Appendix H GRADE profiles and results for peripheral neuropathic pain

Transcription

1 Appendix H GRADE profile and reult for peripheral neuropathic pain Outcome Profile ID Follow-up (day) Critical Patient-reported global improvement 1 (at leat moderate improvement) Sleep interference normalied 10- point cale 1 Withdrawal due to advere effect Number of RCT Intervention 1a (pg2) 28 +/- 7 1 pregabalin 1b (pg3) 56 +/- 7 7 capaicin patch gabapentin pregabalin valproate 1c (pg7) 84 +/ capaicin patch lacoamide lamotrigine pregabalin 2a (pg11) 28 +/- 7 3 ecitalopram gabapentin gabapentin+nortriptyline nortriptyline 2b (pg14) 56 +/- 7 2 gabapentin 2c (pg15) 84 +/ duloxetine topiramate 3 (pg19) All time point Specific advere 3a-t All time effect 2 point Important (ee below) See Appendix J 30% pain relief 4a (pg31) 28 +/- 7 6 cannabi ativa extract capaicin cream gabapentin pregabalin tramadol 4b (pg35) 56 +/- 7 4 capaicin patch pregabalin 4c (pg39) 84 +/ cannabi ativa extract capaicin patch duloxetine lacoamide lamotrigine pregabalin topiramate 50% pain relief 5a (pg42) 28 +/- 7 6 amitriptyline cannabi ativa extract gabapentin pregabalin tramadol Pain relief normalied 10-point cale 5b (pg46) 56 +/- 7 7 gabapentin lamotrigine nortriptyline pregabalin 5c (pg49) 84 +/ capaicin patch duloxetine pregabalin topiramate 6a (pg53) 28 +/ (ee below) 6b (pg62) 56 +/ (ee below) 6c (pg68) 84 +/ (ee below) 1 meaured uing the 7-point PGIC (patient-reported global impreion of change) tool 2 thi i the only ynthei poible for the outcome patient reported improvement in daily phyical and emotional functioning including leep 3 completed for all neuropathic pain only. (it wa not poible to yntheie any reult for the outcome ue of recue medication ) CG173: Neuropathic pain pharmacological management appendix H 1 of 71

2 CRITICAL OUTCOMES (profile 1 to 3) Summary GRADE profile 1a: Patient-reported global improvement (at leat moderate improvement) (28 +/-7 day) pregabalin v placebo Outcome Patientreported global improvem ent at leat moderate improvem ent (28 +/-7 day) Numb er of Studi e 1 RCT a n=252 Limitati on eriou 1 Inconite ncy not applicable 2 Indirectn e not eriou 3 Impreci ion eriou4 Effect/ outco me OR: (95% CI 2.94 to 9.19) Qualit y moder ate 1 it wa unclear if group were comparable at baeline in concomitant SSRI ue; during the tudy recue analgeic uage permitted but not reported; inadequate length of follow-up (5 week) 2 only 1 trial o no poibility of inconitency between tudie for a pairwie comparion 3 all apect of PICO conform to review protocol 4 wide confidence interval for effect etimate compared to placebo a pregabalin v placebo (n=252): Leer et al. (2004); only SSRI permitted Importa nce Critical Abbreviation: CI confidence interval; OR odd ratio; PICO patient intervention comparator outcome; RCT randomied controlled trial; SSRI elective erotonin reuptake inhibitor Figure 1 Patient-reported global improvement (at leat moderate improvement) /- 7 day - evidence diagram Table 1 Patient-reported global improvement (at leat moderate improvement) /- 7 day - note none CG173: Neuropathic pain pharmacological management appendix H 2 of 71

3 Summary GRADE profile 1b: Network meta-analyi for Patient-reported global improvement (at leat moderate improvement) (56 +/-7 day) Outcome Patientreported global improveme nt at leat moderate improveme nt (56 +/-7 day) Numbe r of Studie 7 RCT a n=1477 Limitation Inconiten cy Indirectne Impreciio n very eriou 1 not eriou2 not eriou 3 very eriou 4 Qualit y Very low Importanc e Critical 1 over half of tudie do not report about allocation concealment; concomitant drug ue between arm within each tudy appear to be imilar but concomitant drug permitted varie acro the tudie in the network 2 I 2 wa 17% for gabapentin v placebo which may indicate that any inconitency might not be important; no loop in network o no poibility of inconitency between direct and indirect etimate 3 all apect of PICO conform to review protocol 4 there are no head-to-head trial; mot link in the network contain only one trial; wide confidence interval for effect etimate compared to placebo for at leat half of the intervention but particularly for valproate which i likely due to very mall tudy ize cauing uncertainty of the ranking within the network a Capaicin Patch (n=416): Irving et al. (2011); concomitant drug permitted if table (n=778): Backonja et al. (1998) Rice & Maton (2001) Rowbotham et al. (1998) Simpon (2001); concomitant drug not permitted in 1 but permitted in 3 (but anti-convulant excluded in 1 and SSRI excluded in another) (n=238): Sabatowki et al. (2004); concomitant drug permitted if table Valproate (n=45): Kochar et al. (2005); no concomitant drug permitted [all compared to placebo] Abbreviation: PICO patient intervention comparator outcome; RCT randomied controlled trial; SSRI elective erotonin reuptake inhibitor Capaicin Patch Valproate Figure 2 Patient-reported global improvement (at leat moderate improvement) /- 7 day - evidence network CG173: Neuropathic pain pharmacological management appendix H 3 of 71

4 Table 2 Patient-reported global improvement (at leat moderate improvement) /- 7 day - trial included in analyi Capaicin Patch Valproate Capaicin Patch 1 RCT 2 total n=416 4 RCT 1457 total n=778 1 RCT 6 total n=238 1 RCT 3 total n= (1) Backonja et al. (1998); (2) Irving et al. (2011); (3) Kochar et al. (2005); (4) Rice & Maton (2001); (5) Rowbotham et al. (1998); (6) Sabatowki et al. (2004); (7) Simpon (2001) Table 3 Patient-reported global improvement (at leat moderate improvement) /- 7 day - relative effectivene of all pairwie combination Capaicin Patch Valproate Value given are odd ratio (6 3.88) 3.20 ( ) 3.44 ( ) 9.25 ( ) Capaicin Patch 1.59 ( ) 2.00 ( ) 2.16 ( ) 5.83 ( ) Valproate 3.14 ( ) 3.34 ( ) ( ) 2.89 ( ) ( ) 8.23 ( ) The egment below and to the left of the haded cell i derived from the network meta-analyi reflecting direct and indirect evidence of treatment effect (row veru column). The point etimate reflect the mean of the poterior ditribution and number in parenthee are 95% credible interval. The egment above and to the right of the haded cell give pooled direct evidence (random-effect pairwie meta-analyi) where available (column veru row). Number in parenthee are 95% confidence interval. - CG173: Neuropathic pain pharmacological management appendix H 4 of 71

