Low-dose Initiation of Buprenorphine/naloxone for the Management of Chronic Non-cancer Pain in Patients on Long-term Opioid Therapy: A Case Series

ABSTRACT Background Buprenorphine may provide superior analgesia to full opioid agonist therapy and reverse the effects of opioid-induced hyperalgesia, while having a favorable safety profile and fewer adverse effects, in chronic non-cancer pain treatment. Low-dose initiation of buprenorphine is a useful strategy for patients on long-term opioid therapy because it avoids the need for moderate opioid withdrawal required for traditional buprenorphine initiations. However, there are few published reports of low-dose initiation regimens in the setting of chronic pain. Aims The aim of the study was to describe a case series of individuals living with chronic pain who were transitioned from long-term full opioid agonist therapy onto sublingual buprenorphine/naloxone using low-dose initiation regimens. Methods This study is a retrospective case series that included all patients who received care at an outpatient chronic pain clinic and were scheduled for low-dose initiation of buprenorphine/naloxone between March 2020 and December 2022. Data were collected through a retrospective review of electronic medical records and results were analyzed using descriptive statistics. Results Eighteen patients underwent transitions from their baseline opioids onto buprenorphine/naloxone using a low-dose initiation regimen. Of those patients, 17 successfully completed the initiation (94.44%), 12 experienced adverse effects during the initiation (66.67%), with only one patient requiring treatment discontinuation, and all adverse effects resolved once maintenance doses of buprenorphine/naloxone were established. The mean Clinical Global Impression–Improvement score after initiation was 2 (1–5). Conclusion Low-dose initiation is an effective approach to transition patients with chronic non-cancer pain from long-term opioid therapy to buprenorphine/naloxone without major complications or worsening pain.


Introduction
][5] CNCP affects approximately 7.6 million Canadians, and this estimate is expected to rise in light of the growing proportion of older adults. 5Historically, prescription opioids were falsely promoted as low-risk, nonaddictive, and effective treatments for CNCP. 6owever, this has long been disproven, as long-term opioid therapy (LTOT) can lead to many adverse effects, including opioid dependence and opioid tolerance.This may result in escalating opioid doses in an attempt to address uncontrolled pain. 6The relationship between chronic pain and LTOT has posed many challenges for health care providers and has given rise to the off-label use of bup/nal as a safer alternative for the management of CNCP, especially in the setting of comorbid opioid dependence, which is the physiologic adaption to chronic opioid use through the development of tolerance and withdrawal. 7,8uprenorphine has a unique pharmacokinetic profile in that it is a partial mu-opioid receptor (MOR) agonist, kappa-opioid receptor antagonist, delta-opioid receptor antagonist, and orphan-like receptor 1 agonist. 7ompared to full opioid agonists, the action of buprenorphine at MORs produces a high-potency analgesic effect with fewer adverse effects, such as physical dependence, respiratory depression, and constipation. 7,9owever, due to buprenorphine's high MOR affinity and slow dissociation, the competitive binding of MORs can precipitate opioid withdrawal in the presence of full opioid agonists. 7,10As such, current bup/nal product monographs require patients to discontinue their existing opioid therapy and experience mild-tomoderate withdrawal symptoms prior to bup/nal initiation to avoid abrupt displacement at MORs. 11,12 This practice is often referred to as "traditional initiation" and is the dosing strategy recommend in the bup/nal product monograph for OUD management. 11,12pioid withdrawal symptoms, such as anxiety, sweating, and bone or joint pain, can cause significant patient discomfort, and avoiding withdrawal has been reported as the most important reason for current opioid use by patients with concurrent chronic pain and opioid dependence. 13,14Perceived intensity and emotional fear of withdrawal-associated pain can cause severe emotional and physical stress for certain patients and may be a significant barrier to successful opioid cessation. 15pioid tapers may be an option for individuals living with CNCP who have been receiving LTOT with little or no benefit and/or are experiencing adverse effects. 16owever, this approach increases the risk of accidental overdoses, opioid withdrawal, and pain crisis and has been associated with an increase in emergency department visits and hospitalizations. 17,18 more recent strategy termed "low-dose initiation," also known as "microdosing" or the "Bernese method," has emerged as an alternate buprenorphine initiation strategy that is hoped to eliminate the need for attaining withdrawal symptoms prior to traditional bup/nal initiation and also decrease the chance for precipitated withdrawals with buprenorphine. 18Low-dose initiation involves starting bup/nal at very low doses while the patient continues their existing opioid to allow for slow accumulation at opioid receptors, resulting in the gradual displacement of their full opioid agonist.This novel approach has grown increasingly common among prescribers for the management of OUD; however, there are sparse published data regarding its use in the setting of chronic pain. 7,19,20ublished studies on low-dose initiation methods of buprenorphine have primarily focused on the treatment of OUD.There are nine published case reports/series describing the use of low-dose initiation bup/nal for the indication of CNCP in a total of 23 adult patients (Appendix).Of these 23 cases, 4 were initiated using transdermal buprenorphine before transitioning onto bup/nal. 19,213][24][25][26][27] These cases highlight the potentially utility of low-dose bup/nal initiations in the treatment of patients with CNCP; however, there is a need for further research in this area to strengthen the evidence base for this practice.
This case series aims to summarize the use of lowdose initiation regimens of sublingual bup/nal in patients living with CNCP who were switched to sublingual bup/nal using low-dose initiation regimens at an interdisciplinary chronic pain clinic in Canada.

