eful

in p

atie

nts

refr

acto

ry to

the

abov

e ag

ents

.Re

volu

tiona

ry n

ew a

gent

.M

uch

prog

ress

has

bee

n m

ade

in th

e m

anag

emen

t of N

P ov

er th

e pa

st 5

year

s.

[76]

TCA

s, s

tand

ard

and

new

er a

ntie

pile

ptic

s,

opio

ids,

tram

adol

, sys

tem

ic a

nd to

pica

l loc

al

anes

thet

ics,

som

e N

MD

A re

cept

or

anta

goni

sts

SSRI

s, a

ntia

rrhy

thm

ics

(mex

iletin

e), c

apsa

icin

Phar

mac

olog

ical

test

s (sh

ort-

term

infu

sions

of

barb

itura

tes,

pro

pofo

l, op

ioid

s, k

etam

ine,

lid

ocai

n)

Effe

ctiv

e.

Less

evi

denc

e fo

r eff

icac

y.Ph

arm

acol

ogic

al te

sts:

pro

pose

d fo

r pre

dict

ing

the

effe

ctiv

enes

s of

long

-ter

m tr

eatm

ents

but

not

per

form

ed ro

utin

ely.

Ther

e is

no c

onse

nsus

con

cern

ing

the

optim

al th

erap

eutic

str

ateg

y fo

r NP,

des

pite

an

incr

easin

g nu

mbe

r of c

linic

al tr

ials

dem

onst

ratin

g su

cces

sful

pai

n re

lief w

ith s

ever

al d

rugs

.

[77]

Ant

icon

vulsa

nts,

ant

iarr

hyth

mic

s, A

Ds

Can

nabi

noid

s C

onot

oxin

s, e

piba

tidin

e

Oft

en le

ss th

an s

atisf

acto

ry.

Con

trov

ersia

l.N

ew d

rug

clas

ses.

The

trea

tmen

t of N

P co

ntin

ues

to b

e a

chal

leng

e to

the

clin

icia

n.

[78]

AD

: An

tid

epre

ssan

t d

rug

; AED

: An

tiep

ilep

tic

dru

g; C

BZ:

Car

bam

azep

ine;

CPS

P: C

entr

al p

ost

stro

ke p

ain

; DN

: Dia

bet

ic n

euro

pat

hy;

i.t.

: In

trat

hec

al; i

.v.:

Intr

aven

ou

s; L

A: L

oca

l an

esth

etic

; NaR

I:N

ora

dre

nal

ine

reu

pta

ke in

hib

ito

rs; N

aSSA

: No

rad

ren

erg

ic a

nd

sp

ecif

ic s

ero

ton

iner

gic

an

tid

epre

ssan

ts; N

GF:

Ner

ve g

row

th f

acto

r; N

P: N

euro

pat

hic

pai

n; N

MD

A:N

-met

hyl

- D-a

spar

tic

acid

NSA

ID: N

on

ster

oid

al a

nti

-in

flam

mat

ory

dru

g; P

HN

: Po

sth

erp

etic

neu

ralg

ia; R

CT:

Ran

do

miz

ed c

on

tro

lled

tri

al; r

hN

GF:

Rec

om

bin

ant

hu

man

ner

ve g

row

th f

acto

r; R

SD: R

efle

x sy

mp

atet

hic

dys

tro

ph

y; R

TX: R

esin

ifer

ato

xin

; SC

I: Sp

inal

co

rd in

jury

; SN

aRI:

Sero

ton

in a

nd

no

rad

ren

erg

ic r

eup

take

inh

ibit

ors

; SSR

I: Se

lect

ive

sero

ton

in r

eup

take

inh

ibit

or;

TC

A: T

ricy

clic

an

tid

epre

ssan

t; T

N: T

rig

emin

al n

eura

lgia

; VR

: Van

illo

id r

ecep

tor.


