pregabalin in the treatment of chronic pain

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Pregabalin in the Treatment of Chronic PainAn Overview

S. Chiechio,1 M. Zammataro,1 F. Caraci,1 L. Rampello,2 A. Copani,1 A.F. Sabato3 and F. Nicoletti4,5

1 Department of Pharmaceutical Sciences, University of Catania, Catania, Italy

2 Department of Neuroscience, University of Catania, Catania, Italy

3 Emergency Department, Anesthesiology and Resuscitation Unit, Service of Physiopathology and Therapy

of Pain, Tor Vergata University, Rome, Italy

4 Department of Human Physiology and Pharmacology, University of Rome ‘La Sapienza’, Rome, Italy

5 INM Neuromed, Pozzilli, Italy

Contents

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2031. The a2d Subunit of Voltage-Sensitive Ca2+ Channels as a Target for Analgesic Drugs . . . . . . . . . . . . . 2052. Pregabalin for Chronic Pain: a ‘Better Gabapentin’ or a New Analgesic with

Independent Features?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2053. Clinical Applications of Pregabalin in the Treatment of Chronic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . 206

3.1 Pain Related to Diabetic Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2063.2 Pain Associated with Postherpetic Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2063.3 Pain Associated with Spinal Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2073.4 Postoperative Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2073.5 Restless Legs Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2073.6 Cervicobrachialgia and Lumbosciatalgia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2083.7 Neuropathic Cancer Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208

4. Pregabalin: More Than a Pharmacological Evolution of Gabapentin . . . . . . . . . . . . . . . . . . . . . . . . . . 2085. European and American Guidelines for the Treatment of Neuropathic Pain:

Pregabalin and Gabapentin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2096. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210

Abstract Chronic ‘pathological’ pain is sustained by mechanisms of peripheral andcentral sensitization, which are being increasingly investigated at the mole-cular and cellular levels. The molecular determinants of nociceptive sensitiza-tion are natural targets for potential analgesic drugs used in the treatment ofdifferent forms of pain. Most of these determinants are common to all formsof chronic pain, and it is therefore not surprising that drugs specifically targetedfor the treatment of neuropathic pain are effective in relieving nociceptiveinflammatory pain and vice versa. Themolecular mechanisms of sensitizationthat occur in peripheral nociceptors and the dorsal horns of the spinal cordare putative targets for context-dependent drugs, i.e. drugs that are able todiscriminate between ‘normal’ and ‘pathological’ pain transmission. Amongthese, pregabalin and gabapentin bind to the a2d subunit of voltage-sensitiveCa2+ channels, which sustain the enhanced release of pain transmitters at thesynapses between primary afferent fibres and second-order sensory neurons

REVIEW ARTICLEClin Drug Invest 2009; 29 (3): 203-213

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under conditions of chronic pain. Pregabalin in particular represents a remark-able example of a context-dependent analgesic drug that acts at a criticalstep of nociceptive sensitization. Preclinical and clinical data suggest thatpregabalin is more than a structural and functional analogue of gabapentinandmay be effective in the treatment of nociceptive inflammatory pain that isresistant to gabapentin.

The nociceptive system is prone to amplifica-tion processes particularly aimed at generatingmore efficient responses to potential dangerousstimuli. Under pathological conditions, this fea-ture of the nociceptive system is translated intothemajor hallmarks of chronic pain: hyperalgesia(a decreased threshold to painful stimuli),mechanical allodynia (pain arisen from tactilenon-painful stimuli) and spontaneous pain. Themolecular mechanisms underlying these pheno-mena are usually described in the context ofneuropathic pain, which results from injury to thecentral and peripheral nervous system. However,similar mechanisms also underlie chronic painarising from different origins, including inflam-matory ‘nociceptive’ pain, cancer pain (that oftenincorporates inflammatory and neuropathiccomponents) and even neurovascular pain typicalof migraine. Distinguishing among differentsubcategories of chronic pain is helpful from aclinical standpoint but might represent a limitingfactor for the correct use of analgesic drugs.

