The Impact of Street-Based Fentanyl on Suboxone Treatment: Challenges and Solutions

Medication-Assisted Therapy for Fentanyl Addiction

In the clinical setting, the patient's addiction to opiates can be transitioned to Suboxone® and stabilized so that they are not seeking or using dangerous or deadly street-based opiates that contain unknown concentrations and impurities. However, some patients are ambivalent about this therapeutic approach, suggesting it substitutes one opioid for another.

A good argument for using Suboxone in the face of street-based fentanyl (SBF) addiction is that it can help reduce the risk of overdose and death from opioid addiction, especially when the illicit opioid is street-based fentanyl. Suboxone is made up of buprenorphine and naloxone and is an effective treatment for opioid dependence (including fentanyl), as it helps to reduce cravings and withdrawal symptoms while providing a safer alternative to other opioids.

Buprenorphine has the unique quality of not increasing opioid receptor activation with increasing doses over 24 mg. Furthermore, Suboxone has a greater affinity for opioid receptors than other opiates. This protects Suboxone users from an overdose should they relapse to another opiate because the higher affinity of Suboxone will block the effects of other opioids taken simultaneously, at least up to a point.1

Therefore, while some critics may suggest that Suboxone is just substituting one opioid addiction for another, its use should be considered part of a comprehensive treatment plan, including therapeutic interventions such as counseling and psychotherapy.2

Suboxone, a medication specifically engineered to combat opioid addiction, is composed of two primary ingredients: buprenorphine and naloxone. Buprenorphine works to curb opiate cravings and prevent relapse, serving as an essential part of the recovery process. Naloxone, on the other hand, known as Narcan, has a different role.

Naloxone serves as an opioid antagonist that blocks the effects of opioids. Its purpose within Suboxone is to act as a safeguard against misuse and abuse. If the medication is misused, for instance, by injecting or snorting, naloxone triggers withdrawal symptoms, discouraging such behavior. In addition to these effects, Suboxone also has a significant impact on neurotransmitter levels in the brain. It specifically targets and blocks receptors associated with dopamine, serotonin, and endorphins. These neurotransmitters typically play roles in mood regulation and cognitive function. However, when it comes to norepinephrine, Suboxone has a different effect.

Suboxone increases the levels of norepinephrine in the body, which can enhance mood, reduce anxiety, and aid in maintaining alertness, focus, and motivation. This action is achieved through the activation of opioid receptors by Suboxone, leading to a surge in the release of norepinephrine into the brain.

Interestingly, when opioid receptors are blocked, it results in an increased secretion of norepinephrine. This occurs because the brain compensates for the absence of opioids' usual effects, such as pain reduction and euphoria induction, by boosting norepinephrine to maintain normal levels of alertness and focus. When combined with therapy, Suboxone can be an effective tool to help patients regain control of their lives. As parents, comprehending how this medication works can provide valuable insight into the recovery process of a loved one battling opioid addiction. A significant take-home point for parents is that increasing doses of Suboxone does not encourage increasing risk for respiratory depression like most opiates, especially street-based fentanyl.

Suboxone as a therapeutic approach

Among users, a growing opinion on the street is that Suboxone will only make you sick and is ineffective in treating street-based fentanyl addiction. In routine practice with short-acting opiates (e.g., Vicodin, Heroin, Percocet) excluding methadone, patients can be easily transitioned to Suboxone after 12-24 hours of abstinence or when they have been determined to be in a state of minor to moderate withdrawal with a COWS score of 12 or more (look this up and print out). While Suboxone is an evidence-based, first-line partial opioid agonist for the management of opioid use disorder, our method of induction has been altered since it can precipitate opioid withdrawal during the initial induction process for patients suffering from street-based fentanyl addiction.

There is minimal literature on the buprenorphine-naloxone (generic form of Suboxone) induction process for individuals who regularly use illicit street-based fentanyl.3 

This provider recently treated a patient with fentanyl addiction with a COWS score of 15+ and who was visibly in withdrawal. The induction was initiated with the standard approach, starting with 2 mg, and slowly titrating up to stability using 2 mg dose increases as needed. Over several hours, the patient reached 24 mg of Suboxone but never achieved physiologic stability and comfort. 

The patient had to be stabilized the next day by adding another 8 mg of Suboxone. From a pharmacologic perspective, we appreciate that Suboxone (buprenorphine-naloxone) is a partial agonist acting at the mu-opioid receptors with higher receptor affinity than fentanyl. In a fentanyl-dependent person, buprenorphine will displace opioid agonists of lower receptor affinity (e.g., heroin, methadone, and fentanyl) from the receptors, but with street-based fentanyl buprenorphine may not have sufficient receptor affinity to displace fentanyl, leading to partial agonism or 'precipitated' withdrawal. 

The risk factors for precipitated withdrawal include transferring from long-acting agents such as methadone, recent benzodiazepine use, no past patient experience with buprenorphine, or a low initial dose of buprenorphine-naloxone.4 Some clinicians recommend rapid increases in buprenorphine doses, which can be a more effective treatment for avoiding buprenorphine-induced precipitated opioid withdrawal.