670 Therapy (2006) 3(5)

SSRI

s, T

CA

sSN

aRI:

venl

afax

ine

and

nefa

zodo

neN

aSSA

: mirt

azap

ine

NaR

I: re

boxe

tine

Ava

ilabl

e lit

erat

ure

did

not s

how

an

effe

ctiv

e su

perio

rity

for S

SRIs

over

TC

As,

alth

ough

ther

e w

as a

n im

prov

ed s

ide-

effe

ct p

rofil

e.Ve

nlaf

axin

e is

effe

ctiv

e, w

ith a

bet

ter s

ide-

effe

ct p

rofil

e th

an T

CA

s.O

nly

anec

dota

l the

rape

utic

resu

lts a

nd e

xper

imen

tal w

orks

repo

rted

.

[79]

NG

Frh

NG

FPh

ase

III c

linic

al tr

ail f

aile

d to

con

firm

the

earli

er in

dica

tions

of e

ffic

acy.

G

enen

tech

has

dec

ided

not

to p

roce

ed w

ith fu

rthe

r dev

elop

men

t of r

hNG

F.[8

0]

CBZ

Phen

ytoi

nG

abap

entin

Lam

otrig

ine

Posit

ive

resu

lts in

RC

Ts a

re o

vers

hado

wed

by

limita

tions

in s

tudy

met

hodo

logy

; CBZ

has

bee

n ve

ry d

iffic

ult t

o us

e in

clin

ical

pra

ctic

e.RC

Ts p

rovi

de s

ome

evid

ence

for t

he e

ffic

acy

of p

heny

toin

in N

P, b

ut d

ata

on it

s ut

ility

are

stil

l lac

king

.Ef

fect

ive

in re

lievi

ng p

ain

in p

ainf

ul D

N a

nd P

HN

, is

wel

l tol

erat

ed a

nd is

sim

ilar t

o pl

aceb

o w

ith re

gard

to o

vera

ll oc

curr

ence

of a

dver

se

even

ts. S

tudi

es a

re w

arra

nted

to in

vest

igat

e th

e us

e of

gab

apen

tin in

oth

er p

ainf

ul n

euro

path

ic d

isord

ers,

suc

h as

CPS

P, S

CI a

nd

phan

tom

lim

b pa

in.

Effe

ctiv

e in

relie

ving

refr

acto

ry T

N, H

IV-a

ssoc

iate

d ne

urop

athy

and

CPS

P. A

dver

se e

vent

s co

uld

be a

sig

nific

ant l

imiti

ng fa

ctor

s in

its

use.

[81]

Topi

cal a

nd o

ther

form

s of

per

iphe

ral

adm

inist

ratio

n of

: N

SAID

s, o

pioi

ds, c

apsa

icin

, loc

al a

nest

hetic

s,

α-a

dren

ocep

tor a

goni

sts,

ant

idep

ress

ants

, gl

utam

ate

rece

ptor

ant

agon

ists

NSA

IDs,

opi

oids

, cap

saic

in, L

A, α

-adr

enoc

epto

r ago

nist

s: u

sed

at p

rese

nt.

AD

s, g

luta

mat

e re

cept

or a

ntag

onist

s: s

ome

clin

ical

dat

a on

thei

r use

.[8

2]

Gab

apen

tin (A

ED),

5% li

doca

ine

patc

h,

opio

id a

nalg

esic

s, tr

amad

ol h

ydro

chlo

ride,

tr

ycic

lic a

ntid

epre

ssan

ts

(nor

trip

tylin

e/de

sipra

min

e)A

ntic

onvu

lsant

s (la

mot

rigin

e,

carb

amaz

epin

e), a

ntid

epre

ssan

ts (S

SRI:

bupr

opio

n, c

italo

pram

, par

oxet

ine,

ve

nlaf

axin

e)A

ntic

onvu

lsant

s (le

vetir

acet

am,

oxca

rbam

azep

in, t

iaga

bin,

pre

gaba

lin,

topi

ram

ate,

zon

isam

ide)

Oth

er m

edic

atio

ns: c

apsa

icin

, clo

nidi

ne,

dext

rom

etho

rpha

n, m

exile

tine

Firs

t-lin

e m

edic

atio

ns fo

r NP.

