Buprenorphine/naloxone for chronic non-cancer pain

Author

Katelyn Halpape BSP ACPR PharmD BCPP (biography and disclosures)

Disclosures: Received research funding from Health Canada’s Substance Use and Actions Program and Indigenous Services Canada. Mitigating potential bias: Recommendations are consistent with published Canadian guidelines and with current practice patterns. Treatments or recommendations in this article are unrelated to the research grants from the disclosure statement.  

What frequently asked questions I have noticed

What role does buprenorphine/naloxone have in the treatment of chronic non-cancer pain (CNCP)?

How should buprenorphine/naloxone be initiated for a patient living with CNCP currently on full μ-opioid agonist therapy?

One in five Canadians live with chronic non-cancer pain (CNCP).¹ Due to the historical role opioids had as a key component of CNCP treatment, a number of patients living with CNCP are on long-term opioid therapy (LTOT).² This contrasts with the 2017 Canadian guideline for opioid therapy and CNCP which recommends a cautious approach to opioid use in CNCP.³

LTOT typically does not improve pain or function and may cause adverse effects such as constipation, depression, anxiety, cognitive impairment, hyperalgesia, opioid use disorder and increased mortality.^2,4 The risks of LTOT for CNCP often outweigh the benefits. However, tapering patients with CNCP off opioids can be difficult and is not always a feasible goal.⁵ Thus, buprenorphine, a partial μ-opioid agonist, is increasingly used for CNCP due to its improved safety profile compared to full μ-opioid agonists.⁶ Buprenorphine must be initiated carefully in a patient on full μ-opioid agonist therapy to avoid precipitated withdrawal.⁷ Thus, off-label low-dose (or microdosing) buprenorphine initiations may be an ideal strategy.⁸

Data that answers these questions/gaps

The 2017 Canadian guideline for opioid therapy and CNCP highlights that opioid use for CNCP provides recommendations on reasons to consider opioid tapering (see Table 1).³

Table 1. Reasons to consider opioid tapering³

However, opioid tapering for patients living with CNCP on LTOT is challenging, and complete cessation of opioids may not be feasible.⁵ Opioid tapers must be completed cautiously to avoid an acute pain crisis, exacerbation of comorbid mental health conditions and to avoid increased opioid-related harms.^9-11 Given the complexity of opioid tapering in the setting of CNCP and LTOT, alternative treatment strategies, such as the use of buprenorphine, have emerged.⁵

Buprenorphine, developed as an analgesic in the 1960s, became widely used in Canada for treating opioid use disorder (OUD).¹⁴ As a partial μ-opioid agonist, buprenorphine has a ceiling effect on respiratory depression and it may be better tolerated than full μ-opioid agonists.¹⁴ It is available in several forms: transdermal patch, sublingual tablet, buccal film and subcutaneous injection. For CNCP and LTOT, sublingual tablets are most commonly used (off-label) due to their dosing flexibility, cost and formulary coverage.¹² The active ingredient in the sublingual tablets and buccal films is buprenorphine, which is combined with naloxone to prevent diversion if the tablets or films are used through parenteral or intranasal routes.^12,16 The once-monthly extended-release buprenorphine injectable has not been studied for CNCP.¹³

In 2020, an expert panel highlighted the favorable pharmacologic properties and safety of buprenorphine for CNCP.¹⁴ A 2021 systematic review of 22 CNCP studies found that switching to buprenorphine from full μ-opioid agonists reduced pain and avoided serious adverse effects.¹⁵ This review highlighted the need for further research on the best methods for transitioning patients from full μ-opioid agonists to buprenorphine.¹⁵

Transitioning a patient from a full μ-opioid agonist to buprenorphine risks precipitated opioid withdrawal due to an abrupt transition from full to partial receptor activation, and due to buprenorphine’s high affinity for the μ-opioid receptor which allows it to out-compete most other full agonists.⁷ The on-label, traditional approach to buprenorphine/naloxone initiation requires patients to be in moderate opioid withdrawal before starting buprenorphine, which can be uncomfortable and worsen pain.¹⁶ A more tolerable approach is a low-dose (a.k.a. microdosing) buprenorphine/naloxone initiation.¹⁷ This off-label strategy was developed to mitigate the risk of precipitated withdrawal via repetitive administration of small buprenorphine doses while the patient continues to take their original full μ-opioid agonist for approximately 3-14 days.¹⁸ The high affinity and long half-life of buprenorphine allows it to accumulate at the μ-opioid receptor which, over time, leads to increasing amounts of the buprenorphine replacing the full opioid at the μ-opioid receptor.^17,18

Low-dose buprenorphine initiation strategies have been increasingly utilized in patients with OUD, however, less data is available to guide this strategy in CNCP. Several case reports highlight the benefits of low-dose buprenorphine initiation for patients with CNCP. Four are summarized below in Table 2.