Methods
This study is a case series that included patients who received chronic pain care at the USask Chronic Pain Clinic (UCPC) in Saskatoon, Saskatchewan, Canada, from March 2020 to December 2022.The information collected for this case series was gathered by retrospective review of electronic medical records.Results were analyzed using descriptive statistics.The protocol was approved by the University of Saskatchewan Research Ethics Board (Beh ID 2076), and all patients provided informed consent to research.
The UCPC provides interdisciplinary chronic pain care to patients alongside their current primary care team.The details of the UCPC are described elsewhere. 28,29The UCPC provides care to patients with CNCP but does not provide care to patients with known active illicit opioid use or to patients who are known to manipulate the formulation of their prescription opioid medications (e.g., snort or inject them) because patients meeting these criteria are referred to addiction medicine specialists separate from the UCPC.However, because there is overlap between CNCP and opioid dependence, some UCPC patients may meet criteria for mild-to-moderate OUD.
Most patients in this case series were referred to the UCPC by their primary prescriber due to inadequate pain control and/or opioid-related harms.At the time of referral to the UCPC, background patient information is collected and a clinical assessment is completed to obtain demographic information, diagnoses, medication history, pain history, psychiatric history, and substance use history.This information is stored within UCPC electronic medical records, which were retrospectively reviewed to obtain the information for this case series.
The pharmacists and physician at UCPC provided support to the patient's primary prescriber to initiate bup/nal, including mentorship, education, and followup discussions, as needed.The case patients were identified for inclusion in this case series by retrospectively screening the electronic medical records of all UCPC patients to identify those whose treatment plan included a transition to bup/nal using a low-dose induction regimen for the treatment of CNCP.
Bup/nal initiation regimens were created using a standardized low-dose initiation protocol.The protocol involved gradual titration from 0.5 to 12 mg of sublingual bup/nal over a 7-day period while the patient continued to take their baseline opioid(s).The baseline opioid therapy was stopped on day 7 of the bup/nal initiation regimen.Although the low-dose initiation protocol was standardized, the regimens were adjusted by the UCPC clinicians based on patient-related factors such as baseline opioid use, comorbidities, and clinical status (Figure 1). 7,30During the low-dose initiation protocol, the UCPC offered flexibility in the discontinuation of baseline full opioid agonist based on patient preference (i.e., fear of withdrawal) and clinician assessment of their baseline dose of opioids.Patients were either tapered off their baseline opioids, stopped opioids in a stepwise approach (e.g., stopped hydromorphone immediate release on day 4 and then stopped hydromorphone long-acting on day 7), stopped baseline opioids abruptly without taper, or a combination of methods was used.
UCPC patient data were retrospectively collected from each patient's electronic medical record.Extracted data points included patient demographics, clinical status pre and post bup/nal initiation (e.g., comorbidities, medications, baseline opioid use characteristics, pain rating scales).UCPC clinicians were encouraged to record a Clinical Global Impression-Improvement (CGI-I) score following each appointment with the patient.A CGI-I score is based on the clinician's observation of the patient's overall functioning compared to previous appointments and is a recommended monitoring parameter in CNCP treatment studies. 31Patient data were collected by one research assistant (D.K.) and reviewed and validated by a second research assistant (M.R.).K.H. provided supervisory support for data collection and resolved any data discrepancies.The extracted data were analyzed using descriptive statistics.

