Intravenous Patient-Controlled Analgesia Versus Oral Opioid to Maintain Analgesia for Severe Cancer Pain: A Randomized Phase II Trial

View More View Less
  • 1 Gastrointestinal Medical Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou;
  • | 2 College of Clinical Medicine for Oncology, Fujian Medical University, Fuzhou;
  • | 3 Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou;
  • | 4 Fujian Key Laboratory of Advanced Technology for Cancer Screening and Early Diagnosis, Fuzhou;
  • | 5 Medical Oncology, Quanzhou First Hospital, Quanzhou;
  • | 6 Medical Oncology, Qinghai University Affiliated Hospital, Xining;
  • | 7 Medical Oncology, Xiamen Humanity Hospital & Fujian Medical University Xiamen Humanity Hospital, Xiamen;
  • | 8 Medical Oncology, Yichang Central People’s Hospital, Yichang;
  • | 9 Medical Oncology, Liuzhou Workers’ Hospital, Liuzhou;
  • | 10 Pain Medicine, Cancer Hospital Affiliated with Harbin Medical University, Harbin;
  • | 11 Pain Medicine, Hainan Cancer Hospital, Haikou;
  • | 12 School of Public Health, Fujian Medical University, Fuzhou;
  • | 13 Medical Oncology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi; and
  • | 14 Thoracic Oncology, Fujian Cancer Hospital, Fuzhou, China.

Background: Optimal analgesic maintenance for severe cancer pain is unknown. This study evaluated the efficacy and safety of intravenous patient-controlled analgesia (IPCA) with continuous infusion plus rescue dose or bolus-only dose versus conventional oral extended-release morphine as a background dose with normal-release morphine as a rescue dose to maintain analgesia in patients with severe cancer pain after successful opioid titration. Methods: Patients with persistent severe cancer pain (≥7 at rest on the 11-point numeric rating scale [NRS]) were randomly assigned to 1 of 3 treatment arms: (A1) IPCA hydromorphone with bolus-only dose where dosage was 10% to 20% of the total equianalgesic over the previous 24 hours (TEOP24H) administered as needed, (A2) IPCA hydromorphone with continuous infusion where dose per hour was the TEOP24H divided by 24 and bolus dosage for breakthrough pain was 10% to 20% of the TEOP24H, and (B) oral extended-release morphine based on TEOP24H/2 × 75% (because of incomplete cross-tolerance) every 12 hours plus normal-release morphine based on TEOP24H × 10% to 20% for breakthrough pain. After randomization, patients underwent IPCA hydromorphone titration for 24 hours to achieve pain control before beginning their assigned treatment. The primary endpoint was NRS over days 1 to 3. Results: A total of 95 patients from 9 oncology study sites underwent randomization: 30 into arm A1, 32 into arm A2, and 33 into arm B. Arm B produced a significantly higher NRS over days 1 to 3 compared with arm A1 or A2 (P<.001). Daily NRS from day 1 to day 6 and patient satisfaction scores on day 3 and day 6 were worse in arm B. Median equivalent-morphine consumption increase was significantly lower in A1 (P=.024) among the 3 arms. No severe adverse event occurred in any arm. Conclusions: Compared with oral morphine maintenance, IPCA hydromorphone for analgesia maintenance improves control of severe cancer pain after successful titration. Furthermore, IPCA hydromorphone without continuous infusion may consume less opioid.

Background

Opioid titration is required to rapidly relieve severe cancer pain; thereafter, it is necessary to identify the appropriate dose to allow patients to achieve their functional or quality-of-life goals. Intravenous administration of opioid titration should be used for rapid pain control in patients with severe cancer pain.1,2 Intravenous opioid titration with patient-controlled analgesia (PCA) provides earlier analgesia and higher patient satisfaction for pain control than conventional titration administrated by medical staff, as reported in our previous study.3

After successful opioid titration, it is appropriate to maintain analgesia with regularly scheduled medication plus supplemental doses for breakthrough cancer pain (BTcP).1,2 Compared with regularly scheduled doses, continuous infusion using a PCA pump can confer a more stable effective plasma concentration to control background pain. An on-demand bolus dose allows the patient to voluntarily control BTcP.4 Therefore, continuous infusion plus an on-demand bolus dose is an alternative method in intravenous PCA (IPCA) for maintenance therapy.510

Regularly scheduled or continuously administered analgesics for chronic cancer-related pain is recommended in cancer pain guidelines.1,2 However, the recommendation is based more on clinical experience than on high-level evidence.11,12 The purpose of this phase II study was to evaluate the efficacy and safety of IPCA with continuous-infusion hydromorphone plus rescue dose or bolus-only dose versus conventional oral extended-release (ER) morphine plus normal-release (NR) morphine as a rescue dose to maintain analgesia for severe cancer pain after successful opioid titration. We also sought to determine the feasibility of comparison between IPCA methods, namely continuous infusion plus rescue dose versus bolus-only dose, for further study.