Pain is usually generated from nociceptors onperipheral C (unmyelinated) and Ad fibre term-inals. However, large myelinated Ab fibres arealso involved in the pathophysiology of chronicpain, in particular the generation of mechanicalallodynia.[1,2] Fibres that convey nociceptive sig-nals from the periphery to the spinal cord origi-nate from pseudounipolar neurons that arelocated in the dorsal root ganglia (DRG) and insensory ganglia of the cranial nerves (e.g. theGasser ganglion of the trigeminal nerve).[3] Inperipheral terminals, pathological pain may arisefrom and be sustained by an increased sensitivityof transient receptor potential subfamily V(TRPV) receptors and voltage-sensitive Na+

channels (VSSC), which sense thermal stimula-tion and generate action potentials, respectively.

TRPV receptors belong to the transient re-ceptor potential (TRP) family of ion channels.The TRPV1 receptor, also called VR1 or vanil-loid receptor, is a non-selective cation channelexpressed in C and Ad nociceptors,[4] and isimplicated in the pathophysiology of chronicpain.[5,6] A number of different stimuli canactivate TRPV1 receptors, including capsaicin,temperature >42�C, a low ambient pH, severallipoxygenase metabolites, and extracellularmonovalent and divalent cations.[4,7-10] Ananda-mide, one of the two major endocannabinoidsactivating cannabinoid receptor type 1 receptors,can also bind to and activate TRPV1 receptors athigh concentrations.[11]

TRPV1 receptors form membrane ion chan-nels permeable to Na+ and Ca2+, and their acti-vation leads to membrane depolarization andopening of VSSCs. The activity of TRPV1 re-ceptors is regulated by phosphorylation mediatedby protein kinaseA,[12] protein kinaseC (PKC)[13,14]

and Src kinase.[15]

Activation of VSSCs leads to the generation ofaction potentials that convey sensory informationfrom the nociceptors to the dorsal horns of thespinal cord. The properties of VSSCs dependstrictly on the type of a-subunit that form thechannel pore.[16] In the CNS, most VSSCs aresensitive to the inhibitory action of tetrodotoxin(TTX). DRG neurons, which give rise to Cand Ad fibres, express both TTX-sensitive andTTX-insensitive VSSCs.[17,18] TTX-insensitivechannels are rapidly activated but slowly inacti-vated, thus being able to generate persistent ioncurrents.[19]

There are two major types of nociceptive fi-bres that project to the dorsal horns of the spinalcord: (i) unmyelinated, non-peptidergic fibresand (ii) peptidergic fibres containing substance

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P, neurokinin A, and calcitonin gene-relatedpeptide (CGRP). Glutamate acts as an excitatoryneurotransmitter released from both types offibres.[20-22] Release of glutamate and nociceptivepeptides from primary afferent fibres followsactivation of N-type voltage-sensitive Ca2+ chan-nels (VSCCs) and is negatively modulated bypresynaptic group II metabotropic glutamatereceptors.[23]

1. The a2d Subunit of Voltage-SensitiveCa2+++ Channels as a Target for AnalgesicDrugs

VSCCs, ion channels permeable to Ca2+ thatare composed of subunits a1, a2, d, b and g, areactivated by membrane depolarization.[16]

The a1 subunit forms the ion channel pore andcontains the voltage sensor. VSCCs are classifiedinto L-type, P/Q-type, N-type, R-type andT-type, based on the type of a1 subunit.[24-26]

N-type VSCCs mediate the release of glutamateand peptides from primary afferent fibres andtherefore modulate pain transmission.[27-33]

The a2d subunit represents an ancillary sub-unit that regulates the activity of VSCCs.[34] Thea2d subunit has recently attracted interest in thepharmacological treatment of chronic pain be-cause it contains the binding site for two drugsused largely for analgesic therapy: pregabalin andgabapentin.[35-40] Compared with gabapentin,pregabalin exhibits a slightly higher binding affin-ity to the a2d subunit (32 nmol/L vs 40 nmol/L fordisplacement of [3H]-gabapentin binding in braintissue). An arginine residue in position 217(Arg217) of the a2d subunit seems to be essentialfor both pregabalin and gabapentin binding.[41,42]