Seco

nd-li

ne m

edic

atio

ns.

Aw

aitin

g re

sults

of R

CTs

.

They

may

occ

asio

nally

be

effe

ctiv

e in

indi

vidu

al c

ircum

stan

ces.

[83]

Tab

le 6

. Exp

erts

’ op

inio

n o

n p

har

mac

olo

gic

al t

reat

men

t o

pti

on

s fo

r n

euro

pat

hic

pai

n (

2000

–200

5) (

Co

nt.

).

Dru

g(s

)A

uth

ors

’ co

mm

ents

Ref

.

AD

: An

tid

epre

ssan

t d

rug

; AED

: An

tiep

ilep

tic

dru

g; C

BZ:

Car

bam

azep

ine;

CPS

P: C

entr

al p

ost

stro

ke p

ain

; DN

: Dia

bet

ic n

euro

pat

hy;

i.t.

: In

trat

hec

al; i

.v.:

Intr

aven

ou

s; L

A: L

oca

l an

esth

etic

; NaR

I:N

ora

dre

nal

ine

reu

pta

ke in

hib

ito

rs; N

aSSA

: No

rad

ren

erg

ic a

nd

sp

ecif

ic s

ero

ton

iner

gic

an

tid

epre

ssan

ts; N

GF:

Ner

ve g

row

th f

acto

r; N

P: N

euro

pat

hic

pai

n; N

MD

A:N

-met

hyl

-D-a

spar

tic

acid

NSA

ID: N

on

ster

oid

al a

nti

-in

flam

mat

ory

dru

g; P

HN

: Po

sth

erp

etic

neu

ralg

ia; R

CT:

Ran

do

miz

ed c

on

tro

lled

tri

al; r

hN

GF:

Rec

om

bin

ant

hu

man

ner

ve g

row

th f

acto

r; R

SD: R

efle

x sy

mp

atet

hic

dys

tro

ph

y; R

TX: R

esin

ifer

ato

xin

; SC

I: Sp

inal

co

rd in

jury

; SN

aRI:

Sero

ton

in a

nd

no

rad

ren

erg

ic r

eup

take

inh

ibit

ors

; SSR

I: Se

lect

ive

sero

ton

in r

eup

take

inh

ibit

or;

TC

A: T

ricy

clic

an

tid

epre

ssan

t; T

N: T

rig

emin

al n

eura

lgia

; VR

: Van

illo

id r

ecep

tor.



NSA

IDs

Opi

oids

Na+

cha

nnel

s bl

ocke

rs (l

idoc

aine

, mex

iletin

e)A

ntic

onvu

lsant

s (c

arba

maz

epin

e, N

a va

lpro

ate,

lam

otrig

ine)

Gab

apen

tinTC

As

Topi

cal c

apsa

icin

Lim

ited

effic

acy

in N

P.Ef

icac

ious

aga

inst

ner

ve le

sions

or D

N; p

artia

lly e

ffic

acio

us a

gain

st d

eaff

eren

tatio

n pa

in; n

ot e

ffic

acio

us a

gain

st P

HN

. Use

fuln

ess

limite

d by

adv

erse

eff

ects

.A

llevi

ate

pain

in P

HN

, ner

ve in

jury

and

DN

. Use

fuln

ess

limite

d by

sid

e ef

fect

s.C

linic

al a

ctiv

ity a

gain

st T

N a

nd la

ncin

atin

g pa

in.

Effic

acy

agai

nst P

HN

, DN

, per

iphe

ral n

erve

inju

ry a

nd R

SD.

Mod

erat

e ac

tivity

aga

inst

DN

, PH

N a

nd R

SD. E

ffic

acy

limite

d by

into

lera

ble

side

effe

cts.