Methods

Trial Design

A 7-day, open-label, randomized controlled phase II trial was performed at 9 oncology centers in China. Patients were randomly assigned in a 1:1:1 ratio to 1 of 3 arms: (A1) IPCA hydromorphone with bolus-only dose as needed (PRN), (A2) IPCA hydromorphone with continuous infusion for background pain plus bolus for BTcP, or (B) oral ER morphine around the clock (ATC) for background pain and NR morphine PRN for BTcP. Participating center was a stratification factor. Opioid tolerance was defined as having received ≥25 mcg/h fentanyl patch, ≥60 mg oral morphine daily, ≥30 mg oral oxycodone daily, or an equianalgesic dose of another opioid for ≥1 week.1,2 Opioid tolerance or naïveté was not a stratification factor because of small sample size and the exploratory nature of the study.

The protocol was approved by the central ethics committee of the Fujian Cancer Hospital and local ethics committees of all participating sites. All patients provided written informed consent. The study was conducted in accordance with the principles of the Declaration of Helsinki and good clinical practice.

Patients

Patients who were diagnosed with a malignant solid tumor by pathology or cytology and who had persistent severe cancer-related pain (≥7 at rest on the 11-point numeric rating scale [NRS], with 0 = no pain and 10 = excruciating pain) were enrolled after meeting eligibility criteria: age 18 to 80 years, ECOG performance status (PS) ≤3, no cognitive impairment or psychiatric illness, and no radiotherapy, chemotherapy, or hormone, targeted, or bisphosphonate therapy within 7 days before randomization. Exclusion criteria included contraindication to opioid use, paralytic ileus, brain metastasis, severe hepatic or renal failure, uncontrolled nausea or vomiting, and use of hydromorphone, morphine, or PCA devices within 14 days of randomization.

Interventions

Any previous analgesic was stopped before titration. After randomization, patients underwent IPCA hydromorphone titration for 24 hours (this 24-hour period was defined as day 0) to achieve pain control before initiating the assigned treatment. Pump settings were: continuous dose = 0, and bolus = hydromorphone 10% to 20% of the total equianalgesic over the past 24 hours (TEOP24H) for opioid-tolerant patients (see supplemental eTable 1 for a common opioid conversion chart, available with this article at JNCCN.org),2,3 and 0.5 mg hydromorphone for opioid-naïve patients.3 All patients were trained and tested to score pain according to NRS criteria and to use the PCA pump. Lockout time was set to 10 minutes; patients were educated to self-press the PCA pump button every 10 minutes if NRS ≥4. Subsequent to NRS ≤3, self-press was by demand in 10-minute minimum intervals. Successful titration was defined as NRS ≤3 at 2 consecutive intervals. If the NRS score reincreased to ≥7, successful titration was reestablished and reassessed every 10 minutes until NRS ≤3 at 2 consecutive intervals. The pump setting was not changed within the 24-hour period.3

Patients who were successfully titrated began the treatment to which they were randomly assigned: (A1) bolus-only arm: IPCA hydromorphone with bolus-only (dosage was 10%–20% of the TEOP24H) PRN; (A2) continuous infusion plus bolus arm: IPCA hydromorphone with continuous infusion (dosage per hour was the TEOP24H divided by 24) for background pain plus bolus (dosage was 10%–20% of TEOP24H) PRN for BTcP; or (B) oral ER plus NR arm: oral ER morphine (TEOP24H/2 × 75%, every 12 h/d) ATC for background pain and NR morphine (10%–20% of the TEOP24H) PRN (minimal 60-minute interval1) for BTcP. Pain was evaluated and dosages adjusted once every 24 hours from day 1 to day 6. From day 1 to day 3, no radiotherapy, chemotherapy, or hormone, targeted, or bisphosphonate therapy was permitted, but such therapies were allowed from day 4 to day 6.

All clinical research personnel received training in Chinese good pain management and opioid titration according to NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Adult Cancer Pain1 and proper use of PCA pumps according to manufacturer guidelines.

At baseline (day −1), medical history, physical examination, ECOG PS, average/maximum/minimum NRS (avNRS/maNRS/miNRS) in the last 24 hours, physical symptoms, overall well-being using the Edmonton Symptom Assessment System (ESAS), and adverse effects (AEs) were recorded. From day 0 to day 6, physical examination, ECOG PS, maNRS, frequency and duration of BTcP, opioid dose and frequency, continuation or change in treatment, and AEs were recorded daily. ESAS and patient satisfaction scores were recorded on days 0, 3, and 6. Opioid (hydromorphone or morphine) dosage, time of administration, and number of PCA pump presses were obtained from medical records or the PCA pump.

The ESAS (Chinese version) assesses 10 symptoms (supplemental eTable 2) commonly experienced by patients during a 24-hour period. Symptom severity was scored from 0 to 10, with 0 = no symptoms and 10 = worst severity.1315 Patient satisfaction score (PSS) for pain control was rated 0 to 10, with 0 = extremely unsatisfied and 10 = extremely satisfied. Patients were asked about expected opioid-related AEs, including vomiting, constipation, dry mouth, itch, dizziness, somnolence, cognitive impairment, pseudohallucinations, and myoclonic jerks. Use of concomitant analgesics was prohibited, although management of AEs was permitted.