The a2d subunit is a prime target for analgesicdrugs because its function is context-dependent.Under physiological conditions, the a2d subunitexhibits low expression levels and exerts little ifany influence on Ca2+ channel activity. In con-trast, the subunit becomes overexpressed andcontributes significantly to the activity of VSCCsunder pathological conditions, as in models ofchronic pain.[43-45] Accordingly, both pregabalinand gabapentin reduce the evoked release ofsubstance P and CGRP only in spinal cord slices

that have been sensitized by proinflammatorycytokines or PKC.[46-48] In addition, gabapentindecreases excitatory synaptic transmission in thedorsal horn of the spinal cord in animals devel-oping chronic pain, but not in control animals.[48]

The ability of pregabalin and gabapentin to in-hibit activated Ca2+ channels under pathologicalconditions is the basis of the good tolerability ofthese compounds. Finally, the presence of a spe-cific receptor for pregabalin and gabapentin inthe a2d subunit suggests the existence of en-dogenous ligands of the subunit. Interestingly, anumber of branched chain L-amino acids such asL-leucine, L-isoleucine and L-methionine areable to interact with the a2d subunit with nano-molar affinity and in some experimental modelsincreases in L-amino acid concentrations inhibitthe action of both pregabalin and gabapentin.This favours the action of pregabalin over gaba-pentin, on the assumption that a drug with a higheraffinity for its recognition sites can more easilycompete with putative endogenous ligands.[37]

2. Pregabalin for Chronic Pain: a ‘BetterGabapentin’ or a New Analgesic withIndependent Features?

The success of gabapentin in the treatment ofchronic pain has stimulated the search for addi-tional drugs interacting with the a2d subunit ofVSCCs. Pregabalin, which is currently used forthe treatment of different forms of pain, shows anincreased binding affinity to the a2d subunit anda better pharmacokinetic profile than gaba-pentin.[49] As a result, pregabalin is particularlypotent and effective as an analgesic, and is char-acterized by linear kinetics across a wide rangeof doses. Similar to gabapentin, pregabalin isnot metabolized by cytochrome P450 (CYP)enzymes, and is neither a metabolic inhibitor noran inducer of drug-metabolizing enzymes.[49-52]

These features make pregabalin particularly sui-table in terms of its lack of interactions with otherdrugs currently used for the treatment of chronicpain or associated psychiatric disorders (e.g.anxiety and depression). Although pregabalinshares an ability tomodulate VSCCs[50] with gaba-pentin, its analgesic activity in patients resistant to

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gabapentin (see sections 3.1, 3.2 and 3.6) suggeststhe existence of additional mechanisms that arespecific to pregabalin. Recent evidence suggeststhat pregabalin has a direct impact on the releasemachinery of neurotransmitters by inhibitingmem-brane fusion of synaptic vesicles in nerve term-inals.[53] The action of pregabalin is specific for acertain pool of synaptic vesicles defined as the‘ready releasable pool’.[53] Synaptic vesicles of theready releasable pool are the first to be recruitedin the release of neurotransmitters in response toCa2+ entry in presynaptic terminals.[54] Pregabalininhibits the fusion of approximately 25% of ve-sicles in the ready releasable pool and, interest-ingly, NMDA receptor antagonists prevent thisaction. It is unclear whether the action of pregabalininvolves presynaptic NMDA receptors or ratherpostsynaptic receptors that communicate with theaxon terminal via the production of retrogrademessengers.[53,55] Whether or not gabapentin regu-lates membrane fusion of the ready releasable poolof synaptic vesicles is also presently unknown.

