REVIEWS IN PAIN A BPS publication VOL.
5-
NO.2 - JUNE 20 1 1 - ISSN 2°42- 12 49
NEUROPATHIC
PAIN
........ "" ......"." .. E D IT O R IA L BO A R D
Ne uropathic pain (Nc P) is curren tly defined by the lnrern adonal Association for the
Stud y of Pain (IASP), as "pain arising as a direct consequence of a lesion o r d isease affect ing the somarusensory syste m," The large majority or Ner cases (approx. 90% ) arise from inj ury to per iphera l sensory nerves fibres as opposed to central neuronal damage. with initiat ing factors as varied as the hu man pain experience itself; ar ising fro m e.g. cancer, metabolic d isorders and viral infections as well as hum medical int ervent ions them selves e.g. surgery and chemothe rapy. C linica lly. cha racteristic sym p lOlfiS include an increased evoked pain respo nse to noxio us (hyperalgesia) and innocuous (allody nia) stimuli. and
SJX )JU 3 Il l'O US
shoo ting electric shock like pain . Pain has an affective
co mponent. a nd so co-mo rbid ities suc h as fatigue. anxiety and dep ression ca n complica te pain sym ptomatology These co- morbidities interact with the sensory aspects of the pain to
subs tantially redu ce qu ality of life in NeP pat ients and m ust also be considered as pa n
of the med ical prob lem. Nd~
and irs treatmcn t, represents a highly com plex med ical problem bu t curre n t
treatm ents are un satisfactory in Illany pat ients. Thi s is due to many facto rs. w hich include d isease pro gression . low efficacy and intol erab le side effects of available drugs. 'Ihls large unmcr clinical need has served as a powerful research stim ulus into the pathophysiological mechanisms that underlie NeI~ thu s form ing the basis for ta rgeted
Or M ikc Plait EdilOT-in...hitj' London /tn'ICIMJUl " nd Pain MnJirint' Ms Fclida Co. London, Nrmin: Professor J on H Rap hacl Birmintham, Pain Mt'tiirint' Professor Sa m H Ah m«h.ai Sh4fimJ. P"llialiVt' Mt'tiirint'
Dr Eloise Carr & umn nourh. Nunin: Dr Lori mcr Mo seley SyJ1/ry. Australia PhpiothmlpJ
ProfcS5or Richard Langford Lo1l401l. Arou Pail, Dr Pauida Schofield Abmum, Nurling D r Miles Tho mpson &l/h, AJchology D r Justin Durham Nt'l/If{mlt', OMI Surgrry
d rug therapy. Mechanism s o f NeP include ecto pic (spo ran cous) nerve ac tivity, perip heral and central sensitisarion, phenotypic switching o f perip heral nerve fibres a nd struc tu ral plasticity. TI)
D r jane Quinlan OxfOrd. AI/'lmhnia Im d ACIItt' filii/
th is end . therapeutic opportun ities include reducing aberrant neu ronal hyperexcitability. increasin g in hibitions, neuroinuaune modulation and resto rat ion o f the neu r onal ph enot ype (reversing path ology). Accordingly. recent guid elines su pport the lise o f hyperexcita bility blockers such as gabapen rin and pregabalin. which act to modulate voltage gated calcium chan nel activity. and agents that increase descending in hibition via modulation of act ivity at monoaminergic synapses such as tricyclic anddepressants (T CAs) and seroro nlnerglc - norepineph rine re-uprake inhibitors (SN RIs) as first line medication for Nd~ Other licensed excita bility blockers incl ude the lidocaine patch . a first line treatm ent for painful diabetic neu ropathy. and car bam ezcpinc. altho ugh th is is on ly recommended for pa tients who are intolerant to first or seco nd line treat ment s. Tramadol (a single molecule with both m u opioid and SNRI acriviry) and opioids alone. acti vate neu ron al inhibitions
10
restore no rma l neuronal excitability, and arc second
lin e treatments. Ca psaicin pa tches arc pro mising for pai nfu l HI V neuropath ies or po st herpetic neura lgia. in particular the recen tly developed , 8% patch (Q utenza) has had
I'ROD U CTIO N T EAM
Rikkc Susgaard-Vigon Y"es Lcbuc
1l.!! V l f W S
I N
PAI N
V O L.