Outcome Measures

The primary endpoint was avNRS over days 1 to 3 (3DNRS; sum of previous 24-hour average pain scores for days 1–3 divided by 3). Secondary outcomes included daily avNRS for day 0 to day 6; number of patients with NRS >3 or 6; daily frequency and duration of BTcP; maNRS for day 1 to day 6; improvement in physical symptoms and overall well-being as assessed by ESAS; PSS; and equivalent morphine consumption increase (EMCI) calculated as the opioid escalation index percentage according to the following formula: (maximum daily EMC – day 0 EMC)/day 0 EMC.14,16 Type, frequency, and severity of AEs and therapy discontinuation due to AEs were evaluated every day on day 0 to day 6. BTcP was defined as transient exacerbated pain intensity ≥4.1719

Statistical Methods

Sample size calculation was based on multiple comparisons of arm A1 or A2 versus arm B. Assuming as clinically significant a 30% decrease in 3DNRS from an expected 4.5 in arm B to 3 in either arm A1 or A2 with a power of 85% and level of significance alpha = 0.05, a sample size of 72 patients (24 per group) was needed. Considering a dropout rate of 15%, the sample size was calculated as ≥84 (28 per group). Assignment numbers were generated centrally using the block randomization method stratified by site, with a block size of 6.

Efficacy outcomes in the full analysis set included all patients who underwent randomization. The last observation carried forward was used to handle missing data. The safety analysis set consisted of all patients who received at least one dose of study medication and who completed safety data collection. The primary endpoint, 3DNRS, was subject to a superiority test, and difference testing was used for other hypotheses. Continuous variables were described as medians with interquartile ranges (IQRs) and ANOVA or Kruskal-Wallis test with Bonferroni correction were employed according to whether the distribution type satisfied the normality. Categorical variables were presented as frequencies/proportions and were analyzed using the chi-square test or Fisher exact test. The superiority test was one-sided with alpha = 0.025; other tests were two-sided with alpha = 0.05; P<.05 was considered statistically significant. Data were analyzed using R version 4.0 (R Foundation for Statistical Computing).

Results

Patients

Between April 2020 and October 2020, 95 patients with persistent cancer-related severe pain were randomly assigned to arm A1 (n=30; 31.6%), arm A2 (n=32; 33.7%), or arm B (n=33; 34.7%) from 9 Chinese oncology centers (12 patients each for 6 centers, 9 for 1 center, and 7 each for 2 centers) (Figure 1). From day 0 to day 3, 1 patient in arm B refused to switch to oral morphine, titration was unsuccessful in another, and a third patient withdrew from the study on day 2. From day 4 to day 6, 9 patients withdrew from the study (2 from A1, 3 from A2, and 4 from B) (Figure 1). There were more opioid-tolerant patients in arm A2 (Pdifference=.003). On day −1, maNRS in arm A2 was significantly higher (Pdifference=.029); however, there were no significant differences for miNRS or avNRS among the 3 arms (Table 1). Other baseline characteristics were well balanced between the 3 groups, with comparable ESAS symptom severity (supplemental eTable 2 and Table 1).

Figure 1.
Figure 1.

Study profile.

(A1) Bolus-only arm, (A2) continuous infusion plus bolus arm, and (B) oral extended-release and normal-release arm.

Abbreviations: ER, extended-release; NR, normal-release; PCA, patient-controlled analgesia.

Citation: Journal of the National Comprehensive Cancer Network 20, 9; 10.6004/jnccn.2022.7034

Table 1.

Patient Demographics and Baseline Characteristics

Table 1.

Efficacy

Among 95 patients, median (IQR) avNRS on day 0 was 4 (3–4) in arms A1, A2, and B (Table 2); this was not significantly different among the 3 arms (Pdifference=.610). There was a median 50.0% decrease in 3DNRS in arm A1 (2 [IQR, 2–3]; Psuperiority=.039) and arm A2 (2 [IQR, 2–3]; Psuperiority=.037) compared with arm B (4 [IQR, 3–4]) (Figure 2). The number of patients with 3DNRS >3 was 0 (0.00%), 1 (3.12%), and 19 (59.38%) in arms A1, A2, and B, respectively; this was a significant difference (Pdifference<.001). 3DNRS in all patients was ≤6.

Table 2.

Daily NRS Score, EMCI, and PSS

Table 2.
Figure 2.
Figure 2.

3DNRS is the sum of previous 24-hour average pain scores for the first 3 days (day 1 to day 3) divided by 3. Arm A1: bolus-only arm; Arm A2: continuous infusion plus bolus arm; and Arm B: oral extended-release and normal-release arm.

Abbreviation: 3DNRS, average numeric rating scale of first 3 days (from day 1 to day 3).

