Efficacy of transdermal buprenorphine patch for managing withdrawal symptoms in patients with cancer physically dependent on prescription opioids

Abstract

Background

The physical dependence on prescription opioids among cancer survivors remains an under-investigated area, with a scarcity of well-designed prospective studies.

Methods

This single-arm, phase-2 clinical trial in Korea assessed the efficacy and safety of a transdermal buprenorphine patch (TBP) in managing physical dependence on prescription opioids in cancer survivors, as confirmed through the DSM-5 criteria or psychiatric consultation for opioid withdrawal. This study involved a 4-phase treatment protocol of screening, induction/stabilization, discontinuation, and monitoring. The primary outcome was the rate of successful opioid discontinuation, as measured by a negative urine-drug screening at 8 weeks. Key secondary outcomes included the resumption of prescribed opioids, changes in both the Clinical Opioid Withdrawal Scale (COWS) and morphine equivalent daily dose (MEDD), and assessments related to the psychological and physiological aspects of dependence and safety.

Results

Thirty-one participants were enrolled. In the intention-to-treat population, the success rate of opioid discontinuation was 58%, with only 2 participants experiencing a resumption of prescribed opioids. Significant reductions were observed in MEDD, which decreased from 98 to 26 mg/day (P < .001), and COWS scores, which decreased from 5.5 to 2.8 (P < .001). Desire to use opioids reduced from 7.0 to 3.0 on a 10-point numeric rating scale (P < .001). Toxicities related to TBP were mild and manageable, without severe precipitated withdrawal symptoms.

Conclusion

TBP may be considered as an alternative therapeutic option in cancer survivors physically dependent on prescription opioids, especially where sublingual formulations are unavailable.

The transdermal buprenorphine patch may offer a promising approach for managing physical dependence on prescription opioids in cancer survivors.

Graphical Abstract

Graphical Abstract.

Implications for Practice.

Transdermal buprenorphine patch may offer a promising approach for managing physical dependence on prescription opioids in cancer survivors, particularly where sublingual formulations are unavailable. Primary care physicians may be effectively able to initiate this treatment in patients with mild withdrawal symptoms, potentially reducing the need for immediate referral to addiction specialists and mitigating undertreatment of cancer-related pain due to concerns about physical dependence.

Introduction

Aberrant opioid-related behavior has become a major issue worldwide, owing to an increased usage of prescription opioids to manage chronic pain. In the United States, opioid overdose crisis has emerged as a significant social problem among patients without cancer. Deaths due to synthetic opioid-related overdoses increased by more than 6-fold between 2010 and 2016.¹ Conversely, Chino et al² revealed that from 2006 to 2016, while the rate of opioid-related deaths increased from 5.3 to 9.0 per 100 000 people in the general population, it increased from 0.5 to 0.7 per 100 000 only in cancer survivors. Similarly, in Korea, the incidence of high risk for aberrant opioid-related behavior in patients with cancer was low (0.2%), and the rate of nonmedical use of prescription opioids was also low (0.23%).^3,4 Nevertheless, between 2013 and 2018, a significant decrease in opioid prescriptions was noted in patients with cancer in the United States, with the annual prevalence of opioid claims decreasing from 40.2% to 34.5%⁵ This trend is likely influenced by increased awareness of the opioid crisis and its consequences, leading to a more conservative approach to opioid prescriptions. Enhanced regulations and concerns regarding the long-term use of opioids, even in patients with cancer near the end-of-life, have also contributed to this shift in practice.⁶