Results
A total of 21 patients were initiated onto bup/nal for CNCP at the UCPC and were included in this case series.Patient baseline characteristics were identified as follows: the mean age was 53 years (range, 22-81), and the majority were female (66.7%).Patients had a median of 9 (range, 2-21) comorbidities.Several patients had comorbid psychiatric conditions, most commonly major depressive disorder (52.4%) and generalized anxiety disorder (23.8%).Additionally, 17 patients had a mild to severe score on the Patient Health Questionnaire-9 (PHQ-9; 81.0%) and 13 patients scored mild to severe on the General Anxiety Disorder-7 (GAD-7; 61.9%). 32,33he majority of patients did not have a formal substance use disorder (SUD) diagnosis (71.4%)-only 4 patients had a formal diagnosis of OUD (19.1%).Of the patients diagnosed with OUD met the following Diagnostic and Statistical Manual of Mental Disorders, fifth edition 34 criteria: opioids are often taken in larger amounts than intended (n = 4); continued use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by opioids (n = 4); a great deal of time is spent in activities necessary to obtain the opioid, use the opioid, or recover from its effects (n = 1); tolerance (n = 4); and withdrawal (n = 4).One of the patients had a remote history of illicit opioid use, but this was in remission at the time of referral and throughout care with the UCPC.Eight patients scored clinically significant (≥2) on the Prescription Opioid Misuse Index (POMI; 38.1%), 3 of whom were patients with a formal OUD diagnosis.
All patients were planned to undergo low-dose initiation onto bup/nal; however, 3 of the 21 patients completed traditional bup/nal initiation regimens (14.3%).Traditional initiations occurred for the following reasons: 2 patients were initiated in acute care facilities following unintended abstinence from their baseline opioids, and 1 patient opted for a traditional initiation as a personal preference.These 3 patients were excluded, resulting in 18 patients who were included in the final data analysis (Figure 2).
Low-dose bup/nal initiation regimens varied based on baseline opioid(s), daily OME, and comorbidities/ frailty (Figure 3).Of the 18 patients who underwent lowdose initiation to bup/nal, the median duration of initiation was 7 days (range, 2-28 days), and the median stop date of the previous opioid was on day 7 (range, 1-21 days).Two patients tapered off their baseline opioids (11.1%), 4 patients stopped their opioids in a stepwise approach (22.2%), and 13 patients opted to discontinue their opioids without tapering on the stop date (72.2%).Seventeen patients successfully completed the low-dose initiation regimen (94.4%; i.e., they were transitioned from their baseline full opioid agonist to bup/nal utilizing a low-dose initiation regimen) and the mean final daily bup/nal dose was 10.5 mg (range, 1-24 mg).One patient did not complete the initiation due to adverse effects, including nausea and drowsiness.
During low-dose initiation, 12 patients experienced adverse effects (66.7%), with the most common being nausea (33.3%) and aches/pain (27.8%).Nine patients required supportive medications during the initiation (50.0%), with clonidine being the most common (38.9%).All adverse effects that occurred during the initiation of bup/nal resolved once the final maintenance dose of bup/nal was established.
Following low-dose initiation, 14 patients remained stable on bup/nal throughout their follow-up appointments with the UCPC (77.8%), 2 were lost to follow-up (11.1%), and 2 had not yet had follow-up appointments prior to data extraction (11.1%).The median CGI-I score after initiation was 2 (much improved) with a range between 1 (very much improved) and 5 (minimally worse).Patients were planned for follow-up at the UCPC until they reached a stable maintenance dose of bup/nal and could be managed by their primary outpatient health care team; thus, the duration of the follow-up period varied for each patient.At the final visit, patients were taking a median of 3 (range, 1-8) analgesics and 8.5 (range, 5-27) total medications, 25% and 22.7% reductions from baseline, respectively.Bup/nal doses were titrated, as needed, by the clinical team during the followup period to find the optimal dose for each individual patient.Patients were taking a mean daily bup/nal dose of 11.5 mg (range, 1-28 mg) at the final visit (Table 2).

