Comparing Patient-Controlled Analgesia Versus Non-PCA Hydromorphone Titration for Severe Cancer Pain: A Randomized Phase III Trial

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  • 1 Department of Gastrointestinal Medical Oncology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou;
  • | 2 Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou;
  • | 3 Department of Pain Medicine, Mindong Hospital, Ningde;
  • | 4 Department of Medical Oncology, Xiamen Haicang Hospital, Xiamen;
  • | 5 Department of Medical Oncology, Guangqian Hospital, Quanzhou;
  • | 6 Department of Medical Oncology, Xiamen Fifth Hospital, Xiamen;
  • | 7 Department of Medical Oncology, Longyan Hospital of Traditional Chinese Medicine, Longyan;
  • | 8 Department of Medical Oncology, Quanzhou First Hospital, Quanzhou;
  • | 9 Department of Oncology, Shouning Hospital, Ningde;
  • | 10 Department of Oncology, Putian People Hospital, Putian;
  • | 11 Department of Medical Oncology, Fujian Armed Police Corps Hospital, Fuzhou;
  • | 12 Department of Medical Oncology, Longyan Boai Hospital, Longyan;
  • | 13 Department of Medical Oncology, Xiamen Humanity Hospital and Fujian Medical University Xiamen Humanity Hospital, Xiamen;
  • | 14 Department of Medical Oncology, Rehabilitation Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou;
  • | 15 Department of Gastroenterology, Hanjiang Hospital, Putian;
  • | 16 Department of Pain Medicine, The First Affiliated Hospital of Xiamen University, Xiamen;
  • | 17 Department of Thoracic Oncology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou; and
  • | 18 School of Public Health, Fujian Medical University, Fuzhou, China.

Background: Opioid titration is necessary to achieve rapid, safe pain relief. Medication can be administered via patient-controlled analgesia (PCA) or by a healthcare provider (non-PCA). We evaluated the efficacy of intravenous PCA versus non-PCA hydromorphone titration for severe cancer pain (≥7 at rest on the 11-point numeric rating scale [NRS]). Patients and Methods: Patients with severe cancer pain were randomized 1:1 to PCA or non-PCA titration, stratified by opioid-tolerant or opioid-naïve status. The PCA pump was set to no continuous dose, with a hydromorphone bolus dose 10% to 20% of the total previous 24-hour equianalgesic (for opioid-tolerant patients) or 0.5 mg (for opioid-naïve patients). For the non-PCA group, the initial hydromorphone bolus dose was identical to that in the PCA group, with the subsequent dose increased by 50% to 100% (for NRS unchanged or increased) or repeated at the current dose (for NRS 4–6). Hydromorphone delivery was initiated every 15 minutes (for NRS ≥4) or as needed (for NRS ≤3). The primary endpoint was time to successful titration (TST; time from first hydromorphone dose to first occurrence of NRS ≤3 in 2 consecutive 15-minute intervals). Results: Among 214 patients (PCA, n=106; non-PCA, n=108), median TSTs (95% CI) were 0.50 hours (0.25–0.50) and 0.79 hours (0.50–1.42) for the PCA and non-PCA groups, respectively (hazard ratio [HR], 1.64; 95% CI, 1.23–2.17; P=.001). TSTs in opioid-tolerant patients were 0.50 hours (0.25–0.75) and 1.00 hours (0.50–2.00) for the PCA and non-PCA groups, respectively (HR, 1.92; 95% CI, 1.32–2.78; P=.003); in opioid-naive patients, TST was not significantly different for the PCA versus non-PCA groups (HR, 1.35; 95% CI, 0.88–2.04; P=.162). Pain score (median NRS; interquartile range) over 24 hours was significantly lower in the PCA group (2.80; 2.15–3.22) than in the non-PCA group (3.00; 2.47–3.53; P=.020). PCA administration produces significantly higher patient satisfaction with pain control than non-PCA administration (P<.001). Conclusions: Intravenous hydromorphone titration for severe cancer pain was achieved more effectively with PCA than with non-PCA administration.

Submitted October 1, 2020; final revision received December 9, 2020; accepted for publication December 9, 2020. Published online August 3, 2021.

Author contributions: Study concept and design: R. Lin, Huang. Provision of study material or patients: R. Lin, Sunzhi Lin, Feng, Wu, Fu, F. Wang, H. Li, X. Li, Zhang, Yao, Xin, Lai, Lv, Chen, Yang, Y. Lin, Hong, Cai, J. Wang, G. Lin, Zhao, Zhu. Administrative support: R. Lin, Zhu, Huang. Data collection and assembly: R. Lin, Zhao. Data analysis and interpretation: R. Lin, Shaowei Lin, Zhao, Huang. Manuscript writing: All authors. Final approval of manuscript: All authors.