Prim

arily

use

d as

adj

unct

s to

oth

er tr

eatm

ents

.M

odes

t, pr

obab

ly a

rtef

actu

al e

ffec

ts; c

an e

xace

rbat

e N

P in

HIV

.N

P is

gene

rally

refr

acto

ry to

trea

tmen

t and

resp

onds

poo

rly o

r onl

y pa

rtia

lly to

ava

ilabl

e th

erap

ies.

The

re is

a h

igh

unm

et m

edic

al n

eed

for t

hera

pies

that

trea

t NP

effe

ctiv

ely.

[84]

Opi

oids

Gab

apen

tinSo

me

relie

f, lim

ited

by to

lera

nce

and

unac

cept

able

sid

e ef

fect

s.Ef

fect

ive

in a

ppro

xim

atel

y ha

lf th

e pa

tient

pop

ulat

ion;

mod

est p

ain

relie

f; lim

ited

by s

ide

effe

cts.

Cur

rent

ther

apie

s fo

r NP

are

of li

mite

d be

nefit

.

[85]

Gab

apen

tin

Oft

en u

sed

to tr

eat N

P; h

owev

er, a

sub

stan

tial p

ropo

rtio

n of

pat

ient

s fin

d th

is dr

ug in

effe

ctiv

e, p

artia

lly e

ffec

tive

or p

oorly

tole

rate

d.[8

6]

i.t. b

aclo

fen

Seve

ral s

tudi

es h

ave

indi

cate

d th

at i.

t. ba

clof

en p

rovi

des

relie

f of C

P in

pat

ient

s w

ith s

past

icity

. To

date

, onl

y th

ree

stud

ies

have

sho

wn

it to

be

effe

ctiv

e in

pat

ient

s w

ith p

erip

hera

l noc

icep

tive

or N

P. C

ombi

natio

ns o

f bac

lofe

n an

d m

orph

ine

or c

loni

dine

are

mor

e ef

fect

ive

than

eac

h dr

ug a

lone

.

[87]

5% li

doca

ine

patc

hO

win

g to

its

prov

en e

ffic

acy

and

safe

ty p

rofil

e, th

e 5%

lido

cain

e pa

tch

has

been

reco

mm

ende

d as

a fi

rst-

line

ther

apy

for t

he

trea

tmen

t of t

he n

euro

path

ic p

ain

of P

HN

.[8

8]

Lido

cain

eM

exile

tine

Opi

oids

Am

itrip

tylin

eG

abap

entin

Lam

otrig

ine

Effe

ctiv

e tr

eatm

ent o

ptio

ns fo

r CP

are

limite

d in

num

ber a

nd e

ffic

acy.

Phar

mac

olog

ical

inte

rven

tions

with

dem

onst

rate

d ef

ficac

y in

CP

synd

rom

es: i

.v. l

idoc

aine

, opi

oids

, am

itrip

tylin

e, g

abap

entin

and

la

mot

rigin

e.i.v

. lid

ocai

ne is

pro

babl

y th

e m

ost e

ffec

tive

agen

t ava

ilabl

e fo

r CP

sym

ptom

s, a

lthou

gh it

s or

al a

nalo

g m

exile

tine

is no

t sim

ilarly

ef

fect

ive.

The

use

of o

pioi

ds is

con

trov

ersia

l but

evo

lvin

g ev

iden

ce s

uppo

rts

thei

r eff

icac

y in

the

trea

tmen

t of N

P. A

mon

g 15

pat

ient

s w

ith C

P (C

PSP

six, S

CI n

ine)

at t

he e

nd o

f 1 y

ear,

all b

ut th

ree

(one

CPS

P, tw

o SC

I) ha

d di

scon

tinue

d or

al m

orph

ine

due

to m

inim

al e

ffic

acy

and/

or p

oor t

oler

abili

ty.