Another barrier in prescribing opioids to patients with cancer is that many primary care physicians, especially in Korea, are unfamiliar with proper management of opioid use disorder (OUD). Management of OUD typically begins with behavioral therapy and supportive care, followed by Medication for Opioid Use Disorder (MOUD). Behavioral therapies, such as cognitive-behavioral therapy and motivational interviewing, address the psychological aspects of addiction and help patients modify their behaviors and attitudes related to drug-use.⁷ Counseling and peer support services are effective in managing OUD and sustaining recovery from drug-related problems.^8,9 Subsequently, MOUD is introduced using methadone, buprenorphine, or naltrexone, which are effective in reducing withdrawal symptoms and cravings, significantly enhancing the chances of long-term recovery.¹⁰ Sublingual buprenorphine, a partial mu-opioid agonist, is used clinically for managing withdrawal symptoms caused by opioids because it has a lower risk of respiratory depression than full agonists such as methadone. Buprenorphine is particularly beneficial owing to its unique pharmacological properties, including a ceiling effect, which reduces the risk of overdose. Moreover, the combination of buprenorphine and naloxone in certain formulations decreases the risk of misuse, making it a safer and more controlled option for managing OUD. Therefore, buprenorphine is the preferred choice for many opioid replacement therapy programs.^11-13

However, data on the role of buprenorphine in the management of OUD in patients with cancer are limited. In a qualitative study using the modified Delphi process, experts agreed on continuing treatment with buprenorphine-naloxone in patients with advanced cancer, pain, and OUD simultaneously and on adding a full opioid agonist in patients with a prognosis of weeks to months.^14,15 A case series showed that 8/11 patients with cancer with OUD successfully discontinued opioids using buprenorphine-naloxone MOUD without resumption of opioid use.¹⁶ To the best of our knowledge, no phase II or III studies have assessed the role of buprenorphine in managing OUD or physical dependence on prescription opioids in patients with cancer. Importantly, a sublingual formulation of buprenorphine is not available in Korea; only a transdermal patch formulation is available. In North America, among patients without cancer with chronic pain or individuals dependent on nonprescription opioids, a transdermal buprenorphine patch (TBP) used as a bridging therapy before sublingual buprenorphine induction therapy or as monotherapy effectively managed withdrawal symptoms related to opioids.^17-20 Additionally, successful discontinuation of prescription opioids using TBP was achieved in 10 patients with cancer who were physically dependent on their prescribed opioids. The duration of TBP application ranged from 2 to 14 weeks. No resumption of prescribed opioids have been reported.²¹

Given these findings and the challenges of managing OUD and withdrawal symptoms associated with prescription opioids in cancer survivors, we aimed to assess and validate the efficacy and safety of TBP in managing physical dependence on prescription opioids in this population. Although physical dependence alone is not sufficient to diagnose OUD and is distinct from OUD, it is a common feature of OUD and can contribute to the diagnosis of mild OUD if it is associated with tolerance.²² In addition, we expected that the low incidence of OUD in Korea would have made it difficult to conduct a study focusing solely on OUD.^3,4 Therefore, in this study, we focused on physical dependence on prescription opioids rather than OUD in cancer survivors.

Materials and methods

Study design and participants

This single-arm phase II clinical trial was performed at 12 institutions in Korea. Inclusion criteria were age 19 years and older, patients willing to discontinue prescription opioids and voluntarily participated in clinical trials, patients previously managed with prescription opioids for cancer pain, but currently not requiring opioids due to the absence of pain, patients who met the Opioid Withdrawal DSM-5 diagnostic criteria²³ or whose physical dependence on prescription opioids had been confirmed through a psychiatric consultation, appropriate bone marrow and liver functions, and failure to discontinue prescription opioids through a simple tapering process due to withdrawal symptoms. Additionally, patients whose cancer was in complete response, showed no progression, or had not relapsed for a period of 6 months or more were eligible to participate, focusing on stable cancer survivors. Exclusion criteria were dependence on high-dose benzodiazepines or other CNS depressants and alcohol, history of hypersensitivity to buprenorphine, currently taking a monoamine oxidase inhibitor or taken it within the last 2 weeks, pregnant or who may become pregnant, severe respiratory disorders or in a state of respiratory suppression, uncontrolled psychiatric disorders, acute/chronic suicidal ideation or history, serious illness that needs to be managed prior to participating in a clinical trial, difficulty in controlling cancer pain when discontinuing opioids, or cases where buprenorphine has been prescribed once or more for any reason within the last 8 weeks. The study was approved by the Institutional Review Board of Gyeongsang National University Changwon Hospital (the principal investigator’s institution, GNUCH 2019-12-003-001), and by the IRBs of all co-investigator institutions. The study was registered with the Clinical Research Information Service (CRiS; KCT0005159).