Citation: Journal of the National Comprehensive Cancer Network 20, 9; 10.6004/jnccn.2022.7034

There were persistently significant differences in daily avNRS from day 1 to day 6 among the 3 groups. In pairwise comparison testing, daily avNRS in arm A2 was significantly lower than in arm B from day 1 to day 6, and on days 1, 2, 3, and 6 in arm A1, it was significantly lower than in arm B. Although avNRS on days 4 and 5 in arm A1 was not significantly lower than in arm B, the between-group curves were quite separated. There were no differences between arms A1 and A2 from day 1 to day 6 (Table 2).

The median EMCI was 0.10 (IQR, 0.00–0.31), 0.26 (IQR, 0.10–0.81), and 0.25 (IQR, 0.10–0.40) in arms A1, A2, and B, respectively. Arm A1 was significantly lower than arm A2 (P=.029). There were no significant differences between arms A1 and B (P=1.0) or between arms A2 and B (P=1.0). However, although arm A2 and B values were close, they were largely different from the A1 value (Table 2).

PSS on day 0 was 8 (IQR, 6.25–8.00), 8 (IQR, 7.00–9.00), and 7 (IQR, 6.00–8.25) in arms A1, A2, and B, respectively, a nonsignificant difference (P=.440). However, PSS in arms A1 and A2 was significantly better than in arm B on day 3 and day 6, respectively, with no significant difference between arms A1 and A2 (Figure 2 and Table 2).

There were no significant differences among the 3 groups in ESAS total score or individual item scores on day −1 or day 0. On days 3 and 6, respectively, only median pain score in arm A1 (2.00 [IQR, 2.00–3.00]; P<.001, and 2.00 [IQR, 2.00–3.00]; P=.012) and arm A2 (2.00 [IQR, 2.00–2.25]; P<.001, and 2.00 [IQR, 1.00–3.00]; P=.001) was significantly higher than in arm B (4.00 [IQR, 3.00–4.00], and 3.00 [IQR, 2.00–3.00]). Pain score was not significantly different between arms A1 and A2 for day 3 (Pdifference=1.0) or day 6 (Pdifference=1.0) (supplemental eTable 2). Total ESAS score was significantly lower on day 0 than on day −1 in each arm (all P<.05), and significantly lower on day 3 or day 6 than on day 0 in each arm (all P<.05) (Table 2 and supplemental eFigure 1).

We also tested the daily frequency, duration, and maNRS of BTcP from day 1 to day 6. Median daily frequency or maNRS of BTcP was not different among the 3 arms. Median duration of BTcP was 12.25 minutes (IQR, 10.02–18.73 minutes) in arm A1, 11.76 minutes (IQR, 9.48–13.35 minutes) in arm A2, and 16.00 minutes (IQR, 12.82–20.30 minutes) in arm B. There was a significant difference among the 3 arms (P=.032). By pairwise comparison, the P value was .633 for arm A1 versus B, .025 for arm A2 versus B, and .509 for arm A1 versus A2 (Table 3).

Table 3.

Breakthrough Cancer Pain

Table 3.

Safety

AEs among the 3 groups were similar and were well tolerated. No unexpected AE was reported, and there was no difference in frequency of opioid-related AEs (supplemental eTable 3). No patient using PCA attempted suicide or committed opioid abuse, and there was no other catheter-related or pump-related AE.

Discussion

In this multicenter, 7-day, open-label, randomized phase II trial, IPCA hydromorphone with bolus-only or continuous infusion plus bolus as maintenance analgesic significantly reduced 3DNRS and increased PSS compared with oral (ER plus NR) morphine after successful titration for persistent severe cancer pain. avNRS on day 0 was not different among the 3 arms, but there was a persistent improvement in daily avNRS in both arms A1 and A2 from day 1 to day 6. No severe opioid-related, catheter-related, or pump-related AE occurred.

The fundamental principle of managing cancer pain effectively is that it requires stable opioid blood levels to provide continuous relief. ATC dosing of opioids results in more stable opioid blood levels and better pain relief with fewer AEs, less reinforcement of pain behaviors, lower addiction risk, and greater adherence to an analgesic regimen compared with PRN dosing.1,2,12,2023 Therefore, ATC for background pain with PRN for BTcP was recommended after successful opioid titration.1,2 In our study, arm A2 provided significantly better pain control than arm B by either 3DNRS or daily avNRS. Moreover, although more patients in arm A2 at baseline were opioid-tolerant with higher maNRS, maNRS from day 0 to day 6 was not different. Meanwhile, the duration of BTcP was lower in arm A2 than in ArmB. It may be that continuous intravenous infusion provides a more stable opioid blood level, but more likely the hydromorphone intravenous bolus with PCA is responsible for mitigating BTcP.510

BTcP from onset to peak pain intensity is <15 minutes, and median duration is 60 minutes.18,19 Oral NR morphine has been used for BTcP for many years.1,2 However, oral NR morphine typically produces analgesic onset after 30 minutes with a peak effect after 60 minutes.24,25 The mismatch between BTcP profile and oral morphine pharmacokinetics is an issue for BTcP rescue.18,19,25 The analgesic onset of intravenous hydromorphone was rapid, within 5 minutes, and maximum analgesic effect was seen between 8 and 20 minutes after the maximum plasma concentration.26,27 Moreover, self-administered IPCA can provide analgesia without delay. Therefore, the IPCA model is better matched to the profile of BTcP.510 Better pain control also brings greater PSS.3,28 Notably, 1 patient declined to switch to oral morphine on ATC dosing because the patient achieved good pain control via IPCA titration.

