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Opiáceos para el dolor neuropático

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References

Referencias de los estudios incluidos en esta revisión

Arner 1988 {published data only}

Arner S, Meyerson BA. Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain. Pain 1988;33:11‐23. CENTRAL

Attal 2002 {published data only}

Attal N, Guirimand F, Brasseur L, Gaude V, Chauvin M, Bouhassira D. Effects of IV morphine in central pain: a randomized placebo‐controlled study. Neurology 2002;58:554‐63. CENTRAL

Dellemijn 1997 {published data only}

Dellemijn PL, Vanneste JA. Randomised double‐blind active‐placebo‐controlled crossover trial of intravenous fentanyl in neuropathic pain. Lancet 1997;349:753‐8. CENTRAL

Eide 1994 {published data only}

Eide PK, Jorum E, Stubhaug A, Bremnes J, Breivik H. Relief of post‐herpetic neuralgia with the N‐methyl‐D‐aspartic acid receptor antagonist ketamine: a double‐blind, cross‐over comparison with morphine and placebo. Pain 1994;58:347‐54. CENTRAL

Eide 1995 {published data only}

Eide PK, Stubhaug A, Stenehjem AE. Central dysesthesia pain after traumatic spinal cord injury is dependent on N‐methyl‐D‐aspartate receptor activation. Neurosurgery 1995;37:1080‐7. CENTRAL

Frank 2008 {published data only}

Frank B, Serpell MG, Hughes J, Matthews JN, Kapur D. Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study. BMJ 2008;336:199‐201. CENTRAL

Gilron 2005 {published data only}

Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, gabapentin, or their combination for neuropathic pain. New England Journal of Medicine 2005;352:1324‐34. CENTRAL

Gimbel 2003 {published data only}

Gimbel JS, Richards P, Portenoy RK. Controlled‐release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology 2003;60:927‐34. CENTRAL
Jensen MP, Friedman M, Bonzo D, Richards P. The validity of the neuropathic pain scale for assessing diabetic neuropathic pain in a clinical trial. Clinical Journal of Pain 2006;22:97‐103. CENTRAL

Hanna 2008 {published data only}

Hanna M, O'Brien C, Wilson MC. Prolonged‐release oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients. European Journal of Pain 2008;12:804‐13. CENTRAL

Harke 2001 {published data only}

Harke H, Gretenkort P, Ladleif HU, Rahman S, Harke O. The response of neuropathic pain and pain in complex regional pain syndrome I to carbamazepine and sustained‐release morphine in patients pretreated with spinal cord stimulation: a double‐blinded randomized study. Anesthesia and Analgesia 2001;92:488‐95. CENTRAL

Huse 2001 {published data only}

Huse E, Larbig W, Flor H, Birbaumer N. The effect of opioids on phantom limb pain and cortical reorganization. Pain 2001;90:47‐55. CENTRAL

Jadad 1992 {published data only}

Jadad AR, Carroll D, Glynn CJ, Moore RA, McQuay HJ. Morphine responsiveness of chronic pain: double‐blind randomised crossover study with patient‐controlled analgesia. Lancet 1992;339:1367‐71. CENTRAL

Jorum 2003 {published data only}

Jorum E, Warncke T, Stubhaug A. Cold allodynia and hyperalgesia in neuropathic pain: the effect of N‐methyl‐D‐aspartate (NMDA) receptor antagonist ketamine‐a double‐blind, cross‐over comparison with alfentanil and placebo. Pain 2003;101:229‐35. CENTRAL

Juarez‐Pichardo 2009 {published data only}

Juarez Pichardo JS, Kassian Rank AA, Hernandez Perez AL, Ramirez Tapia Y. Comparison of the efficacy of oxycodone plus lidocaine versus tramadol plus lidocaine in continuous infusion in relieving acute neuropathic pain. Revista de la Sociedad Espanola del Dolor 2009;16:307‐13. CENTRAL

Khoromi 2007 {published data only}

Khoromi S, Cui L, Nackers L, Max MB. Morphine, nortriptyline and their combination vs. placebo in patients with chronic lumbar root pain. Pain 2007;130:66‐75. CENTRAL

Kupers 1991 central {published data only}

Kupers RC, Konings H, Adriaensen H, Gybels JM. Morphine differentially affects the sensory and affective pain ratings in neurogenic and idiopathic forms of pain. Pain 1991;47:5‐12. CENTRAL

Kupers 1991 peripheral {published data only}

Kupers RC, Konings H, Adriaensen H, Gybels JM. Morphine differentially affects the sensory and affective pain ratings in neurogenic and idiopathic forms of pain. Pain 1991;47:5‐12. CENTRAL

Leung 2001 {published data only}

Leung A, Wallace MS, Ridgeway B, Yaksh T. Concentration‐effect relationship of intravenous alfentanil and ketamine on peripheral neurosensory thresholds, allodynia and hyperalgesia of neuropathic pain. Pain 2001;91:177‐87. CENTRAL

Max 1988 {published data only}

Max MB, Schafer SC, Culnane M, Dubner R, Gracely RH. Association of pain relief with drug side effects in postherpetic neuralgia: a single‐dose study of clonidine, codeine, ibuprofen, and placebo. Clinical Pharmacology and Therapeutics 1988;43:363‐71. CENTRAL

Max 1995 {published data only}

Max MB, Byas‐Smith MG, Gracely RH, Bennett GJ. Intravenous infusion of the NMDA antagonist, ketamine, in chronic posttraumatic pain with allodynia: a double‐blind comparison to alfentanil and placebo. Clinical Neuropharmacology 1995;18:360‐8. CENTRAL

Morley 2003 {published data only}

Morley JS, Bridson J, Nash TP, Miles JB, White S, Makin MK. Low‐dose methadone has an analgesic effect in neuropathic pain: a double‐blind randomized controlled crossover trial. Palliative Medicine 2003;17:576‐87. CENTRAL

Rabben 1999 {published data only}

Rabben T, Skjelbred P, Oye I. Prolonged analgesic effect of ketamine, an N‐methyl‐D‐aspartate receptor inhibitor, in patients with chronic pain. Journal of Pharmacology and Experimental Therapeutics 1999;289:1060‐6. CENTRAL

Raja 2002 {published data only}

Raja SN, Haythornthwaite JA, Pappagallo M, Clark MR, Travison TG, Sabeen S, et al. Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo‐controlled trial. Neurology 2002;59:1015‐21. CENTRAL

Rowbotham 1991 {published data only}

Rowbotham MC, Reisner‐Keller LA, Fields HL. Both intravenous lidocaine and morphine reduce the pain of postherpetic neuralgia. Neurology 1991;41:1024‐8. CENTRAL

Rowbotham 2003 {published data only}

Rowbotham MC, Twilling L, Davies PS, Reisner L, Taylor K, Mohr D. Oral opioid therapy for chronic peripheral and central neuropathic pain. New England Journal of Medicine 2003;348:1223‐32. CENTRAL

Simpson 2007 {published data only}

Simpson DM, Messina J, Xie F, Hale M. Fentanyl buccal tablet for the relief of breakthrough pain in opioid‐tolerant adult patients with chronic neuropathic pain: a multicenter, randomized, double‐blind, placebo‐controlled study. Clinical Therapeutics 2007;29:588‐601. CENTRAL

Wallace 2006 {published data only}

Wallace MS, Moulin D, Clark AJ, Wasserman R, Neale A, Morley‐Forster P, et al. A Phase II, multicenter, randomized, double‐blind, placebo‐controlled crossover study of CJC‐1008 ‐ a long‐acting, parenteral opioid analgesic ‐ in the treatment of postherpetic neuralgia. Journal of Opioid Management 2006;2:167‐73. CENTRAL

Watson 1998 {published data only}

Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology 1998;50:1837‐41. CENTRAL

Watson 2003 {published data only}

Watson CP, Moulin D, Watt‐Watson J, Gordon A, Eisenhoffer J. Controlled‐release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy. Pain 2003;105:71‐8. CENTRAL

Wu 2002 phantom limb {published data only}

Wu CL, Tella P, Staats PS, Vaslav R, Kazim DA, Wesselmann U, et al. Analgesic effects of intravenous lidocaine and morphine on postamputation pain: a randomized double‐blind, active placebo‐controlled, crossover trial. Anesthesiology 2002;96:841‐8. CENTRAL

Wu 2002 stump {published data only}

Wu CL, Tella P, Staats PS, Vaslav R, Kazim DA, Wesselmann U, et al. Analgesic effects of intravenous lidocaine and morphine on postamputation pain: a randomized double‐blind, active placebo‐controlled, crossover trial. Anesthesiology 2002;96:841‐8. CENTRAL

Wu 2008 {published data only}

Wu CL, Agarwal S, Tella PK, Klick B, Clark MR, Haythornthwaite JA, et al. Morphine versus mexiletine for treatment of postamputation pain: a randomized, placebo‐controlled, crossover trial. Anesthesiology 2008;109:289‐96. CENTRAL

Zin 2010 {published data only}

Zin CS, Nissen LM, O'Callaghan JP, Duffull SB, Smith MT, Moore BJ. A randomized, controlled trial of oxycodone versus placebo in patients with postherpetic neuralgia and painful diabetic neuropathy treated with pregabalin. Journal of Pain 2010;11:462‐71. CENTRAL

Referencias de los estudios excluidos de esta revisión

Arita 2008 {published data only}

Arita H, Hayashida M, Mizuno J, Ogawa S, Hanaoka K. Pharmacological classification of intractable chronic pain (drug challenge tests). Japanese Journal of Anesthesiology 2008;57:1330‐6. CENTRAL

Arkinstall 1995 {published data only}

Arkinstall W, Sandler A, Goughnour B, Babul N, Harsanyi Z, Darke AC. Efficacy of controlled‐release codeine in chronic non‐malignant pain: a randomized, placebo‐controlled clinical trial. Pain 1995;62(2):169‐78. CENTRAL

Ashburn 2011 {published data only}

Ashburn MA, Slevin KA, Messina J, Xie F. The efficacy and safety of fentanyl buccal tablet compared with immediate‐release oxycodone for the management of breakthrough pain in opioid‐tolerant patients with chronic pain. Anesthesia and Analgesia 2011;112:693‐702. CENTRAL

Benedetti 1998 {published data only}

Benedetti F, Vighetti S, Amanzio M, Casadio C, Oliaro A, Bergamasco B, et al. Dose‐response relationship of opioids in nociceptive and neuropathic postoperative pain. Pain 1998;74:205‐11. CENTRAL

Bohme 2002 {published data only}

Bohme K. Buprenorphine in a transdermal therapeutic system‐a new option. Clinical Rheumatology 2002;21(Suppl 1):S13‐6. CENTRAL

Buynak 2009 {published data only}

Buynak R, Shapiro D, Okamoto A, Van Hove I, Etropolski M. Efficacy and safety of tapentadol ER for chronic low back pain: results of a randomized, double‐blind, placebo‐ and active‐controlled phase III study. Journal of Pain 2009;10:s50. CENTRAL

Cathelin 1980a {published data only}

Cathelin M, Vignes R, Viars P. Comparison between the analgesic effects of buprenorphine and morphine in conscious man [La buprenorphine et la morphine administrees chez l'homme conscient. Comparaison de l'activite analgesique]. Anesthésie, Analgésie, Réanimation 1980;37(5‐6):275‐82. CENTRAL

Cathelin 1980b {published data only}

Cathelin M, Vignes R, Malki M, Viars P. Comparison between the analgesic effects of fentanyl and morphine in conscious man [Le citrate de fentanyl administre par voie intramusculaire chez l'homme conscient]. Anesthésie, Analgésie, Réanimation 1980;37(5‐6):257‐62. CENTRAL

Cruciani 2012 {published data only}

Cruciani RA, Katz N, Portenoy RK. Dose equivalence of immediate‐release hydromorphone and once‐daily osmotic‐controlled extended‐release hydromorphone: A randomized, double‐blind trial incorporating a measure of assay sensitivity. Journal of Pain 2012;13:379‐89. CENTRAL

Dworkin 2009 {published data only}

Dworkin RH, Barbano RL, Tyring SK, Betts RF, McDermott MP, Pennella‐Vaughan J, et al. A randomized, placebo‐controlled trial of oxycodone and of gabapentin for acute pain in herpes zoster. Pain 2009;142:209‐17. CENTRAL

Gatti 2009 {published data only}

Gatti A, Sabato AF, Occhioni R, Colini Baldeschi G, Reale C. Controlled‐release oxycodone and pregabalin in the treatment of neuropathic pain: results of a multicenter Italian study. European Neurology 2009;61:129‐37. CENTRAL