Street-based fentanyl, also called "Blues", is a short-acting, highly lipophilic full-agonist, causing fentanyl to be redistributed into fatty tissue throughout the body. Given fentanyl's distribution pattern, one can expect a protracted excretion and, therefore, a prolonged mu activation pattern, making fentanyl more closely related to methadone regarding how inductions are managed. Buprenorphine-naloxone induction now presents a significant clinical challenge in patients with prolonged exposure to street-based fentanyl - namely, an increased risk of precipitated withdrawal that is related to its lipophilic distribution pattern and perhaps the concomitant compounds within street-based fentanyl (SBF), which seemingly supports prolonged mu activation.

Research on rats suggests buprenorphine may have reduced benefits for treating individuals using SBF, as the effects of high-efficacy opioid agonists are more challenging to antagonize with buprenorphine.5 Some clinicians report that some patients experience euphoria using SBF while fully adherent to therapeutic doses of buprenorphine – suggesting SBF has a higher affinity for opioid receptors than buprenorphine.6 

This should not happen since Suboxone has a higher opioid receptor affinity than fentanyl (i.e., pharmaceutical-grade fentanyl). However, clinicians in the recovery industry are discovering that SBF is stronger than Suboxone and, at least in some cases, is demonstrating a higher affinity for opioid receptors than Suboxone (e.g., SBF is kicking Suboxone off the opioid receptors). 

One researcher reported in a clinical vignette about a 29-year-old woman who presented to detox for treatment for an opioid use disorder with illicit fentanyl. While in detox, she was started on opioid agonist treatment with buprenorphine-naloxone. Unfortunately, she continued to have withdrawal symptoms despite being optimized to a dose of 32 mg.7  In this case, the patient was eventually given additional doses of buprenorphine-naloxone and eventually was stabilized on 40 mg daily without side effects and subsequently discharged to a rehabilitation center.

Other independent researchers have found that patients exposed to illicit fentanyl were at risk for precipitated withdrawal using typical buprenorphine-naloxone induction procedures –  suggesting illicit street-based fentanyl drugs may be conferring extended mu-opioid receptor agonist effects, with some fentanyl patients who self-treated with buprenorphine developing precipitated withdrawal after more than 72 hours after their last use.8,9 

The unique pharmacokinetic profile of current street-based fentanyl drugs encouraged these researchers to modify their induction protocols to include only beginning when COWS score >12 and administering 2 mg sublingual buprenorphine-naloxone at 60-90 min intervals - thereby allowing buprenorphine-naloxone more time to establish a partial agonist effect without precipitating withdrawal. The researchers also noted that some SBF users could abstain from opioids for extended periods (~48 hours) without severe withdrawal.

Some researchers are suggesting in this time of synthetic fentanyl use that traditional induction protocols can be a challenge due to difficulties in successfully achieving the desired "opioid washout" when patients are asked to place themselves in minor to moderate withdrawal for purposes of starting buprenorphine-naloxone.10

Suboxone, indeed, was not designed for the induction against the power of SBF. Therefore, another induction approach is needed, given the pharmacokinetics of street-based fentanyl and the increasing incidence of precipitated withdrawal during the induction process of buprenorphine–naloxone. However, others have acknowledged improved outcomes when using a "micro-dosing" approach for buprenorphine–naloxone inductions (Bernese method).

This author uses micro-dosing with some success, especially with patients with higher levels of self-efficacy and resilience. In this approach, buprenorphine–naloxone is prescribed in a small initial dose (e.g., 0.25 to 0.5 mg ) with incremental increases to both amount and frequency over time – generally over a 7- to 10-day period with the patient continuing to use their "preferred" drug (either prescribed or illicit) until a therapeutic dose of buprenorphine-naloxone has been achieved (e.g., usually > 8 mg daily), and at which time their full opioid agonists are discontinued.

One researcher developed the Mariani protocol for rapidly administering Sublocade to support quick induction and protection against overdose. Sublocade is a monthly injection of buprenorphine with the same active ingredient in Suboxone. It provides a steady dose of medication over an extended period and has proven effective for those struggling with opioid addiction. 

Sublocade is administered through subcutaneous injection at a doctor's office and can relieve opioid cravings and withdrawal symptoms. The Mariani protocol initially involved administering 16 mg of sublingual buprenorphine over two days, and if tolerated, their treatment course would be advanced to the extended-release injectable buprenorphine (Sublocade). The researchers conceded this induction process was a more rapid injection schedule than provided in the Sublocade formulation's prescribing instructions.11 

Comfort medications employed in the Mariani protocol included clonidine, 0.1 up to six times daily, clonazepam 0.5 mg TID, zolpidem 10 mg, and prochlorperazine 10 mg QD - all to ease break-through withdrawal symptoms during the induction and for two days after the depot injection. Mariani et al. also observed that the study participants often developed rapid and severe withdrawal symptoms in some cases despite treatment with up to 24 mg of sublingual buprenorphine. In addition, the researchers observed that once withdrawals began, symptoms could escalate rapidly despite administering what are usually clinically effective doses of sublingual buprenorphine (16–24 mg).