Intervention and outcome measures

The intervention protocol was structured into 4 phases (Figure 1); each designed to reflect the principles and structure of the Substance Abuse and Mental Health Services Administration’s (SAMHSA) Treatment Improvement Protocol (TIP) series.^12,13 A psychiatric expert (D.-Y.L.) in our research team played a pivotal role in reviewing the protocol and developing the motivational enhancement therapy program administered by the researchers throughout the study phases (Supplementary Figure S1).

Figure 1.

Treatment protocol for managing physical dependence on prescription opioids in cancer survivors. The induction phase involves discontinuing all prescription opioids responsible for physical dependence, followed by an immediate transition to transdermal buprenorphine patch (TBP) due to its slower onset. For doses exceeding 170 mg morphine equivalent daily dose, TBP is combined with a reduced dose of the offending opioid.

• [1] The first phase, screening, focused on the identification and enrollment of suitable participants for the trial. Written informed consent and urinary drug screening (UDS) were obtained from all participants.

• [2] The second phase comprised induction and stabilization. The process began by ceasing the use of all offending prescription opioids that had led to physical dependence. This was followed by rotation to TBP without an opioid-free interval because of the slower onset time of TBP compared to that of the sublingual formulation. The patch was attached to undamaged skin on the outer upper arm, upper chest, upper abdomen, or lateral aspect of the chest. Dosages for TBPs were 5, 10, 20, 35, 52.5, and 70 mcg/h. The frequency of change usually depends on the patch brand. One brand was designed to be replaced every 4 days, whereas the other brand was intended for replacement every 7 days. Simultaneous application of 2 different brands of TBP was not recommended. Dose of TBP was determined to be 75%-100% equianalgesic dose of the offending opioid (Supplementary Table S1).^24-26 For participants using a morphine equivalent daily dose (MEDD) exceeding the maximum allowable TBP dose of 70 mcg/h (MEDD, 170 mg), a combination of TBP and reduced dose of their offending opioid was permitted. For example, if a patient’s MEDD was 200 mg, they would be prescribed TBP at 70 mcg/h plus an additional 30 mg of offending opioids, with the aim to reduce and discontinue the offending opioids within a few days to weeks. After the initial application of TBP, a 2-4 h observation period was recommended, although the protocol allowed for home-based or unobserved induction, depending on the researcher’s discretion. If TBP application alone did not sufficiently alleviate withdrawal symptoms, the protocol allowed the use of adjunctive medications²⁷ and rescue opioids. If the patient had not yet reached the maximum TBP dose of 70 mcg/h, an increase in the TBP dose was considered, potentially increasing by 5-10 mcg/h every 1-7 days based on the researcher’s discretion. Regular follow-ups were conducted at least every 2 weeks to assess whether the participant was stable with the current TBP dose.

• [3] The third phase was initiated only when certain criteria referred to as indications for TBP discontinuation, were met. These criteria (all of which must be met) include the absence of withdrawal symptoms and cravings at the current TBP dose, no need for rescue medication, no usage of other opioids, and clear motivation from the patient to discontinue opioid use. Once a participant met these criteria, the process of tapering off TBP began by gradually reducing TBP dose, typically by 5-10 mcg/h every 7-14 days to minimize any withdrawal symptoms.

• [4] The final phase, monitoring, is extended over 2-4 months. This phase was crucial for observing the reappearance of withdrawal symptoms and resumption of prescribed opioids. Regular follow-ups were scheduled to monitor the participants for resumption of prescribed opioids, side effects from TBP, and any abnormal behaviors related to opioid use.