Guo 2007 {published data only}

Guo W, Xiao Z, Yang Y. Effectiveness of transdermal fentanyl combined with clodine for pain control of acute herpes zoster. Journal of Dalian Medical University 2007;29:255‐6. CENTRAL

Gustorff 2005 {published data only}

Gustorff B. Intravenous opioid testing in patients with chronic non‐cancer pain. European Journal of Pain 2005;9(2):123‐5. CENTRAL

Hale 2009 {published data only}

Hale M, Rauck R, Li S, Kutch M. A randomized, double‐blind study of OROS® hydromorphone extended release compared to placebo in opioid‐tolerant patients with moderate‐to‐severe chronic low back pain. Journal of Pain 2009;10:S50. CENTRAL

Heiskanen 2002 {published data only}

Heiskanen T, Hartel B, Dahl ML, Seppala T, Kalso E. Analgesic effects of dextromethorphan and morphine in patients with chronic pain. Pain 2002;96(3):261‐7. CENTRAL

Kalman 2002 {published data only}

Kalman S, Osterberg A, Sorensen J, Boivie J, Bertler A. Morphine responsiveness in a group of well‐defined multiple sclerosis patients: a study with IV morphine. European Journal of Pain 2002;6:69‐80. CENTRAL

Kalso 2007 {published data only}

Kalso E, Simpson KH, Slappendel R, Dejonckheere J, Richarz U. Predicting long‐term response to strong opioids in patients with low back pain: findings from a randomized, controlled trial of transdermal fentanyl and morphine. BMC Medicine 2007;5:39. CENTRAL

Katz 2000 {published data only}

Katz NP. MorphiDex (MS:DM) double‐blind, multiple‐dose studies in chronic pain patients. Journal of Pain and Symptom Management 2000;19(1 Suppl):S37‐41. CENTRAL

Likar 2003 {published data only}

Likar R, Griessinger N, Sadjak A, Sittl R. Transdermal buprenorphine for treatment of chronic tumor and non‐tumor pain [Transdermales buprenorphin fur die behandlung chronischer tumor‐ und nicht‐tumorschmerzen]. Wiener Medizinische Wochenschrift 2003;153:317‐22. CENTRAL

Maier 2002 {published data only}

Maier C, Hildebrandt J, Klinger R, Henrich‐Eberl C, Lindena G, MONTAS Study Group. Morphine responsiveness, efficacy and tolerability in patients with chronic non‐tumor associated pain‐results of a double‐blind placebo‐controlled trial (MONTAS). Pain 2002;97:223‐33. CENTRAL

McLeane 2003 {published data only}

McCleane GJ. A randomised, double blind, placebo controlled crossover study of the cholecystokinin 2 antagonist L‐365,260 as an adjunct to strong opioids in chronic human neuropathic pain. Neuroscience Letters 2003;338(2):151‐4. CENTRAL

McQuay 1992 {published data only}

McQuay HJ, Jadad AR, Carroll D, Faura C, Glynn CJ, Moore RA, et al. Opioid sensitivity of chronic pain: a patient‐controlled analgesia method. Anaesthesia 1992;47(9):757‐67. CENTRAL

Mok 1981 {published data only}

Mok MS, Lippmann M, Steen SN. Multidose/observational, comparative clinical analgetic evaluation of buprenorphine. Journal of Clinical Pharmacology 1981;21(7):323‐9. CENTRAL

Mordarski 2009 {published data only}

Mordarski S, Lysenko L, Gerber H, Zietek M, Gredes T, Dominiak M. The effect of treatment with fentanyl patches on pain relief and improvement in overall daily functioning in patients with postherpetic neuralgia. Journal of Physiology and Pharmacology 2009;60:S8: 31‐5. CENTRAL

Nicholson 2006a {published data only}

Nicholson B, Ross E, Weil A, Sasaki J, Sacks G. Treatment of chronic moderate‐to‐severe non‐malignant pain with polymer‐coated extended‐release morphine sulfate capsules. Current Medical Research and Opinion 2006;22:539‐50. CENTRAL

Nicholson 2006b {published data only}

Nicholson B, Ross E, Sasaki J, Weil A. Randomized trial comparing polymer‐coated extended‐release morphine sulfate to controlled‐release oxycodone HCl in moderate to severe nonmalignant pain. Current Medical Research and Opinion 2006;22:1503‐14. CENTRAL

Niesters 2011 {published data only}

Niesters M, Hoitsma E, Sarton E, Aarts L, Dahan A. Offset analgesia in neuropathic pain patients and effect of treatment with morphine and ketamine. Anesthesiology 2011;115:1063‐71. CENTRAL

Oh 2012 {published data only}

Oh C, Biondi DM, Xiang J, Etropolski M. The efficacy and tolerability of tapentadol Immediate Release (IR) Versus Oxycodone IR for moderate to severe acute low back pain with radicular leg pain. Pain Medicine 2012;13:330‐1. CENTRAL

Palangio 2000 {published data only}

Palangio M, Damask MJ, Morris E, Doyle RT, Jiang JG, Landau CJ, et al. Combination hydrocodone and ibuprofen versus combination codeine and acetaminophen for the treatment of chronic pain. Clinical Therapeutics 2000;22(7):879‐92. CENTRAL

Parker 1982 {published data only}

Parker CE, Langrick AF. A double‐blind comparison of meptazinol and placebo in patients with acute and chronic pain presenting to the general practitioner. Journal of International Medical Research 1982;10(6):408‐13. CENTRAL

Peat 1999 {published data only}

Peat S, Sweet P, Miah Y, Barklamb M, Larsen U. Assessment of analgesia in human chronic pain. Randomized double‐blind crossover study of once daily repro‐dose morphine versus MST continus. European Journal of Clinical Pharmacology 1999;55(8):577‐81. CENTRAL

Podolsky 2009 {published data only}

Podolsky G, Ahdieh H, Ma T. Randomized clinical trial of the safety and efficacy of oxymorphone extended release for degenerative disc disease in opioid‐naive patients. Journal of Pain 2009;10:S48. CENTRAL

Price 1982 {published data only}

Price RK, Latham AN. Double‐blind comparison of meptazinol (200 mg) and dextropropoxyphene / paracetamol in a multi‐centre, general practice setting. Current Medical Research and Opinion 1982;8(1):54‐60. CENTRAL

Sheather‐Reid 1998 {published data only}

Sheather‐Reid RB, Cohen M. Efficacy of analgesics in chronic pain: a series of N‐of‐1 studies. Journal of Pain and Symptom Management 1998;15(4):244‐52. CENTRAL

Sittl 2003 {published data only}

Sittl R, Griessinger N, Likar R. Analgesic efficacy and tolerability of transdermal buprenorphine in patients with inadequately controlled chronic pain related to cancer and other disorders: a multicenter, randomized, double‐blind, placebo‐controlled trial. Clinical Therapeutics 2003;25(1):150‐68. CENTRAL

Sorge 2004 {published data only}

Sorge J, Sittl R. Transdermal buprenorphine in the treatment of chronic pain: results of a phase III, multicenter, randomized, double‐blind, placebo‐controlled study. Clinical Therapeutics 2004;26(11):1808‐20. CENTRAL

Vargha 1983 {published data only}

Vargha von Szeged A, Michos N. Experience with suprofen for acute and chronic pain in neurologic practice [Erfahrungen mit Suprofen bei akuten und chronischen Schmerzen in der neurologischen Praxis]. Arzneimittelforschung 1983;33(9):1334‐8. CENTRAL

Varrassi 2011 {published data only}

Varrassi G, Ashburn M, Slevin KA, Narayana A, Xie F. Fentanyl buccal tablet vs immediate‐release oxycodone for the management of breakthrough pain in opioid‐tolerant patients with chronic pain. European Journal of Pain 2011;5:S87. CENTRAL

Webster 2010 {published data only}

Webster LR, Brewer R, Wang C, Sekora D, Johnson FK, Morris D, et al. Long‐term safety and efficacy of morphine sulfate and naltrexone hydrochloride extended release capsules, a novel formulation containing morphine and sequestered naltrexone, in patients with chronic, moderate to severe pain. Journal of Pain and Symptom Management 2010;40:734‐46. CENTRAL

Webster 2011 {published data only}

Webster L, Narayana A, Janka L. Functioning/satisfaction with fentanyl buccal tablet compared to traditional short‐acting opioids for the management of breakthrough pain in opioid‐tolerant patients with chronic pain. Journal of Pain 2011;12:P62. CENTRAL

Weil 2009 {published data only}

Weil AJ, Nicholson B, Sasaki J. Factors affecting dosing regimens of morphine sulfate extended‐release (KADIAN) capsules. Journal of Opioid Management 2009;5:39‐45. CENTRAL

Worz 2003 {published data only}

Worz R, Frank M, Achenbach U. Controlled‐release oxycodone ‐‐ a therapeutic option for severe neuropathic pain [Zwei praxisstudien zeigen: Opioid lindert starke neuropathische schmerzen]. MMW Fortschritte der Medizin 2003;145:45. CENTRAL

Yao 2012 {published data only}

Yao P, Meng LX, Ma JM, Ding YY, Wang ZB, Zhao GL, et al. Sustained‐release oxycodone tablets for moderate to severe painful diabetic peripheral neuropathy: a multicenter, open‐labeled, postmarketing clinical observation. Pain Medicine 2012;13:107‐14. CENTRAL

Attal 2010

Attal N, Cruccu G, Baron R, Haanpää M, Hansson P, Jensen TS, et al. European Federation of Neurological Societies. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. European Journal of Neurology 2010;17:1113‐e88.

Ballantyne 2003

Ballantyne JC, Mao J. Opioid therapy for chronic pain. New England Journal of Medicine 2003;349:1943‐53.

Baron 2010

Baron R, Binder A. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurology 2010;9:807‐19.

Bouhassira 2008

Bouhassira D, Lanteri‐Minet M. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain 2008;136:380‐7.

Breivik 2004

Breivik H, Bond MJ. Why pain control matters in a world full of killer diseases. www.iasp‐pain.org/PCU04‐4.pdf (accessed 23 August 2005).

Breivik 2006

Breivik H, Collett B. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. European Journal of Pain 2006;10:287‐33.

Canavero 2003

Canavero S, Bonicalzi V. Chronic neuropathic pain. New England Journal of Medicine 2003;348:2688‐9.

Cook 1995

Cook RJ, Sackett DL. The number needed to treat: a clinically useful measure of treatment effect. BMJ 1995;310:452‐4.

Deeks 2011

Deeks JJ, Higgins JPT, Altman DG (editors). Chapter 9: Analysing data and undertaking meta‐analyses. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions 5.1. Chichester: John Wiley & Sons, 2011.

Dellemijn 1999

Dellemijn P. Are opioids effective in relieving neuropathic pain?. Pain 1999;80:453‐62.

Duehmke 2006

Duehmke RM, Hollingshead J, Cornblath DR. Tramadol for neuropathic pain. Cochrane Database of Systematic Reviews 2006, Issue 3. [DOI: 10.1002/14651858.CD003726.pub3]

Dunbar 1996

Dunbar SA, Katz NP. Chronic opioid therapy for nonmalignant pain in patients with a history of substance abuse: report of 20 cases. Journal of Pain and Symptom Management 1996;11:163‐71.

Dworkin 2008

Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, et al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. Journal of Pain 2008;9:105‐21.

Dworkin 2010

Dworkin RH, O'Connor AB. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clinic Proceedings 2010;83:S3‐14.

Farrar 2001

Farrar JT, Young JP, LaMoreaux L, Werth JL, Poole RM. Clinical importance of changes in chronic pain intensity measured on an 11‐point numerical pain rating scale. Pain 2001;94:149‐58.

Finnerup 2010

Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain 2010;150:573‐81.

Gomes 2011

Gomes T, Mamdani MM, Dhalla IA, Paterson M, Juurlink DN. Opioid dose and drug‐related mortality in patients with nonmalignant pain. Archives of Internal Medicine 2011;171:686‐91.

Higgins 2003

Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in metaanalyses. BMJ 2003;327:557‐60.

Higgins 2011

Higgins JPT, Deeks JJ, Altman DG (editors). Chapter 16: Special topics in statistics In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.

Jadad 1996

Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Controlled Clinical Trials 1996;17:1‐12.

Jensen 2007

Jensen MP, Chodroff MJ. The impact of neuropathic pain on health‐related quality of life: review and implications. Neurology 2007;68:1178‐82.

Maier 2010

Maier C, Baron R. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. Pain 2010;150:439‐50.