3. Clinical Applications of Pregabalin inthe Treatment of Chronic Pain

3.1 Pain Related to Diabetic Neuropathy

Polyneuropathy, mononeuropathy and/orneuropathy of the autonomic nervous systemexacerbate the course of type 1 and type 2 dia-betes mellitus in approximately 20–24% of pa-tients.[56] Diabetic neuropathy is characterized bythe loss of myelinated and unmyelinated fibres.The most frequent form of diabetic neuropathy isdistal symmetric polyneuropathy, characterizedby hyperaesthesia, dysaesthesia and paraesthesia.Neuropathic pain arises in some patients affectedby diabetic polyneuropathy and is sometimespreceded by an improvement in glycaemic con-trol.[57] Pain involves the distal end of inferiorlimbs, is usually present at rest, and progressesduring the night. Diabetic polyradiculopathy ischaracterized by highly invalidating pain in thereceptive fields of pain fibres. Intercostal radicu-lopathy causes pain in thoracic and abdominalregions. Involvement of the lumbar plexus orfemoral nerve causes pain of the thigh and hip,

and is associated with muscular asthenia. Neuro-pathy is one of the consequences of diabeticmicroangiopathy affecting the vasa nervorum,and also results from a direct toxic effect of highglucose levels on peripheral nerves. The majorfour pathogenetic theories include: (i) productionof advanced glycosylation end products by enzy-matic and non-enzymatic glycosylation of intra-and extracellular proteins;[58,59] (ii) conversion ofglucose into sorbitol by the enzyme aldose re-ductase (sorbitol causes damage to the peripheralnerves by osmotic mechanisms and formation ofreactive oxygen species[60]); (iii) increased pro-duction of diacylglycerol, which activates PKC;[61]

and (iv) activation of the hexosamine pathway,which affects the formation of nitric oxide, andalters the expression of genes encoding fortransforming-growth factor-b and plasminogenactivator inhibitor type 1.[62,63]

Pregabalin has shown great efficacy andrapid onset of action in relieving pain associa-ted with diabetic polyneuropathy.[64-68] Pregaba-lin can also improve sleep disorders, depressionand anxiety secondary to painful neuro-pathies.[65,69-71] In the authors’ experience, preg-abalin 75–600mg/day is effective in decreasingpain associated with diabetic neuropathy byabout 30–35% within 1 month (unpublisheddata, A. Sabato, Physiopathology and PainTherapy Service, University of Tor Vergata,Rome). Interestingly, pregabalin was found toreduce neuropathic pain by at least 2 pointson a 10-point visual analogue scale (VAS; range1–10) in five of eight patients resistant to gaba-pentin. Adverse effects of pregabalin (drowsiness,dizziness, dry mouth and constipation) weremodest and, with the exception of water reten-tion, decreased progressively during treatment.

3.2 Pain Associated with PostherpeticNeuropathy

Pain associated with acute neuritis or post-herpetic neuropathy represents the most debili-tating complication in herpes zoster infectionsboth in normal and in immunocompromisedpatients.[72] Postherpetic neuropathy is infrequentin young people but occurs in more than half of

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patients aged >50 years, in whom pain is localizedin the dermatome affected by the virus. Pain isusually associated with hypo- or hyperaesthesia.Besides old age, other risk factors for post-herpetic neuropathy include delayed treatmentwith antiviral drugs, severe skin eruption, acutepain during skin eruption, White race, and emo-tional or traumatic stress.[56] Pain can be persis-tent or paroxysmal and throbbing, and is usuallyincreased by sensory stimulation. Painful post-herpetic neuropathy is difficult to treat and canpersist for 5–6 years.[73] A number of studies haveshown the efficacy and tolerability of pregabalinin the treatment of postherpetic neuropathy.[69,74-77]

For example, in a double-blind randomized studyinvolving 370 patients with postherpetic neuro-pathy, pregabalin (150–600mg twice daily for13 weeks) was shown to relieve pain and improvesleep disturbances associated with pain.[75] Sabatoet al. have found that pregabalin progressivelyimproves pain associated with postherpetic neuro-pathy over about 6 months, and is effective in halfof patients (8 out of 16) resistant to gabapentin(1200–2400mg/day) [unpublished data, Physio-pathology and Pain Therapy Service, Universityof Tor Vergata, Rome].