Although ATC or continuous intravenous dosing are commonly recommended for chronic pain management, no high-level study previously supported this recommendation.1,2 One study used data from 137 oncology patients with pain from bone metastasis in a large randomized controlled trial to compare oral opioid analgesics on an ATC versus PRN basis. No significant differences in pain intensity scores or number of hours per day in pain were found between the 2 arms. However, the average total opioid dose (prescribed and taken) was significantly greater for ATC than for PRN.11 ATC prescription type and total dose are significant risk factors for the prevalence and severity of opioid AEs.29 A survey of 1,781 patients receiving long-term opioid therapy for chronic noncancer pain reported by Von Korff et al20 and a randomized clinical trial of postoperative pain in children after tonsillectomy30 also support the finding that pain intensity is comparable between ATC and PRN and that total opioid dose with a PRN model is less than with ATC dosing. A 5-week study of outpatient oncology patients reported that ATC dosing provided greater adherence to their analgesic regimen than did PRN, although pain intensity was not different.22 However, Von Korff et al20 reported that ATC was associated with greater concern regarding opioid control. Some studies of noncancer pain have reported that ATC confers less pain intensity than PRN; however, methodological flaws make interpretation of results difficult.31,32

IPCA continuous infusion produces a more stable opioid blood concentration than oral opioid ATC; therefore, we considered that a comparison between arm A1 and arm A2 in our study is akin to comparing ATC with PRN administration. We report that arm A1 provided significantly better pain control and greater PSS than arm B and that median EMCI in arm A1 is less than in arm A2. These results are similar to those of several studies of ATC versus PRN.11,20,30 There was no significant difference between arms A1 and A2 in pain control, PSS, and ESAS score or in frequency, duration, or maNRS for BTcP. We concluded that the superiority of arm A1 is due to intravenous hydromorphone with PCA administration. Hydromorphone provides rapid analgesia onset (within 5 minutes) with peak effect 8 to 20 minutes after the maximum plasma concentration and a half-life of 2 to 3 hours.26,27 Autonomy and immediacy of PCA administration are also important.3,8,9 Only bolus intravenous hydromorphone PRN was associated with a short interval from pain recognition to pain resolution. Importantly, we educated patients to administer analgesic concurrent with prodromal symptoms of pain to further mitigate pain intensity. With a half-life of 2 to 3 hours, hydromorphone provides an appropriate PRN interval; furthermore, if pain persists, additional dosing 10 minutes apart permits a higher blood concentration.

PRN administration does have some advantages. First, in ATC or continuous infusion models, opioid blood concentration is relatively stable despite fluctuations in pain intensity. Patients who experience substantial fluctuation of pain intensity can be at risk for underdose/overdose, although opioid blood concentration is relatively stable, which can lead to poor pain control and/or AEs.33 In PRN bolus-only administration, opioid blood concentration may better reflect fluctuations in pain intensity; similarities in pain control, patient satisfaction, and reported symptoms with low EMCI in arm A1 versus arm A2 may reflect this concept.

The frequency of the most common AEs was not different in arm A2 compared with the other 2 arms, despite a higher number of opioid-tolerant patients and higher median daily or total morphine equivalent dose (supplemental eTable 4). Existing data on the frequency of morbidity and mortality associated with opioid consumption among commonly prescribed opioids are somewhat conflicting.34,35

Our trial had some limitations. First, it was not designed to compare arm A1 and arm A2 for noninferiority. A large, multicenter phase III trial is ongoing to address this issue.36 Second, the portable pump may not be feasible for all patients with persistent cancer pain needing a long-term intervention, although it is appropriate for short-term use. We believe that even more convenient formulations, such as intranasal drug delivery with rapid onset and appropriate half-life opioids, can be developed when the safety and efficacy of bolus-only PRN is established.37 Third, the comparator is oral morphine, not hydromorphone. Oral hydromorphone is not available in China. The dose of oral morphine must be reduced for cross-tolerance when converting from hydromorphone after titration1,2; however, it is a standard conversion supported by recommended guidelines. Fourth, double-blinding was not possible; however, because patient perception of pain is subjective, an open-label design is appropriate. Fifth, as a phase II study, the sample size is small; however, any imbalance between the 3 arms does not impact the study results. The small sample also limits a comparison of opioid-naïve versus opioid-tolerant patients; however, this will be resolved in a future phase III study with a larger sample size.36

Conclusions

Our study evaluated oral ER plus NR morphine, IPCA with bolus only, or background infusion plus bolus as analgesia maintenance for severe cancer pain after successful titration. Both arm A1 and arm A2 were superior to arm B, with good tolerability and improved patient satisfaction, indicating that intravenous administration combined with PCA, regardless of background infusion, is superior to oral administration as maintenance analgesia for severe cancer pain. To our knowledge, this is the first randomized controlled trial to confirm this superiority. In addition, an important concept was established in our study in terms of arm A1 versus A2: PRN may be noninferior to continuous infusion or ATC for persistent cancer pain. With the development of responsive analgesic delivery systems and improvements in rapid-onset opioids with an appropriate half-life, the PRN model may convey additional advantages. For these reasons, our results warrant a further phase III study with a larger sample size.