Manchikanti 2008

Manchikanti L, Singh A. Therapeutic opioids: a ten‐year perspective on the complexities and complications of the escalating use, abuse, and nonmedical use of opioids. Pain Physician 2008;11:S63‐88.

McQuay 1997

McQuay HJ. Opioid use in chronic pain. Acta Anaesthesiologica Scandinavica 1997;41:175‐83.

Meyer‐Rosberg 2001

Meyer‐Rosberg K, Kvarnström A. Peripheral neuropathic pain ‐ a multidimensional burden for patients. European Journal of Pain 2001;5:379‐89.

Moore 1998

Moore RA, Gavaghan D, Tramèr MR, Collins SL, McQuay HJ. Size is everything ‐ large amounts of information are needed to overcome random effects in estimating direction and magnitude of treatment effects. Pain 1998;7:209‐16.

Moore 2010a

Moore RA, Eccleston C, Derry S, Wiffen P, Bell RF, Straube S, et al. "Evidence" in chronic pain ‐ establishing best practice in the reporting of systematic reviews. Pain 2010;150:386‐9.

Moore 2010b

Moore RA, Moore OA, Derry S, Peloso PM, Gammaitoni AR, Wang H. Responder analysis for pain relief and numbers needed to treat in a meta‐analysis of etoricoxib osteoarthritis trials: bridging a gap between clinical trials and clinical practice. Annals of the Rheumatic Diseases 2010;69:374‐9.

Moore 2011

Moore RA, Wiffen PJ, Derry S, McQuay HJ. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database of Systematic Reviews 2011, Issue 3. [DOI: 10.1002/14651858.CD007938.pub2]

Moore 2012

Moore RA, Straube S, Eccleston C, Derry S, Aldington D, Wiffen P, et al. Estimate at your peril: Imputation methods for patient withdrawal can bias efficacy outcomes in chronic pain trials using responder analyses. Pain 2012;153:265‐8.

Moulin 2007

Moulin DE, Clark AJ, Gilron I, Ware MA, Watson CP, Sessle BJ, et al. Canadian Pain Society. Pharmacological management of chronic neuropathic pain ‐ consensus statement and guidelines from the Canadian Pain Society. Pain Research and Management 2007;12:13‐21.

Nicholson 2004

Nicholson BD. Evaluation and treatment of central pain syndromes. Neurology 2004;62 (Suppl 2):S30‐6.

Nuesch 2010

Nüesch E, Trelle S, Reichenbach S, Rutjes AW, Tschannen B, Altman DG, et al. Small study effects in meta‐analyses of osteoarthritis trials: meta‐epidemiological study. BMJ 2010;341:c3515.

O'Connor 2009

O'Connor AB, Dworkin RH. Treatment of neuropathic pain: an overview of recent guidelines. American Journal of Medicine 2009;122:S22‐32.

Pergolizzi 2008

Pergolizzi J, Böger RH, Budd K, Dahan A, Erdine S, Hans G, et al. Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone). Pain Practice 2008;8:287‐313.

Rhodin 2010

Rhodin A, Stridsberg M. Opioid endocrinopathy: a clinical problem in patients with chronic pain and long‐term oral opioid treatment. Clinical Journal of Pain 2010;26:374‐80.

Seghal 2012

Sehgal N, Manchikanti L. Prescription opioid abuse in chronic pain: a review of opioid abuse predictors and strategies to curb opioid abuse. Pain Physician 2012;15:ES67‐92.

Sindrup 1999

Sindrup HJ, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 1999;83:389‐400.

Sullivan 2005

Sullivan M, Ferrell B. Ethical challenges in the management of chronic nonmalignant pain: negotiating through the cloud of doubt. Pain 2005;6:2‐9.

Tompkin 2011

Tompkin DA, Campbell CM. Opioid‐induced hyperalgesia: clinically relevant or extraneous research phenomenon?. Current Pain and Headache Reports 2011;15:129‐36.

Torrance 2006

Torrance N, Smith BH. The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. Journal of Pain 2006;7:281‐9.

Vallejo 2004

Vallejo R, De Leon‐Casasola O. Opioid therapy and immunosuppression: a review. American Journal of Therapeutics 2004;11:354‐65.

Wittink 2005

Wittink H, Carr DB, Eds. Pain management: Evidence, outcomes and quality of life. A sourcebook. Amsterdam, The Netherlands: Elsevier, 2005.

Referencias de otras versiones publicadas de esta revisión

Eisenberg 2005

Eisenberg E, McNicol ED, Carr DB. Efficacy and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin: systematic review and meta‐analysis of randomized controlled trials. JAMA 2005;293(24):3043‐52.

Eisenberg 2006

Eisenberg E, McNicol E, Carr DB. Opioids for neuropathic pain. Cochrane Database of Systematic Reviews 2006, Issue 3. [DOI: 10.1002/14651858.CD006146]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Jump to:

Arner 1988

Methods

Cross‐over ‐ at least 4 test infusions with active drug or placebo given

Participants

Participants enrolled: 8

Neuropathic pain diagnosis: Mixed deafferentation

Interventions

Morphine: 15 mg IV over 15 mins
Placebo

Outcomes

VAS pain intensity, before and 15 mins after infusion. Means of VAS pain reduction compared between active and placebo phases. In some participants, categorical pain relief was assessed (reasons for only some participants not given). 'Positive' outcome defined as moderate or complete pain relief.

Notes

Adverse events, withdrawals not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No description of methods

Allocation concealment (selection bias)

Unclear risk

No description of methods

Blinding (performance bias and detection bias)
All outcomes

Low risk

"Test infusions were prepared with saline or opioids by a nurse who was not a regular member of the ward staff. The infusions were coded and handed over to another nurse".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants appear to have completed the study

Selective reporting (reporting bias)

Unclear risk

All outcomes described in Methods section are reported in Results section, but are difficult to interpret. No protocol available.

Attal 2002

Methods

Cross‐over, single doses, separated by at least 2 weeks

Participants

Participants enrolled: 15

Neuropathic pain diagnosis: central: SC (n = 9), post‐stroke pain (n = 6)

Interventions

Morphine IV: 9 to 30 mg (mean 16 ± 6), previously individually titrated to maximum dose tolerated, over 20 mins
Placebo

Outcomes

Spontaneous pain intensity at baseline, every 15 mins up to 1 hr, then at 90 and 120 minutes (0 ‐ 100 VAS). Total relief = 100% reduction in pain intensity, major relief = at least 50% reduction, no relief or worse pain = decreased by less than 5% or increased.

Tactile allodynia

Mechanical detection and pain thresholds

Thermal detection and pain

Global assessment of pain relief (complete through worse pain), blindness.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Methods not described

Allocation concealment (selection bias)

Low risk

"A study nurse maintained the blind nature of the study and performed the randomization by means of sealed envelopes that contained study medication and order of administration".

Blinding (performance bias and detection bias)
All outcomes

Low risk

"IV morphine or saline in the same volume was administered using the dosage determined during the unblinded phase. IV infusion was performed over a 20‐minute period by an anesthesiologist unaware of the treatment and who did not participate in the unblinded phase". 7/15 subjects correctly identified the active treatment. The examiner identified active treatment in 10/15 cases.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Data from completers only; however only 1 of 16 participants withdrew post‐randomization "because he did not wish to continue".

Selective reporting (reporting bias)

Low risk

All outcomes described in Methods section are reported in Results section. Data for outcome analyzed are provided.

Dellemijn 1997

Methods

Cross‐over, single doses (fentanyl vs saline or fentanyl vs diazepam)

Participants

Participants enrolled: 53

Neuropathic pain diagnosis: peripheral (n = 50), central (n = 3)

Interventions

Fentanyl: 5 mcg/kg/min for maximum of 5 hrs
Diazepam: 0.2 mcg/kg/min for maximum of 5 hrs
Saline

Outcomes

Pain intensity and pain unpleasantness (0 ‐ 100 NRS). Pain intensity difference expressed as percentage of baseline pain intensity. Peak pain intensity difference and average pain intensity difference over 8 hrs. Responders defined as those in whom pain intensity or unpleasantness reduced by 50% at any time point.

Notes

90% of fentanyl infusions vs 46% diazepam infusions vs 8% saline infusions stopped early due to adverse events

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Performed in the hospital pharmacy in blocks of 4.

Allocation concealment (selection bias)

Low risk

Sealed envelopes from hospital pharmacy

Blinding (performance bias and detection bias)
All outcomes

Low risk

Infusions prepared in pharmacy and delivered to study nurse. All infusions identical in appearance.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Minimal dropouts and for non‐intervention‐related reasons

Selective reporting (reporting bias)

Low risk

All outcomes described in Methods section are reported in Results section.

Eide 1994

Methods

Cross‐over, single doses, separated by one week

Participants

Participants enrolled: 8

Neuropathic pain diagnosis: PHN

Interventions

Morphine IV: 0.075 mg/kg over 10 mins
Ketamine IV: 0.15 mg/kg over 10 mins
Placebo

Outcomes

VAS 0 ‐ 100 (no relief through very significant relief) pain relief

Assessment of allodynia, wind‐up‐like pain, tactile sensibility and thermal sensibility.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

It appears that all participants completed the study

Selective reporting (reporting bias)

Low risk

All outcomes described in Methods section are reported in Results section.

Eide 1995

Methods

Cross‐over, single doses, separated by 2 hrs

Participants

Participants enrolled: 9

Neuropathic pain diagnosis: central spinal cord injury

Interventions

Alfentanil IV: 7 mcg/kg over 5 mins + 0.6 mcg/kg/min for 17 to 21 mins
Ketamine IV: 60 mcg/kg over 5 mins + 6 mcg/kg/min for 17 to 21 mins
Placebo

Outcomes

Median % reduction in VAS (0 = no pain, 100 = unbearable pain) continuous pain intensity

Allodynia

Wind‐up‐like pain

Thermal pain threshold

Notes

Pain intensity reduction data extracted from figure

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Latin square

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Described as double‐blind, but no details

Incomplete outcome data (attrition bias)
All outcomes

Low risk

It appears that all participants completed the study

Selective reporting (reporting bias)

Low risk

All outcomes described in Methods section are reported in Results section.

Frank 2008

Methods

Cross‐over, each arm 6 weeks, with 2‐week washout between

Participants

Participants enrolled: 96

Neuropathic pain diagnosis: mixed

Interventions

Dihydrocodeine: oral 30 ‐ 240 mg/day

Nabilone: oral 0.25 ‐ 2 mg/day

Outcomes

Pain intensity: Mean VAS 0 ‐ 100 computed over the last 2 weeks of each treatment period

SF‐36

Hospital Anxiety and Depression Score

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Treatment was allocated by random permuted blocks of 10".

Allocation concealment (selection bias)

Low risk

Coded envelopes retained in pharmacy

Blinding (performance bias and detection bias)
All outcomes

Low risk

"The pharmacy supplied identical white capsules containing 250 mcg nabilone or 30 mg dihydrocodeine".

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Both available case analysis and per protocol analysis presented. Similar outcomes in each population. Greater number of participants withdrew due to side effects in dihydrocodeine phases.

Selective reporting (reporting bias)

Low risk

All outcomes described in Methods section are reported in Results section.

Gilron 2005

Methods

Cross‐over, each arm 5 weeks (including titration and washout).

Participants

Neuropathic pain diagnosis: Diabetic neuropathy (n = 35), PHN (n = 22)

Interventions

Morphine oral long‐acting: up to 120 mg/day
Gabapentin: up to 3200 mg/day
Morphine/Gabapentin combination: up to 60 mg/2400 mg combined/day
Placebo (lorazepam): up to 1.6 mg/day
All drugs titrated upwards over 3 weeks, maintained at maximum tolerated dose for one week, then tapered and 3‐day washout on 5th week.

Outcomes

VAS 0 ‐ 10 (0 = no pain, 10 = worst imaginable) pain intensity at maximum tolerated dose averaged over 7 days
McGill Pain Questionnaire

Brief Pain Inventory

Beck Depression Inventory

SF‐36

Mini‐Mental State Examination

Global pain relief (worse through complete relief)

Incidence and severity (mild, moderate, severe) of adverse events

Notes

Baseline pain intensity: 5.72 ± 0.23 (SE)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Balanced Latin‐square cross‐over design assigned by hospital pharmacist.

Allocation concealment (selection bias)

Low risk

Allocation concealed by a hospital pharmacist

Blinding (performance bias and detection bias)
All outcomes

Low risk

Participants received identical‐appearing capsules in a double‐dummy design. Active placebo (lorazepam) used. Participants asked to guess treatment allocation ‐ slightly higher correct responses when receiving placebo.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Withdrawals (16/57) evenly distributed amongst groups, but reasons for withdrawal not fully described.