The primary endpoint was the success rate of opioid discontinuation as defined by negative UDS after 8 weeks (± 7 days) of the first TBP application, considering the mean duration of TBP application in our previous report.²¹ Secondary endpoints included failure to maintain abstinence of the offending opioids, indicating resumption of prescribed opioids; rate of TBP retention and discontinuation; changes in the Clinical Opioid Withdrawal Scale (COWS)²⁸; changes in the MEDD measured with the inclusion and exclusion of TBP; changes in the numeric rating scale (NRS; range, 0-10) for the desire to use opioids; changes in the NRS for willingness and distress to discontinue opioids which were specifically developed by the investigators for this study; impact on quality of life through FACT-G questionnaires (as there were no Korean translations available for the validated tools specifically designed to evaluate OUD or physical dependence on prescription opioids); and adverse events according to CTCAE version 5.0.

Statistical analysis

This study aimed to enroll 53 participants, aligning with 15% non-inferiority margin and 60% baseline successful discontinuation rate in the intention-to-treat (ITT) population, which included all enrolled participants regardless of their adherence to the protocol. Power analysis, performed using PASS statistical software, indicated a study power of 0.82 (α = 0.10; β = 0.18). Analyses were conducted across 3 distinct populations: ITT, full analysis set (FAS), and per-protocol (PP). FAS comprised all participants who received at least one dose of the study treatment and had at least one post-baseline assessment, whereas PP included those assessed at the 8-week follow-up visit, aligning with the timepoint for the primary endpoint assessment. For continuous variables in the matched samples, paired t-test or Wilcoxon signed-rank test was applied based on data normality. For categorical variables, Chi-squared or Fisher’s exact test was used. A 2-sided P < .05 was considered statistically significant. All statistical analyses were performed using STATA 16.1 (StataCorp LLC, College Station, TX, USA).

Results

Study enrollment, baseline characteristics, and opioid use patterns in participants

Thirty-one participants (ITT population) were enrolled between October 2020 and May 2023 (Figure 2). The enrollment was closed prematurely owing to the slow recruitment rate and consensus among all researchers that there might be no additional enrollment. Baseline UDS was all positive, except for one female participant who used tapentadol, for whom UDS could not be tested using our UDS kit. In this participant, UDS was considered negative if all of the following conditions were met: denial of tapentadol use, negative UDS for other opioids, and no prescription of any opioids by researchers or other health care professionals at the 8-week follow-up visit. Among the 31 ITT participants, 3 withdrew before the first follow-up visit: 2 were lost to follow up, and one withdrew consent. Consequently, 28 participants (FAS population) were assessed for efficacy and safety at least once after enrollment. Additionally, 3 participants withdrew before the 8-week follow-up visit; TBP was discontinued owing to lack of efficacy (n = 2) and toxicity (n = 1). Finally, UDS was performed at the 8-week follow-up visit in 25 participants (PP population).

Figure 2.

CONSORT diagram of the study.

Baseline characteristics of ITT population are tabulated (Table 1). Most patients were male (58.1%, n = 18) with median age 61 years. Among them, 35.5% (n = 11) were current or ex-smokers and a small proportion reported a lack of social support. Cancer types represented in the study were diverse, with colorectal being the most common (25.8%, n = 8), followed by head and neck (19.4%, n = 6). Most participants (83.9%, n = 26) had completed their anticancer therapy and were under follow-up, whereas 16.1% (n = 5) were still receiving chemotherapy and had not reported cancer progression in the previous 6 months.

Table 1.

Baseline characteristics.