3.3 Pain Associated with Spinal Trauma

More than half of patients with spinal traumashow pain, which is particularly severe in one-third of patients. This type of pain includes bothnociceptive and neuropathic components,[78] al-though as mentioned in the introductory section,the distinction between chronic nociceptive (i.e.inflammatory pain) and neuropathic pain is some-what artificial since the two types of pain sharecommon molecular mechanisms,[79] and thereforedrugs used in neuropathic pain may also be ef-fective in nociceptive pain and vice versa. In thestudy by Siddall et al.,[80] 137 patients recruited1 year after spinal trauma with paraplegia ortetraplegia were randomized and treated withpregabalin or placebo. Approximately 88% ofpatients experienced persistent central pain for atleast 3 months, whilst 12% of patients had remis-sions and relapses of pain for at least 6 months,prior to study start. The majority of patients were

taking other analgesic drugs, including opioids,tricyclic antidepressants, antiepileptic drugs (exceptgabapentin), NSAIDs and selective serotoninreuptake inhibitors (SSRIs)/selective norepineph-rine reuptake inhibitors (SNRIs), in addition tobenzodiazepines. Treatment with pregabalin(150–600mg/day for 3 weeks) relieved pain (as-sessed by the Short-Form McGill Pain Ques-tionnaire, VAS and the Present Pain Intensitysubscale), and improved sleep disturbances asso-ciated with pain. In addition, pregabalin reducedanxiety in patients with spinal trauma. Despitethe severity of the patients’ pathology and use ofthe drug in combination with other agents, preg-abalin was well tolerated by patients.

3.4 Postoperative Pain

Postoperative pain is responsive to gabapentinand represents a new target for pregabalin.[81]

Pregabalin has been tested in patientsundergoing surgery for the removal of thirdmolars,[82] spinal surgery,[83] and laparoscopichysterectomy.[84] In the first of these studies,pregabalin (single administration of 300mg) de-creased postoperative dental pain, achieving amore sustained analgesic action than ibuprofen400mg.[82] In the other studies, pregabalin150mg administered 1 hour before and 12 hoursafter spinal surgery or laparoscopic hysterectomyrelieved postoperative pain and decreased theneed for opioids.[83,84]

3.5 Restless Legs Syndrome

Restless legs syndrome (RLS) is a commonneurological disorder characterized by distaldysaesthesias associated with an intense need tomove the legs. In most patients, symptoms wor-sen at night and cause sleep abnormalities.[85-87]

Dopamine receptor agonists, such as prami-pexole[88] and ropinirole,[89] are first-choice drugs,whereas opioids, antiepileptics and benzodiaze-pines are second-choice drugs in the treatment ofRLS. Pregabalin was tested in 16 patients withRLS secondary to painful neuropathies and threepatients with idiopathic RLS.[90] Most patientshad a good response to pregabalin and continuedto take the drugs for about 6 months.



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3.6 Cervicobrachialgia and Lumbosciatalgia

Cervicobrachialgia is characterized by pain inthe peripheral territories of the last four cervicalnerves and the first thoracic nerve. The mostcommon cause is cervical spondylosis. Lumbo-sciatalgia represents a form of mixed nociceptive/neuropathic pain originating from the dorsalroots and localized in the lumbar region or in theterritory of the sciatic nerve. Sabato et al. havestudied the efficacy of pregabalin (75–600mg/dayfor 6 months) in 86 patients affected by cervico-brachialgia and in 257 patients affected bylumbosacral radiculopathy (unpublished data,Physiopathology and Pain Therapy Service,University of Tor Vergata, Rome). Pregabalinshowed considerable efficacy in both groups ofpatients, decreasing a 10-point VAS score byabout 3 points after 90 days of treatment. In bothstudies, pregabalin was effective in about two-thirds of patients resistant to gabapentin (21 of32 patients affected by cervicobrachialgia, and51 of 84 patients affected by lumbosciatalgia).These results suggest that the analgesic actionof pregabalin is not restricted to neuropathicpain and support the hypothesis that the me-chanism of action of pregabalin incorporatesas yet unidentified components that make thedrug effective in patients resistant to gabapentin(see section 4).