Selective reporting (reporting bias)

Low risk

All outcomes described in Methods section are reported in Results section.

Gimbel 2003

Methods

Parallel, 6 weeks

Participants

Study arms enrolled: Opioid group: 82; Control group: 77
Neuropathic pain diagnosis: Diabetic neuropathy

Interventions

Oxycodone oral long‐acting: 10 to 60 mg twice daily (mean: 37 ± 21)
Placebo

Outcomes

Average, current and worst daily NRS (0 ‐ 10) pain intensity

Satisfaction with pain medication

Sleep Quality

Brief Pain Inventory
Rand Mental Health Inventory

Sickness Impact Profile

SF‐36

Incidence and severity of adverse events

Notes

Average pain intensity of ≥ 5 required for enrolment.

Jensen 2006 reported on the same study and participants, but also presented scores for each item on the Neuropathic Pain Scale, from which we were able to extract data for Analysis 2.1.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"A computer generated randomization schedule with permuted blocks of size 4 was used to assign subjects to study treatment".

Allocation concealment (selection bias)

Low risk

Randomized information sealed at sponsor site

Blinding (performance bias and detection bias)
All outcomes

Low risk

Placebo described as being identical to opioid

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Although a relatively large number of dropouts (44/159), they were equally distributed between the groups (19 vs. 25) and reasons specified. Analysis performed on ITT population using LOCF.

Selective reporting (reporting bias)

Low risk

Data provided for primary outcome and most secondary outcomes described in Methods section. Some secondary outcomes only listed as being NS between groups.

Hanna 2008

Methods

Parallel, 12 weeks

Participants

Study arms enrolled: Oxycodone group: 169; Placebo group: 169

Neuropathic pain diagnosis: Diabetic neuropathy

Interventions

Oxycodone oral long‐acting: 10 ‐ 80 mg/day

Placebo

Outcomes

Primary: Pain intensity difference (Box‐scale 11 pain scores)

Secondary: escape medication use; sleep disturbance/sleep quality; participants’ global assessment of pain.

Exploratory: SF‐BPI; Short‐Form McGill Pain Questionnaire; EuroQoL, EQ‐5D; and subject resource utilization.

Notes

Oxycodone or placebo was added to participants' standing gabapentin therapy. Gabapentin dose ranged from 100 ‐ 4800 mg/day.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Randomisation was performed using a validated interactive voice response system that automated the assignment of treatment groups to randomization numbers in accordance with a randomization schedule. Treatment allocation was in balanced blocks of 4 and was stratified by country".

Allocation concealment (selection bias)

Low risk

Central allocation

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

"matched placebo oxycodone tablets", but not stated whether they appeared identical

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Missing data imputed using LOCF

Selective reporting (reporting bias)

Low risk

All outcomes described in Methods section are reported in Results section.

Harke 2001

Methods

Parallel, 2‐phase, 8 days each phase

Participants

Study arms enrolled: Morphine group: 21; Placebo group I: 17; Carbamazepine group: 22; Placebo group II: 21
Neuropathic pain diagnosis: Mixed peripheral

Interventions

Morphine oral long‐acting: 30 mg 3 times daily
Placebo
Carbamazepine: 200 mg oral 3 times daily

Outcomes

Pain intensity NRS (0 ‐ 10)

Time to reactivation of spinal cord stimulator

Notes

Participants had peripheral neuropathic pain reduced by spinal cord stimulation. They were switched into a painful state after device deactivation. In Phase 1, participants were randomly allocated to receive either carbamazepine (600 mg/day) or placebo during an spinal cord stimulator‐free period of 8 days. In Phase 2, oral morphine or placebo were administered under similar conditions.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Minimal withdrawals

Selective reporting (reporting bias)

Unclear risk

Not clear from Methods section what outcomes were considered

Huse 2001

Methods

Cross‐over, 4 weeks

Participants

Participants enrolled: 12
Neuropathic pain diagnosis: Phantom limb

Interventions

Morphine oral long‐acting: 70 ‐ 300 mg/day
Placebo

Outcomes

Pain intensity VAS (0 ‐ 1): mean and numbers with 50% reduction
Electrical pain threshold (mA)
Pain‐Related Self‐Treatment Scale

Brief Stress Scale

West Haven‐Yale Multidimensional Pain Inventory

'd2‐test' (test for attention performance)

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Low risk

Morphine and placebo described as identical and were prepared by the pharmacy

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Participants were required to complete hourly pain diaries for 4 weeks ‐ no mention of imputation of missing values

Selective reporting (reporting bias)

Unclear risk

Large number of outcomes assessed, but not all reported

Jadad 1992

Methods

Cross‐over, 8 hrs, separated by 24 hrs.

Participants

Participants enrolled: 7
Neuropathic pain diagnosis: central (n = 1), peripheral (n = 6)

Interventions

Morphine (low vs high dose): PCA up to 30 mg/hr for up to 8 hrs, or up to 90 mg/hr for up to 8 hrs

Outcomes

% maximal total pain relief

Notes

Study compared responses in participants with nociceptive and neuropathic pain. Participant information reflects only those with neuropathic pain.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Coin toss

Allocation concealment (selection bias)

Unclear risk

"codes kept in a sealed envelope until the patients had completed both sessions", but no mention of who generated the codes

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

"The syringes were filled by a nurse and connected by a nurse not involved with the assessments", but no description of whether comparator syringes appeared identical

Incomplete outcome data (attrition bias)
All outcomes

Low risk

1 participant withdrew after first session. Reasons for dropout described and unlikely to be related to true outcome.

Selective reporting (reporting bias)

Unclear risk

Some outcomes reported only as P values, but none used in analyses.

Jorum 2003

Methods

Cross‐over, single doses, separated by at least 2 hrs

Participants

Participants enrolled: 12
Neuropathic pain diagnosis: PTN (n = 11), PHN (n = 1)

Interventions

Alfentanil: 7 µg/kg over 5 mins + 0.6 µg/kg/min over 20 mins
Ketamine: 60 µg/kg over 5 mins + 6 µg/kg/min over 20 mins
Placebo

Outcomes

Pain elicited at threshold level for cold pain (0 ‐ 10 VAS)

Radiation of pain from site of stimulation (Y or N)

Mechanical allodynia and ongoing pain (0 ‐ 10 VAS)

All measurements taken before (baseline) and during drug infusion

Notes

Data extracted from figure

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Using a Latin square design, the participants were randomized to one of 12 possible sequences by the use of random numbers".

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Intervention preparation performed "by someone not present during the examination", but no mention of whether syringes appeared identical.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

It appears that all participants completed the study and contributed data for all outcomes.

Selective reporting (reporting bias)

Low risk

All outcomes described in Methods section are reported in Results section. 

Juarez‐Pichardo 2009

Methods

Parallel, single doses

Participants

Participants enrolled: oxycodone/lidocaine group 14; tramadol/lidocaine group 13

Neuropathic pain diagnosis: mixed

Interventions

Oxcodone: 10 mg plus lidocaine 3 mg/kg

Tramadol: 100 mg plus lidocaine 3 mg/kg

Both administered over 2 hrs as single intravenous infusions

Outcomes

VAS (0 ‐ 10): spontaneous pain, tactile and thermal (cold) allodynia, hyperalgesia

Nausea and vomiting (VAS)

Satisfaction

Sedation

Vital signs

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Table of random numbers

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Authors state that investigators were unaware of intervention administered (no mention of participant blinding), but methods to ensure blinding not described.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants completed the study

Selective reporting (reporting bias)

Unclear risk

All outcomes described in Methods section are reported in Results section, but method of presenting outcomes not described in Methods section

Khoromi 2007

Methods

Cross‐over, 9 weeks each phase

Participants

Participants enrolled: 55 (28 participants received all 4 treatments)
Neuropathic pain diagnosis: Chronic lumbar root pain

Interventions

Morphine: 15‐90 mg/day (mean: 62 ± 29)

Nortriptyline: 25 ‐ 100 mg/day (mean: 84 ± 24)

Morphine + nortriptyline (not included in our analysis)

Placebo (benztropine as 'active' placebo)

Outcomes

NRS: average and worst leg pain

Global pain relief

SF‐36

Beck Depression Inventory

Oswestry Disability Index

Notes

Negative results may be due to small groups, newspaper recruitment, or type of neuropathic pain (lumbar radiculopathy)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"patients were assigned by random numbers within blocks of four to one of four treatment sequences "  

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Low risk

Identical blue and pink pills for all groups of treatment

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Only 28 of 55 randomized participants completed all 4 arms of the study. Efficacy analysis included participants who completed at least 2 treatment arms. Dropouts adequately described

Selective reporting (reporting bias)

Low risk

All outcomes described in Methods section are reported in Results section. 

Kupers 1991 central

Methods

Cross‐over, 50 mins, separated by at least 24 hrs

Participants

Participants enrolled: 6
Neuropathic pain diagnosis: central

Interventions

Morphine: 0.3 mg/kg in 5 divided bolus doses every 10 mins
Placebo

Outcomes

Change (pre‐ to post‐injection) in affective and sensory dimensions of pain sensation (McGill Pain Questionnaire, 0 ‐ 100 NRS)

Notes

Data extracted in part from figure

Results refer to the "affective" component of pain

Adverse events not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method not described

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

"All drugs were administered intravenously by a third person. Both the patient and the clinician who made the assessments were not told which of the two drugs was being given", but no mention of whether interventions appeared identical.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants completed the study

Selective reporting (reporting bias)

Low risk

All outcomes described in Methods section are reported in Results section. 

Kupers 1991 peripheral

Methods

Cross‐over, 50 mins, separated by at least 24 hrs

Participants

Participants enrolled: 8
Neuropathic pain diagnosis: peripheral

Interventions

Morphine: 0.3 mg/kg in 5 divided bolus doses every 10 mins
Placebo

Outcomes

See Kupers 1991 central

Notes

See Kupers 1991 central

Kupers 1991 central and Kupers 1991 peripheral are same study ‐ we divided results by participants with peripheral pain or with central pain

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method not described

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

"All drugs were administered intravenously by a third person. Both the patient and the clinician who made the assessments were not told which of the two drugs was being given", but no mention of whether interventions appeared identical.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants completed the study

Selective reporting (reporting bias)

Low risk

All outcomes described in Methods section are reported in Results section. 

Leung 2001

Methods

Cross‐over, single doses, separated by 1 week

Participants

Participants enrolled: 12
Neuropathic pain diagnosis: RSD (n = 6), PHN (n = 4), SC (n = 1), causalgia (n = 1)

Interventions

Alfentanil: 20 min infusion aimed at achieving plasma levels of 25, 50 and 75 ng/ml
Ketamine: 20 min infusion aimed at achieving plasma levels of 50, 100 and 150 ng/ml
Placebo (diphenhydramine)

Outcomes

% VAS (0 ‐ 100) reduction in spontaneous and evoked pain

Effect on neurosensory threshold and allodynic area

Notes

Data extracted from figures

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method not described

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Diphenhydramine used as a placebo due to side effect profile similar to other interventions, but no mention of whether interventions appeared identical

Incomplete outcome data (attrition bias)
All outcomes

Low risk

It appears that all participants completed the study

Selective reporting (reporting bias)

Low risk

All outcomes described in Methods section are reported in Results section. 

Max 1988

Methods

Cross‐over, single doses, separated by at least 48 hrs

Participants

Participants enrolled: 46
Neuropathic pain diagnosis: PHN

Interventions

Codeine: 120 mg single oral dose
Clonidine: 0.2 mg single oral dose
Ibuprofen: 800 mg single oral dose
Placebo

Outcomes

Pain intensity and relief at baseline, and each hr through 6 hrs

Categorical scales of pain (severe = 3, none = 0) and relief (complete = 4, none = 0); VAS for pain and relief (100 mm)

McGill Pain Questionnaire and verbal descriptor scales (13‐word lists of descriptors for pain intensity, pain unpleasantness, and "overall" pain)

SPID and TOTPAR derived from above scales

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method not described

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding (performance bias and detection bias)
All outcomes

Low risk

Capsules had identical appearance

Incomplete outcome data (attrition bias)
All outcomes

Low risk

7/46 did not provide data, but only 1 case was due to opioid side effect

Selective reporting (reporting bias)

Low risk

All outcomes described in Methods section are reported in Results section. 