References

  • 1.

    Swarm RA, Youngwerth JM, Agne JL, et al. NCCN Clinical Practice Guidelines in Oncology: Adult Cancer Pain. Version 1.2022. Accessed March 1, 2022. To view the most recent version, visit NCCN.org

    • Search Google Scholar
    • Export Citation
  • 2.

    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
  • 3.

    Lin R, Lin S, Feng S, et al. Comparing patient-controlled analgesia versus non-PCA hydromorphone titration for severe cancer pain: a randomized phase III trial. J Natl Compr Canc Netw 2021;19:11481155.

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

    Reale C, Vernaglione E, Reale CA, et al. Advantages of totally implanted port over impromptu short-term central venous catheter in oncological pain therapy. J Vasc Access 2003;4:5055.

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

    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
  • 7.

    Citron ML, Kalra JM, Seltzer VL, et al. Patient-controlled analgesia for cancer pain: a long-term study of inpatient and outpatient use. Cancer Invest 1992;10:335341.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Meuret G, Jocham H. Patient-controlled analgesia (PCA) in the domiciliary care of tumour patients. Cancer Treat Rev 1996;22(Suppl A):137140.

  • 9.

    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
  • 10.

    Fitzgibbon DR, Ready BL. Intravenous high-dose methadone administered by patient controlled analgesia and continuous infusion for the treatment of cancer pain refractory to high-dose morphine. Pain 1997;73:259261.

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

    Miaskowski C, Mack KA, Dodd M, et al. Oncology outpatients with pain from bone metastasis require more than around-the-clock dosing of analgesics to achieve adequate pain control. J Pain 2002;3:1220.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Pasero C. Around-the-clock (ATC) dosing of analgesics. J Perianesth Nurs 2010;25:3639.

  • 13.

    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
  • 14.

    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.

  • 15.

    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
  • 16.

    Bruera E, Palmer JL, Bosnjak S, et al. Methadone versus morphine as a first-line strong opioid for cancer pain: a randomized, double-blind study. J Clin Oncol 2004;22:185192.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Refractory Cancer Pain Group of Committee of Rehabilitation and Palliative Care of China Anti-cancer Association, Cancer Pain Group of Pain Branch of Chinese Medical Association. Expert consensus on breakthrough cancer pain (2019 edition). Chin J Clin Oncol 2019;46:267271.

    • Search Google Scholar
    • Export Citation
  • 18.

    Davies A, Buchanan A, Zeppetella G, et al. Breakthrough cancer pain: an observational study of 1000 European oncology patients. J Pain Symptom Manage 2013;46:619628.

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

    Davies A, Zeppetella G, Andersen S, et al. Multi-centre European study of breakthrough cancer pain: pain characteristics and patient perceptions of current and potential management strategies. Eur J Pain 2011;15:756763.

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

    Von Korff M, Merrill JO, Rutter CM, et al. Time-scheduled vs. pain-contingent opioid dosing in chronic opioid therapy. Pain 2011;152:12561262.

  • 21.

    Ballantyne JC. Opioids around the clock? Pain 2011;152:12211222.

  • 22.

    Miaskowski C, Dodd MJ, West C, et al. Lack of adherence with the analgesic regimen: a significant barrier to effective cancer pain management. J Clin Oncol 2001;19:42754279.

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

    Jovey RD, Ennis J, Gardner-Nix J, et al. Use of opioid analgesics for the treatment of chronic noncancer pain–a consensus statement and guidelines from the Canadian Pain Society, 2002. Pain Res Manag 2003;8(Suppl A):3A28A.

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

    Collins SL, Faura CC, Moore RA, et al. Peak plasma concentrations after oral morphine: a systematic review. J Pain Symptom Manage 1998;16:388402.

  • 25.

    Zeppetella G. Dynamics of breakthrough pain vs. pharmacokinetics of oral morphine: implications for management. Eur J Cancer Care (Engl) 2009;18:331337.

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

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

  • 27.

    Parab PV, Ritschel WA, Coyle DE, et al. Pharmacokinetics of hydromorphone after intravenous, peroral and rectal administration to human subjects. Biopharm Drug Dispos 1988;9:187199.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Wang JH, Wang LW, Liang SY, et al. Relationship between prescribed opioids, pain management satisfaction, and pain intensity in oncology outpatients. Support Care Cancer 2022;30:32333240.

