Cite as: Wong VCY, Osborn J, Varshney V. How I do it: weaning strategy for intrathecal drug delivery systems for chronic non-cancer pain: sublingual buprenorphine-naloxone microdosing schedule. ASRA Pain Medicine News 2023;48. https://doi.org/10.52211/asra080123.011.

Introduction

Chronic pain is a common reason to seek medical care as it impacts quality of life and activity for a substantial number of people.¹ Opioids have become a commonly prescribed medication for chronic pain conditions that are refractory to conventional medical management, such as oral pharmacologic therapy.² In light of our opioid epidemic, however, opioids present serious risks, such as hyperalgesia, overdose at high doses, withdrawal symptoms, and dependence after chronic use.^3,4

Colloquially referred to as “pain pumps” or “pumps,” intrathecal drug delivery systems (IDDS) are a safe and effective interventional therapy for patients suffering from refractory cancer and non-cancer chronic pain. IDDS consist of a surgically implanted programmable pump, a medication reservoir, and an intrathecal catheter placed into the cerebrospinal fluid (CSF) space.^2,5 Administration of medications through this mechanism cause high CSF drug concentrations but low systemic circulation, resulting in relatively decreased adverse effects.^2,5–8 Medications currently approved for IDDS by the United States Food and Drug Administration include morphine, ziconotide, and baclofen, although other opioids and local anesthetics are commonly used.⁶

However, this therapy does come with challenges. Risks and complications can be attributed to the pharmacology (eg, drug side effects, withdrawal symptoms), procedure (eg, spinal cord injury, infection at surgical site, or granulomas), catheter malfunction (eg, occlusion, dislodgement) and programming (eg, subcutaneous drug administration, reprogramming error).² Any sudden reduction of intrathecal drug delivery due to device malfunction (eg, pump or catheter failure) or programming errors carries significant risks of withdrawal.⁹ Withdrawal symptoms include myalgia, diarrhea, nausea/vomiting, anxiety, pupillary dilation, insomnia, autonomic hyperactivity, and hyperthermia.¹⁰ IDDS medication reservoirs need to be refilled regularly, which can be challenging for patients who live far away from the clinical sites managing their systems. Patients who wish to explant their IDDS must have safe planning and monitoring to successfully transition off their intrathecal delivery of medications, especially when transitioning off intrathecal opioid delivery.

Traditional Intrathecal Opioid Weaning Strategy

Traditional intrathecal opioid weaning consists of alternating dose reductions (usually 10%-25%) and stabilization periods (usually 4-7 days) to assess for opioid withdrawal symptoms.¹¹ Complications, such as overdose, may occur when adjustments to the drug dilution and flow rate are made simultaneously.¹¹ Other limitations include inadequate analgesia, opioid withdrawal symptoms, and requiring non-opioid adjuncts. In one study, for transition to ziconotide monotherapy, Thompson et al¹² weaned three patients off their intrathecal opioids via weekly 25% dose reductions for 4 weeks. However, during the weaning process, each patient described various opioid withdrawal symptoms. During the last weeks, two of those patients needed higher than prescribed doses of oral opioids for withdrawal symptoms. All patients endorsed high pain scores.¹²

Sublingual Buprenorphine-Naloxone Microdosing Strategy

Our approach is to use our established microdosing protocol using sublingual buprenorphine-naloxone to safely facilitate IDDS explantation. It is a 6-day titration regimen with a subsequent saline fill of the pump on the last day as outlined in Table 1. We chose a 6-day approach as per standard buprenorphine-naloxone micro-induction protocols that exist and are effective for patients with opioid use disorder. The saline fill maintains catheter patency and flushes any residual drug from the IDDS reservoir and catheter. This helps mitigate potential toxicity or withdrawal symptoms during the transition to oral medications.

The IDDS is safe to explant when the scheduled incremental doses are effective in abating patients’ withdrawal symptoms and stabilizing their pain.

Once the protocol is initiated, pain physicians should closely monitor for withdrawal symptoms using the Clinical Opiate Withdrawal Scale (COWS) as well as the need for supplemental sublingual buprenorphine-naloxone. The IDDS is safe to explant when the scheduled incremental doses are effective in abating patients’ withdrawal symptoms and stabilizing their pain. At subsequent follow up visits, care providers should continue to inquire about withdrawal symptoms and pain control.

Table 1: Microdosing Protocol of Buprenorphine-Naloxone to Facilitate Safe Explant of IDDS System.