In c

oncl

usio

n, th

e ef

ficac

y of

lido

cain

e an

d m

orph

ine

for t

he tr

eatm

ent o

f CP

has

been

dem

onst

rate

d. H

owev

er, o

win

g to

logi

stic

and

sid

e-ef

fect

issu

es, t

hese

ther

apie

s ar

e no

t opt

imal

for l

ong-

term

man

agem

ent o

f CP.

[89]

Gab

apen

tinO

ther

sC

ritic

al s

elec

tion

of R

CTs

. Eff

icac

y ev

alua

ted

as a

per

cent

age

of th

e im

prov

emen

t in

pain

inte

nsity

bet

wee

n ba

selin

e an

d en

d po

int,

tole

rabi

lity

by n

umbe

r of s

tudy

disc

ontin

uatio

ns b

ecau

se o

f adv

erse

eve

nts

and

inci

denc

e of

adv

erse

eve

nts.

Sm

all p

atie

nt n

umbe

rs,

diff

eren

ces

in p

atie

nt p

opul

atio

ns, v

aria

biliy

in tr

eatm

ent s

ched

ules

and

stu

dy d

esig

n an

d fla

ws

mad

e co

mpa

rison

bet

wee

n di

ffer

ent

stud

ies

scie

ntifi

cally

impo

ssib

le. A

utho

rs’ c

oncl

usio

n: o

nly

gaba

pent

in is

stu

died

in la

rge

(ove

r 200

patie

nts)

, pla

cebo

-con

trol

led

stud

ies

show

ing

good

eff

icac

y an

d sa

fety

.

[90]

Tab

le 6

. Exp

erts

’ op

inio

n o

n p

har

mac

olo

gic

al t

reat

men

t o

pti

on

s fo

r n

euro

pat

hic

pai

n (

2000

–200

5) (

Co

nt.

).

Dru

g(s

)A

uth

ors

’ co

mm

ents

Ref

.

AD

: An

tid

epre

ssan

t d

rug

; AED

: An

tiep

ilep

tic

dru

g; C

BZ:

Car

bam

azep

ine;

CPS

P: C

entr

al p

ost

stro

ke p

ain

; DN

: Dia

bet

ic n

euro

pat

hy;

i.t.

: In

trat

hec

al; i

.v.:

Intr

aven

ou

s; L

A: L

oca

l an

esth

etic

; NaR

I:N

ora

dre

nal

ine

reu

pta

ke in

hib

ito

rs; N

aSSA

: No

rad

ren

erg

ic a

nd

sp

ecif

ic s

ero

ton

iner

gic

an

tid

epre

ssan

ts; N

GF:

Ner

ve g

row

th f

acto

r; N

P: N

euro

pat

hic

pai

n; N

MD

A:N

-met

hyl

-D-a

spar

tic

acid

NSA

ID: N

on

ster

oid

al a

nti

-in

flam

mat

ory

dru

g; P

HN

: Po

sth

erp

etic

neu

ralg

ia; R

CT:

Ran

do

miz

ed c

on

tro

lled

tri

al; r

hN

GF:

Rec

om

bin

ant

hu

man

ner

ve g

row

th f

acto

r; R

SD: R

efle

x sy

mp

atet

hic

dys

tro

ph

y; R

TX: R

esin

ifer

ato

xin

; SC

I: Sp

inal

co

rd in

jury

; SN

aRI:

Sero

ton

in a

nd

no

rad

ren

erg

ic r

eup

take

inh

ibit

ors

; SSR

I: Se

lect

ive

sero

ton

in r

eup

take

inh

ibit

or;

TC

A: T

ricy

clic

an

tid

epre

ssan

t; T

N: T

rig

emin

al n

eura

lgia

; VR

: Van

illo

id r

ecep

tor.


672 Therapy (2006) 3(5)

TCA

s

Gab

apen

tin, l

idoc

aine

pat

ch

Opi

oids

and

oth

ers

Unt

il re

cent

ly, T

CA

s w

ere

the

trea

tmen

t of c

hoic

e fo

r PH

N; h

owev

er, R

CTs

hav

e de

mon

stra

ted

that

eff

ectiv

e pa

in re

lief w

ith T

CA

is

repo

rted

in o

nly

appr

oxim

atel

y ha

lf of

all

patie

nts.