S -
~ O.
2 -
J U~E
20 1 1
significant success in recent clinical tr ials. The role of capsaicin. an ago nist at T RPV l receptors. whic h are located on peripheral nerve endings as well as cent rally, and its r ole in Ne P is d iscussed in detail in the review by Bhaskar and Mittal. The an algesic effects of cannabinoids remain unclear but targetin g of this inh ibitory receptor holds rherapeuric promise, and they are current ly proposed fin refracto ry cases. Futu re srudies and clinical tria ls will reveal the o utcome of neuroimmune modulators and disease modify ing agen ts for Ne P relief Multip le pathological mecha nisms at multiple sensory sites may underlie Ne P and th is forms the basis for combination therapy. Accordin gly gabapend n combined with TCA or oploids appeats useful for patients who show partial response to d rugs ad ministered alone. This avenue is being explo ited th rough the develcpm enr of single compounds that combine d ifferent mechanisms of analgesic action in a single mo lecule and are gaining momentu m. For instance a novel slow-inacti varion-spccific ion channel modulator that stabilizes voltage gated sodium and calcium channels in their inactivated state attenua tes neuropathic pain in a rat mod el of peripheral nerve inj ury, has recently been described. Tapenradol, which stimulates mu-opioid recepto rs (MO R) and acts as a noradrenaline rcuprake inhi bitor (NRI) in the eNS, appears to be an advance on its predecessor rramadol. a licensed drug, which has weak op ioid acriviry and inhibits noradrena line and 5-HT reuprake. Despite the majo r advances made in u nravelling t he cellular and mole cular mechanisms that underlie Ne f'; translation to the pain clinic has been mu ch less successful with about 1/3 of Nc l' pa tients respo nding to active d rugs and often no advancem ent seen over placebo in ma ny tr ials. There arc many reasons for these findings, e.g. large placebo effec t or current d rugs nor acting on relevant pat hophysiological targets. An intriguing possibiliry gat hering recognit ion is that many trials have failed because they did nor take inro account the herercg eneiry of Ne P symptoms and signs that are presumably linked to distinct mechanisms. An impo rtan t step forw ard to imp rove NNT:~ (number of pati ent s needed to be treated before one parlenr achieves 50% pain relief) , therefore. would be to idcn rify those potent ial patients who might respond to a dr ug. An advance is the d ivision of patient s into groups based o n symptoms assessed by quanti tati ve sensory testing (QST). The next stage wou ld be to determine which groups respond to wh ich agen rs, since if different drugs have d ifferent ial effects, analysis of sensory respon ses in patients woul d aid effective treatm ent s. In this regard . it may also be possible to usc questionnaires. Finally. current therapeut ic treat ment of NeP cent res largely arou nd pharmaco logical agents. delivered orally, rransdermally and intra veno usly and in rare cases via int rathecal methods. however, newer more invasive approaches hold promise. These include gene therapy using VI."CtOl delivery systems and cell therapy ut ilising stem and chromaffi n cells. Furthermore non-pharmacological treatment opt ions are gaining ground, such as spinal COld stimulation and radiofrequency ablation techn iques. 1l1is latter ncurom odulatory ap proach is discussed in the review by Bhaskar and M itral.