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

    Villars P, Dodd M, West C, et al. Differences in the prevalence and severity of side effects based on type of analgesic prescription in patients with chronic cancer pain. J Pain Symptom Manage 2007;33:6777.

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

    Sutters KA, Miaskowski C, Holdridge-Zeuner D, et al. A randomized clinical trial of the effectiveness of a scheduled oral analgesic dosing regimen for the management of postoperative pain in children following tonsillectomy. Pain 2004;110:4955.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Paice JA, Noskin GA, Vanagunas A, et al. Efficacy and safety of scheduled dosing of opioid analgesics: a quality improvement study. J Pain 2005;6:639643.

  • 32.

    Beaulieu AD, Peloso P, Bensen W, et al. A randomized, double-blind, 8-week crossover study of once-daily controlled-release tramadol versus immediate-release tramadol taken as needed for chronic noncancer pain. Clin Ther 2007;29:4960.

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

    Smith HS. Rapid onset opioids in palliative medicine. Ann Palliat Med 2012;1:4552.

  • 34.

    Dasgupta N, Kramer ED, Zalman MA, et al. Association between non-medical and prescriptive usage of opioids. Drug Alcohol Depend 2006;82:135142.

  • 35.

    Kurteva S, Abrahamowicz M, Gomes T, et al. Association of opioid consumption profiles after hospitalization with risk of adverse health care events. JAMA Netw Open 2021;4:e218782.

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

    Lin R, Zhu J, Li X, et al. 1444P intravenous (IV) patient-controlled analgesia (PCA) vs oral opioid to maintain analgesia for severe cancer pain after successful hydromorphone (HM) titration: a multi-center, phase II randomized trial (HMORCT09-2) [abstract]. Ann Oncol 2021;32(Suppl 5):Abstract 1444P.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    Keller LA, Merkel O, Popp A. Intranasal drug delivery: opportunities and toxicologic challenges during drug development. Drug Deliv Transl Res 2022;12:735757.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

Submitted March 6, 2022; final revision received May 14, 2022; accepted for publication May 16, 2022.

Author contributions: Study concept and design: R. Lin, Huang. Provision of study material or patients: R. Lin, Zhu, Luo, Lv, Lu, Chen, Zou, Zhang, Wu, Li, Zhou, Zhao, Su, Liu. Administrative support: R. Lin, Liu, Huang. Data collection and assembly: R. Lin, Zhou, Zhao. Data analysis and interpretation: R. Lin, S. 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: Research reported in this publication was supported by the Fujian Cancer Hospital (R. Lin).

Correspondence: Cheng Huang, MD, Thoracic Oncology, Fujian Cancer Hospital, No. 420 Fuma Road, Jinan District, Fuzhou, 350014, China. Email: cheng671@sina.com; and Jiang Liu, MD, Medical Oncology, People's Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Tianshan District, Urumqi, 830002, China. Email: liujiang@csco.org.cn

Supplementary Materials

  • View in gallery

    Study profile.

    (A1) Bolus-only arm, (A2) continuous infusion plus bolus arm, and (B) oral extended-release and normal-release arm.

    Abbreviations: ER, extended-release; NR, normal-release; PCA, patient-controlled analgesia.

  • View in gallery

    3DNRS is the sum of previous 24-hour average pain scores for the first 3 days (day 1 to day 3) divided by 3. Arm A1: bolus-only arm; Arm A2: continuous infusion plus bolus arm; and Arm B: oral extended-release and normal-release arm.

    Abbreviation: 3DNRS, average numeric rating scale of first 3 days (from day 1 to day 3).

  • 1.

    Swarm RA, Youngwerth JM, Agne JL, et al. NCCN Clinical Practice Guidelines in Oncology: Adult Cancer Pain. Version 1.2022. Accessed March 1, 2022. To view the most recent version, visit NCCN.org

    • Search Google Scholar
    • Export Citation
  • 2.

    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
  • 3.

    Lin R, Lin S, Feng S, et al. Comparing patient-controlled analgesia versus non-PCA hydromorphone titration for severe cancer pain: a randomized phase III trial. J Natl Compr Canc Netw 2021;19:11481155.

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

    Reale C, Vernaglione E, Reale CA, et al. Advantages of totally implanted port over impromptu short-term central venous catheter in oncological pain therapy. J Vasc Access 2003;4:5055.

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

    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
  • 7.

    Citron ML, Kalra JM, Seltzer VL, et al. Patient-controlled analgesia for cancer pain: a long-term study of inpatient and outpatient use. Cancer Invest 1992;10:335341.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Meuret G, Jocham H. Patient-controlled analgesia (PCA) in the domiciliary care of tumour patients. Cancer Treat Rev 1996;22(Suppl A):137140.

  • 9.

    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
  • 10.

    Fitzgibbon DR, Ready BL. Intravenous high-dose methadone administered by patient controlled analgesia and continuous infusion for the treatment of cancer pain refractory to high-dose morphine. Pain 1997;73:259261.