Max 1995

Methods

Cross‐over, single infusions, separated by 1 day

Participants

Participants enrolled: 8
Neuropathic pain diagnosis: PTN

Interventions

Alfentanil: 1.5 µg/kg/min for 60 mins; rate doubled as required at 60 and 90 mins for a total of 2 hrs
Ketamine: 0.75 mg/kg/hr for 20 mins; rate doubled as required at 60 and 90 mins for a total of 2 hrs
Placebo

Outcomes

Background pain (0 ‐ 100 VAS)

Mechanical allodynia (0 ‐ 100 VAS)

% pain relief from both of above

Notes

SD calculated from data

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method not described

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Solutions prepared by third party, but no mention of appearing identical

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants completed the study

Selective reporting (reporting bias)

Low risk

All outcomes described in Methods section are reported in Results section. 

Morley 2003

Methods

Randomized, double‐blind, placebo‐controlled cross‐over. Two phases, each 20 days.

Participants

Participants enrolled:
Low‐dose phase: 19
High‐dose phase: 17
Neuropathic pain diagnosis: Mixed lasting > 3 months

Interventions

Phase I: Methadone oral: 5 mg twice daily alternating with placebo on odd days and rest on even days
Phase II: Methadone oral: 10 mg twice daily alternating with placebo on odd days and rest on even days

Outcomes

All outcomes assessed each evening in patient diaries.

Maxium and average pain intensity, pain relief (VAS).

Adverse effects with severity (mild, moderate, severe).

Any additional "prn" medications required

Notes

For each phase, results of 5 days with active intervention were compared with results of 5 days with placebo. Analyses of safety and efficacy in this review are based on Phase I (low‐dose phase). Participants had neuropathic pain that had not been satisfactorily relieved by other interventions or by current or previous drug regimens. Participants were permitted to continue with concurrent medications, some of which were opioids.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Eight replications of a Latin square design

Allocation concealment (selection bias)

Low risk

Central allocation

Blinding (performance bias and detection bias)
All outcomes

Low risk

Medication containers appeared identical, and medications "were not distinguishable by taste or appearance"

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Only participants completing study were analyzed, 6 participants withdrew from high‐dose phase due to severe nausea ‐ 3 while taking placebo, 3 while taking methadone

Selective reporting (reporting bias)

Low risk

All outcomes described in Methods section are reported in Results section. 

Rabben 1999

Methods

Cross‐over, single doses, separated by 1 week

Participants

Participants enrolled: 30
Neuropathic pain diagnosis: Trigeminal neuropathic pain

Interventions

Meperidine: 1.0 mg/kg IM
Ketamine: 0.4 mg/kg IM + midazolam: 0.05 mg/kg IM

Outcomes

Pain intensity (VAS 0 ‐ 100) pre‐ and post‐intervention
% of initial pain at best time point ( = maximal response)

Three different subgroups of response were defined: no analgesic effect, short‐term analgesic effect, and long‐term analgesic effect

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Patients were randomized in blocks of four according to sex, age, and duration of pain"

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Method not described

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

3 participants receiving pethidine withdrew due to nausea

Selective reporting (reporting bias)

Low risk

All outcomes described in Methods section are reported in Results section. 

Raja 2002

Methods

Randomized, double‐blind, active‐ and placebo‐controlled, cross‐over. Each treatment period lasted approximately 8 weeks and had a titration, maintenance, and taper phase. The treatment periods were separated by a 1‐week drug‐free, washout period.

Participants

Participants enrolled:
Opioid arm: 76
Control arm: 76
Placebo arm: 76
Neuropathic pain diagnosis: PHN (pain persisting ≥ 3 months after resolution of cutaneous lesions)

Interventions

Morphine oral: 15 to 240 mg/day or methadone oral 5 to 80 mg/day (means 91 ± 49.3 and 15 ± 2.0)
Nortriptyline or desipramine: 10 to 160 mg/day (means 89 ± 27.1 and 63 ± 3.6 )
Placebo

Outcomes

Primary outcomes: pain intensity, pain relief, cognitive function (symbol substitution task)

Secondary outcomes: physical functioning, sleep, mood, side effects, treatment preference

Pain intensity (0 ‐ 10 NRS) and pain relief (0 ‐ 100 NRS) values were collected by twice‐weekly telephone interviews during the trial. All other outcome measures were obtained during clinic visits at the end of the drug‐free baseline period and at the end of the maintenance phase for each drug

Notes

Study compared opioid (morphine or methadone) vs tricyclic antidepressant (nortriptyline or desipramine) vs placebo. Participants received methadone only if they did not tolerate morphine.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"The randomization sequence was computer generated by the biostatistician"

Allocation concealment (selection bias)

Low risk

Sealed envelopes

Blinding (performance bias and detection bias)
All outcomes

Low risk

"The pharmacist formulated the study drugs in identical gel capsules to maintain the blinding. All investigators were blinded to the drug treatments during the study".

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

ITT analysis employed. For participants who did not complete a treatment period, the last 3 available pain ratings were used. Number of participants who did not complete methadone phase not reported.

Selective reporting (reporting bias)

Low risk

All outcomes described in Methods section are reported in Results section. 

Rowbotham 1991

Methods

Cross‐over, single infusions, separated by at least 48 hrs

Participants

Participants enrolled: 19
Neuropathic pain diagnosis: PHN

Interventions

Morphine: 0.3 mg/kg (max 25 mg) over 1 hr
Lidocaine: 5 mg/kg (max 450 mg) over 1 hr
Placebo

Outcomes

Pain intensity pre‐ and post‐infusion, and pain relief (0 ‐ 100 VAS)

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method not described

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Method not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Only one participant did not complete all 3 sessions, withdrawing from lidocaine session due to side effects, but supplying data for first 30 minutes.

Selective reporting (reporting bias)

Low risk

All outcomes described in Methods section are reported in Results section. 

Rowbotham 2003

Methods

Parallel, 8 weeks

Participants

Study arms enrolled:
Levorphanol high‐dose group: 43
Levorphanol low‐dose group: 38
Neuropathic pain diagnosis: Mixed

Interventions

Levorphanol: 0.75 mg (1 ‐ 7 capsules) 3 times daily (mean 8.9 mg/day)
Levorphanol: 0.15 mg (1 ‐ 7 capsules) 3 times daily (mean 2.7 mg/day)

Outcomes

Pain intensity (0 ‐ 100 VAS): change in weekly average from baseline to 8th week of treatment

Pain relief (categorical, 0 ‐ 5)

Profile of Mood States Questionnaire

Symbol‐Digit Modalities Test

Multidimensional Pain Inventory

Opiate‐Agonist Effects Scale and Opiate Withdrawal Scale

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method not described

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding (performance bias and detection bias)
All outcomes

Low risk

" Low‐strength capsules and high‐strength capsules were identical in appearance and were packaged in patient‐specific bottles".

Incomplete outcome data (attrition bias)
All outcomes

High risk

Withdrawals due to adverse events: 12 in the high‐strength group vs. 3 in the low‐strength group

Selective reporting (reporting bias)

Unclear risk

Data not provided for some secondary outcomes

Simpson 2007

Methods

Randomized, double‐blind, placebo‐controlled cross‐over. Single doses for each of 9 consecutive breakthrough pain episodes separated by at least 2 hours. Maximum study duration of 21 days.

Participants

N = 79 (77 completed); had a ≥ 3 month history of chronic persistent neuropathic pain; mean age 48 years; mean pain intensity = 5.1/10

Interventions

Fentanyl buccal tablets 100 ‐ 800 mcg, based on effective dose established during open‐label phase

Placebo

Participants received 6 doses of active intervention and 3 of placebo, according to 1 of 3 prespecified treatment sequences. Placebo tablets were not supplied in consecutive episodes.

Outcomes

Primary efficacy measure: SPID from 5 ‐ 60 mins after administration of study drug.

Secondary efficacy measures: PIDs at 5, 10, 15, 30, 45, 60, 90, and 120 mins after administration of study drug;

Proportion of breakthrough pain episodes with > 33% and > 50% improvement in PI from baseline;

PR at 5, 10, 15, 30, 45, 60, 90, and 120 minutes (0 = none to 4 = complete);

Proportion of breakthrough pain episodes in which participants reported achieving meaningful PR;

Time to meaningful PR;
Proportion of BTP episodes in which pre‐study supplemental opioids were required.
AEs reported by the participants or recorded by the investigators; serious AEs; withdrawals due to AEs; and the results of physical examinations, examinations of the oral mucosa, clinical laboratory tests, and vital signs.

Notes

Dose‐titration phase before study enrolled 103 participants. 23 participants withdrew during this phase, 12 because of adverse events.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random code

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

"matching" placebo. "Both patients and investigators were blinded". No further information.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

77 (97%) participants completed the study. When supplemental opioid was used for inadequate pain reduction, LOCF was used for efficacy measures. Participants used supplemental opioid for 59 (14%) of the 432 episodes treated with FBT and for 77 (36%) of the 213 episodes in which placebo was administered.

Selective reporting (reporting bias)

Low risk

All outcomes described in Methods section are reported in Results section.

Wallace 2006

Methods

Randomized, double‐blind, placebo‐controlled cross‐over.

Participants

N = 32 (26 completed); PHN for at least 3 months with baseline VAS ≥ 45/100

Interventions

CJC‐1008 (experimental dynorphin analog): 3 mg/kg single dose

Placebo

Outcomes

Pain intensity difference VAS, overall and for each of 3 pain types (constant, spontaneous or allodynia);

Categorical pain intensity;

Categorical pain relief;

Physical examination, vital signs.

Evaluations every 15 mins for first hr; 2, 3, 4, 6 and 8 hrs; and during return visits to study site at 2, 7 and 28 days post‐dose.

Notes

Participants crossed over to alternative intervention once pain returned to baseline level

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

26/32 participants completed study. Efficacy outcomes only in those completing the study for all but primary outcome. Reasons for dropouts not described. LOCF used for missing data.

Selective reporting (reporting bias)

Unclear risk

Not all data are presented in results section; all data presented are in graphical form only

Watson 1998

Methods

Cross‐over, 4 weeks

Participants

Participants enrolled: 50
Neuropathic pain diagnosis: PHN

Interventions

Oxycodone oral long‐acting: 10 ‐ 30 mg twice daily (mean: 45 ± 17)
Placebo

Outcomes

Daily pain intensity (0 ‐ 100 VAS) and pain relief (categorical 0 ‐ 5)
Allodynia weekly intensity (0 ‐ 100 VAS) and relief (categorical 0 ‐ 5)
Disability (categorical 0 ‐ 3)
Effectiveness rating (categorical 0 ‐ 3)
Profile of Mood States Questionnaire

Beck Depression Inventory

Notes

Adverse events in placebo group not listed.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method not described

Allocation concealment (selection bias)

Low risk

Opaque, patient‐specific envelopes

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Method not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Numbers of dropouts, reasons, similar in both groups

Selective reporting (reporting bias)

Unclear risk

Data not provided for some secondary outcomes

Watson 2003

Methods

Cross‐over, 4 weeks

Participants

Participants enrolled:
Opioid phase: 45
Active placebo phase: 45
Neuropathic pain diagnosis: Diabetic neuropathy

Interventions

Oxycodone oral long‐acting: 10 ‐ 40 mg twice daily (mean: 40.0 ± 18.5)
Benztropine: 0.25 to 1.0 mg twice daily (mean: 1.2 ± 0.6)

Outcomes

Daily pain, steady pain, brief pain, and skin (allodynia) pain intensity (0 ‐ 100 VAS and categorical 0 ‐ 4)
Pain relief (categorical 0 ‐ 5, lower score = more relief): NNTB for moderate pain relief derived
Pain Disability Index
Pain and Sleep Questionnaire

SF‐36

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Method not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Data for both evaluable and ITT populations presented ‐ similar results

Selective reporting (reporting bias)

Unclear risk

Data not presented for some secondary outcomes

Wu 2002 phantom limb

Methods

Cross‐over, single infusions, separated by 24 hrs

Participants

Participants enrolled: 20
Neuropathic pain diagnosis: Phantom limb pain

Interventions

Morphine: 0.05 mg/kg bolus + 0.2 mg/kg over 40 mins
Lidocaine: 1.0 mg/kg bolus + 4.0 mg/kg over 40 mins
Active placebo (diphenhydramine) 10 mg bolus + 40 mg over 40 mins

Outcomes

Phantom and stump pain intensity (0 ‐ 100 VAS) pre‐ and post‐infusion
% pain relief

% overall satisfaction

Notes

Data on initial and end VAS extracted from figures. SD data received from direct communication with one of the authors

25% of participants had only mild pain on days of infusion

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"subjects were randomized in balanced blocks of 12"

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding (performance bias and detection bias)
All outcomes

Low risk

Interventions were prepared by a pharmacist and were identical in appearance

Incomplete outcome data (attrition bias)
All outcomes

Low risk

1 dropout because of absence of pain before initiation of infusion

Selective reporting (reporting bias)

Low risk

All outcomes described in Methods section are reported in Results section. 