5 Valproate Capaicin Patch NMA Direct pairwie Odd Ratio -v- Figure 3 Patient-reported global improvement (at leat moderate improvement) /- 7 day - relative effect of all option compared with placebo (value le than 1 favour placebo; value greater than 1 favour the treatment; olid error bar are 95% credible interval while dahed error bar are 95% confidence interval) Table 4 Patient-reported global improvement (at leat moderate improvement) /- 7 day - ranking for each comparator Probability bet 00 5 (4 5) Capaicin Patch 08 4 (2 5) 53 3 (1 4) (1 4) Valproate 21 1 (1 3) Median rank (95%CI) Capaicin Patch Valproate Figure 4 Patient-reported global improvement (at leat moderate improvement) /- 7 day - rank probability hitogram CG173: Neuropathic pain pharmacological management appendix H 5 of 71

6 Table 5 Patient-reported global improvement (at leat moderate improvement) /- 7 day - model fit tatitic Reidual deviance Dbar Dhat pd DIC tau-quared (compared to 16 datapoint) (95%CI: ) Table 6 Patient-reported global improvement (at leat moderate improvement) /- 7 day - note Random-effect model wa ued burn-in and iteration. Model convergence: autocorrelation relatively poor for valproate becaue of mall number of event in placebo arm. Valproate ha a high median ranking but the tudy ize are relatively mall and there are large credible interval around the etimate. The coniderable uncertainty about the true effect for valproate and how it rank overall in the network i reflected in the ize of the confidence interval around the ranking. CG173: Neuropathic pain pharmacological management appendix H 6 of 71

7 Summary GRADE profile 1c: Network meta-analyi for Patient-reported global improvement (at leat moderate improvement) (84 +/- 14 day) Outcome Patientreported global improveme nt at leat moderate improveme nt (follow up 84 day) Numbe r of Studie 8 RCT a n=2337 Limitation Inconiten cy Indirectne Impreciio n Qualit y very eriou 1 not eriou2 not eriou 3 eriou 4 low Importanc e Critical 1 6 tudie do not report the method of randomiation and 5 were unclear about allocation concealment; there i uncertainty about comparability at baeline between group in 5 tudie (particularly for ue of concomitant drug); during the tudie concomitant drug and recue medication ue wa unclear in 5 tudie; concomitant drug permitted varie acro the tudie in the network 2 I 2 wa 0% for capaicin patch or pregabalin v placebo which may indicate that any inconitency might not be important (heterogeneity not poible for comparion with only one trial); no loop in network o no poibility of inconitency between direct and indirect etimate 3 all apect of PICO conform to review protocol 4 there are no head-to-head trial; half of the link in network include only 1 trial; wide confidence interval around ranking in the network a capaicin patch (n=723): Irving et al. (2011); Simpon et al. (2008); concomitant drug permitted if table lacoamide (n=119): Rauck et al. (2007); only SSRI permitted but other were permitted during the trial if the invetigator conidered it neceary lamotrigine (n=227): Simpon et al. (2003); concomitant drug permitted if table (n=1268): Arezzo et al. (2008) Freynhagen et al. (2005)Tolle et al. (2008) van Seventer et al. (2006); concomitant drug permitted if table in one tudy but only SSRI permitted in 3 tudie [all compared to placebo] Abbreviation: PICO patient intervention comparator outcome; RCT randomied controlled trial; SSRI elective erotonin reuptake inhibitor Capaicin Patch 3 Lacoamide 4 5 Figure 5 Patient-reported global improvement (at leat moderate improvement) /- 12 day - evidence network CG173: Neuropathic pain pharmacological management appendix H 7 of 71

8 Table 7 Patient-reported global improvement (at leat moderate improvement) /- 12 day - trial included in analyi Capaicin Patch Lacoamide Capaicin Patch Lacoamide 2 RCT 36 total n=723 1 RCT 4 total n=119 1 RCT 5 total n=227 4 RCT 1278 total n= (1) Arezzo et al. (2008); (2) Freynhagen et al. (2005); (3) Irving et al. (2011); (4) Rauck et al. (2007); (5) Simpon et al. (2003); (6) Simpon et al. (2008); (7) Tolle et al. (2008); (8) van Seventer et al. (2006) Table 8 Patient-reported global improvement (at leat moderate improvement) /- 12 day - relative effectivene of all pairwie combination Capaicin Patch Lacoamide Value given are odd ratio ( ) 2.07 ( ) 8 (4 1.86) 2.10 ( ) Capaicin Patch 2.40 ( ) 9 ( ) 0.39 ( ) 0.91 (9 1.58) Lacoamide 2.04 ( ) 8 (8 1.62) ( ) 1.02 (2 2.45) ( ) 2.07 ( ) The egment below and to the left of the haded cell i derived from the network meta-analyi reflecting direct and indirect evidence of treatment effect (row veru column). The point etimate reflect the mean of the poterior ditribution and number in parenthee are 95% credible interval. The egment above and to the right of the haded cell give pooled direct evidence (random-effect pairwie meta-analyi) where available (column veru row). Number in parenthee are 95% confidence interval. - CG173: Neuropathic pain pharmacological management appendix H 8 of 71

9 Lacoamide Capaicin Patch NMA Direct pairwie Odd Ratio -v- Figure 6 Patient-reported global improvement (at leat moderate improvement) /- 12 day - relative effect of all option compared with placebo (value le than 1 favour placebo; value greater than 1 favour the treatment; olid error bar are 95% credible interval while dahed error bar are 95% confidence interval) Table 9 Patient-reported global improvement (at leat moderate improvement) /- 12 day - ranking for each comparator Probability bet 00 4 (3 5) Capaicin Patch 40 2 (1 3) Lacoamide (1 4) 04 5 (3 5) 17 2 (1 3) Median rank (95%CI) Capaicin Patch Lacoamide Figure 7 Patient-reported global improvement (at leat moderate improvement) /- 12 day - rank probability hitogram CG173: Neuropathic pain pharmacological management appendix H 9 of 71