Professor Anthony H Dickenson, PhD Department ofNeuroscienee, Physiology and Pharmacology University College London, GOlller Street, London UK Wel E 6BT Tid: 0207·679-3737. mralnnall @lld.ru.uk
Cu rr~n l
Co ncep15 in ad ull CRPS - Dr. Andml' Go~b~{
J
Local Therllpi... for Locali...... Neu ropath ic Pain - An", Bhmk" r, Rtlhul Mi fltll
12
R« ent d C'Vdopn, en u in neuropat hic pain OI«han uOls : in' pliulion s for treal n,ent · IKM,;d" Rtlh",,,,,
21
5-
NO.2 - JUNE 20 1 1 - ISSN 2°42- 12 49
NEUROPATHIC
PAIN
........ "" ......"." .. E D IT O R IA L BO A R D
Ne uropathic pain (Nc P) is curren tly defined by the lnrern adonal Association for the
Stud y of Pain (IASP), as "pain arising as a direct consequence of a lesion o r d isease affect ing the somarusensory syste m," The large majority or Ner cases (approx. 90% ) arise from inj ury to per iphera l sensory nerves fibres as opposed to central neuronal damage. with initiat ing factors as varied as the hu man pain experience itself; ar ising fro m e.g. cancer, metabolic d isorders and viral infections as well as hum medical int ervent ions them selves e.g. surgery and chemothe rapy. C linica lly. cha racteristic sym p lOlfiS include an increased evoked pain respo nse to noxio us (hyperalgesia) and innocuous (allody nia) stimuli. and
SJX )JU 3 Il l'O US
shoo ting electric shock like pain . Pain has an affective
co mponent. a nd so co-mo rbid ities suc h as fatigue. anxiety and dep ression ca n complica te pain sym ptomatology These co- morbidities interact with the sensory aspects of the pain to
subs tantially redu ce qu ality of life in NeP pat ients and m ust also be considered as pa n
of the med ical prob lem. Nd~
and irs treatmcn t, represents a highly com plex med ical problem bu t curre n t
treatm ents are un satisfactory in Illany pat ients. Thi s is due to many facto rs. w hich include d isease pro gression . low efficacy and intol erab le side effects of available drugs. 'Ihls large unmcr clinical need has served as a powerful research stim ulus into the pathophysiological mechanisms that underlie NeI~ thu s form ing the basis for ta rgeted
Or M ikc Plait EdilOT-in...hitj' London /tn'ICIMJUl " nd Pain MnJirint' Ms Fclida Co. London, Nrmin: Professor J on H Rap hacl Birmintham, Pain Mt'tiirint' Professor Sa m H Ah m«h.ai Sh4fimJ. P"llialiVt' Mt'tiirint'
Dr Eloise Carr & umn nourh. Nunin: Dr Lori mcr Mo seley SyJ1/ry. Australia PhpiothmlpJ
ProfcS5or Richard Langford Lo1l401l. Arou Pail, Dr Pauida Schofield Abmum, Nurling D r Miles Tho mpson &l/h, AJchology D r Justin Durham Nt'l/If{mlt', OMI Surgrry
d rug therapy. Mechanism s o f NeP include ecto pic (spo ran cous) nerve ac tivity, perip heral and central sensitisarion, phenotypic switching o f perip heral nerve fibres a nd struc tu ral plasticity. TI)
D r jane Quinlan OxfOrd. AI/'lmhnia Im d ACIItt' filii/
th is end . therapeutic opportun ities include reducing aberrant neu ronal hyperexcitability. increasin g in hibitions, neuroinuaune modulation and resto rat ion o f the neu r onal ph enot ype (reversing path ology). Accordingly. recent guid elines su pport the lise o f hyperexcita bility blockers such as gabapen rin and pregabalin. which act to modulate voltage gated calcium chan nel activity. and agents that increase descending in hibition via modulation of act ivity at monoaminergic synapses such as tricyclic anddepressants (T CAs) and seroro nlnerglc - norepineph rine re-uprake inhibitors (SN RIs) as first line medication for Nd~ Other licensed excita bility blockers incl ude the lidocaine patch . a first line treatm ent for painful diabetic neu ropathy. and car bam ezcpinc. altho ugh th is is on ly recommended for pa tients who are intolerant to first or seco nd line treat ment s. Tramadol (a single molecule with both m u opioid and SNRI acriviry) and opioids alone. acti vate neu ron al inhibitions
10
restore no rma l neuronal excitability, and arc second
lin e treatments. Ca psaicin pa tches arc pro mising for pai nfu l HI V neuropath ies or po st herpetic neura lgia. in particular the recen tly developed , 8% patch (Q utenza) has had
I'ROD U CTIO N T EAM
Rikkc Susgaard-Vigon Y"es Lcbuc
1l.!! V l f W S
I N
PAI N
V O L.