SL BID – sublingually twice a day; SL TID - sublingually three times a day; SL QID – sublingually four times a day

Buprenorphine-Naloxone and Micro-Induction Protocol

Sublingual buprenorphine-naloxone was developed as an analgesic and is now an effective opioid agonist therapy (OAT) as well as recently becoming popular for its off-label use for chronic pain management.¹³Buprenorphine is a partial agonist at the μ-opioid receptor with a higher binding affinity and slow dissociation rate.^13,14 The higher binding affinity allows effective competition with other full agonist opioids at the same receptors. The slow dissociation rate results in longer duration of action. The partial agonism provides analgesia similar to full μ-opioid receptor agonists.¹⁵ Buprenorphine is unique in that it regulates analgesic signalling at spinal receptors while having less effects on brain receptors, thus having a ceiling effect on the respiratory system and prevention of opioid withdrawal.¹⁵ In addition, where the k-opioid receptor is associated with spinal analgesia and psychotomimetic effects, buprenorphine’s full antagonism potentially reduces opioid-induced hyperalgesia and its dysphoric effects.^13,16,17 Buprenorphine is extremely lipophilic and rapidly crosses the blood-brain barrier, but its metabolite norbuprenorphine does not and thus has negligible effects. ¹⁵ Buprenorphine is shown to be safe to use in chronic pain populations. Transition from an opioid towards buprenorphine is associated with reduced pain severity, possibly related to its role in opioid-induced hyperalgesia.¹⁸

Naloxone is a short-acting, competitive, broad opioid receptor antagonist that can reverse opioid side effects, such as respiratory depression and sedation at low doses, but cause precipitated opioid withdrawal at higher doses.¹³ It is often added to buprenorphine as a sublingual tablet to minimize diversion and discourage misuse due to its limited oral but higher intravenous bioavailability.¹⁷ Thus, sublingual buprenorphine-naloxone’s unique pharmacologic properties and more favourable safety profile makes it an extremely effective first line therapy for OAT.^13,17,19

Due to buprenorphine’s higher binding affinity, in the presence of full opioid agonists, buprenorphine-naloxone will displace full agonist opioids from the μ receptor and precipitate withdrawal.¹⁴ Thus, for conventional buprenorphine-naloxone inductions, patients are required to abstain from other opioid use and experience moderate withdrawal.²⁰ Microdose inductions were first described as the Bernese method, where repetitive and low-dose exposure (Bernese method started at 0.2 mg.) allowed the partial and full opioid agonists to occupy receptors concurrently without precipitated withdrawal. The buprenorphine builds up and occupies an increasing number of receptors due to its high affinity and long half-life and eventually displaces the full μ-agonists.^19,20 Microinduction has been improving patient care in OAT as it minimizes withdrawal symptoms, decreases risk of precipitated withdrawal, reduces patient-initiated discontinuation of induction, and shortens length of induction.^14,21

Our Experience

Our weaning strategy for chronic pain patients with IDDS is a microdosing sublingual buprenorphine-naloxone induction protocol. The dosing schedule is designed to provide adequate pain relief as well as prevent opioid withdrawal and respiratory depression. So far, we have successfully trialed the weaning strategy in four patients to transition off their intrathecal opioids. These patients were highly motivated to wean off their pumps and were consistently involved in the process. These patients received adequate pain control and tolerated the process well. They denied withdrawal symptoms (COWS score of 0) throughout multiple visits and did not require additional non-opioid medications, such as clonidine or benzodiazepines to treat withdrawal or anxiety symptoms.

With careful and consistent monitoring, this protocol has been shown to transition our patients successfully and safely off IDDS with no withdrawal symptoms, pointing us towards more patient-centered pain management strategies.

Vanessa Choi Yin Wong, BSc, MD, is in the faculty of medicine at the University of British Columbia in Vancouver, BC, Canada. (Candidate Class of 2023)

Jill Osborn, MD, PhD, FRCPC, is in the department of anesthesia at Providence Healthcare in Vancouver, BC, Canada.

Vishal Varshney, MD, FRCPC, FRCPC, is with the department of anesthesiology, pharmacology and therapeutics at the University of British Columbia and the department of anesthesia at Providence Healthcare, both in Vancouver, BC, Canada.