10 Table 10 Patient-reported global improvement (at leat moderate improvement) /- 12 day - model fit tatitic Reidual deviance Dbar Dhat pd DIC tau-quared (compared to 23 datapoint) (95%CI: ) Table 11 Patient-reported global improvement (at leat moderate improvement) /- 12 day - note Random-effect model wa ued burn-in and iteration. Include Rauck (2007) which reported outcome at 70 day allowing u to include lacoamide into thi network (adding thi into the network doe not make any dramatic change to the reult but it doe make u le certain that pregabalin rank in the top 2). CG173: Neuropathic pain pharmacological management appendix H 10 of 71

11 Summary GRADE profile 2a: Network meta-analyi for leep interference on normalied 10-point cale (28 +/- 7d) Outcome Sleep interferenc e on normalie d 10-point cale (follow up 28 day) Numbe r of Studie 3 RCT a n=326 Limitation Inconiten cy Indirectne Impreciio n Qualit y very eriou 1 not eriou2 not eriou 3 eriou 4 very low Importanc e Critical 1 more than half of tudie are croover tudie; it wa unclear if group were comparable in the other particularly regarding concomitant drug ue; during the tudy there were difference in concomitant drug ue between group in one tudy (though the ignificance i unknown) and it wa not clear if ue wa ignificantly different between group in the other tudie; concomitant drug permitted varie acro the tudie in the network; inadequate length of follow-up (no more than 5 week for included tudie) 2 only 1 trial for each arm o no poibility of inconitency between tudie for a pairwie comparion; the network i not uceptible to inconitency becaue the only loop i from a multi-armed trial 3 all apect of PICO conform to review protocol 4 mot link in network include only 1 trial wide confidence around ranking in the network a -controlled comparion: Ecitalopram (n=82): Otto et al. (2008); no concomitant drug permitted (n=196): Gordh et al. (2008) ; no concomitant drug permitted Head-to-head comparion: v gabapentin+nortriptyline (n=96): Gilron et al. (2012); concomitant opioid permitted in table doe but tricyclic gabapentin pregabalin excluded v gabapentin+nortriptyline (n=100): Gilron et al. (2012); concomitant opioid permitted in table doe but tricyclic gabapentin pregabalin excluded v gabapentin (n=96): Gilron et al. (2012); concomitant opioid permitted in table doe but tricyclic gabapentin pregabalin excluded Abbreviation: PICO patient intervention comparator outcome; RCT randomied controlled trial Ecitalopram Figure 8 leep interference /- 7 day - evidence network CG173: Neuropathic pain pharmacological management appendix H 11 of 71

12 Table 12 leep interference /- 7 day - trial included in analyi Ecitalopram + Ecitalopram 1 RCT 3 total n=82 1 RCT 2 total n= (1) Gilron et al. (2012); (2) Gordh et al. (2008); (3) Otto et al. (2008) - 1 RCT 1 total n=96 1 RCT 1 total n= RCT 1 total n=100 Table 13 leep interference /- 7 day - relative effectivene of all pairwie combination Ecitalopram + Ecitalopram ( ) ( ) ( ) -9 ( ) Value given are mean difference ( ) 1 ( ) -0 ( ) 0.70 ( ) ( ) ( ) 0.10 ( ) ( ) 1.30 (9 1.91) 0.10 ( ) 1.30 (9 1.91) The egment below and to the left of the haded cell i derived from the network meta-analyi reflecting direct and indirect evidence of treatment effect (row veru column). The point etimate reflect the mean of the poterior ditribution and number in parenthee are 95% credible interval. The egment above and to the right of the haded cell give pooled direct evidence (random-effect pairwie meta-analyi) where available (column veru row). Number in parenthee are 95% confidence interval. + Ecitalopram NMA Direct pairwie Mean Difference -v- Figure 9 leep interference /- 7 day - relative effect of all option compared with placebo (value le than 0 favour the treatment; value greater than 0 favour placebo; olid error bar are 95% credible interval while dahed error bar are 95% confidence interval) CG173: Neuropathic pain pharmacological management appendix H 12 of 71

13 Table 14 peripheral - leep interference /- 7 day - ranking for each comparator Probability bet 00 5 (3 5) Ecitalopram (1 4) 00 3 (2 5) (1 2) 00 4 (2 5) Median rank (95%CI) Ecitalopram Nortrip tyline Figure 10 leep interference /- 7 day - rank probability hitogram Table 15 leep interference /- 7 day - model fit tatitic Reidual deviance Dbar Dhat pd DIC (compared to 7 data-point) Table 16 leep interference /- 7 day - note Fixed-effect model wa ued burn-in and iteration. CG173: Neuropathic pain pharmacological management appendix H 13 of 71

14 Summary GRADE profile 2b: Meta-analyi for leep interference on normalied 10-point cale (56 +/- 7d) gabapentin v placebo Outcom e Sleep interfere nce on normali ed 10- point cale (follow up 56 day) Num ber of Studi e 2 RCT a n=36 0 Limitati on eriou 1 Inconit ency not eriou 2 Indirectn e not eriou 3 Impreci ion not eriou 4 Effect/outc ome MD: (95% CI: to -8) Qualit y moder ate Importa nce Critical 1 1 of the 2 tudie doe not report the method of randomiation and neither were clear about allocation concealment; there i uncertainty about SSRI uage at baeline between group in 1 of the tudie 2 I 2 wa 0% for the pairwie comparion which may indicate that any inconitency might not be important 3 all apect of PICO conform to review protocol a v placebo (n=1543): Irving et al. (2011); Irving et al. (2012); concomitant tricyclic antidepreant permitted in one but only SSRI in the other Abbreviation: CI confidence interval; MD mean difference; PICO patient intervention comparator outcome; RCT randomied controlled trial; SSRI elective erotonin reuptake inhibitor Figure 11 leep interference /- 7 day - evidence diagram Table 17 leep interference /- 7 day - model fit tatitic Reidual deviance Dbar Dhat pd DIC tau-quared (compared to 4 data-point) (95%CrI: ) Table 18 leep interference /- 7 day - note Random-effect model wa ued burn-in and iteration. CG173: Neuropathic pain pharmacological management appendix H 14 of 71