Mor

eove

r, TC

As

pres

ent r

isks

of n

umer

ous

side

effe

cts

that

are

of p

artic

ular

co

ncer

n am

ong

the

elde

rly, w

ho c

ompr

ise th

e m

ajor

ity o

f PH

N p

atie

nts.

Base

d on

RC

Ts in

PH

N p

atie

nts,

the

US

FDA

has

app

rove

d th

e an

ticon

vulsa

nt g

abap

entin

and

the

LA li

doca

ine

(adh

esiv

e pa

tch)

for

pain

in P

HN

. Unl

ike

TCA

s, b

oth

of th

ese

agen

ts a

ppea

r to

be w

ell t

oler

ated

and

pre

sent

litt

le ri

sk o

f dru

g–dr

ug in

tera

ctio

n.O

ther

ther

apie

s, in

clud

ing

long

-act

ing

opio

id tr

eatm

ent,

have

also

sho

wn

prom

ise in

con

trol

led

clin

ical

tria

ls fo

r PH

N m

anag

emen

t

[91]

TCA

s an

d ga

bape

ntin

Topi

cal l

idoc

aine

Opi

oids

Cap

saic

inN

MD

A a

ntag

onist

s

PHN

requ

ires

thor

ough

eva

luat

ion

and

deve

lopm

ent o

f a m

anag

emen

t str

ateg

y fo

r eac

h in

divi

dual

pat

ient

. In

itial

ther

apy

is w

ith T

CA

s (e

.g.,

nort

ripty

line)

or t

he A

ED g

abap

entin

.Re

duce

s al

lody

nia

freq

uent

ly.St

rong

opi

oids

are

som

etim

es re

quire

d.To

pica

l cre

am is

ben

efic

ial f

or a

sm

all p

ropo

rtio

n of

pat

ient

s, b

ut is

poo

rly to

lera

ted.

Not

pro

ved

bene

ficia

l, w

ith th

e ex

cept

ion

of k

etam

ine.

[92]

Topi

ram

ate

Ther

e is

now

evi

denc

e th

at to

pira

mat

e is

effe

ctiv

e in

the

trea

tmen

t of N

P. H

owev

er, f

urth

er R

CTs

are

nee

ded

to c

onfir

m th

is.[9

3]

VR1

ago

nist

sSm

all m

olec

ule

agon

ists

of V

R1, i

nclu

ding

cap

saic

in a

nd R

TX, a

re c

urre

ntly

use

d fo

r a n

umbe

r of c

linic

al s

yndr

omes

, inc

ludi

ng

intr

acta

ble

NP.

[94]

Ant

idep

ress

ants

and

AED

s TC

As (

e.g.

, am

itrip

tylin

e, n

ortr

ipty

line,

des

ipra

min

e), c

erta

in n

ovel

AD

s (i.e

., bu

prop

ion,

ven

lafa

xine

, dul

oxet

ine)

, firs

t-ge

nera

tion

AED

s (C

BZ, p

heny

toin

) and

sec

ond-

gene

ratio

n A

EDs

(gab

apen

tin, p

rega

balin

) are

eff

ectiv

e in

the

trea

tmen

t of N

P. T

he e

ffic

acy

and

tole

rabi

lity

of A

Ds

and

AED

s ar

e co

mpa

rabl

e, a

lthou

gh s

afet

y an

d sid

e-ef

fect

pro

files

diff

er. T

CA

s ar

e th

e m

ost c

ost–

effe

ctiv

e ag

ents

, bu

t sec

ond-

gene

ratio

n A

EDs

are

asso

ciat

ed w

ith fe

wer

saf

ety

conc

erns

in e

lder

ly p

atie

nts.

