Buprenorphine-naloxone microdosing

Pharmacology.

It is hypothesized that microdosing does not precipitate withdrawal, as small repetitive doses allow for gradual accumulation and occupation of buprenorphine at opioid receptors owing to the drug’s high µ-receptor affinity and slow dissociation. This receptor occupation slowly displaces other opioids, and once doses of approximately 4 mg and 1 mg^4,5 of buprenorphine-naloxone are reached, the receptors should be sufficiently occupied by buprenorphine to allow for rapid discontinuation of short-acting opioids without severe withdrawal.⁵ Higher doses of buprenorphine might be required for longer-acting opioids (Table 1).^4-8

The role of naloxone in buprenorphine-naloxone is to discourage injection or snorting of the drug, as the naloxone would become an active compound and precipitate withdrawal.⁹ When taken orally or sublingually, naloxone has minimal absorption and does not antagonize buprenorphine or other opioids in the central nervous system.⁹

Starting treatment.

There is no standard microdosing initiation protocol that exists at the time of this publication. Table 1 demonstrates potential approaches to microdosing initiation.^4-8 Once-daily dosing (option 1) offers the benefit of convenience and can eliminate the need for carries (ie, take-home doses) in situations where prescribers feel uncomfortable providing them to patients; however, owing to a shorter half-life at lower doses of buprenorphine, twice-daily dosing (options 2 and 3) might alleviate the risk of a “wearing-off” effect and potential risk of subsequent precipitated withdrawal. Patients who are using short-acting opioids, such as morphine, oxycodone, hydromorphone, or heroin, might attempt to cease their opioid once a dose of 4 mg and 1 mg to 12 mg and 4 mg is achieved. For those using longer-acting formulations, such as fentanyl patches or methadone, it is advisable to discontinue or quickly taper down the long-acting medication when the buprenorphine dose is higher and occupying more receptors. Patients are more likely to experience withdrawal symptoms when their full opioid agonist is discontinued at lower doses of buprenorphine-naloxone (ie, less than 12 mg and 4 mg).⁴ It might be advisable to provide patients with as-needed doses in the form of 2 mg and 0.5 mg buprenorphine-naloxone to combat minor withdrawal symptoms, should they occur, once the opioid has been stopped (Table 1).^4-8 Other medications, such as clonidine, dimenhydrinate, ibuprofen, acetaminophen, and loperamide, might be prescribed along with buprenorphine-naloxone to manage withdrawal symptoms, should they occur.⁶ Starting with lower doses (option 3) might be possible in a patient who has had exceptionally bad withdrawal experiences in the past, is at a higher risk of precipitated withdrawal, or is being rotated from methadone to buprenorphine-naloxone. Given the (albeit low) risk of precipitated withdrawal, it might be prudent for someone (eg, prescriber, clinic nurse, pharmacist) to witness patients taking doses to identify and treat distressing symptoms quickly.

Pharmacists can aid patients in this process by ensuring the accuracy of titration and minimizing confusion by witnessing patients taking doses. If choosing option 2 or 3, one dose might be witnessed and the other given as a carry. Doses might also be prepared and packaged in a blister pack for patients for whom daily witnessing might not be viable. Currently, the lowest available dose in Canada of buprenorphine-naloxone is 2 mg and 0.5 mg. To achieve the doses required for microdosing regimens, tablets must be split. This results in potentially inconsistent dosing in the beginning, but it is important to remember that these doses serve to gradually build the receptor blockade, and as long as the doses are similar (eg, quartered vs halved tablets), microdosing is still effective. If a patient misses a dose during induction, the patient can repeat the previous day’s dose and then proceed with the induction. If 2 or more doses are missed, consider restarting the initiation process.⁴

Identifying withdrawal.

One of the benefits of microdosing is the potential to mitigate the moderate to severe withdrawal that is required for standard buprenorphine-naloxone induction. It is expected that some patients might experience mild withdrawal once they cease their opioid. There are many available easy-to-use tools to aid prescribers in quantifying the extent of their patients’ withdrawal and therefore assist in providing appropriate management. The Clinical Opiate Withdrawal Scale is a validated 11-point scale based on objective information such as heart rate, myalgia, rhinorrhea, gastrointestinal upset, and other symptoms,¹⁰ and the Subjective Opiate Withdrawal Scale can be readily completed by patients themselves to categorize their withdrawal symptoms. Both scales are available at CFPlus.*

Maintaining treatment.

A maintenance dose of buprenorphine-naloxone is one that adequately manages withdrawal symptoms and cravings without causing bothersome adverse effects (nausea, constipation, sedation, abdominal cramps).¹¹ Many patients might be stable at 12 mg and 3 mg daily; however, others will still experience withdrawal symptoms and frequently take 2-mg and 0.5-mg as-needed doses. These patients might benefit from titrating the dose up to a maximum of 24 mg and 6 mg daily.¹² To aid patients in finding the optimal maintenance dose, frequent follow-up, either in person or over the telephone, might be necessary. Community pharmacists can also play a vital role in communication with patients to evaluate their response to therapy and potential withdrawal symptoms.