Wu 2002 stump

Methods

See Wu 2002 phantom limb

Participants

Participants enrolled: 22
Neuropathic pain diagnosis: Stump pain

Interventions

See Wu 2002 phantom limb

Outcomes

See Wu 2002 phantom limb

Notes

See Wu 2002 phantom limb.

Wu 2002 phantom limb refers to those participants with phantom limb pain; Wu 2002 stump to those with stump pain. Total number of participants = 31; 11 participants had stump pain alone, 9 had phantom pain alone, and 11 had both stump and phantom pains

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

See Wu 2002 phantom limb

Allocation concealment (selection bias)

Unclear risk

See Wu 2002 phantom limb

Blinding (performance bias and detection bias)
All outcomes

Low risk

See Wu 2002 phantom limb

Incomplete outcome data (attrition bias)
All outcomes

Low risk

See Wu 2002 phantom limb

Selective reporting (reporting bias)

Low risk

See Wu 2002 phantom limb

Wu 2008

Methods

Cross‐over, 8 weeks each phase

Participants

Participants enrolled: 60
Neuropathic pain diagnosis: Post‐amputation stump pain (n = 8), phantom pain (n = 8) or both (n = 44)

Interventions

Morphine: oral sustained release 15 ‐ 180 mg/day (mean 112 ± 62.7)

Mexiletine: 300 ‐ 1200mg/day (mean: 933 ± 257)

Placebo

Outcomes

Change in pain intensity (0 ‐ 10 NRS) from baseline to end of therapy

Pain relief (0 ‐ 100%)

Multidimensional Pain Inventory

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"The subjects were randomized in balanced blocks of 12"  

Allocation concealment (selection bias)

Low risk

"The sequence of drug and placebo .. for each subject was provided in sealed envelops to the investigational pharmacy and the monitoring committee"

Blinding (performance bias and detection bias)
All outcomes

Low risk

"Mexiletine and placebo were similarly packaged in sealed capsules that were identical in appearance"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Dropouts described, equally distributed. Both case analysis of all randomized participants and per protocol analysis performed. 

Selective reporting (reporting bias)

Low risk

Data provided for primary outcome and for most secondary outcomes. Some secondary outcomes only listed as being NS between groups.

Zin 2010

Methods

Parallel, 5 weeks

Participants

Study arms enrolled:
Oxycodone (plus pregabalin) group: 29
Placebo (plus pregabalin) group: 33
Neuropathic pain diagnosis: Postherpetic neuralgia, painful diabetic neuropathy

Interventions

Oxycodone: liquid 5 mg twice daily

Placebo: identical liquid twice daily

Pregabilin (in both groups): 75 ‐ 600 mg/day

Outcomes

2‐cm drop in pain‐intensity score and a pain‐intensity score of < 4 cm measured by VAS from baseline, following pregabalin dosage escalation

> 50% pain reduction from baseline

Sleep interference score

Neuropathic pain scale

SF‐36 questionnaire

Profile of Mood States

Trail‐making test

Patient global impression of change

Clinician global impression of change

Notes

Participants were randomized to receive either oxycodone or placebo for 1 week, and were then started on open‐label pregabalin (75, 150, 300 and 600 mg/day) according to a forced titration dosing regimen, while continuing the same dosage of oxycodone or placebo for 4 weeks.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"patients were assigned to 1 of 2 treatment group using a computer generated randomization number in block size of 10 "  

Allocation concealment (selection bias)

Unclear risk

"All the study medications were supplied to patient by the clinical–trial pharmacist at the GPH"

Blinding (performance bias and detection bias)
All outcomes

Low risk

"All of the characteristics (appearance,taste,and method of administration) of the oxycodone and placebo mixture were identical to ensure that study blinding was maintained "

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Dropouts and AEs adequately presented. ITT analysis with attention to missing observation (LOCF)

Selective reporting (reporting bias)

Low risk

All outcomes described in Methods section are reported in Results section. 

 

AE = adverse event; CI = 95% confidence interval; ITT = intention‐to‐treat; IV = intravenous; LOCF = last observation carried forward; NNTB = number needed to treat for an additional beneficial outcome; NNTH = number needed to treat for an additional harmful outcome; NR = not reported; NRS = numerical rating scale; NS = non significant (P > 0.05); PCA = patient controlled analgesia; PHN = postherpetic neuralgia; PTN = post‐traumatic neuralgia; RSD = reflex sympathetic dystrophy; SD = standard deviation; SE = standard error; SF‐36 = Short‐Form 36 Questionnaire; VAS = visual analog scale;

Characteristics of excluded studies [ordered by study ID]

Jump to:

Study

Reason for exclusion

Arita 2008

Not an RCT

Arkinstall 1995

Non‐neuropathic pain

Ashburn 2011

Study group had mixed pain syndromes ‐ both neuropathic and nociceptive; results not presented independently

Benedetti 1998

Opioid studied ‐ buprenorphine ‐ is not a full mu receptor agonist

Bohme 2002

Opioid studied ‐ buprenorphine ‐ is not a full mu receptor agonist

Buynak 2009

Presented in abstract form only

Cathelin 1980a

Opioid studied ‐ buprenorphine ‐ is not a full mu receptor agonist

Cathelin 1980b

Presented in abstract form only

Cruciani 2012

Study group had mixed pain syndromes ‐ both neuropathic and nociceptive; results not presented independently

Dworkin 2009

Participants had mixed nociceptive and neuropathic pain (acute herpes zoster) ‐ effects of opioid on each not presented separately

Gatti 2009

Not an RCT

Guo 2007

Study group had mixed pain syndromes ‐ both neuropathic and nociceptive; results not presented independently

Gustorff 2005

Only 5 participants had neuropathic pain (information provided by contacting author); data not presented separately

Hale 2009

Presented in abstract form only

Heiskanen 2002

Morphine plus placebo versus morphine plus dextromethorphan

Kalman 2002

Non‐randomized and single‐blinded study

Kalso 2007

Participants had mixed nociceptive and neuropathic pain (low back pain) ‐ effects of opioid on each not presented separately

Katz 2000

Study group had mixed pain syndromes ‐ both neuropathic and nociceptive; results not presented independently

Likar 2003

Opioid studied ‐ buprenorphine ‐ is not a full mu receptor agonist

Maier 2002

Study group had mixed pain syndromes ‐ both neuropathic and nociceptive; results not presented independently

McLeane 2003

Non‐neuropathic pain

McQuay 1992

No control group

Mok 1981

Non‐neuropathic pain

Mordarski 2009

No control group

Nicholson 2006a

Study group had mixed pain syndromes ‐ both neuropathic and nociceptive; results not presented independently

Nicholson 2006b

Study group had mixed pain syndromes ‐ both neuropathic and nociceptive; results not presented independently

Niesters 2011

Control group did not have neuropathic pain

Oh 2012

Abstract only

Palangio 2000

Non‐neuropathic pain

Parker 1982

Combination of opioid plus other drug

Peat 1999

Study group had mixed pain syndromes ‐ both neuropathic and nociceptive; results not presented independently

Podolsky 2009

Presented in abstract form only

Price 1982

Study group had mixed pain syndromes ‐ both neuropathic and nociceptive; results not presented independently

Sheather‐Reid 1998

Study group had mixed pain syndromes ‐ both neuropathic and nociceptive; results not presented independently

Sittl 2003

Non‐randomized

Sorge 2004

Opioid combined with cholecystokinin versus opioid

Vargha 1983

Opioid studied ‐ buprenorphine ‐ is not a full mu receptor agonist. Non‐neuropathic pain

Varrassi 2011

Abstract only

Webster 2010

Study group had mixed pain syndromes ‐ both neuropathic and nociceptive; results not presented independently

Webster 2011

Abstract only

Weil 2009

Study group had mixed pain syndromes ‐ both neuropathic and nociceptive; results not presented independently

Worz 2003

Opioid studied ‐ buprenorphine ‐ is not a full mu receptor agonist

Yao 2012

No control group

RCT = randomized controlled trial

Data and analyses

Open in table viewer
Comparison 1. Short‐term Efficacy Studies: opioid vs placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Pain intensity post‐opioid/placebo Show forest plot

6

180

Mean Difference (IV, Random, 95% CI)

‐15.81 [‐22.54, ‐9.07]

Analysis 1.1

Comparison 1 Short‐term Efficacy Studies: opioid vs placebo, Outcome 1 Pain intensity post‐opioid/placebo.

Comparison 1 Short‐term Efficacy Studies: opioid vs placebo, Outcome 1 Pain intensity post‐opioid/placebo.

1.1 Peripheral Pain

4

138

Mean Difference (IV, Random, 95% CI)

‐15.01 [‐22.97, ‐7.06]

1.2 Central Pain

2

42

Mean Difference (IV, Random, 95% CI)

‐17.81 [‐30.48, ‐5.15]

2 % Pain reduction post‐opioid/placebo Show forest plot

2

38

Mean Difference (IV, Random, 95% CI)

25.78 [16.91, 34.65]

Analysis 1.2

Comparison 1 Short‐term Efficacy Studies: opioid vs placebo, Outcome 2 % Pain reduction post‐opioid/placebo.

Comparison 1 Short‐term Efficacy Studies: opioid vs placebo, Outcome 2 % Pain reduction post‐opioid/placebo.

Open in table viewer
Comparison 2. Intermediate‐term Efficacy Studies: Opioid vs. Placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Number of participants with at least 33% pain relief Show forest plot

6

727

Risk Difference (M‐H, Random, 95% CI)

0.25 [0.13, 0.37]

Analysis 2.1

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 1 Number of participants with at least 33% pain relief.

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 1 Number of participants with at least 33% pain relief.

2 Number of participants with at least 50% pain relief Show forest plot

5

305

Risk Difference (M‐H, Random, 95% CI)

0.17 [0.02, 0.33]

Analysis 2.2

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 2 Number of participants with at least 50% pain relief.

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 2 Number of participants with at least 50% pain relief.

3 Pain intensity post‐opioid/placebo Show forest plot

9

725

Mean Difference (IV, Random, 95% CI)

‐12.01 [‐15.40, ‐8.62]

Analysis 2.3

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 3 Pain intensity post‐opioid/placebo.

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 3 Pain intensity post‐opioid/placebo.

4 Evoked pain intensity post‐opioid/placebo Show forest plot

2

148

Mean Difference (IV, Random, 95% CI)

‐23.73 [‐34.50, ‐12.96]

Analysis 2.4

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 4 Evoked pain intensity post‐opioid/placebo.

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 4 Evoked pain intensity post‐opioid/placebo.

5 SF‐36 Health Survey Show forest plot

2

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 2.5

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 5 SF‐36 Health Survey.

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 5 SF‐36 Health Survey.

5.1 Physical functioning

2

142

Mean Difference (IV, Random, 95% CI)

3.16 [‐5.46, 11.77]

5.2 Role‐physical

2

142

Mean Difference (IV, Random, 95% CI)

9.62 [‐7.73, 26.97]

5.3 Bodily pain

2

142

Mean Difference (IV, Random, 95% CI)

6.78 [0.08, 13.48]

5.4 General health

2

142

Mean Difference (IV, Random, 95% CI)

‐0.62 [‐8.08, 6.85]

5.5 Vitality

2

142

Mean Difference (IV, Random, 95% CI)

1.62 [‐5.82, 9.07]

5.6 Social functioning

2

142

Mean Difference (IV, Random, 95% CI)

3.40 [‐5.09, 11.88]

5.7 Role‐emotional

2

142

Mean Difference (IV, Random, 95% CI)

7.97 [‐5.06, 21.00]

5.8 Mental health

2

142

Mean Difference (IV, Random, 95% CI)

3.09 [‐3.05, 9.23]

6 Brief Pain Inventory: Pain Interference items Show forest plot

2

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 2.6

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 6 Brief Pain Inventory: Pain Interference items.

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 6 Brief Pain Inventory: Pain Interference items.