[95]

Tab

le 6

. Exp

erts

’ op

inio

n o

n p

har

mac

olo

gic

al t

reat

men

t o

pti

on

s fo

r n

euro

pat

hic

pai

n (

2000

–200

5) (

Co

nt.

).

Dru

g(s

)A

uth

ors

’ co

mm

ents

Ref

.

AD

: An

tid

epre

ssan

t d

rug

; AED

: An

tiep

ilep

tic

dru

g; C

BZ:

Car

bam

azep

ine;

CPS

P: C

entr

al p

ost

stro

ke p

ain

; DN

: Dia

bet

ic n

euro

pat

hy;

i.t.

: In

trat

hec

al; i

.v.:

Intr

aven

ou

s; L

A: L

oca

l an

esth

etic

; NaR

I:N

ora

dre

nal

ine

reu

pta

ke in

hib

ito

rs; N

aSSA

: No

rad

ren

erg

ic a

nd

sp

ecif

ic s

ero

ton

iner

gic

an

tid

epre

ssan

ts; N

GF:

Ner

ve g

row

th f

acto

r; N

P: N

euro

pat

hic

pai

n; N

MD

A:N

-met

hyl

-D-a

spar

tic

acid

NSA

ID: N

on

ster

oid

al a

nti

-in

flam

mat

ory

dru

g; P

HN

: Po

sth

erp

etic

neu

ralg

ia; R

CT:

Ran

do

miz

ed c

on

tro

lled

tri

al; r

hN

GF:

Rec

om

bin

ant

hu

man

ner

ve g

row

th f

acto

r; R

SD: R

efle

x sy

mp

atet

hic

dys

tro

ph

y; R

TX: R

esin

ifer

ato

xin

; SC

I: Sp

inal

co

rd in

jury

; SN

aRI:

Sero

ton

in a

nd

no

rad

ren

erg

ic r

eup

take

inh

ibit

ors

; SSR

I: Se

lect

ive

sero

ton

in r

eup

take

inh

ibit

or;

TC

A: T

ricy

clic

an

tid

epre

ssan

t; T

N: T

rig

emin

al n

eura

lgia

; VR

: Van

illo

id r

ecep

tor.



Topi

cal m

edic

atio

ns: 5

% li

doca

ine

patc

h,

Cap

saic

inA

EDs:

C

BZ

Gab

apen

tinLa

mot

rigin

e

Leve

tirac

etam

OX

CBZ

Preg

abal

inTi

agab

ine

Topi

ram

ate

Valp

roat

eA

ntid

epre

ssan

ts:

TCA

sSS

RIs

SNRI

s

Dul

oxet

ine

ND

RIs

Benz

odia

zepi

nes

Ana

lges

ics:

Tram

adol

Opi

oids

Effe

ctiv

e in

PH

N.

No

signi

fican

t ove

rall

effe

ct (s

ix R

CTs

).

CBZ

: US

FDA

-app

rove

d fo

r TN

. Sug

gest

ed a

s a

seco

nd-li

ne A

ED fo

r NP

in p

atie

nts

unre

spon

sive

to g

abap

entin

Gab

apen

tin h

as th

e br

oade

st e

vide

nce

for e

ffic

acy

agai

nst N

P. F

DA

-app

rove

d fo

r PH

N. I

t has

yie

lded

pos

itive

resu

lts in

a n

umbe

r of

RCTs

in N

P (p

ainf

ul D

N, P

HN

, pha

ntom

lim

b pa

in, G

uilla

in–B

arré

syn

drom

e, S

CI,

CRP

S 1)

.D

wor

kin

and

colle

ague

s su

gges

t tha

t gab

apen

tin s

houl

d be

use

d as

a fi

rst-

line

med

icat

ion

for N

PSh

own

effic

acy

in R

CTs

aga

inst

NP

due

to D

N, C

PSP,

SC

I, H

IV. I

t is

sugg

este

d as

a s

econ

d-lin

e A

ED fo

r NP

in p

atie

nts

unre

spon

sive

to

gaba

pent

in.