References

1. Dahlhamer J, Lucas J, Zelaya C, et al. Prevalence of chronic pain and high-impact chronic pain among adults – United States, 2016. MMWR Morb Mortal Wkly Rep 2018;67(36):1001-06. https://doi.org/10.15585/mmwr.mm6736a2
2. Jain S, Malinowski M, Chopra P, et al. Intrathecal drug delivery for pain management: recent advances and future developments. Expert Opin Drug Deliv 2019;16(8):815-22. https://doi.org/10.1080/17425247.2019.1642870
3. Busse JW, Craigie S, Juurlink DN, et al. Guideline for opioid therapy and chronic noncancer pain. CMAJ2017;189(18):E659-E66. https://doi.org/10.1503/cmaj.170363
4. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain–United States, 2016. JAMA 2016;315(15):1624-45. https://doi.org/10.1001/jama.2016.1464
5. Bolash R, Udeh B, Saweris Y, et al. Longevity and cost of implantable intrathecal drug delivery systems for chronic pain management: a retrospective analysis of 365 patients. Neuromodulation Technol Neural Interface2015;18(2):150-56. https://doi.org/10.1111/ner.12235
6. Deer TR, Pope JE, Hayek SM, et al. The Polyanalgesic Consensus Conference (PACC): recommendations on intrathecal drug infusion systems best practices and guidelines. Neuromodulation 2017;20(2):96-132. https://doi.org/10.1111/ner.12538
7. Kleinmann B, Wolter T. Intrathecal opioid therapy for non-malignant chronic pain: a long-term perspective. Neuromodulation 2017;20(7):719-26. https://doi.org/10.1111/ner.12617
8. Moore RA, McQuay HJ. Prevalence of opioid adverse events in chronic non-malignant pain: systematic review of randomised trials of oral opioids. Arthritis Res Ther 2005;7(5):R1046. https://doi.org/10.1186/ar1782
9. Delhaas EM, Huygen FJPM. Complications associated with intrathecal drug delivery systems. BJA Educ2020;20(2):51-7. https://doi.org/1016/j.bjae.2019.11.002
10. World Health Organization, ed. Clinical Guidelines for Withdrawal Management and Treatment of Drug Dependence in Closed Settings. Geneva: World Health Organization, Western Pacific Region; 2009.
11. Rosenblum S, Fisher R, Caraway D. A clinical guide to weaning off intrathecal opioids. Pract Pain Manag2011;7(8). https://www.practicalpainmanagement.com/treatments/pharmacological/opioids/clinical-guide-weaning-intrathecal-opioids. Accessed October 20, 2022.
12. Thompson JC, Dunbar E, Laye RR. Treatment challenges and complications with ziconotide monotherapy in established pump patients. Pain Physician 2006;9(2):147-52.
13. Chen KY, Chen L, Mao J. Buprenorphine-Naloxone therapy in pain management. Anesthesiology2014;120(5):1262-74. https://doi.org/10.1097/ALN.0000000000000170
14. Robbins JL, Englander H, Gregg J. Buprenorphine microdose induction for the management of prescription opioid dependence. J Am Board Fam Med 2021;34(Supplement):S141-S46. https://doi.org/10.3122/jabfm.2021.S1.200236
15. Gudin J, Fudin J. A narrative pharmacological review of buprenorphine: a unique opioid for the treatment of chronic pain. Pain Ther 2020;9(1):41-54. https://doi.org/10.1007/s40122-019-00143-6
16. De Aquino JP, Parida S, Sofuoglu M. The pharmacology of buprenorphine microinduction for opioid use disorder. Clin Drug Investig 2021;41(5):425-36. https://doi.org/10.1007/s40261-021-01032-7
17. Lee DS, Hann JE, Klaire SS, et al. Rapid induction of buprenorphine/naloxone for chronic pain using a microdosing regimen: a case report. AA Pract 2020;14(2):44-7. https://doi.org/10.1213/XAA.0000000000001138
18. 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. https://doi.org/10.1001/jamanetworkopen.2021.24152
19. Rozylo J, Mitchell K, Nikoo M, et al. Case report: successful induction of buprenorphine/naloxone using a microdosing schedule and assertive outreach. Addict Sci Clin Pract 2020;15(1):2. https://doi.org/10.1186/s13722-020-0177-x
20. Hämmig R, Kemter A, Strasser J, et al. Use of microdoses for induction of buprenorphine treatment with overlapping full opioid agonist use: the Bernese method. Subst Abuse Rehabil 2016;7:99-105. https://doi.org/10.2147/SAR.S109919
21. Wong JSH, Nikoo M, Westenberg JN, et al. Comparing rapid micro-induction and standard induction of buprenorphine/naloxone for treatment of opioid use disorder: protocol for an open-label, parallel-group, superiority, randomized controlled trial. Addict Sci Clin Pract 2021;16(1):11. https://doi.org/10.1186/s13722-021-00220-2