Variables	n = 31
Male sex	18 (58.1%)
Median age, years (IQR)	61 (50–69)
Current or ex-smoker	11 (35.5%)
Lack of social support	2 (6.5%)
Type of cancer
Colorectal	8 (25.8%)
Head and neck	6 (19.4%)
Pancreato-biliary	3 (9.7%)
Sarcoma	3 (9.7%)
Othersa	11 (35.5%)
Anticancer therapy
Completed	26 (83.9%)
Ongoing	5 (16.1%)
Secondary endpoints, mean (SD)
Morphine equivalent daily dose, mg/day	118 (157)
Clinical Opioid Withdrawal Scale (COWS; 0–48)	6.0 (3.2)
Desire to use opioids (0–10)	6.8 (2.6)
Will to discontinue opioids (0–10)	7.4 (2.6)
Distress to discontinue opioids (0–10)	6.5 (2.4)
Type of opioids (n = 50)
Oxycodone (short-acting)	17 (34%)
Oxycodone (long-acting)	15 (30%)
Fentanyl (short-acting)	7 (14%)
Fentanyl (long-acting)	5 (10%)
Othersb	6 (12%)

^aIncluding gastric, genitourinary, gynecologic, lung, lymphoid, thymic, and thyroid malignancy.

^bIncluding hydromorphone, hydrocodone, tapentadol, and codeine.

Mean MEDD in this study was 118 mg/day, suggesting that most patients were likely opioid-tolerant.²⁹ Among the 6 participants with a MEDD greater than 170 mg/day, 5 received TBP simultaneously with a reduced dose of opioids, in accordance with the study protocol. Mean COWS score was 6.0, suggesting mild withdrawal symptoms. Nevertheless, the mean NRS score for the desire to use opioids, rated at 6.8 on a 10-point scale, was moderately high. The participants had a high willingness to discontinue opioids (mean NRS: 7.4) and a slightly lower level of distress associated with opioid discontinuation (mean NRS: 6.5). On average, the participants were prescribed 1.6 different types of opioids (range, 1-3). Of the opioids prescribed, 64% were oxycodone and 24% were fentanyl. The distributions of short- and long-acting opioids were nearly equal, at 52% and 48%, respectively.

Success rate of opioid discontinuation

Median follow-up duration was 14.4 (IQR, 7.3-29.7) weeks in the ITT and 17.6 (IQR, 9.4-30.1) weeks in the PP populations. Success rate of opioid discontinuation was determined by a negative UDS at the 8-week follow-up visit (Figure 3A). ITT, FAS, and PP populations showed success rates of 58% (18/31), 64% (18/28), and 72% (18/25), respectively. In ITT population, the 8-week success rate of opioid discontinuation was significantly higher in participants prescribed with long-acting opioids only compared with those on short-acting opioids (90% vs 43%, P = .020), in those using a single opioid versus multiple opioids (80% vs 38%, P = .017), and in those using opioids other than fentanyl versus those using fentanyl with or without other opioids (75% vs 27%, P = .021; Figure 3B).

Figure 3.

Success rate of opioid discontinuation at 8 weeks in the intention-to-treat (ITT) population using transdermal buprenorphine patch (TBP). (A) Overall success rate. (B) Factors affecting success rate.

Table 2 describes the data for resumption of prescribed opioids, and the discontinuation or retention of TBP. In ITT population, 11/31 participants (35%) were able to discontinue both TBP and the offending opioids at the 8-week follow-up visit, adhering to the study protocol criteria for TBP discontinuation. None of these 11 participants experienced resumption of prescribed opioids during the study period. A male participant who had successfully stopped using long-acting oxycodone developed a physical dependence on TBP that manifested as agitation following its cessation. Consequently, he resumed and has since retained a TBP dose of 35 mcg/h. At the final analysis, 9/25 participants in the PP population retained their TBP. Of them, 4 successfully discontinued the offending opioids. However, another 4 participants were unable to discontinue their offending opioids, and one experienced resumption of prescribed opioids after initially discontinuing them. Including another case, there were consequently 2 participants who experienced resumption of prescribed opioids after discontinuing the offending opioids.

Table 2.

Rates of resumption of prescribed opioids and TBP discontinuation.