No

publ

ished

con

trol

led

stud

ies

on N

P.Sh

own

bene

fit in

one

RC

T in

DN

. FD

A-a

ppro

ved

for P

HN

and

pai

nful

DN

.N

o RC

Ts in

dica

ting

its u

sefu

lnes

s fo

r NP

Neg

ativ

e re

sults

in th

ree

RCTs

in D

N, p

ositi

ve re

sults

in o

ne.

Posit

ive

resu

lts in

one

stu

dy fo

r pai

nful

DN

.

Hav

e be

en s

how

n in

man

y sm

all R

CTs

to b

e us

eful

for t

he tr

eatm

ent o

f NP.

.Le

ss e

ffec

tive

agai

nst N

P th

an A

Ds

that

incr

ease

the

activ

ity o

f bot

h no

repi

neph

rine

and

sero

toni

n.N

o di

ffer

ence

bet

wee

n th

e TC

A im

ipra

min

e an

d ve

nlaf

axin

e in

a R

CT

in p

atie

nts

with

pai

nful

DN

. Eff

ectiv

e vs

pla

cebo

at

high

erdo

sage

.FD

A-a

ppro

ved

for t

he tr

eatm

ent o

f pai

nful

DN

.SR

bup

ropi

on m

ore

effe

ctiv

e th

an p

lace

bo in

pat

ient

s w

ith d

iffer

ent N

P st

ates

. NB:

maj

or s

afet

y co

ncer

ns.

Not

reco

mm

ende

d fo

r the

trea

tmen

t of c

hron

ic p

ain

cond

ition

s.

Posit

ive

resu

lts fr

om R

CTs

in p

ainf

ul D

N, d

iffer

ent N

P st

ates

, PH

N.

Oxy

codo

ne: e

ffec

tive

in P

HN

and

DN

(stu

dies

of o

nly

8–12

wee

ks d

urat

ion)

. NB:

saf

ety

conc

erns

: lon

g-te

rm u

se o

f opi

oids

raise

s co

ncer

ns a

bout

incr

easin

g hy

pera

lges

ia. T

he p

ract

ition

er w

ho p

resc

ribes

opi

oids

sho

uld

obta

in a

sig

ned

opio

id a

gree

men

tan

d us

e ra

ndom

urin

e sc

reen

ing

to c

heck

for c

ompl

ianc

e. F

ollo

w-u

p di

scus

sions

on

side

effe

cts

and

func

tiona

l im

prov

emen

t with

use

of

the

opio

id s

houl

d be

doc

umen

ted.

Dw

orki

n an

d co

lleag

ues

sugg

este

d th

at th

e fir

st-li

ne tr

eatm

ents

for N

P sh

ould

be

gaba

pent

in, t

he 5

% li

doca

ine

patc

h, o

pioi

ds,

tram

adol

, and

TC

As.

It s

houl

d be

not

ed th

at th

ese

reco

mm

enda

tions

wer

e m

ade

befo

re th

e FD

A a

ppro

val o

f dul

oxet

ine

and

preg

abal

in.

[96]

Tab

le 6

. Exp

erts

’ op

inio

n o

n p

har

mac

olo

gic

al t

reat

men

t o

pti

on

s fo

r n

euro

pat

hic

pai

n (

2000

–200

5) (

Co

nt.

).

Dru

g(s

)A

uth

ors

’ co

mm

ents

Ref

.

AD

: An

tid

epre

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674 Therapy (2006) 3(5)

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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Website201. Worldwide Marketing Research & Strategic

consulting, ER Publications. www.wwmr.com

AffiliationsVincenzo Bonicalzi, MD

Turin Advanced Neuromodulation Group, Cso Einaudi 2, 10128 Torino, ItalyTel.: +39 349 471 [email protected] Canavero, MD

Turin Advanced Neuromodulation Group, Cso Einaudi 2, 10128 Torino, ItalyTel.: +39 349 471 [email protected]

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