3.7 Neuropathic Cancer Pain

Cancer-related neuropathic pain may occur asa result of nerve damage from penetration of thetumour into nerves and plexuses, radiation fibro-sis, surgical injury or through the neurotoxiceffects of some chemotherapies.[91] There is in-creasing interest in the use of adjuvant analgesics,such as pregabalin, in the treatment of neuro-pathic cancer pain and two clinical trials arecurrently registered for adults aged ‡18 years(NCT00740571 and NCT00637975). A recentoff-label study that assessed pregabalin(150–300mg/day for 8 weeks) in the treatment ofchemotherapy-induced neuropathic pain in apaediatric population (n = 30; mean age 13.5years) reported a significant improvement of pain

symptoms in 86% of patients and concluded thatpregabalin appeared to be a safe and effectivetherapeutic option.[92]

4. Pregabalin: More Than aPharmacological Evolution ofGabapentin

Both preclinical and clinical studies suggestthat the mechanism of action of pregabalin is notlimited to the interaction with the a2d subunit ofVSCCs but rather incorporates additional com-ponents that may be found within the secretorypathway of synaptic vesicles.[53,55] Unravellingthese components will help to understand whypregabalin is effective in patients resistant togabapentin. The pharmacokinetic profiles ofpregabalin and gabapentin are different. Prega-balin has greater oral bioavailability than gaba-pentin,[49,93] and its oral absorption is linearacross a wide range of doses (>90%, independen-tly of the dose).[94] Conversely, absorption ofgabapentin is saturable because it involves theactivity of an L-amino acid transporter (the oralbioavailability of gabapentin decreases from 60%to 40% if the dose is increased from 300 to600mg).[95] The time to reach the plasma peakconcentration (tmax) is about 1 hour for prega-balin and 2–3 hours for gabapentin.[94] The twodrugs are not metabolized by CYP, are elimi-nated by the kidney, and show a similar elimina-tion half-life (t1=2) of between 4 and 9 hours.[94]

Antacids decrease the oral bioavailability ofgabapentin by 20–30%, but do not affect theabsorption of pregabalin.[49]

Pregabalin is also remarkably more potent thangabapentin.[95] The starting dose of pregabalin isusually 75–150mg/day (although there are con-ditions in which pregabalin has shown efficacy atlower doses), whereas the starting dose of gaba-pentin is 100–900mg/day.[96] In addition, treat-ment with gabapentin requires a long titrationperiod (usually different weeks), whereas themaximal dose of pregabalin is reached within afew days.[94] Maximal doses are 3600mg/day forgabapentin and 600mg/day for pregabalin (table I).

No direct comparison of the efficacy of preg-abalin and gabapentin is available. Data can be

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obtained from a meta-analysis of studies on theanalgesic activity of pregabalin and gabapentin indiabetic neuropathy. These include four double-blind studies of pregabalin versus placebo,[64-68]

three studies of gabapentin versus placebo,[97-99]

and a study of gabapentin versus amitripty-line.[100] In addition, there are two controlledstudies (pregabalin vs placebo and gabapentin vsplacebo) conducted in a mixed populationof patients with diabetic neuropathy and post-herpetic neuropathy.[67,92] In two of four stu-dies, gabapentin showed greater efficacy thanplacebo.[97,99] In the studies by Gorson et al.[98]

and Gilron et al.,[94] gabapentin was not superiorto placebo. In contrast, in all four controlledstudies, pregabalin showed greater analgesicefficacy than placebo, with a therapeutic gainranging from 35–40% to 50%.[64-66,68]

A recent study examined the cost-benefit ratioof pregabalin and gabapentin in the treatment ofdiabetic and postherpetic neuropathy.[76] Thestudy was based on a simulation model thatincorporated results of clinical studies withpregabalin (150–600mg/day) and gabapentin(900–3600mg/day). The economic analysis wasexpressed in terms of increases in annual costsof the drugs normalized for the quality-of-lifeindex (QALY) or increases in costs normalizedfor days spent without pain or with mild pain.