Description	Value
Discontinued both TBP and offending opioids at the 8-week follow-up visit (ITT population)	11/31 (35%)
Resumption of prescribed opioids after discontinuing offending opioids at the 8-week follow-up visit	0/11
Retained TBP at final analysis (PP population)	9/25 (36%)
Discontinued offending opioids at final analysis	4/9 (44%)
Unable to discontinue offending opioids at final analysis	4/9 (44%)
Resumption of prescribed opioids after discontinuing offending opioids at the 8-week follow-up visit	1/9 (11%)
Total resumption of prescribed opioids after discontinuing offending opioids at the 8-week follow-up visit	2/18 (11%)*

^*One case discontinued TBP after the 8-week follow-up visit.

Abbreviations: TBP, transdermal buprenorphine patch; ITT, intention-to-treat; PP, per-protocol.

Five participants received rescue opioids other than the offending opioids and TBP before the 8-week follow-up visit. The success rate of opioid discontinuation at the 8-week follow-up visit in the ITT population was 40 % (2/5) in those who received rescue opioids and 62% (16/26) in those who did not. However, this difference was not statistically significant (P = .625).

Evaluations for secondary efficacy endpoints

Secondary efficacy endpoints were compared at baseline and 8-week follow-up visit in the PP population (Figure 4). Mean MEDD, excluding the TBP dose, decreased from 98 to 26 mg/day (P < .001; Figure 4A). This trend remained significant when TBP was included, with a decrease in MEDD from 98 to 58 mg/day (P = .035, Figure 4B). In the participants with positive UDS at the 8-week follow-up visit, the mean MEDD changed from 193 (± 201) mg/day to 92 (± 147) mg/day excluding TBP (P = .018) and to 165 (± 147) mg/day including TBP (P = .735).

Figure 4.

Evaluation of secondary efficacy endpoints at baseline and 8-week follow-up. Change in (A) mean morphine equivalent daily dose (MEDD) excluding transdermal buprenorphine patch (TBP), (B) mean MEDD including TBP, (C) Clinical Opiate Withdrawal Scale (COWS) scores, (D) numeric rating scale (NRS) scores for desire to use opioids, (E) NRS scores for participants’ will to discontinue opioids, and (F) NRS scores for distress to discontinue opioids.

The mean COWS score reduced from 5.5 to 2.8 (P < .001, Figure 4C), indicating the successful management of withdrawal symptoms. The mean NRS score for the desire to use opioids decreased from 7.0 to 3.0 (P < .001, Figure 4D), indicating reduced craving for opioids among the participants. Participants’ will to discontinue opioids increased from 7.1 to 8.5 (P < .001, Figure 4E), and distress to discontinue opioids decreased from 6.5 to 3.4 (P < .001, Figure 4F), suggesting an enhanced motivation to discontinue opioids and a significant reduction in the emotional difficulty associated with the process. Of the 25 participants in the PP population, 20 completed the FACT-G questionnaire at baseline and the 8-week follow-up visit. Over the 8-week study period, the total FACT-G score and its subscales increased, indicating a potential improvement in quality of life. However, these improvements were modest and did not reach statistical significance (Supplementary Table S2).

Safety profile

None of the participants, including the 5 who received TBP simultaneously with a reduced dose of offending opioids, experienced severe precipitated withdrawal by TBP that led to withdrawal from the study during the induction and stabilization phase. Other adverse events reported by 8 of the 31 participants were generally mild, primarily grade 1 symptoms, such as constipation, diarrhea, abdominal pain, dizziness, insomnia, dry mouth, nausea, and itching. Two participants experienced grade 2 symptoms. One participant with grade 2 scalp pain unrelated to TBP, discontinued TBP before the 8-week follow-up visit and continued using his offending opioid. Another patient who experienced grade 2 itching sensation related to TBP, discontinued TBP after the 8-week follow-up visit and successfully discontinued the long-acting oxycodone.