Table 2. Case reports of successful buprenorphine/naloxone low-dose initiations for CNCP

mg: milligrams, SL: sublingual, BID: twice daily

Table 3 provides a sample low-dose initiation regimen for switching to buprenorphine/naloxone from a full μ-opioid agonist. There is no standardized low-dose buprenorphine/naloxone initiation; duration and dosing should be individualized.¹⁸ A 2023 case series of 17 CNCP patients who transitioned to low-dose buprenorphine/naloxone reported a mean final dose of 10.5 mg (range 1-24 mg) and noted variability in regimens based on individual needs.²³

Table 3. Sample low-dose initiation regimen for switching to buprenorphine/naloxone from a full μ-opioid receptor agonist¹⁸

SL: sublingual

Low-dose initiation of buprenorphine/naloxone provides a distinctive treatment option for CNCP and LTOT, but it may not be suitable for all patients. While the initiation regimen can be managed in an outpatient general practitioner setting, effective communication between the prescribing physician, community pharmacy, patient and their family members or caregivers is crucial due to the complexity of dosing. Using blister packs can help reduce stress and confusion. Frequent monitoring and dose adjustments can also be challenging for both patients and healthcare providers. Additionally, a treatment agreement can be helpful. The optimal duration of treatment with buprenorphine/naloxone is undefined in the literature and must be individualized for each patient with the goal of improving their overall function.

What I recommend (practice tip)

In patients living with CNCP and on LTOT:

1. Screen for problematic opioid use/OUD and refer to an addiction specialist if necessary. For example, use the Prescription Opioid Misuse Index and screen for inappropriate medication use.
   1. View article on Misuse of and dependence on opioids.
   2. Managing opioid use disorder in primary care: PEER simplified guideline is a useful resource.
2. Offer a take home naloxone kit and opioid toxicity education to all patients on opioids.
3. Explore if the harms of opioids exceed the potential benefits for CNCP and assess if there is a reason to consider opioid tapering (see Table 1).
4. Work with the patient to develop realistic, functional goals for their CNCP.
   1. View 12 Quick Tips for Setting Goals with Chronic Pain on Northern Pain Centre.
5. Connect the patient with community resources and care providers to optimize non-pharmacological pain management strategies (e.g. chronic pain education, mind-based strategies, physical therapy) to promote patient self-management of chronic pain. For example, Pain BC’s Live Plan Be.
6. Optimize non-opioid analgesics. Refer to the RxFiles Chronic Pain Guide.
7. Once the patient is as biopsychosocially stable as possible (which may take several weeks or months) and prepared for a change to their opioid therapy, consider a switch to buprenorphine/naloxone using a low-dose initiation regimen.
   1. View Buprenorphine/Naloxone Microdosing: The Bernese Method on the Canadian Mental Health Association.
   2. View article on Buprenorphine-naloxone microdosing on CFP.
8. Ensure the patient has pharmacological (e.g. clonidine, acetaminophen) and non-pharmacological supports (e.g. support person) available during the initiation of buprenorphine/naloxone. Ensure informed consent and utilize a treatment agreement.
   1. View Sample Patient Agreement for Long-term Opioid Therapy on RxFiles.
9. Provide frequent follow-up and support during the transition. Note that buprenorphine/naloxone dose range may be lower in CNCP compared to OUD.^19,21–23 Use periodic urine drug tests if you have concerns regarding diversion.
10. Adjust buprenorphine/naloxone dose, as needed, to achieve optimal control of opioid withdrawal symptoms as well as CNCP management. Focus on functional goals instead of complete elimination of pain.

Resources

• 24/7 Addiction Medicine Clinician Support Line (778-945-7619) provides telephone consultation for healthcare providers and addiction support staff calling from Indigenous communities within BC who are involved in addiction and substance use care and treatment in British Columbia.
• Rapid Access to Consultative Expertise (RACE) (1-877-696-2131) provides telephone consultation service that connects primary care providers to their specialist colleagues for urgent advice within two hours.

Handout for Patients

View and download the RxFiles Patient Booklet you can use in practice – Questions about Buprenorphine-Naloxone for Chronic Pain and the answers that may surprise you. Download PDF.