Participants who received an average of 16 mg daily for 2 or 3 days had no difficulty tolerating the Sublocade 300 mg depot injection. In addition, the researchers noted that withdrawal symptoms were generally well controlled within 24 hours after the depot Sublocade injection. The authors noted that the 24-hour stability horizon for the Sublocade was consistent with the known pharmacokinetics of the depot formulation, known for its serum blood level spike approximately 24 hours after administration.

In general, the direction of induction research is pushing for higher dosing strategies for SBF rather than starting low and going slow. Therefore, it is reasonable for providers to ask if it is safe to begin with higher levels of buprenorphine to "wash out" the mu receptors and stabilize an untreated patient with opioid dependence.  In one case study, the authors ask, "Is high-dose (>12 mg) buprenorphine induction safe and well tolerated in patients with untreated opioid use disorder who present to the emergency department?"

In one study in a single-site, urban emergency department involving 579 patient cases, 54 clinicians who followed a high-dose buprenorphine (mono-product) protocol found no documented episodes of respiratory depression or excessive sedation. Additionally, the authors found precipitated withdrawal rare (0.8% of cases).12.

The federal Substance Abuse and Mental Health Services Administration's (SAMHSA) opioid treatment guidelines provide induction guidelines that suggest that patients should begin buprenorphine-naloxone when they are exhibiting clear signs of opioid withdrawal. The guidelines suggest the induction should start with a 2 to 4 mg dose of buprenorphine/nx with an additional 2 mg dose after 2 hours if there is continued withdrawal and lack of sedation.13  

The FDA further suggests a maximum buprenorphine dose of 8 mg on Day 1 and 16 mg on Day 2. While the government's Treatment Improvement Protocol (TIP 63) guidelines are generally appropriate for the induction of most short-acting opiates, street-based fentanyl has presented a problem for the standard induction protocols using Suboxone as a therapeutic approach. The problem of transitioning SBF to Suboxone will likely be experienced across the addiction recovery industry. This review should encourage parents to review induction procedures with the provider who may be transitioning their adolescent teen or young adult from SBF to Suboxone.

References

1. lldredge, D. J., & Kosten, T. R. (2008). Suboxone: A review of its use in opioid dependence. CNS Drugs, 22(7), 559-571).

2. Substance Abuse and Mental Health Services Administration. (2020). Medication-Assisted Treatment for Opioid Use Disorder. Retrieved from https://www.samhsa.gov/medication-assisted-treatment/treatment).

3. Shearer, D., Young, S., Fairbairn, N., & Brar, R. (2022). Challenges with buprenorphine inductions in the context of the fentanyl overdose crisis: A case series. Drug and alcohol review, 41(2), 444–448. 

4. Oakley, B., Wilson, H., Hayes, V., & Lintzeris, N. (2021). Managing opioid withdrawal precipitated by buprenorphine with buprenorphine. Drug Alcohol Rev 40, 67–571.

5. Walker, E. A., & Young, A. M.  (2001). Differential tolerance to antinociceptive effects of mu opioids during repeated treatment with etonitazene, morphine, or buprenorphine in rats. Psychopharmacology (Berl), 154, 131–142.

6. Bisaga, A. (2019). What should clinicians do as fentanyl replaces heroin? Addiction (Abingdon, England), 114(5), 782–783. 

7. Danilewitz, M., & McLean, M. (2020). High-dose buprenorphine for treatment of high potency opioid use disorder. Drug Alcohol Rev., 39, 135-137.

8. Antoine, D., Huhn, A.S., Strain, E.C., Turner, G., Jardot, J., Hammond, A.S.  & Dunn, K.E. (2021). Method for Successfully Inducting Individuals Who Use Illicit Fentanyl on to Buprenorphine/Naloxone. Am J Addict, 30: 83-87.

9. Silverstein, S., Daniulaityte, R., Martins, S., et al. (2019). Everything is not right anymore: buprenorphine experiences in an era of illicit fentanyl. Int J Drug Policy, 74, 76-93.

10. Randhawa, P., Brar, R., & Nolan, S. (2020). Buprenorphine–naloxone “microdosing”: an alternative induction approach for treating opioid use disorder in the wake of North America’s increasingly potent illicit drug market. CMAJ, 192 (3) E73.

11. Mariani, J. J., Mahony, A., Iqbal, M. N., Luo, S. X., Naqvi, N. H., & Levin, F. R. (2020). Case Series: Rapid Induction to Long-Acting Buprenorphine Injection for High Potency Synthetic Opioid Users. The American journal on addictions, 29(4), 345–348.

12. Herring, A.A., Vosooghi, A.A., Luftig, J., et al. (2021). High-Dose Buprenorphine Induction in the Emergency Department for Treatment of Opioid Use Disorder. JAMA Netw Open.; 4 (7):e2117128.

13. Substance Abuse and Mental Health Services Administration. Medications for Opioid Use Disorder. Treatment Improvement Protocol (TIP) Series 63 Publication No. PEP21-02-01-002. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2021.