15 Summary GRADE profile 2c: Network meta-analyi for leep interference on normalied 10-point cale (84 +/- 14d) Outcome Sleep interferenc e on normalie d 10-point cale (follow up 84 day) Numbe r of Studie 5 RCT a n=1515 Limitation Inconiten cy Indirectne Impreciio n Qualit y very eriou 1 not eriou2 not eriou 3 eriou 4 Low Importanc e Critical 1 one tudy ued inadequate allocation concealment and 2 were unclear about allocation concealment; treatment group were not comparable at baeline in two tudie and it wa unclear if group were comparable in 3 of the other particularly regarding concomitant drug ue; during the tudy there were difference in recue medication uage in one tudy and it wa not clear if there were difference between group for concomitant and recue medication uage in 2 other tudie; concomitant drug permitted varie acro the tudie in the network 2 I 2 wa 0% for duloxetine v placebo which may indicate that any inconitency might not be important (heterogeneity not poible for topiramate v placebo ince the comparion contain only one trial); no loop in network o no poibility of inconitency between direct and indirect etimate 3 all apect of PICO conform to review protocol 4 there are no head-to-head trial; 1 of 2 link in network include only 1 trial; confidence interval for effect etimate againt placebo appear mall enough but confidence interval around ranking are wide (both intervention could be ranked either 1 or 2) a Duloxetine (n=1198): Gao et al. (2010) Rakin et al. (2005) Wernicke et al. (2006) Yauda et al. (2011); mot did not permit concomitant pain medication but one wa unclear (n=317): Rakin et al. (2004); only SSRI permitted [all compared to placebo] Abbreviation: PICO patient intervention comparator outcome; RCT randomied controlled trial; SSRI elective erotonin reuptake inhibitor Duloxetine 3 1 Figure 12 leep interference /- 12 day - evidence network CG173: Neuropathic pain pharmacological management appendix H 15 of 71

16 Table 19 leep interference /- 12 day - trial included in analyi Duloxetine 4 RCT 1345 total n= RCT 2 total n=317 Duloxetine - (1) Gao et al. (2010); (2) Rakin et al. (2004); (3) Rakin et al. (2005); (4) Wernicke et al. (2006); (5) Yauda et al. (2011) Table 20 leep interference /- 12 day - relative effectivene of all pairwie combination Duloxetine Duloxetine -2 ( ) ( ) Value given are mean difference. -2 ( ) ( ) ( ) The egment below and to the left of the haded cell i derived from the network meta-analyi reflecting direct and indirect evidence of treatment effect (row veru column). The point etimate reflect the mean of the poterior ditribution and number in parenthee are 95% credible interval. The egment above and to the right of the haded cell give pooled direct evidence (random-effect pairwie meta-analyi) where available (column veru row). Number in parenthee are 95% confidence interval. - Duloxetine NMA Direct pairwie Mean Difference -v- Figure 13 leep interference /- 12 day - relative effect of all option compared with placebo (value le than 0 favour the treatment; value greater than 0 favour placebo; olid error bar are 95% credible interval while dahed error bar are 95% confidence interval) Table 21 leep interference /- 12 day - ranking for each comparator Probability bet 01 3 (3 3) Duloxetine (1 2) 06 1 (1 2) Median rank (95%CI) CG173: Neuropathic pain pharmacological management appendix H 16 of 71

17 Duloxetine Figure 14 leep interference /- 12 day - rank probability hitogram Table 22 leep interference /- 12 day - model fit tatitic Reidual deviance Dbar Dhat pd DIC tau-quared 18 (compared to 13 data-point) (95%CrI: ) Table 23 leep interference /- 12 day - note Random-effect model wa ued burn-in and iteration. CG173: Neuropathic pain pharmacological management appendix H 17 of 71

18 Summary GRADE profile 3: Network meta-analyi for withdrawal due to advere effect at any time point Outcome Withdraw al due to advere effect at any time Numbe r of Studie 75 RCT a n= Limitation Inconitenc y Indirectne Impreciio n very eriou 2 not eriou3 not eriou 4 very eriou 5 Qualit y Very low Importanc e Critical 1 in jut over half of the tudie group were either not comparable or it wa unclear if they were comparable at baeline; concomitant drug permitted varie acro the tudie in the network 2 it wa not poible to ae heterogeneity for pairwie comparion; there appear to be conitency between direct and indirect etimate 3 all apect of PICO conform to review protocol 4 only a very mall proportion of link in the network are connected with head-to-head trial; wide confidence interval for effect etimate for the majority of intervention againt placebo and around ranking in the network a placebo-controlled comparion: amitriptyline (n=250): Graff-Radford et al. (2000) Kautio et al. (2008) Max et al. (1988) Vrethem et al. (1997); concomitant drug permitted in one but it wa unclear if they were permitted in the other cannabi ativa extract (n=125): Nurmikko et al. (2007); concomitant drug permitted capaicin cream (n=547): Donofrio & Capaicin tudy (1992) Paice et al. (2000) Scheffler et al. (1991) Tandan et al. (1992) Waton & Evan (1992) Waton et al. (1993); concomitant drug permitted but topical medication excluded in mot capaicin patch (n=1918): Backonja et al. (2008) Clifford et al. (2012) Irving et al. (2011) Simpon et al. (2008) Webter et al. (2010); concomitant drug permitted but topical medication excluded in mot duloxetine (n=1692): Gao et al. (2010) Goldtein et al. (2005) Rakin et al. (2005) Wernicke et al. (2006) Yauda et al. (2011); concomitant drug not permitted in mot except one tudy that wa unclear ecitalopram (n=96): Otto et al. (2008); concomitant drug not permitted gabapentin (n=1054): Backonja et al. (1998) Gordh et al. (2008) Hahn et al. (2004) Rice & Maton (2001) Simpon (2001); concomitant drug not permitted in three permitted in two (only SSRI in one and oxycodone wa ued a a recue medication in another which i in the cope of the guideline for the ue in NP o conidered a concomitant medication) imipramine (n=80): Sindrup et al. (2003); unclear if concomitant drug permitted lacoamide (n=1314): Rauck et al. (2007) Shaibani et al. (2009) Wymer et al. (2009) Ziegler et al. (2010); concomitant drug were permitted in all but one (but anti-convulant excluded in thee) lamotrigine (n=1207): Eienberg et al. (2001) Luria et al. (2000) Rao et al. (2008) Simpon et al. (2000) Simpon et al. (2003) Vinik et al. (2007) Vinik et al. (2007); two tudie did not permit concomitant drug one wa unclear and the ret permitted concomitant drug levetiracetam (n=74): Holbech et al. (2011); concomitant drug not permitted lidocaine (n=56): Cheville et al. (2009); concomitant drug not permitted morphine (n=110): Khoromi et al. (2007); opioid SSRI and tricylic anti-depreant not permitted but it appear ome other medication for ciatica wa permitted nortriptyline (n=110): Khoromi et al. (2007); (a above) nortriptyline+morphine (n=110): Khoromi et al. (2007); (a above) oxcarbamazepine (n=493): Beydoun et al. (2006) Dogra et al. (2005); SSRI only oxycodone (n=159): Gimbel et al. (2003); unclear if concomitant drug permitted pregabalin (n=3840): Arezzo et al. (2008) Dworkin et al. (2003) Freynhagen et al. (2005) Guan et al. (2011) Leer et al. (2004) Moon et al. (2010) Richter et al. (2005) Roentock et al. (2004) Sabatowki et al. (2004) Satoh et al. (2011) Simpon et al. (2010); Stacey et al. (2008) Tolle et al. (2008) van Seventer et al. (2006); ome concomitant drug were permitted in all but one tudy which wa unclear (however SSRI were the only drug permitted in 7) topiramate (n=1674): Khoromi et al. (2005) Rakin et al. (2004) Thienel et al. (2004); two tudie permitted concomitant drug but only SSRI in one and anti-convulant were excluded in the other (the other tudy did not permit concomitant drug) CG173: Neuropathic pain pharmacological management appendix H 18 of 71