6.1 General activity

2

245

Mean Difference (IV, Random, 95% CI)

‐0.91 [‐1.67, ‐0.14]

6.2 Mood

2

245

Mean Difference (IV, Random, 95% CI)

‐0.62 [‐1.31, 0.07]

6.3 Walking

2

245

Mean Difference (IV, Random, 95% CI)

‐0.54 [‐1.28, 0.20]

6.4 Normal work

2

245

Mean Difference (IV, Random, 95% CI)

‐0.82 [‐1.59, ‐0.05]

6.5 Social relations

2

245

Mean Difference (IV, Random, 95% CI)

‐0.71 [‐1.25, ‐0.16]

6.6 Sleep

2

245

Mean Difference (IV, Random, 95% CI)

‐1.74 [‐2.42, ‐1.06]

6.7 Enjoyment of life

2

245

Mean Difference (IV, Random, 95% CI)

‐1.18 [‐1.91, ‐0.44]

7 Beck Depression Inventory Show forest plot

3

273

Mean Difference (IV, Random, 95% CI)

0.21 [‐2.29, 2.71]

Analysis 2.7

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 7 Beck Depression Inventory.

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 7 Beck Depression Inventory.

Open in table viewer
Comparison 3. Intermediate‐term Efficacy Studies: opioid vs active control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Number of participants with at least 33% pain relief Show forest plot

3

243

Risk Difference (M‐H, Random, 95% CI)

0.17 [0.04, 0.31]

Analysis 3.1

Comparison 3 Intermediate‐term Efficacy Studies: opioid vs active control, Outcome 1 Number of participants with at least 33% pain relief.

Comparison 3 Intermediate‐term Efficacy Studies: opioid vs active control, Outcome 1 Number of participants with at least 33% pain relief.

1.1 opioid vs gabapentin

1

88

Risk Difference (M‐H, Random, 95% CI)

0.18 [‐0.01, 0.37]

1.2 opioid vs tricyclic antidepressant

1

63

Risk Difference (M‐H, Random, 95% CI)

0.02 [‐0.22, 0.26]

1.3 opioid vs antiarrythmic

1

92

Risk Difference (M‐H, Random, 95% CI)

0.28 [0.08, 0.48]

2 Number of participants with at least 50% pain relief Show forest plot

2

155

Risk Difference (M‐H, Random, 95% CI)

0.07 [‐0.20, 0.33]

Analysis 3.2

Comparison 3 Intermediate‐term Efficacy Studies: opioid vs active control, Outcome 2 Number of participants with at least 50% pain relief.

Comparison 3 Intermediate‐term Efficacy Studies: opioid vs active control, Outcome 2 Number of participants with at least 50% pain relief.

2.1 opioid vs tricyclic antidepressant

1

63

Risk Difference (M‐H, Random, 95% CI)

‐0.07 [‐0.30, 0.15]

2.2 opioid vs antiarrythmic

1

92

Risk Difference (M‐H, Random, 95% CI)

0.20 [0.01, 0.39]

3 Pain intensity post‐opioid/active control Show forest plot

4

388

Mean Difference (IV, Random, 95% CI)

‐7.19 [‐13.13, ‐1.25]

Analysis 3.3

Comparison 3 Intermediate‐term Efficacy Studies: opioid vs active control, Outcome 3 Pain intensity post‐opioid/active control.

Comparison 3 Intermediate‐term Efficacy Studies: opioid vs active control, Outcome 3 Pain intensity post‐opioid/active control.

3.1 opioid vs gabapentin

1

88

Mean Difference (IV, Random, 95% CI)

‐5.0 [‐14.40, 4.40]

3.2 opioid vs tricyclic antidepressant

2

208

Mean Difference (IV, Random, 95% CI)

‐3.30 [‐13.48, 6.89]

3.3 opioid vs antiarrythmic

1

92

Mean Difference (IV, Random, 95% CI)

‐13.0 [‐19.12, ‐6.88]

4 SF‐36 Health Survey Show forest plot

2

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 3.4

Comparison 3 Intermediate‐term Efficacy Studies: opioid vs active control, Outcome 4 SF‐36 Health Survey.

Comparison 3 Intermediate‐term Efficacy Studies: opioid vs active control, Outcome 4 SF‐36 Health Survey.

4.1 Physical functioning

2

144

Mean Difference (IV, Random, 95% CI)

‐5.09 [‐13.81, 3.63]

4.2 Role‐physical

2

144

Mean Difference (IV, Random, 95% CI)

‐5.38 [‐19.05, 8.29]

4.3 Bodily pain

2

144

Mean Difference (IV, Random, 95% CI)

‐3.11 [‐9.91, 3.70]

4.4 General health

2

144

Mean Difference (IV, Random, 95% CI)

‐4.44 [‐11.75, 2.86]

4.5 Vitality

2

144

Mean Difference (IV, Random, 95% CI)

‐6.60 [‐13.63, 0.44]

4.6 Social functioning

2

144

Mean Difference (IV, Random, 95% CI)

‐6.04 [‐14.44, 2.35]

4.7 Role‐emotional

2

144

Mean Difference (IV, Random, 95% CI)

‐6.39 [‐19.37, 6.60]

4.8 Mental health

2

144

Mean Difference (IV, Random, 95% CI)

‐6.24 [‐14.06, 1.57]

5 Beck Depression Inventory Show forest plot

3

276

Mean Difference (IV, Random, 95% CI)

1.40 [‐0.38, 3.17]

Analysis 3.5

Comparison 3 Intermediate‐term Efficacy Studies: opioid vs active control, Outcome 5 Beck Depression Inventory.

Comparison 3 Intermediate‐term Efficacy Studies: opioid vs active control, Outcome 5 Beck Depression Inventory.

5.1 opioid vs gabapentin

1

88

Mean Difference (IV, Random, 95% CI)

0.30 [‐2.46, 3.06]

5.2 opioid vs tricyclic antidepressant

2

188

Mean Difference (IV, Random, 95% CI)

2.17 [‐0.14, 4.49]

Open in table viewer
Comparison 4. Adverse Events from Intermediate‐term Studies: opioid vs placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Participants reporting constipation Show forest plot

10

1114

Risk Difference (M‐H, Random, 95% CI)

0.25 [0.18, 0.33]

Analysis 4.1

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 1 Participants reporting constipation.

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 1 Participants reporting constipation.

2 Participants reporting dizziness Show forest plot

10

1114

Risk Difference (M‐H, Fixed, 95% CI)

0.14 [0.10, 0.18]

Analysis 4.2

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 2 Participants reporting dizziness.

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 2 Participants reporting dizziness.

3 Participants reporting drowsiness/somnolence Show forest plot

8

738

Risk Difference (M‐H, Random, 95% CI)

0.14 [0.03, 0.25]

Analysis 4.3

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 3 Participants reporting drowsiness/somnolence.

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 3 Participants reporting drowsiness/somnolence.

4 Participants reporting nausea Show forest plot

10

1114

Risk Difference (M‐H, Random, 95% CI)

0.16 [0.08, 0.25]

Analysis 4.4

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 4 Participants reporting nausea.

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 4 Participants reporting nausea.

5 Participants reporting vomiting Show forest plot

7

813

Risk Difference (M‐H, Random, 95% CI)

0.08 [0.01, 0.15]

Analysis 4.5

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 5 Participants reporting vomiting.

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 5 Participants reporting vomiting.

6 Particpants withdrawing due to adverse events Show forest plot

7

867

Risk Difference (M‐H, Random, 95% CI)

0.08 [0.04, 0.12]

Analysis 4.6

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 6 Particpants withdrawing due to adverse events.

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 6 Particpants withdrawing due to adverse events.

7 Participants withdrawing due to lack of efficacy Show forest plot

5

723

Risk Difference (M‐H, Random, 95% CI)

‐0.09 [‐0.12, ‐0.05]

Analysis 4.7

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 7 Participants withdrawing due to lack of efficacy.

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 7 Participants withdrawing due to lack of efficacy.

Open in table viewer
Comparison 5. Adverse Events from Intermediate‐term Studies: opioid vs active control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Participants reporting constipation Show forest plot

4

397

Risk Difference (M‐H, Random, 95% CI)

0.29 [0.21, 0.38]

Analysis 5.1

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 1 Participants reporting constipation.

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 1 Participants reporting constipation.

2 Participants reporting dizziness Show forest plot

4

397

Risk Difference (M‐H, Random, 95% CI)

‐0.01 [‐0.05, 0.03]

Analysis 5.2

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 2 Participants reporting dizziness.

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 2 Participants reporting dizziness.

3 Participants reporting drowsiness/somnolence Show forest plot

4

397

Risk Difference (M‐H, Random, 95% CI)

0.13 [0.06, 0.20]

Analysis 5.3

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 3 Participants reporting drowsiness/somnolence.

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 3 Participants reporting drowsiness/somnolence.

4 Participants reporting nausea Show forest plot

4

393

Risk Difference (M‐H, Random, 95% CI)

0.13 [‐0.01, 0.26]

Analysis 5.4

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 4 Participants reporting nausea.

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 4 Participants reporting nausea.

5 Participants reporting vomiting Show forest plot

1

97

Risk Difference (M‐H, Random, 95% CI)

0.0 [‐0.04, 0.04]

Analysis 5.5

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 5 Participants reporting vomiting.

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 5 Participants reporting vomiting.

6 Participants withdrawing due to adverse events Show forest plot

1

75

Risk Difference (M‐H, Random, 95% CI)

0.06 [‐0.06, 0.19]

Analysis 5.6

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 6 Participants withdrawing due to adverse events.

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 6 Participants withdrawing due to adverse events.

7 Participants withdrawing due to lack of efficacy Show forest plot

1

75

Risk Difference (M‐H, Random, 95% CI)

0.0 [‐0.05, 0.05]

Analysis 5.7

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 7 Participants withdrawing due to lack of efficacy.

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 7 Participants withdrawing due to lack of efficacy.

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Comparison 1 Short‐term Efficacy Studies: opioid vs placebo, Outcome 1 Pain intensity post‐opioid/placebo.
Figures and Tables -
Analysis 1.1

Comparison 1 Short‐term Efficacy Studies: opioid vs placebo, Outcome 1 Pain intensity post‐opioid/placebo.

Comparison 1 Short‐term Efficacy Studies: opioid vs placebo, Outcome 2 % Pain reduction post‐opioid/placebo.
Figures and Tables -
Analysis 1.2

Comparison 1 Short‐term Efficacy Studies: opioid vs placebo, Outcome 2 % Pain reduction post‐opioid/placebo.

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 1 Number of participants with at least 33% pain relief.
Figures and Tables -
Analysis 2.1

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 1 Number of participants with at least 33% pain relief.

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 2 Number of participants with at least 50% pain relief.
Figures and Tables -
Analysis 2.2

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 2 Number of participants with at least 50% pain relief.

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 3 Pain intensity post‐opioid/placebo.
Figures and Tables -
Analysis 2.3

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 3 Pain intensity post‐opioid/placebo.

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 4 Evoked pain intensity post‐opioid/placebo.
Figures and Tables -
Analysis 2.4

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 4 Evoked pain intensity post‐opioid/placebo.

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 5 SF‐36 Health Survey.
Figures and Tables -
Analysis 2.5

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 5 SF‐36 Health Survey.

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 6 Brief Pain Inventory: Pain Interference items.
Figures and Tables -
Analysis 2.6

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 6 Brief Pain Inventory: Pain Interference items.

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 7 Beck Depression Inventory.
Figures and Tables -
Analysis 2.7

Comparison 2 Intermediate‐term Efficacy Studies: Opioid vs. Placebo, Outcome 7 Beck Depression Inventory.

Comparison 3 Intermediate‐term Efficacy Studies: opioid vs active control, Outcome 1 Number of participants with at least 33% pain relief.
Figures and Tables -
Analysis 3.1

Comparison 3 Intermediate‐term Efficacy Studies: opioid vs active control, Outcome 1 Number of participants with at least 33% pain relief.

Comparison 3 Intermediate‐term Efficacy Studies: opioid vs active control, Outcome 2 Number of participants with at least 50% pain relief.
Figures and Tables -
Analysis 3.2

Comparison 3 Intermediate‐term Efficacy Studies: opioid vs active control, Outcome 2 Number of participants with at least 50% pain relief.

Comparison 3 Intermediate‐term Efficacy Studies: opioid vs active control, Outcome 3 Pain intensity post‐opioid/active control.
Figures and Tables -
Analysis 3.3

Comparison 3 Intermediate‐term Efficacy Studies: opioid vs active control, Outcome 3 Pain intensity post‐opioid/active control.