S -
~ O.
2 -
J U~E
20 1 1
significant success in recent clinical tr ials. The role of capsaicin. an ago nist at T RPV l receptors. whic h are located on peripheral nerve endings as well as cent rally, and its r ole in Ne P is d iscussed in detail in the review by Bhaskar and Mittal. The an algesic effects of cannabinoids remain unclear but targetin g of this inh ibitory receptor holds rherapeuric promise, and they are current ly proposed fin refracto ry cases. Futu re srudies and clinical tria ls will reveal the o utcome of neuroimmune modulators and disease modify ing agen ts for Ne P relief Multip le pathological mecha nisms at multiple sensory sites may underlie Ne P and th is forms the basis for combination therapy. Accordin gly gabapend n combined with TCA or oploids appeats useful for patients who show partial response to d rugs ad ministered alone. This avenue is being explo ited th rough the develcpm enr of single compounds that combine d ifferent mechanisms of analgesic action in a single mo lecule and are gaining momentu m. For instance a novel slow-inacti varion-spccific ion channel modulator that stabilizes voltage gated sodium and calcium channels in their inactivated state attenua tes neuropathic pain in a rat mod el of peripheral nerve inj ury, has recently been described. Tapenradol, which stimulates mu-opioid recepto rs (MO R) and acts as a noradrenaline rcuprake inhi bitor (NRI) in the eNS, appears to be an advance on its predecessor rramadol. a licensed drug, which has weak op ioid acriviry and inhibits noradrena line and 5-HT reuprake. Despite the majo r advances made in u nravelling t he cellular and mole cular mechanisms that underlie Ne f'; translation to the pain clinic has been mu ch less successful with about 1/3 of Nc l' pa tients respo nding to active d rugs and often no advancem ent seen over placebo in ma ny tr ials. There arc many reasons for these findings, e.g. large placebo effec t or current d rugs nor acting on relevant pat hophysiological targets. An intriguing possibiliry gat hering recognit ion is that many trials have failed because they did nor take inro account the herercg eneiry of Ne P symptoms and signs that are presumably linked to distinct mechanisms. An impo rtan t step forw ard to imp rove NNT:~ (number of pati ent s needed to be treated before one parlenr achieves 50% pain relief) , therefore. would be to idcn rify those potent ial patients who might respond to a dr ug. An advance is the d ivision of patient s into groups based o n symptoms assessed by quanti tati ve sensory testing (QST). The next stage wou ld be to determine which groups respond to wh ich agen rs, since if different drugs have d ifferent ial effects, analysis of sensory respon ses in patients woul d aid effective treatm ent s. In this regard . it may also be possible to usc questionnaires. Finally. current therapeut ic treat ment of NeP cent res largely arou nd pharmaco logical agents. delivered orally, rransdermally and intra veno usly and in rare cases via int rathecal methods. however, newer more invasive approaches hold promise. These include gene therapy using VI."CtOl delivery systems and cell therapy ut ilising stem and chromaffi n cells. Furthermore non-pharmacological treatment opt ions are gaining ground, such as spinal COld stimulation and radiofrequency ablation techn iques. 1l1is latter ncurom odulatory ap proach is discussed in the review by Bhaskar and M itral.
Professor Anthony H Dickenson, PhD Department ofNeuroscienee, Physiology and Pharmacology University College London, GOlller Street, London UK Wel E 6BT Tid: 0207·679-3737. mralnnall @lld.ru.uk
Cu rr~n l
Co ncep15 in ad ull CRPS - Dr. Andml' Go~b~{
J
Local Therllpi... for Locali...... Neu ropath ic Pain - An", Bhmk" r, Rtlhul Mi fltll
12
R« ent d C'Vdopn, en u in neuropat hic pain OI«han uOls : in' pliulion s for treal n,ent · IKM,;d" Rtlh",,,,,
21