Discussion
This article represents the largest published case series of patients who were successfully transitioned to sublingual bup/nal using a low-dose initiation method for the treatment of CNCP.The low-dose initiation regimens that are reported in this study were generally well tolerated by patients, with only one failed initiation and no serious complications (i.e., no opioid toxicity events or death).
The most common adverse effect of nausea may have been due to precipitated opioid withdrawal or due to buprenorphine itself, which carries a risk of nausea of 16.1%. 11This study thus adds to the available data to support the use of low-dose bup/nal initiation regimens in the setting of CNCP and LTOT.At present, there is limited published literature on bup/nal initiation strategies for the purpose of CNCP.Published literature on patients transitioned to bup/nal using a low-dose initiation method consists only of case  Opioid stop date is defined as the day of initiation at which all prior prescription opioids were stopped.b Duration of initiation is defined as the day of initiation at which all prior prescription opioids were stopped and target initial dose was reached.c Total daily dose at the end of initiation is defined as the maximum allowable total daily dose on the final day of initiation.
d Successful initiation is defined as completion of the bup/nal initiation regimen and abstinence from previous opioids.e Psychosocial stressors are defined as any situations/circumstances that create an unusual or intense level of stress in the patient's life (excluding chronic pain).f Supportive medications are defined as any medications used to relieve symptoms of withdrawal during initiation.g Patient status following initiation was monitored by the UCPC care team.Patient follow-ups were planned to be conducted until the patient was on a stable maintenance dose of bup/nal and could be managed by their personal health care team.Two patients were lost to follow-up prior to establishing a maintenance dose.Two patients did not complete follow-up prior to the case series data collection.h Pain improvement measures were collected at follow-up visits after completion of initiation.There were no standardized time frames during which these values were collected.
series and case reports.The largest previously published case series of patients being transitioned from full opioid agonists to bup/nal for CNCP using a low-dose initiation protocol consisted of eight patients. 8The eight patients were all experiencing opioid dependence and two met Diagnostic and Statistical Manual of Mental Disorders, fifth edition criteria for OUD.Similar to the patients in our case series and the other published cases, Robbins et al. 8 found that low-dose initiation regimens were generally well tolerated, and the majority of patients experienced improved pain control following the transition.Our case series adds to the growing evidence that low-dose initiation of bup/nal is a feasible treatment option for patients experiencing adverse effects, uncontrolled pain, or opioid misuse while taking opioids for CNCP.
Limitations of this study include practitioner bias, inconsistencies in collected data at appointments, and the absence of reported withdrawal and pain scales once patients started their bup/nal initiation regimens.The variability in practitioner reporting of clinical response may lead to unreliable data.It is not possible to distinguish adverse effects reported at appointments as opioid withdrawal, precipitated withdrawal, or adverse effects of bup/nal, and therefore it is not possible to determine that low-dose initiation strategies used by UCPC avoid opioid withdrawal.Clinical Opiate Withdrawal Scale (COWS) scores and pain scales were not routinely completed during follow-up appointments for a variety of reasons, including time limitations, negative impact of measurement-based care tools on clinician patient interactions, and logistical challenges of appointments (i.e., many were completed virtually). 36Given the complexity of CNCP conditions, pain scales completed at one point in time may not accurately reflect a patient's progress.
The generalizability of this case series is limited by the cohort's small sample size and retrospective data collection.Additionally, the cohort in this study exhibited higher rates of opioid misuse (38.1%) and OUD (19.1%) than published averages, which indicates that the rate of misuse in patients taking opioid therapy for CNCP is 21% to 29% and the rate of addiction is 8% to 12%. 37However, the rates of opioid misuse and OUD in patients with CNCP are not well established in published literature.Moreover, the elevated rates observed in this study could be attributed to selection bias, because the patients in this case series were referred to the UCPC based on their complexity and were chosen to transition to bup/nal based on the UCPC clinician's experience in caring for patients with CNCP and may not be reflective of all patients with CNCP.However, heterogeneity of the patients presented in this cohort in terms of demographics, comorbidities, opioid use, and pain characteristics highlights the adaptability of low-dose bup/ nal initiation regimens.
The UCPC staff is committed to providing person-centered care, which includes tailoring pharmacotherapy to the patient's needs, as is demonstrated in this case series, which highlights the importance of flexible initiation regimens.Given that traditional bup/nal initiation regimens require patients to be in mild-to-moderate withdrawal prior to initiation, these patients would have been higher risk for worsening pain and withdrawal symptoms had they undergone a traditional induction protocol. 13,15The initiation regimens used in this study led to an improvement in global functioning and pain scores, further supporting the feasibility of the protocol.
Further research is needed to describe the relationship between CNCP and OUD.We have noted that many patients with CNCP may have a mild OUD that is not formally diagnosed.Moreover, randomized controlled trials evaluating the effectiveness of low-dose initiations versus traditional initiations for reducing psychiatric and physical stress associated with opioid withdrawal during bup/nal initiation are required to support low-dose initiation regimens as the standard of care.