Comparison 3 Intermediate‐term Efficacy Studies: opioid vs active control, Outcome 4 SF‐36 Health Survey.
Figures and Tables -
Analysis 3.4

Comparison 3 Intermediate‐term Efficacy Studies: opioid vs active control, Outcome 4 SF‐36 Health Survey.

Comparison 3 Intermediate‐term Efficacy Studies: opioid vs active control, Outcome 5 Beck Depression Inventory.
Figures and Tables -
Analysis 3.5

Comparison 3 Intermediate‐term Efficacy Studies: opioid vs active control, Outcome 5 Beck Depression Inventory.

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 1 Participants reporting constipation.
Figures and Tables -
Analysis 4.1

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 1 Participants reporting constipation.

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 2 Participants reporting dizziness.
Figures and Tables -
Analysis 4.2

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 2 Participants reporting dizziness.

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 3 Participants reporting drowsiness/somnolence.
Figures and Tables -
Analysis 4.3

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 3 Participants reporting drowsiness/somnolence.

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 4 Participants reporting nausea.
Figures and Tables -
Analysis 4.4

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 4 Participants reporting nausea.

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 5 Participants reporting vomiting.
Figures and Tables -
Analysis 4.5

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 5 Participants reporting vomiting.

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 6 Particpants withdrawing due to adverse events.
Figures and Tables -
Analysis 4.6

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 6 Particpants withdrawing due to adverse events.

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 7 Participants withdrawing due to lack of efficacy.
Figures and Tables -
Analysis 4.7

Comparison 4 Adverse Events from Intermediate‐term Studies: opioid vs placebo, Outcome 7 Participants withdrawing due to lack of efficacy.

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 1 Participants reporting constipation.
Figures and Tables -
Analysis 5.1

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 1 Participants reporting constipation.

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 2 Participants reporting dizziness.
Figures and Tables -
Analysis 5.2

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 2 Participants reporting dizziness.

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 3 Participants reporting drowsiness/somnolence.
Figures and Tables -
Analysis 5.3

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 3 Participants reporting drowsiness/somnolence.

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 4 Participants reporting nausea.
Figures and Tables -
Analysis 5.4

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 4 Participants reporting nausea.

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 5 Participants reporting vomiting.
Figures and Tables -
Analysis 5.5

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 5 Participants reporting vomiting.

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 6 Participants withdrawing due to adverse events.
Figures and Tables -
Analysis 5.6

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 6 Participants withdrawing due to adverse events.

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 7 Participants withdrawing due to lack of efficacy.
Figures and Tables -
Analysis 5.7

Comparison 5 Adverse Events from Intermediate‐term Studies: opioid vs active control, Outcome 7 Participants withdrawing due to lack of efficacy.

Comparison 1. Short‐term Efficacy Studies: opioid vs placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Pain intensity post‐opioid/placebo Show forest plot

6

180

Mean Difference (IV, Random, 95% CI)

‐15.81 [‐22.54, ‐9.07]

1.1 Peripheral Pain

4

138

Mean Difference (IV, Random, 95% CI)

‐15.01 [‐22.97, ‐7.06]

1.2 Central Pain

2

42

Mean Difference (IV, Random, 95% CI)

‐17.81 [‐30.48, ‐5.15]

2 % Pain reduction post‐opioid/placebo Show forest plot

2

38

Mean Difference (IV, Random, 95% CI)

25.78 [16.91, 34.65]

Figures and Tables -
Comparison 1. Short‐term Efficacy Studies: opioid vs placebo
Comparison 2. Intermediate‐term Efficacy Studies: Opioid vs. Placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Number of participants with at least 33% pain relief Show forest plot

6

727

Risk Difference (M‐H, Random, 95% CI)

0.25 [0.13, 0.37]

2 Number of participants with at least 50% pain relief Show forest plot

5

305

Risk Difference (M‐H, Random, 95% CI)

0.17 [0.02, 0.33]

3 Pain intensity post‐opioid/placebo Show forest plot

9

725

Mean Difference (IV, Random, 95% CI)

‐12.01 [‐15.40, ‐8.62]

4 Evoked pain intensity post‐opioid/placebo Show forest plot

2

148

Mean Difference (IV, Random, 95% CI)

‐23.73 [‐34.50, ‐12.96]

5 SF‐36 Health Survey Show forest plot

2

Mean Difference (IV, Random, 95% CI)

Subtotals only

5.1 Physical functioning

2

142

Mean Difference (IV, Random, 95% CI)

3.16 [‐5.46, 11.77]

5.2 Role‐physical

2

142

Mean Difference (IV, Random, 95% CI)

9.62 [‐7.73, 26.97]

5.3 Bodily pain

2

142

Mean Difference (IV, Random, 95% CI)

6.78 [0.08, 13.48]

5.4 General health

2

142

Mean Difference (IV, Random, 95% CI)

‐0.62 [‐8.08, 6.85]

5.5 Vitality

2

142

Mean Difference (IV, Random, 95% CI)

1.62 [‐5.82, 9.07]

5.6 Social functioning

2

142

Mean Difference (IV, Random, 95% CI)

3.40 [‐5.09, 11.88]

5.7 Role‐emotional

2

142

Mean Difference (IV, Random, 95% CI)

7.97 [‐5.06, 21.00]

5.8 Mental health

2

142

Mean Difference (IV, Random, 95% CI)

3.09 [‐3.05, 9.23]

6 Brief Pain Inventory: Pain Interference items Show forest plot

2

Mean Difference (IV, Random, 95% CI)

Subtotals only

6.1 General activity

2

245

Mean Difference (IV, Random, 95% CI)

‐0.91 [‐1.67, ‐0.14]

6.2 Mood

2

245

Mean Difference (IV, Random, 95% CI)

‐0.62 [‐1.31, 0.07]

6.3 Walking

2

245

Mean Difference (IV, Random, 95% CI)

‐0.54 [‐1.28, 0.20]

6.4 Normal work

2

245

Mean Difference (IV, Random, 95% CI)

‐0.82 [‐1.59, ‐0.05]

6.5 Social relations

2

245

Mean Difference (IV, Random, 95% CI)

‐0.71 [‐1.25, ‐0.16]

6.6 Sleep

2

245

Mean Difference (IV, Random, 95% CI)

‐1.74 [‐2.42, ‐1.06]

6.7 Enjoyment of life

2

245

Mean Difference (IV, Random, 95% CI)

‐1.18 [‐1.91, ‐0.44]

7 Beck Depression Inventory Show forest plot

3

273

Mean Difference (IV, Random, 95% CI)

0.21 [‐2.29, 2.71]

Figures and Tables -
Comparison 2. Intermediate‐term Efficacy Studies: Opioid vs. Placebo
Comparison 3. Intermediate‐term Efficacy Studies: opioid vs active control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Number of participants with at least 33% pain relief Show forest plot

3

243

Risk Difference (M‐H, Random, 95% CI)

0.17 [0.04, 0.31]

1.1 opioid vs gabapentin

1

88

Risk Difference (M‐H, Random, 95% CI)

0.18 [‐0.01, 0.37]

1.2 opioid vs tricyclic antidepressant

1

63

Risk Difference (M‐H, Random, 95% CI)

0.02 [‐0.22, 0.26]

1.3 opioid vs antiarrythmic

1

92

Risk Difference (M‐H, Random, 95% CI)

0.28 [0.08, 0.48]

2 Number of participants with at least 50% pain relief Show forest plot

2

155

Risk Difference (M‐H, Random, 95% CI)

0.07 [‐0.20, 0.33]

2.1 opioid vs tricyclic antidepressant

1

63

Risk Difference (M‐H, Random, 95% CI)

‐0.07 [‐0.30, 0.15]

2.2 opioid vs antiarrythmic

1

92

Risk Difference (M‐H, Random, 95% CI)

0.20 [0.01, 0.39]

3 Pain intensity post‐opioid/active control Show forest plot

4

388

Mean Difference (IV, Random, 95% CI)

‐7.19 [‐13.13, ‐1.25]

3.1 opioid vs gabapentin

1

88

Mean Difference (IV, Random, 95% CI)

‐5.0 [‐14.40, 4.40]

3.2 opioid vs tricyclic antidepressant

2

208

Mean Difference (IV, Random, 95% CI)

‐3.30 [‐13.48, 6.89]

3.3 opioid vs antiarrythmic

1

92

Mean Difference (IV, Random, 95% CI)

‐13.0 [‐19.12, ‐6.88]

4 SF‐36 Health Survey Show forest plot

2

Mean Difference (IV, Random, 95% CI)

Subtotals only

4.1 Physical functioning

2

144

Mean Difference (IV, Random, 95% CI)

‐5.09 [‐13.81, 3.63]

4.2 Role‐physical

2

144

Mean Difference (IV, Random, 95% CI)

‐5.38 [‐19.05, 8.29]

4.3 Bodily pain

2

144

Mean Difference (IV, Random, 95% CI)

‐3.11 [‐9.91, 3.70]

4.4 General health

2

144

Mean Difference (IV, Random, 95% CI)

‐4.44 [‐11.75, 2.86]

4.5 Vitality

2

144

Mean Difference (IV, Random, 95% CI)

‐6.60 [‐13.63, 0.44]

4.6 Social functioning

2

144

Mean Difference (IV, Random, 95% CI)

‐6.04 [‐14.44, 2.35]

4.7 Role‐emotional

2

144

Mean Difference (IV, Random, 95% CI)

‐6.39 [‐19.37, 6.60]

4.8 Mental health

2

144

Mean Difference (IV, Random, 95% CI)

‐6.24 [‐14.06, 1.57]

5 Beck Depression Inventory Show forest plot

3

276

Mean Difference (IV, Random, 95% CI)

1.40 [‐0.38, 3.17]

5.1 opioid vs gabapentin

1

88

Mean Difference (IV, Random, 95% CI)

0.30 [‐2.46, 3.06]

5.2 opioid vs tricyclic antidepressant

2

188

Mean Difference (IV, Random, 95% CI)

2.17 [‐0.14, 4.49]

Figures and Tables -
Comparison 3. Intermediate‐term Efficacy Studies: opioid vs active control
Comparison 4. Adverse Events from Intermediate‐term Studies: opioid vs placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Participants reporting constipation Show forest plot

10

1114

Risk Difference (M‐H, Random, 95% CI)

0.25 [0.18, 0.33]

2 Participants reporting dizziness Show forest plot

10

1114

Risk Difference (M‐H, Fixed, 95% CI)

0.14 [0.10, 0.18]

3 Participants reporting drowsiness/somnolence Show forest plot

8

738

Risk Difference (M‐H, Random, 95% CI)

0.14 [0.03, 0.25]

4 Participants reporting nausea Show forest plot

10

1114

Risk Difference (M‐H, Random, 95% CI)

0.16 [0.08, 0.25]

5 Participants reporting vomiting Show forest plot

7

813

Risk Difference (M‐H, Random, 95% CI)

0.08 [0.01, 0.15]

6 Particpants withdrawing due to adverse events Show forest plot

7

867

Risk Difference (M‐H, Random, 95% CI)

0.08 [0.04, 0.12]

7 Participants withdrawing due to lack of efficacy Show forest plot

5

723

Risk Difference (M‐H, Random, 95% CI)

‐0.09 [‐0.12, ‐0.05]

Figures and Tables -
Comparison 4. Adverse Events from Intermediate‐term Studies: opioid vs placebo
Comparison 5. Adverse Events from Intermediate‐term Studies: opioid vs active control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Participants reporting constipation Show forest plot

4

397

Risk Difference (M‐H, Random, 95% CI)

0.29 [0.21, 0.38]

2 Participants reporting dizziness Show forest plot

4

397

Risk Difference (M‐H, Random, 95% CI)

‐0.01 [‐0.05, 0.03]

3 Participants reporting drowsiness/somnolence Show forest plot

4

397

Risk Difference (M‐H, Random, 95% CI)

0.13 [0.06, 0.20]

4 Participants reporting nausea Show forest plot

4

393

Risk Difference (M‐H, Random, 95% CI)

0.13 [‐0.01, 0.26]

5 Participants reporting vomiting Show forest plot

1

97

Risk Difference (M‐H, Random, 95% CI)

0.0 [‐0.04, 0.04]

6 Participants withdrawing due to adverse events Show forest plot

1

75

Risk Difference (M‐H, Random, 95% CI)

0.06 [‐0.06, 0.19]

7 Participants withdrawing due to lack of efficacy Show forest plot

1

75

Risk Difference (M‐H, Random, 95% CI)

0.0 [‐0.05, 0.05]

Figures and Tables -
Comparison 5. Adverse Events from Intermediate‐term Studies: opioid vs active control