Over a period of 4 months, patients treated withpregabalin spent an additional 6–9 days with-out pain or with mild pain as compared withpatients treated with gabapentin. The cost-benefit ratio was lower for pregabalin than forgabapentin.[76]

5. European and American Guidelines forthe Treatment of Neuropathic Pain:Pregabalin and Gabapentin

The choice of analgesic drugs in the treatmentof neuropathic pain is based on safety, toler-ability, efficacy, cost and simplicity. Efficacy isusually expressed as the number needed to treat,which indicates how many patients must betreated to obtain one responsive patient withat least a 50% improvement in pain. In the guide-lines of the European Federation of NeurologicalSocieties (EFNS),[101] the most effective drugs inthe treatment of neuropathic pain includedpregabalin, gabapentin, tricyclic antidepressantsand opioids, followed by SNRIs (duloxetine andvenlafaxine) for diabetic polyneuropathy, andtopical lidocaine (lignocaine) for postherpetic neuro-pathy. However, opioids are considered as drugsof second choice because of their less favourablesafety and tolerability profile. In older patients,use of tricyclic antidepressants is limited by

Table I. Pharmacokinetic profiles of pregabalin and gabapentin (data from Gilron[96], Tassone et al.[95] and Guay[49])

Parameter Pregabalin Gabapentin

Oral bioavailability >90% independently of the dose 60% after single 300 mg dose

40% after single 600 mg dose

Protein binding Minimal Minimal

Time to maximum plasma

concentration

1 h 2–3 h

Metabolism Not metabolized by cytochrome P450 enzymes Not metabolized by cytochrome P450 enzymes

Renally excreted Renally excreted

Elimination half-life 4–7 h 5–9 h

Drug interactions No significant drug interactions reported Antacids decrease the oral bioavailability of

gabapentin by 20–30%

Starting dose 75–150 mg/day 100–900 mg/day

Titration Maximal dose achieved within a few days Over several weeks to attain maximal

tolerated dose

Administration Twice/three times daily Three times daily

Maximal dose 600 mg/day 3600 mg/day



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their anticholinergic, hypotensive, sedative andcardiotoxic effects (more prominent with tertiaryamine tricyclic antidepressants, such as imipra-mine, clomipramine and amitriptyline). Topir-amate, lamotrigine, oxcarbamazepine, NMDAreceptor antagonists and SSRIs show lower effi-cacy as analgesic agents. According to the guide-lines of the Canadian Pain Society, pregabalin,gabapentin and tricyclic antidepressants are re-commended as first-line drugs in the treatment ofneuropathic pain, followed by duloxetine, venla-faxine and topical lidocaine.[102] Tramadol andcontrolled-release opioids are recommended asthird-line treatments for moderate to severe pain,whereas cannabinoids, methadone, lamotrigine,topiramate and valproate are considered fourth-line treatments.

The guidelines of the Cohn Pain ManagementCentre of North Shore University Hospital andthe New York University School of Medi-cine highlight the importance of pregabalin andduloxetine as recently approved drugs for thetreatment of neuropathic pain.[103] Both prega-balin and gabapentin are considered as first-lineanalgesic drugs by Finnerup et al.[104]

6. Conclusion

The molecular mechanisms of sensitizationthat occur in peripheral nociceptors and thedorsal horns of the spinal cord are putative tar-gets for context-dependent drugs. Both pregaba-lin and gabapentin bind to the a2d subunit ofVSCCs; however, pregabalin shows an increasedbinding affinity and superior pharmacokineticprofile compared with gabapentin. Clinical ap-plications of pregabalin in the treatment ofchronic pain demonstrate that pregabalin maybe more than just a structural and functionalanalogue of gabapentin.

Acknowledgements

Melanie Gatt, Wolters Kluwer Health Medical Commu-nications, provided editing assistance in the preparation ofthis manuscript. This assistance was funded by Pfizer Inc. Theauthors have no conflicts of interest that are directly relevantto the content of this review.

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Correspondence: Dr Ferdinando Nicoletti, Department ofHuman Physiology and Pharmacology, University of Rome‘La Sapienza’, Piazzale Aldo Moro 6, 85100, Rome, Italy.E-mail: [email protected]



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