Conclusion
This article represents the largest case series of patients who were successfully transitioned to sublingual bup/nal using a low-dose initiation method for the treatment of CNCP.The initiation regimens were generally well tolerated, flexible, and tailored to meet the patient's needs and led to improved global functioning.A low-dose initiation regimen of bup/nal may be considered as an induction method for patients transitioning to bup/nal for the treatment of CNCP, although the results should be interpreted cautiously based on the small sample size.

g
Mixed/nociplastic pain indicates elements of both nociceptive and neuropathic pain and/or central sensitization.h A CSI score ≥30 indicates a positive screen and greater likelihood of central sensitization.i A DN4 score ≥4 indicates a positive screen and greater likelihood of neuropathic pain.j A PCS score ≥30 indicates a clinically relevant level of pain catastrophizing.OAT = opioid agonist therapy, CSI = Central Sensitization Inventory, DN4 = Douleur Neuropathique en 4 Questions, PCS = Pain Catastrophizing Scale.

Figure 3 .
Figure 3. Low-dose buprenorphine/naloxone initiation regimens of UCPC patients.Baseline opioid: opioid used for CNCP prior to bup/ nal initiation.Target dose: bup/nal dose at the end of the low-dose initiation regimen.Duration of initiation: the day of initiation at which all prior opioids were stopped AND target initial dose was reached.*Milligrams(mg) dosing refers solely to buprenorphine component of bup/nal.†Only two UCPC patients fit into the 90-100 mg daily OME category.‡Only one UCPC patient fit into the clinically significant frailty/comorbidities category.SL = sublingual; BID = twice daily; PRN = as needed.

Table 1 .
(Continued).and GAD-7 scores are based on self-administered scales and are only used as screening tools at UCPC.Not considered diagnostic of major depressive disorder and GAD.b Other SUD includes alcohol use disorder, mixed SUD.c One patient met certain criteria for mixed SUD due to a history of crack cocaine use and prescription opioid misuse; however, the patient had no formal SUD diagnoses.POMI score ≥2 indicates a positive screen and greater probability of OUD.

Table 2 .
Results of 18 UCPC patients initiated onto bup/nal using a low-dose initiation regimen. a