Objective: For chronic pain treatment many health care authorities consider morphine to be the reference standard for strategic decisions in pain therapy. Although morphine's effectiveness is clear and its cost is low, it's unclear whether morphine should remain the first choice or reference treatment.
Research design and methods: We performed a systematic review to evaluate the evidence available to support the position of morphine as the reference standard for step III opioids based on efficacy and tolerability outcomes.
Results: The search yielded 5,675 titles and 56 studies were included. Considerable heterogeneity precluded pair-wise meta-analysis on change of pain intensity and no difference between morphine and other opioids were found for tolerability outcomes. The network meta-analysis showed no statistically significant difference in change of pain intensity between morphine and oxycodone, methadone and oxymorphone. Compared to morphine, patients using buprenorphine are more likely to discontinue treatment due to lack of effect (OR 2.32, 95% CI 1.37 to 3.95). Patients using methadone are more likely to discontinue due to adverse events (OR 3.09, 95% CI 1.14 to 8.36), whereas this risk is decreased for patients using fentanyl (OR 0.29, 95% CI 0.17 to 0.50) or buprenorphine (OR 0.30, 95% CI 0.16 to 0.53). The most important limitation of this review is that the included studies are heterogeneous with regard to study population and intervention, which may affect the pooled effect estimates. The main strength is that we only included parallel RCTs, the strongest design for intervention studies.
Conclusions: The current evidence is moderate, both in respect to the number of directly comparative studies and in the quality of reporting of these studies. No clear superiority in efficacy and tolerability of morphine over other opioids was found in pair-wise and network analyses. Based on these results, a justification for the placement of morphine as the reference standard for the treatment of severe chronic pain cannot be supported.
Pergolizzi J, Böger RH, Budd K, Dahan A, Erdine S, Hans G, Kress HG, Langford R, Likar R, Raffa RB, Sacerdote P. Pergolizzi J, et al. Pain Pract. 2008 Jul-Aug;8(4):287-313. doi: 10.1111/j.1533-2500.2008.00204.x. Epub 2008 May 23. Pain Pract. 2008. PMID: 18503626
Häuser W, Bernardy K, Maier C. Häuser W, et al. Schmerz. 2015 Feb;29(1):96-108. doi: 10.1007/s00482-014-1452-0. Schmerz. 2015. PMID: 25503691 Review. German.
Wolff RF, Aune D, Truyers C, Hernandez AV, Misso K, Riemsma R, Kleijnen J. Wolff RF, et al. Curr Med Res Opin. 2012 May;28(5):833-45. doi: 10.1185/03007995.2012.678938. Epub 2012 Apr 25. Curr Med Res Opin. 2012. PMID: 22443154 Review.
Lauche R, Klose P, Radbruch L, Welsch P, Häuser W. Lauche R, et al. Schmerz. 2015 Feb;29(1):73-84. doi: 10.1007/s00482-014-1432-4. Schmerz. 2015. PMID: 25376545 Review. German.
Manchikanti L, Kaye AM, Knezevic NN, McAnally H, Slavin K, Trescot AM, Blank S, Pampati V, Abdi S, Grider JS, Kaye AD, Manchikanti KN, Cordner H, Gharibo CG, Harned ME, Albers SL, Atluri S, Aydin SM, Bakshi S, Barkin RL, Benyamin RM, Boswell MV, Buenaventura RM, Calodney AK, Cedeno DL, Datta S, Deer TR, Fellows B, Galan V, Grami V, Hansen H, Helm Ii S, Justiz R, Koyyalagunta D, Malla Y, Navani A, Nouri KH, Pasupuleti R, Sehgal N, Silverman SM, Simopoulos TT, Singh V, Solanki DR, Staats PS, Vallejo R, Wargo BW, Watanabe A, Hirsch JA. Manchikanti L, et al. Pain Physician. 2017 Feb;20(2S):S3-S92. Pain Physician. 2017. PMID: 28226332
Wong AK, Somogyi AA, Rubio J, Philip J. Wong AK, et al. Curr Treat Options Oncol. 2022 Oct;23(10):1353-1369. doi: 10.1007/s11864-022-01010-x. Epub 2022 Aug 24. Curr Treat Options Oncol. 2022. PMID: 36001223 Free PMC article. Review.
Schmidt-Hansen M, Bennett MI, Arnold S, Bromham N, Hilgart JS, Page AJ, Chi Y. Schmidt-Hansen M, et al. Cochrane Database Syst Rev. 2022 Jun 9;6(6):CD003870. doi: 10.1002/14651858.CD003870.pub7. Cochrane Database Syst Rev. 2022. PMID: 35679121 Free PMC article. Review.
Moreira de Barros GA, Baradelli R, Rodrigues DG, Toffoletto O, Domingues FS, Gayoso MV, Lopes A, Barros Afiune J, Nunes Guimarães GM. Moreira de Barros GA, et al. Pain Rep. 2021 Dec 16;6(4):e979. doi: 10.1097/PR9.0000000000000979. eCollection 2021 Nov-Dec. Pain Rep. 2021. PMID: 34938934 Free PMC article.
Schmidt-Hansen M, Bennett MI, Arnold S, Bromham N, Hilgart JS. Schmidt-Hansen M, et al. Cochrane Database Syst Rev. 2017 Aug 22;8(8):CD003870. doi: 10.1002/14651858.CD003870.pub6. Cochrane Database Syst Rev. 2017. Update in: Cochrane Database Syst Rev. 2022 Jun 9;6:CD003870. doi: 10.1002/14651858.CD003870.pub7. PMID: 28829910 Free PMC article. Updated. Review.
Zin CS, Chen LC, Knaggs RD. Zin CS, et al. Eur J Pain. 2014 Oct;18(9):1343-51. doi: 10.1002/j.1532-2149.2014.496.x. Epub 2014 Apr 22. Eur J Pain. 2014. PMID: 24756859 Free PMC article.