19 tramadol (n=257): Arbaiza & Vidal (2007) Harati et al. (1998) Sindrup et al. (1999); concomitant drug were permitted in one not permitted in one and unclear in the other valproate (n=145): Kochar et al. (2002) Kochar et al. (2004) Kochar et al. (2005); concomitant drug not permitted in one permitted in one and it wa unclear if they were permitted in the other venlafaxine (n=355): Rowbotham et al. (2004) Sindrup et al. (2003) Tamuth et al. (2002); concomitant drug were not permitted in mot but opioid were permitted in one Head-to-head comparion: amitriptyline v gabapentin (n=50): Morello et al. (1999); concomitant drug not permitted amitriptyline v nortriptyline (n=66): Waton et al. (1998); unclear if concomitant drug permitted amitriptyline v pregabalin (n=102): Banal et al. (2009); concomitant drug not permitted gabapentin v gabapentin+oxycodone (n=338): Hanna et al. (2008); concomitant drug permitted imipramine v venlafaxine (n=80): Sindrup et al. (2003); unclear if concomitant drug permitted nortriptyline+morphine v nortriptyline morphine v nortriptyline+morphine v nortriptyline nortriptyline v morphine (n=110): Khoromi et al. (2007); opioid SSRI and tricylic anti-depreant not permitted but it appear ome other medication for ciatica wa permitted Abbreviation: PICO patient intervention comparator outcome; RCT randomied controlled trial; SSRI elective erotonin reuptake inhibitor Amitriptyline 3 Cannabi Sativa Extract 4 Capaicin Patch 5 Duloxetine 6 Ecitalopram Oxycodone 9 Imipramine 10 Lacoamide Levetiracetam 13 Lidocaine (Topical) 14 Morphine Morphine 17 Oxcarbazepine 18 Oxycodone Valproate Tramadol 23 Venlafaxine 24 Capaicin Cream Figure 15 withdrawal due to advere effect - evidence network CG173: Neuropathic pain pharmacological management appendix H 19 of 71

20 Amitriptyline Cannabi Sativa Extract Capaicin Patch Duloxetine Ecitalopram +Oxycodone Imipramine Lacoamide Levetiracetam Lidocaine (Topical) Morphine +Morphine Oxcarbazepine Oxycodone Valproate Tramadol Venlafaxine Table 24 withdrawal due to advere effect - trial included in analyi Amitriptyline Cannabi Sativa Extract Capaicin Patch Duloxetine Ecitalopram +Oxycodone Imipramine Lacoamide 4 RCT total n=250 1 RCT 36 total n=125 5 RCT total n= RCT total n= RCT 37 total n=96 6 RCT total n= RCT 35 total n= RCT 58 total n=80 4 RCT total n= RCT total n= RCT 21 total n= Levetiracetam 1 RCT23 total n= CG173: Neuropathic pain pharmacological management appendix H 20 of 71

21 Amitriptyline Cannabi Sativa Extract Capaicin Patch Duloxetine Ecitalopram +Oxycodone Imipramine Lacoamide Levetiracetam Lidocaine (Topical) Morphine +Morphine Oxcarbazepine Oxycodone Valproate Tramadol Venlafaxine Lidocaine (Topical) 1 RCT 7 total n= Morphine 1 RCT 27 total n= RCT 27 total n=110 1 RCT 70 total n= RCT 27 total n=110 +Morphine 1 RCT 27 total n= RCT 27 total n=110 1 RCT 27 total n=110 Oxcarbazepine 2 RCT69 total n=493 1 RCT 15 Oxycodone total n=159 Valproate Tramadol Venlafaxine RCT 5 RCT total total n=3840 n=102 3 RCT total n= RCT total n= RCT total n= RCT total n= RCT 58 total CG173: Neuropathic pain pharmacological management appendix H 21 of 71

22 Amitriptyline Cannabi Sativa Extract Capaicin Patch Duloxetine Ecitalopram +Oxycodone Imipramine Lacoamide Levetiracetam Lidocaine (Topical) Morphine +Morphine Oxcarbazepine Oxycodone Valproate Tramadol Venlafaxine Capaicin Cream 6 RCT total n=547 n= (1) Arbaiza & Vidal (2007); (2) Arezzo et al. (2008); (3) Backonja et al. (1998); (4) Backonja et al. (2008); (5) Banal et al. (2009); (6) Beydoun et al. (2006); (7) Cheville et al. (2009); (8) Clifford et al. (2012); (9) Dogra et al. (2005); (10) Donofrio & Capaicin tudy (1992); (11) Dworkin et al. (2003); (12) Eienberg et al. (2001); (13) Freynhagen et al. (2005); (14) Gao et al. (2010); (15) Gimbel et al. (2003); (16) Goldtein et al. (2005); (17) Gordh et al. (2008); (18) Graff-Radford et al. (2000); (19) Guan et al. (2011); (20) Hahn et al. (2004); (21) Hanna et al. (2008); (22) Harati et al. (1998); (23) Holbech et al. (2011); (24) Irving et al. (2011); (25) Kautio et al. (2008); (26) Khoromi et al. (2005); (27) Khoromi et al. (2007); (28) Kochar et al. (2002); (29) Kochar et al. (2004); (30) Kochar et al. (2005); (31) Leer et al. (2004); (32) Luria et al. (2000); (33) Max et al. (1988); (34) Moon et al. (2010); (35) Morello et al. (1999); (36) Nurmikko et al. (2007); (37) Otto et al. (2008); (38) Paice et al. (2000); (39) Rao et al. (2008); (40) Rakin et al. (2004); (41) Rakin et al. (2005); (42) Rauck et al. (2007); (43) Rice & Maton (2001); (44) Richter et al. (2005); (45) Roentock et al. (2004); (46) Rowbotham et al. (1998); (47) Rowbotham et al. (2004); (48) Sabatowki et al. (2004); (49) Satoh et al. (2011); (50) Scheffler et al. (1991); (51) Shaibani et al. (2009); (52) Simpon (2001); (53) Simpon et al. (2000); (54) Simpon et al. (2003); (55) Simpon et al. (2008); (56) Simpon et al. (2010); (57) Sindrup et al. (1999); (58) Sindrup et al. (2003); (59) Stacey et al. (2008); (60) Tandan et al. (1992); (61) Tamuth et al. (2002); (62) Thienel et al. (2004); (63) Tolle et al. (2008); (64) van Seventer et al. (2006); (65) Vinik et al. (2007); (66) Vinik et al. (2007); (67) Vrethem et al. (1997); (68) Waton & Evan (1992); (69) Waton et al. (1993); (70) Waton et al. (1998); (71) Webter et al. (2010); (72) Wernicke et al. (2006); (73) Wymer et al. (2009); (74) Yauda et al. (2011); (75) Ziegler et al. (2010) CG173: Neuropathic pain pharmacological management appendix H 22 of 71