Discussion

This is the first clinical trial to assess the efficacy and safety of TBP in managing physical dependence on prescription opioids among cancer survivors. Discontinuation of offending opioids at the 8-week follow-up visit was achieved in 58% of the ITT population, 64% of the FAS population, and 72% of the PP population. Secondary outcomes revealed significant reductions in MEDD, COWS, and desire to use opioids, and improvements in the willingness and distress to discontinue opioids, indicating the role of TBP in reducing the physical and psychological aspects of opioid dependence. The safety profile of TBP is generally favorable, with mild and manageable adverse events and no severe precipitated withdrawal during the induction and stabilization phases.

The success rate of 58% of the ITT population for discontinuing offending opioids in this study is comparable to that reported in previous studies that assessed the efficacy of sublingual buprenorphine for prescription or nonprescription opioid dependence. In a 42-month follow-up of a prescription opioid addiction treatment study, a success rate of 61% was reported with buprenorphine-naloxone plus standard medical management for prescription opioid dependence in patients without cancer with chronic pain. Specifically, 31.7% of participants abstained from opioids and were not on agonist therapy, and 29.4% were receiving opioid agonist therapy without meeting the criteria for current opioid dependence.³⁰ Long-term follow-up data from a randomized trial comparing buprenorphine/naloxone to methadone demonstrated that 57% of participants who received buprenorphine/naloxone did not use heroin or prescription opioids over the follow-up period.³¹ Furthermore, a recent study showed a 42% retention rate over 6 months, a surrogate marker for treatment adherence, in patients who initiated buprenorphine treatment (94% of buprenorphine/naloxone) for OUD.³² Collectively, these findings suggest the effectiveness of buprenorphine-based treatments for the management of OUD and its related conditions in various settings and populations.

Despite its slower onset and lower dose flexibility than sublingual buprenorphine, TBP has compensatory advantages for managing withdrawal symptoms on prescribed opioids. The reduced risk of diversion owing to the controlled delivery system and favorable safety profile of TBP are beneficial in outpatient and long-term management settings. Continuous buprenorphine release of TBP ensures stable drug levels along with the convenience of non-daily dosing, which enhances patient compliance and adherence. Additionally, TBP does not require an opioid-free interval before rotation from the offending opioids because of its slow and steady release of medication, thus preventing precipitated withdrawal.^33-35 However, our study predominantly involved participants with mild withdrawal symptoms, as indicated by a mean COWS score of 6. The lower success rate in more challenging cases, such as those involving short-acting, multiple, or potent opioids, suggests that TBP might be less effective in managing severe withdrawal symptoms. These patients may require immediate flexible symptom management. Additionally, the follow-up period in our study was relatively short. This shorter follow-up duration may have limited our ability to fully assess the long-term efficacy of TBP, potentially leading to an overestimation of its success rate in discontinuing prescribed opioids and an underestimation of the rate of resumption of prescribed opioids.

In our study, discontinuation of TBP was permitted according to the criteria of the study protocol. However, in the general population or patients without cancer with OUD, retention of buprenorphine is strongly recommended because discontinuation of buprenorphine is frequently associated with an increased risk of resumption of opioid use.³⁶ Contrastingly, in our study, among the 11 participants who were able to discontinue both TBP and their offending opioids, we observed no cases of resumption of prescribed opioids and only one case of physical dependence on TBP. This difference may be attributed to the relatively mild severity of the withdrawal symptoms and less frequent inclusion of cases with psychological dependence in this study. Moreover, the short-term follow-up period in our study may not have been adequate to fully assess the risk of delayed resumption of prescribed opioids. Nonetheless, our findings prompted a reevaluation of the necessity for long-term buprenorphine retention in cancer survivors with mild withdrawal symptoms on prescription opioids. Another methodological issue related to our study is the initial dose of TBP because an equianalgesic dose (as applied in our study) may not be the same as the dose needed to control withdrawal symptoms. The initial dose of sublingual buprenorphine for managing withdrawal symptoms is typically fixed at 2-4 mg and titrated based on the patient’s withdrawal symptoms.¹³ In our study, the initial equianalgesic dose of TBP showed an acceptable safety profile and was effective in managing the initial withdrawal symptoms. Further studies are required to validate the appropriate initial TBP dose.