Disclosures: The authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: This work was supported by funding from Fujian Cancer Hospital (R. Lin).

Correspondence: Cheng Huang, MD, Department of Thoracic Oncology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, No. 420 Fuma Road, Jinan District, Fuzhou 350014, China. Email: cheng671@sina.com; and Jinfeng Zhu, MD, Department of Medical Oncology, Quanzhou First Hospital, No. 248-252 East Street, Licheng District, Quanzhou 362002, China. Email: hlzk_qz@163.com

Supplementary Materials

    • Supplemental Materials (PDF 625 KB)
  • 1.

    LeMay K, Wilson KG, Buenger U, et al. Fear of pain in patients with advanced cancer or in patients with chronic noncancer pain. Clin J Pain 2011;27:116124.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Breivik H, Cherny N, Collett B, et al. Cancer-related pain: a pan-European survey of prevalence, treatment, and patient attitudes. Ann Oncol 2009;20:14201433.

  • 3.

    Caraceni A, Hanks G, Kaasa S, et al. Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations from the EAPC. Lancet Oncol 2012;13:e5868.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Mercadante S. Intravenous morphine for management of cancer pain. Lancet Oncol 2010;11:484489.

  • 5.

    Peng Z, Zhang Y, Guo J, et al. Patient-controlled intravenous analgesia for advanced cancer patients with pain: a retrospective series study. Pain Res Manag 2018;2018:7323581.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Zhao S, Xu C, Lin R. Controlled release of oxycodone as an opioid titration for cancer pain relief: a retrospective study. Med Sci Monit 2020;26:e920598.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Harris JT, Suresh Kumar K, Rajagopal MR. Intravenous morphine for rapid control of severe cancer pain. Palliat Med 2003;17:248256.

  • 8.

    Swarm RA, Youngwerth JM, Anghelescu DL, et al. NCCN Clinical Practice Guidelines in Oncology: Adult Cancer Pain, Version 1.2020. Accessed August 23, 2020. To view the most recent version, visit NCCN.org

    • Search Google Scholar
    • Export Citation
  • 9.

    Korkmazsky M, Ghandehari J, Sanchez A, et al. Feasibility study of rapid opioid rotation and titration. Pain Physician 2011;14:7182.

  • 10.

    Fallon M, Giusti R, Aielli F, et al. Management of cancer pain in adult patients: ESMO clinical practice guidelines. Ann Oncol 2018;29(Suppl 4):iv166191.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Portenoy RK, Ahmed E. Principles of opioid use in cancer pain. J Clin Oncol 2014;32:16621670.

  • 12.

    University of Texas MD Anderson Cancer Center. Cancer Pain – Adult, version 12. Accessed August 23, 2020. Available at: https://www.mdanderson.org/content/dam/mdanderson/documents/for-physicians/algorithms/clinical-management/clin-management-cancer-pain-web-algorithm.pdf

    • Search Google Scholar
    • Export Citation
  • 13.

    Radbruch L, Loick G, Schulzeck S, et al. Intravenous titration with morphine for severe cancer pain: report of 28 cases. Clin J Pain 1999;15:173178.

  • 14.

    Mercadante S, Villari P, Ferrera P, et al. Rapid titration with intravenous morphine for severe cancer pain and immediate oral conversion. Cancer 2002;95:203208.

  • 15.

    Martin EJ, Roeland EJ, Sharp MB, et al. Patient-controlled analgesia for cancer-related pain: clinical predictors of patient outcomes. J Natl Compr Canc Netw 2017;15:595600.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Citron ML, Johnston-Early A, Boyer M, et al. Patient-controlled analgesia for severe cancer pain. Arch Intern Med 1986;146:734736.

  • 17.