23 Amitriptyline Cannabi Sativa Extract Capaicin Patch Duloxetine Ecitalopram +Oxycodone Imipramine Lacoamide Levetiracetam Lidocaine (Topical) Morphine +Morphine Oxcarbazepine Oxycodone Valproate Tramadol Venlafaxine Capaicin Cream Table 25 withdrawal due to advere effect - relative effectivene of all pairwie combination N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A Amitriptylin e Cannabi Sativa Extract Capaicin Patch Duloxetine Ecitalopra m +Oxycodon e Imipramine 2.71 ( ) 6.92 ( ) 1.00 ( ) 2.73 ( ) 2.56 ( ) 0.37 (9 1.58) 1.01 ( ) (7 ( ) ) 1.78 ( ) 5.93 ( ) 0.38 (1 4.12) 6 (4 1.84) 2.18 ( ) 0.14 (0 1.78) N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A 0.14 (1 1.33) 0.39 (4 2.87) 1.04 ( ) 6 (2 1.90) 4 (5 14) 5 (0 1.19) N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A 2.73 ( ) (0.50 ( ) ) 1.79 (5 6.58) 5.89 ( ) 0.37 (1 5.30) N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A 5 (6 1.63) 2.17 ( ) 0.14 (0 1.64) N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A 5 (1 2.93) 0 ( ) 5 (0 1.59) N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A 3.31 ( ) 1 (1 2.51) N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A 6 (0 1.11) N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/ A N/ A N/ A N/ A N/ A N/ A N/ A N/ A N/ A CG173: Neuropathic pain pharmacological management appendix H 23 of 71

24 Amitriptyline Cannabi Sativa Extract Capaicin Patch Duloxetine Ecitalopram +Oxycodone Imipramine Lacoamide Levetiracetam Lidocaine (Topical) Morphine +Morphine Oxcarbazepine Oxycodone Valproate Tramadol Venlafaxine Capaicin Cream Lacoamide Levetiracet am Lidocaine (Topical) Morphine +Morphine 2.46 ( ) 2.09 ( ) ( ) 12 ( ) 0.91 ( ) 0.77 (6 2.35) 5.19 ( ) 3.82 ( ) (0.77 ( ) ) 2.49 ( ) 5.38 ( ) 0.92 ( ) 2.00 ( ) 0.35 (3 2.63) 0.30 (3 2.24) 2.05 ( ) 1.51 ( ) 0.98 ( ) 0.35 (2 7.45) 0.77 (3 23) 2.46 (2 9.13) 2.10 ( ) ( ) 12 ( ) 0.90 ( ) 0.77 ( ) 5.13 ( ) 3.76 ( ) (0.56 ( ) ) 2.48 ( ) 0.91 ( ) (0 ( ) ) 0.34 (1 4.05) 9 (1 3.52) 2.03 ( ) 1.45 ( ) 0.95 ( ) 0.34 ( ) 0.73 ( ) 1.38 ( ) 1.17 (5 3.08) 7.84 ( ) 5.75 ( ) 3.88 ( ) 1.40 ( ) 3.02 ( ) 2 (7 2.27) 0.35 (6 1.96) 2.43 ( ) 1.79 ( ) 1.19 ( ) 2 (3 7.30) 0.92 ( ) 6.57 ( ) 5.60 ( ) ( ) ( ) 5 ( ) 5.71 ( ) 4.17 ( ) (8 ( ) ) 7.09 ( ) 1.01 ( ) (0.50 ( ) ) N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A 6.66 ( ) 4.89 ( ) 3.31 ( ) 1.19 ( ) 2.57 ( ) N/A 0.74 ( ) 8 ( ) 0.17 (0 9.15) 0.37 ( ) N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A 6 ( ) 3 ( ) 0.51 ( ) N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A 0.36 (4 2.49) 0.78 ( ) N/A N/A N/A N/A N/A N/A N/A N/A N/A 2.17 ( ) N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/ A N/ A N/ A N/ A N/ A N/ A N/ A CG173: Neuropathic pain pharmacological management appendix H 24 of 71