The findings of this study should be interpreted with caution owing to several limitations. This study had a single-arm design without a control group, making it difficult to conclusively attribute the outcomes to the intervention alone. Given the low incidence of OUD in Korean patients with cancer,^3,4 this study faced challenges in participant recruitment, resulting in a small sample size, which impacted the reliability and generalizability of the results. Moreover, a follow-up period of 14.4 weeks might not sufficiently capture the long-term efficacy and safety of TBP, especially the potential of the resumption of prescribed opioids. Conducted exclusively in Korea, the findings of this study might not be fully applicable to regions with access to different buprenorphine formulations. The study cohort predominantly comprised participants with milder symptoms of physical dependence, which significantly limits the applicability of the findings to a broader patient population, especially those experiencing more severe forms of withdrawal symptoms. Moreover, by including participants solely based on their withdrawal symptoms and not considering the full diagnostic criteria for OUD, the study results may not be directly applicable for assessing the efficacy of TBP for treating OUD. Additionally, this consideration is crucial because the DSM-5 indicates that tolerance and withdrawal cannot be considered as criteria for diagnosing OUD in patients on long-term opioid therapy.³⁷ Another significant limitation was the lack of direct involvement of psychiatric experts in participant enrollment and management. Although a psychiatric expert reviewed our intervention protocol and developed the motivational enhancement therapy program, it was conducted by a medical oncologist for all participants, and its efficacy was not assessed. This has been criticized for representing an absence of a comprehensive multidisciplinary approach, which is crucial for managing OUD.

To conclude, our research indicates that TBP could serve as an effective alternative to sublingual formulations for managing physical dependence on prescription opioids in cancer survivors, particularly where sublingual options are unavailable. Additionally, this study suggests that primary care physicians can effectively initiate TBP use in cancer survivors who have mild withdrawal symptoms and face difficulty in discontinuing their offending opioids solely through dose tapering; thereby reducing the need for immediate referral to addiction specialists. This approach has the potential to mitigate the undertreatment of cancer pain by reducing unnecessary concerns about opioid dependence. Further research involving larger and more diverse patient groups, and incorporating comprehensive multidisciplinary management with behavioral interventions, is required to validate these findings and evaluate the long-term impact of TBP in managing OUD and physical dependence on prescription opioids in cancer care.

Supplementary Material

Supplementary material is available at The Oncologist online.

Author Contributions

Conceptualization: Jung Hun Kang, Se-Il Go. Methodology: Jung Hun Kang, Kyung Hee Lee, Dong-Yun Lee, Se-Il Go. Formal analysis: Jung Hun Kang, Seok Jae Huh, Se-Il Go. Investigation and data curation: Jung Hun Kang, Kyung Hee Lee, Seok Jae Huh, Seong Hoon Shin, Il Hwan Kim, In Gyu Hwang, Dong-Hoe Koo, Dong-Yun Lee, Su-Jin Koh, Seyoung Seo, Guk Jin Lee, Sang Hoon Chun, Jun Ho Ji, Sung Yong Oh, Jung Woo Choi, Se-Il Go. Resources: Se-Il Go. Supervision: Jung Hun Kang, Se-Il Go. Writing—original draft: Jung Hun Kang, Kyung Hee Lee, Seok Jae Huh, Se-Il Go. Writing—review & editing: All authors. All authors have read and approved the final version of the manuscript

Funding

This study was sponsored and funded by the BCWorld Pharm. Co., Ltd. The company did not play any role in the design of the study, or in the collection, analysis, or interpretation of the data. This study was supported by the Korean Academy of Supportive Care in Cancer (KASCC) and the National R&D Program for Cancer Control through the National Cancer Center (NCC) funded by the Ministry of Health & Welfare, Republic of Korea (HA22C0012).

Conflict of Interest

The authors declare no competing interest.

Data Availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.