References

1. Health Canada. Canadian Pain Task Force Report: March 2021. Government of Canada. May 12, 2021. Accessed June 21, 2023. (View)
2. Karmali RN, Bush C, Raman SR, Campbell CI, Skinner AC, Roberts AW. Long-term opioid therapy definitions and predictors: A systematic review. Pharmacoepidemiol Drug Saf. 2020;29(3):252-269. doi:10.1002/pds.4929. (View)
3. Busse JW, Craigie S, Juurlink DN, et al. Guideline for opioid therapy and chronic noncancer pain. CMAJ. 2017;189(18):E659-E666. doi:10.1503/cmaj.170363 (View)
4. Baldini A, Von Korff M, Lin EH. A review of potential adverse effects of long-term opioid therapy: A practitioner’s guide. Prim Care Companion CNS Disord. 2012;14(3):PCC.11m01326. doi:10.4088/PCC.11m01326 (View)
5. Murphy L, Babaei-Rad R, Buna D, et al. Guidance on opioid tapering in the context of chronic pain: Evidence, practical advice and frequently asked questions. Can Pharm J (Ott). 2018;151(2):114-120. Published 2018 Feb 8. doi:10.1177/1715163518754918 (View)
6. Chen KY, Chen L, Mao J. Buprenorphine-naloxone therapy in pain management. Anesthesiology. 2014;120(5):1262-1274. doi:10.1097/ALN.0000000000000170 (View)
7. Oakley B, Wilson H, Hayes V, Lintzeris N. Managing opioid withdrawal precipitated by buprenorphine with buprenorphine. Drug Alcohol Rev. 2021;40(4):567-571. doi:10.1111/dar.13228 (View)
8. Spreen LA, Dittmar EN, Quirk KC, Smith MA. Buprenorphine initiation strategies for opioid use disorder and pain management: A systematic review. Pharmacotherapy. 2022;42(5):411-427. doi:10.1002/phar.2676 (View)
9. Larochelle MR, Lodi S, Yan S, Clothier BA, Goldsmith ES, Bohnert ASB. Comparative effectiveness of opioid tapering or abrupt discontinuation vs No dosage change for opioid overdose or suicide for patients receiving stable long-term opioid therapy. JAMA Netw Open. 2022;5(8):e2226523. Published 2022 Aug 1. doi:10.1001/jamanetworkopen.2022.26523 (View)
10. Magnan EM, Tancredi DJ, Xing G, Agnoli A, Jerant A, Fenton JJ. Association between opioid tapering and subsequent health care use, medication adherence, and chronic condition control. JAMA Netw Open. 2023;6(2):e2255101. Published 2023 Feb 1. doi:10.1001/jamanetworkopen.2022.55101 (View)
11. Kertesz SG, Varley AL. New data on opioid dose reduction-implications for patient safety. JAMA Netw Open. 2022;5(6):e2216733. Published 2022 Jun 1. doi:10.1001/jamanetworkopen.2022.16733 (View)
12. Dalal S, Chitneni A, Berger AA, et al. Buprenorphine for chronic pain: a safer alternative to traditional opioids. Health Psychol Res. 2021;9(1):27241. Published 2021 Aug 6. doi:10.52965/001c.27241 (View)
13. Cuperfain AB, Costa T, Chopra N. Extended-release monthly buprenorphine injection. CMAJ. 2023;195(1):E14. doi:10.1503/cmaj.220730 (View)
14. Webster L, Gudin J, Raffa RB, et al. Understanding buprenorphine for use in chronic pain: expert opinion. Pain Med. 2020;21(4):714-723. doi:10.1093/pm/pnz356 (View)
15. Powell VD, Rosenberg JM, Yaganti A, et al. Evaluation of buprenorphine rotation in patients receiving long-term opioids for chronic pain: a systematic review. JAMA Netw Open. 2021;4(9):e2124152. Published 2021 Sep 1. doi:10.1001/jamanetworkopen.2021.24152 (View)
16. Indivior UK Limited. Product monograph including patient medication information: Suboxone. Published March 16, 2023. Accessed December 13, 2024. (View)
17. Marwah R, Coons C, Myers J, Dumont Z. Buprenorphine-naloxone microdosing: Tool for opioid agonist therapy induction. Can Fam Physician. 2020;66(12):891-894. doi:10.46747/cfp.6612891 (View)
18. Canadian Mental Health Association, Thames Valley Family Health Team. Buprenorphine/naloxone microdosing: The Bernese method a brief summary for primary care clinicians. Published September 2019. Accessed December 13, 2024. (View)
19. Sandhu R, Zivanovic R, Klaire S, Nikoo M, Rozylo J, Azar P. Buprenorphine/naloxone induction for treatment of acute on chronic pain using a micro-dosing regimen: A case report. Can J Pain. 2019;3(1):79-84. Published 2019 Apr 25. doi:10.1080/24740527.2019.1599279 (View)
20. Lee DS, Hann JE, Klaire SS, Nikoo M, Negraeff MD, Rezazadeh-Azar P. Rapid induction of buprenorphine/naloxone for chronic pain using a microdosing regimen: a case report. A A Pract. 2020;14(2):44-47. doi:10.1213/XAA.0000000000001138 (View)
21. Crum IT, Meyer Karre VM, Balasanova AA. Transitioning from intrathecal hydromorphone to sublingual buprenorphine-naloxone through microdosing: a case report. A A Pract. 2020;14(11):e01316. doi:10.1213/XAA.0000000000001316 (View)
22. MacAusland-Berg J, Wiebe A, Marwah R, Halpape K. Successful conversion from butorphanol nasal spray to buprenorphine/naloxone using a low-dose regimen to assist with opioid tapering in the setting of chronic pain and migraine management in an older adult patient: A case report. Can J Pain. 2022;6(1):135-141. Published 2022 Aug 18. doi:10.1080/24740527.2022.2090911 (View)
23. Rattanavong M, Kwan D, Jorgenson D, Landry E, Marwah R, Halpape K. Low-dose initiation of buprenorphine/naloxone for the management of chronic non-cancer pain in patients on long-term opioid therapy: a case series. Can J Pain. 2024;8(1):2310811. Published 2024 Jan 26. doi:10.1080/24740527.2024.2310811 (View)

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