25 Amitriptyline Cannabi Sativa Extract Capaicin Patch Duloxetine Ecitalopram +Oxycodone Imipramine Lacoamide Levetiracetam Lidocaine (Topical) Morphine +Morphine Oxcarbazepine Oxycodone Valproate Tramadol Venlafaxine Capaicin Cream Oxcarbazep ine Oxycodone Valproate Tramadol 4.09 ( ) 1.76 ( ) 2.16 ( ) 3.74 ( ) 3.78 ( ) 7.04 ( ) 1.51 (1 5.72) 5 (9 4.74) 0 ( ) 1.39 ( ) 1.40 (4 4.51) 2.62 ( ) 0.59 (5 4.97) 5 (1 3.42) 0.31 (3 2.12) 0.55 ( ) 0.54 (5 4.19) 1.02 ( ) 4.09 ( ) 1.75 ( ) 2.17 (2 7.10) 3.78 ( ) 3.79 ( ) 7.09 ( ) 1.50 (7 4.86) 4 ( ) 0.79 ( ) 1.37 ( ) 1.39 ( ) 2.59 ( ) 0.57 (2 7.41) 4 (0 4.84) 0.30 (1 3.33) 0.53 ( ) 0.53 (2 6.42) 0.99 ( ) 2.29 ( ) 0.98 ( ) 1.21 ( ) 2.11 (6 39) 2.12 ( ) 3.97 ( ) 9 ( ) 0.30 (3 3.20) 0.36 (7 1.81) 5 ( ) 4 ( ) 1.20 ( ) ( ) 4.85 ( ) 5.74 ( ) ( ) ( ) ( ) 1.66 ( ) 0.72 ( ) 8 (0 1.93) 1.53 ( ) 1.54 ( ) 2.87 ( ) 1.95 ( ) 4 ( ) 1.03 (6 2.26) 1.80 ( ) 1.81 (5 5.07) 9 (0 7.86) 0.12 (0 4.54) 0.16 (0 3.51) 7 ( ) 7 (0 6.61) 0 ( ) 0.17 (0 6.93) 1 (0 5.42) 0.37 ( ) 0.37 (0 1 3) 0.59 (3 6.68) 5 (1 4.40) 0.31 (2 2.92) 0.55 ( ) 0.55 (3 5.64) 1.65 ( ) 0.70 ( ) 7 (7 7.92) 1.54 ( ) 1.53 ( ) 0.76 (4 9.34) 0.32 (1 5.99) 0 (3 4.07) 0.71 ( ) 0.70 (4 7.86) 3 (6 3.28) 0.53 ( ) 0.92 ( ) 0.92 (6 3.28) N/A N/A N/A N/A N/A N/A 1.23 (0 7.18) 2.18 ( ) 2.15 ( ) N/A N/A N/A N/A N/A 1.73 ( ) 1.75 ( ) N/A N/A N/A N/A 1.01 (7 8.37) N/A N/A N/A N/A N/A Venlafaxine N/ 3.38 ( ) 0.50 ( ) 9 ( ) 1.04 ( ) 2.91 ( ) 1.33 (6 2 9) 1.73 ( ) 4.06 ( ) 3.27 ( ) 1.88 ( ) 1.87 (0 1 1) N/A N/ A N/ A N/ A N/ A N/ A N/ A CG173: Neuropathic pain pharmacological management appendix H 25 of 71

26 Amitriptyline Cannabi Sativa Extract Capaicin Patch Duloxetine Ecitalopram +Oxycodone Imipramine Lacoamide Levetiracetam Lidocaine (Topical) Morphine +Morphine Oxcarbazepine Oxycodone Valproate Tramadol Venlafaxine Capaicin Cream Capaicin Cream (5 9.89) 6.12 ( ) (3 4.68) 2.27 (2 8.77) Value given are hazard ratio. (3 3.85) 8 (8 7.56) ( ) 6.17 ( ) (7 4.14) 2.25 ( ) (1 5.62) 6 ( ) (0 6.39) 3.45 ( ) (6 3.49) 1.04 ( ) ( ) ( ) (8 4.76) 2.49 ( ) ( ) (0 5.79) (0 8.62) (2 5.20) ( ) (3 7.16) ( ) ( ) ( ) (4 7.64) (0.18 ( ) 2.42 ) The egment below and to the left of the haded cell i derived from the network meta-analyi reflecting direct and indirect evidence of treatment effect (row veru column). The point etimate reflect the mean of the poterior ditribution and number in parenthee are 95% credible interval. Becaue it i not eaily poible to derive analogou etimate of hazard ratio from a frequentit analyi of direct data only the egment above and to the right of the haded cell i left blank ( ) 4 ( ) 0 ( ) 9 (5 1 5) 2.50 ( ) 1.14 ( ) 1.51 ( ) 3.51 ( ) 2.83 ( ) 1.64 ( ) 1.62 (8 5.81) 7 ( ) 2.24 (7 1 7) A CG173: Neuropathic pain pharmacological management appendix H 26 of 71

27 Capaicin Cream Venlafaxine Tramadol Valproate Oxycodone Oxcarbazepine +Morphine Morphine Lidocaine (Topical) Levetiracetam Lacoamide Imipramine +Oxycodone Ecitalopram Duloxetine Capaicin Patch Cannabi Sativa Extract Amitriptyline NMA Hazard Ratio -v- Figure 16 withdrawal due to advere effect - relative effect of all option compared with placebo (value le than 1 favour the treatment; value greater than 1 favour placebo; olid error bar are 95% credible interval) CG173: Neuropathic pain pharmacological management appendix H 27 of 71

28 Table 26 withdrawal due to advere effect - ranking for each comparator Probability bet 41 3 (1 6) Amitriptyline (4 19) Cannabi Sativa Extract (4 24) Capaicin Patch (1 14) Duloxetine (5 18) Ecitalopram (2 24) 03 7 (3 15) +Oxycodone (5 24) Imipramine 29 1 (1 15) Lacoamide (4 18) 01 9 (3 16) Levetiracetam (2 24) Lidocaine (Topical) (1 24) Morphine (3 24) (1 22) +Morphine (2 24) Oxcarbazepine (6 22) Oxycodone 64 7 (1 21) 00 9 (5 15) Valproate (2 24) (7 21) Tramadol (7 24) Venlafaxine (3 21) Median rank (95%CI) Capaicin Cream (10 23) CG173: Neuropathic pain pharmacological management appendix H 28 of 71

29 Amitriptyline Cannabi Sativa Extract Capaicin Patch Duloxetine Ecitalopram Oxycodone Imipramine Lacoamide Levetiracetam Lidocaine (Topical) Morphine Morphine Oxcarbazepine Oxycodone Valproate Tramadol Venlafaxine Capaicin Cream Figure 17 withdrawal due to advere effect - rank probability hitogram Table 27 withdrawal due to advere effect - model fit tatitic Reidual deviance Dbar Dhat pd DIC tau-quared (compared to 186 datapoint) (95%CI: ) Table 28 withdrawal due to advere effect - note Random-effect model wa ued with 0.5 added to cell of trial with 1 or more zero cell-count burn-in and iteration. Model convergence: there wa poor autocorrelation for lidocaine and levetiracetam ince there were few tudie and mall event in the tudie for thee intervention. CG173: Neuropathic pain pharmacological management appendix H 29 of 71

30 One of the Webter et al. (2010) tudie wa not included in thi network a it had zero event in all tudy arm. CG173: Neuropathic pain pharmacological management appendix H 30 of 71