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

    Miaskowski C, Mack KA, Dodd M, et al. Oncology outpatients with pain from bone metastasis require more than around-the-clock dosing of analgesics to achieve adequate pain control. J Pain 2002;3:1220.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Pasero C. Around-the-clock (ATC) dosing of analgesics. J Perianesth Nurs 2010;25:3639.

  • 13.

    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
  • 14.

    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.

  • 15.

    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
  • 16.

    Bruera E, Palmer JL, Bosnjak S, et al. Methadone versus morphine as a first-line strong opioid for cancer pain: a randomized, double-blind study. J Clin Oncol 2004;22:185192.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Refractory Cancer Pain Group of Committee of Rehabilitation and Palliative Care of China Anti-cancer Association, Cancer Pain Group of Pain Branch of Chinese Medical Association. Expert consensus on breakthrough cancer pain (2019 edition). Chin J Clin Oncol 2019;46:267271.

    • Search Google Scholar
    • Export Citation
  • 18.

    Davies A, Buchanan A, Zeppetella G, et al. Breakthrough cancer pain: an observational study of 1000 European oncology patients. J Pain Symptom Manage 2013;46:619628.

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

    Davies A, Zeppetella G, Andersen S, et al. Multi-centre European study of breakthrough cancer pain: pain characteristics and patient perceptions of current and potential management strategies. Eur J Pain 2011;15:756763.

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

    Von Korff M, Merrill JO, Rutter CM, et al. Time-scheduled vs. pain-contingent opioid dosing in chronic opioid therapy. Pain 2011;152:12561262.

  • 21.

    Ballantyne JC. Opioids around the clock? Pain 2011;152:12211222.

  • 22.

    Miaskowski C, Dodd MJ, West C, et al. Lack of adherence with the analgesic regimen: a significant barrier to effective cancer pain management. J Clin Oncol 2001;19:42754279.

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

    Jovey RD, Ennis J, Gardner-Nix J, et al. Use of opioid analgesics for the treatment of chronic noncancer pain–a consensus statement and guidelines from the Canadian Pain Society, 2002. Pain Res Manag 2003;8(Suppl A):3A28A.

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

    Collins SL, Faura CC, Moore RA, et al. Peak plasma concentrations after oral morphine: a systematic review. J Pain Symptom Manage 1998;16:388402.

  • 25.

    Zeppetella G. Dynamics of breakthrough pain vs. pharmacokinetics of oral morphine: implications for management. Eur J Cancer Care (Engl) 2009;18:331337.

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

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

  • 27.

    Parab PV, Ritschel WA, Coyle DE, et al. Pharmacokinetics of hydromorphone after intravenous, peroral and rectal administration to human subjects. Biopharm Drug Dispos 1988;9:187199.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Wang JH, Wang LW, Liang SY, et al. Relationship between prescribed opioids, pain management satisfaction, and pain intensity in oncology outpatients. Support Care Cancer 2022;30:32333240.

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

    Villars P, Dodd M, West C, et al. Differences in the prevalence and severity of side effects based on type of analgesic prescription in patients with chronic cancer pain. J Pain Symptom Manage 2007;33:6777.

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

    Sutters KA, Miaskowski C, Holdridge-Zeuner D, et al. A randomized clinical trial of the effectiveness of a scheduled oral analgesic dosing regimen for the management of postoperative pain in children following tonsillectomy. Pain 2004;110:4955.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Paice JA, Noskin GA, Vanagunas A, et al. Efficacy and safety of scheduled dosing of opioid analgesics: a quality improvement study. J Pain 2005;6:639643.

  • 32.

    Beaulieu AD, Peloso P, Bensen W, et al. A randomized, double-blind, 8-week crossover study of once-daily controlled-release tramadol versus immediate-release tramadol taken as needed for chronic noncancer pain. Clin Ther 2007;29:4960.

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

    Smith HS. Rapid onset opioids in palliative medicine. Ann Palliat Med 2012;1:4552.

  • 34.

    Dasgupta N, Kramer ED, Zalman MA, et al. Association between non-medical and prescriptive usage of opioids. Drug Alcohol Depend 2006;82:135142.

  • 35.

    Kurteva S, Abrahamowicz M, Gomes T, et al. Association of opioid consumption profiles after hospitalization with risk of adverse health care events. JAMA Netw Open 2021;4:e218782.

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

    Lin R, Zhu J, Li X, et al. 1444P intravenous (IV) patient-controlled analgesia (PCA) vs oral opioid to maintain analgesia for severe cancer pain after successful hydromorphone (HM) titration: a multi-center, phase II randomized trial (HMORCT09-2) [abstract]. Ann Oncol 2021;32(Suppl 5):Abstract 1444P.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    Keller LA, Merkel O, Popp A. Intranasal drug delivery: opportunities and toxicologic challenges during drug development. Drug Deliv Transl Res 2022;12:735757.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 721 721 721
PDF Downloads 373 373 373
EPUB Downloads 0 0 0