    Elsner F, Radbruch L, Loick G, et al. Intravenous versus subcutaneous morphine titration in patients with persisting exacerbation of cancer pain. J Palliat Med 2005;8:743750.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    McNicol ED, Ferguson MC, Hudcova J. Patient controlled opioid analgesia versus non-patient controlled opioid analgesia for postoperative pain. Cochrane Database Syst Rev 2015:CD003348.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Badner NH, Doyle JA, Smith MH, et al. Effect of varying intravenous patient-controlled analgesia dose and lockout interval while maintaining a constant hourly maximum dose. J Clin Anesth 1996;8:382385.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Weibel S, Jelting Y, Afshari A, et al. Patient-controlled analgesia with remifentanil versus alternative parenteral methods for pain management in labour. Cochrane Database Syst Rev 2017;4:CD011989.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Rahman NH, DeSilva T. A randomized controlled trial of patient-controlled analgesia compared with boluses of analgesia for the control of acute traumatic pain in the emergency department. J Emerg Med 2012;43:951957.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Nijland L, Schmidt P, Frosch M, et al. Subcutaneous or intravenous opioid administration by patient-controlled analgesia in cancer pain: a systematic literature review. Support Care Cancer 2019;27:3342.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Grond S, Zech D, Lehmann KA, et al. Transdermal fentanyl in the long-term treatment of cancer pain: a prospective study of 50 patients with advanced cancer of the gastrointestinal tract or the head and neck region. Pain 1997;69:191198.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    Zech DF, Lehmann KA. Transdermal fentanyl in combination with initial intravenous dose titration by patient-controlled analgesia. Anticancer Drugs 1995;6(Suppl 3):4449.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Fleischman W, Auth D, Shah ND, et al. Association of a risk evaluation and mitigation strategy program with transmucosal fentanyl prescribing. JAMA Netw Open 2019;2:e191340.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Cocoros NM, Larochelle MR, Popovic J, et al. Assessment of prior opioid tolerance among new users of fentanyl transdermal system in FDA’s Sentinel System. Pharmacoepidemiol Drug Saf 2019;28:112116.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Yu SY, Wang JJ, Huang YG, et al. Managing pain in patients with cancer: the Chinese good pain management experience. J Glob Oncol 2016;3:583595.

  • 28.

    Dong Y, Chen H, Zheng Y, et al. Psychometric validation of the Edmonton Symptom Assessment System in Chinese patients. J Pain Symptom Manage 2015;50:712717.e2.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Watanabe SM, Nekolaichuk C, Beaumont C, et al. A multicenter study comparing two numerical versions of the Edmonton Symptom Assessment System in palliative care patients. J Pain Symptom Manage 2011;41:456468.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Bandieri E, Romero M, Ripamonti CI, et al. Randomized trial of low-dose morphine versus weak opioids in moderate cancer pain. J Clin Oncol 2016;34:436442.

  • 31.

    Gerrits MM, van Oppen P, van Marwijk HW, et al. Pain and the onset of depressive and anxiety disorders. Pain 2014;155:5359.

  • 32.

    Nishiura M, Tamura A, Nagai H, et al. Assessment of sleep disturbance in lung cancer patients: relationship between sleep disturbance and pain, fatigue, quality of life, and psychological distress. Palliat Support Care 2015;13:575581.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Lillis TA, Gerhart J, Bouchard LC, et al. Sleep disturbance mediates the association of post-traumatic stress disorder symptoms and pain in patients with cancer. Am J Hosp Palliat Care 2018;35:788793.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Syrjala KL, Jensen MP, Mendoza ME, et al. Psychological and behavioral approaches to cancer pain management. J Clin Oncol 2014;32:17031711.

  • 35.

    Mercadente S. Small repeated boluses are unreliable to provide rapid analgesia with intravenous morphine titration and mislead conversion ratio to oral morphine. Ann Oncol 2018;29:21472148.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Coda B, Tanaka A, Jacobson RC, et al. Hydromorphone analgesia after intravenous bolus administration. Pain 1997;71:4148.

  • 37.

    Anghelescu DL, Zhang K, Faughnan LG, et al. The safety and effectiveness of patient-controlled analgesia in outpatient children and young adults with cancer: a retrospective study. J Pediatr Hematol Oncol 2015;37:378382.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38.

    Kerr IG, Sone M, Deangelis C, et al. Continuous narcotic infusion with patient-controlled analgesia for chronic cancer pain in outpatients. Ann Intern Med 1988;108:554557.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Ruggiero A, Barone G, Liotti L, et al. Safety and efficacy of fentanyl administered by patient controlled analgesia in children with cancer pain. Support Care Cancer 2007;15:569573.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Palmer P, Ji X, Stephens J. Cost of opioid intravenous patient-controlled analgesia: results from a hospital database analysis and literature assessment. Clinicoecon Outcomes Res 2014;6:311318.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    Mordin M, Anastassopoulos K, van Breda A, et al. Clinical staff resource use with intravenous patient-controlled analgesia in acute postoperative pain management: results from a multicenter, prospective, observational study. J Perianesth Nurs 2007;22:243255.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    Mohanty M, Lawal OD, Skeer M, et al. Medication errors involving intravenous patient-controlled analgesia: results from the 2005-2015 MEDMARX database. Ther Adv Drug Saf 2018;9:389404.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Giordano J, Abramson K, Boswell MV. Pain assessment: subjectivity, objectivity, and the use of neurotechnology. Pain Physician 2010;13:305315.

  • 44.

    Johannessen LEF. The commensuration of pain: how nurses transform subjective experience into objective numbers. Soc Sci Med 2019;233:3846.

  • 45.

    Wilcox CE, Mayer AR, Teshiba TM, et al. The subjective experience of pain: an FMRI study of percept-related models and functional connectivity. Pain Med 2015;16:21212133.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
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