31 IMPORTANT OUTCOMES (profile 4 to 6) Summary GRADE profile 4a: Network meta-analyi for at leat 30% pain relief (28 day +/-7 day) Outcom e 30% pain relief on any cale (follow up 28 day) Numbe r of Studie 6 RCT a n=1015 Limitation Inconitenc y Indirectne Impreciio n very eriou 1 not eriou2 not eriou 3 very eriou 4 Qualit y Very low Importanc e Important 1 unclear if group were comparable in 5 tudie particularly regarding concomitant drug ue; during the tudy mot tudie allowed concomitant drug ue but it wa not clear if ue wa different between group in a number of tudie; concomitant drug permitted varie acro the tudie in the network; inufficient follow-up in 5 of the 6 tudie 2 I 2 wa 0% for pregabalin v placebo which may indicate that any inconitency might not be important (heterogeneity not poible for comparion with only one trial); no loop in network o no poibility of inconitency between direct and indirect etimate 3 all apect of PICO conform to review protocol 4 all but one link in network include only 1 trial; no head-to-head trial; wide confidence interval for the effect etimate of all intervention compared to placebo and for overall ranking within the network a cannabi ativa extract (n=125): Nurmikko et al. (2007); concomitant drug permitted gabapentin (n=240): Gordh et al. (2008); no concomitant drug permitted pregabalin (n=528): Leer et al. (2004) Stacey et al. (2008); concomitant drug apart from gabapentin and oxycodone permitted in one and only SSRI permitted in the other tramadol (n=90): Sindrup et al. (1999); unclear if any concomitant drug permitted (tudy ay a number of drug tapered before tudy tart but no detail given) capaicin cream (n=32): Berntein et al. (1989); concomitant drug permitted [all compared to placebo] Abbreviation: PICO patient intervention comparator outcome; RCT randomied controlled trial; SSRI elective erotonin reuptake inhibitor Cannabi Sativa Extract Tramadol 2 6 Capaicin Cream Figure 18 30% pain relief /- 7 day - evidence network CG173: Neuropathic pain pharmacological management appendix H 31 of 71

32 Cannabi Sativa Extract Tramadol Table 29 30% pain relief /- 7 day - trial included in analyi Cannabi Sativa Extract Tramadol Capaicin Cream 1 RCT 4 total n=125 1 RCT 2 total n=240 2 RCT 36 total n=528 1 RCT 5 total n=90 1 RCT 1 total n= (1) Berntein et al. (1989); (2) Gordh et al. (2008); (3) Leer et al. (2004); (4) Nurmikko et al. (2007); (5) Sindrup et al. (1999); (6) Stacey et al. (2008) Table 30 30% pain relief /- 7 day28 +/- 7 day - relative effectivene of all pairwie combination Cannabi Sativa Extract Tramadol Capaicin Cream 2.02 ( ) 2.70 ( ) 3.80 ( ) 3.80 ( ) 6.47 ( ) Value given are odd ratio. Cannabi Sativa Extract 2.00 (1 4.96) 1.34 ( ) 1.88 ( ) 1.87 ( ) 3.20 ( ) Tramadol Capaicin cream 2.64 ( ) 3.75 ( ) 3.59 ( ) (4 8.16) 1.41 ( ) 2.40 ( ) ( ) 1.71 ( ) ( ) 5.57 ( ) The egment below and to the left of the haded cell i derived from the network meta-analyi reflecting direct and indirect evidence of treatment effect (row veru column). The point etimate reflect the mean of the poterior ditribution and number in parenthee are 95% credible interval. The egment above and to the right of the haded cell give pooled direct evidence (random-effect pairwie meta-analyi) where available (column veru row). Number in parenthee are 95% confidence interval. - CG173: Neuropathic pain pharmacological management appendix H 32 of 71

33 Capaicin Cream Tramadol Cannabi Sativa Extract NMA Direct pairwie Odd Ratio -v- Figure 19 30% pain relief /- 7 day - relative effect of all option compared with placebo (value le than 1 favour placebo; value greater than 1 favour the treatment; olid error bar are 95% credible interval while dahed error bar are 95% confidence interval) Table 31 30% pain relief /- 7 day - ranking for each comparator Probability bet 00 6 (4 6) Cannabi Sativa Extract 47 5 (1 6) 73 4 (1 6) (1 5) Tramadol 15 3 (1 6) Capaicin Cream (1 6) Median rank (95%CI) Cannabi Sativa Extract Tramadol Capaicin Cream Figure 20 30% pain relief /- 7 day - rank probability hitogram CG173: Neuropathic pain pharmacological management appendix H 33 of 71

34 Table 32 30% pain relief /- 7 day - model fit tatitic Reidual deviance Dbar Dhat pd DIC tau-quared (compared to 14 datapoint) (95%CI: ) Table 33 30% pain relief /- 7 day - note Random-effect model wa ued burn-in and iteration. CG173: Neuropathic pain pharmacological management appendix H 34 of 71

35 Summary GRADE profile 4b: Network meta-analyi for at leat 30% pain relief (56 day +/-7 day) Outcom e 30% pain relief on any cale (follow up 56 day) Numbe r of Studie 4 RCT a n=1120 Limitation Inconitenc y Indirectne Impreciio n very eriou 1 eriou2 not eriou 3 very eriou 4 Qualit y Very low Importanc e Important 1 half of tudie do not report the method of randomiation; treatment group were not comparable at baeline in two tudie and it wa unclear if group were comparable in one other; concomitant drug permitted varie acro the tudie in the network 2 I 2 wa 0% for capaicin patch v placebo which may indicate that any inconitency might not be important; however I 2 wa 80% for pregabalin v placebo which may indicate coniderable heterogeneity between the tudie that make thi comparion; appear to be conitency between direct and indirect etimate 3 all apect of PICO conform to review protocol 4 no head-to-head comparion; wide confidence interval for the effect etimate of both intervention compared to placebo and for overall ranking within the network (mot intervention could have any ranking) a capaicin patch (n=402): Backonja et al. (2008); concomitant drug were permitted apart from topical medication pregabalin (n=718): Dworkin et al. (2003) Guan et al. (2011) Moon et al. (2010); concomitant antidepreant permitted in two (with the exception of anti-convulant) but only SSRI permitted in the other [all compared to placebo] Abbreviation: PICO patient intervention comparator outcome; RCT randomied controlled trial; SSRI elective erotonin reuptake inhibitor Capaicin Patch 3 1 Figure 21 30% pain relief /- 7 day - evidence network CG173: Neuropathic pain pharmacological management appendix H 35 of 71