Novel Formulations of Buprenorphine for Treatment of Opioid Use Disorder

During the past 20 years in North America, there has been an extraordinary increase in the prevalence of nonmedical opioid use, opioid use disorder (OUD), opioid overdose, and opioid overdose fatality rates, starting with a surge in rates of prescription of pain medications, with later onset of an increase in use of illicit opioids, such as heroin, and followed most recently with a very rapid increase in the use, often unwittingly, of high-potency synthetic opioids, such as fentanyl and its analogs, which contributed to most of the estimated 49,000 opioid-involved overdose deaths in the United States in 2017 (67.8% of all drug overdose fatalities) (1). It is estimated that of the 11.4 million who use prescription pain medications nonmedically and the 886,000 who use illicit opioids, such as heroin (2), 2.1 million persons in the United States have current OUD. When the Council of Economic Advisors (3) included estimated costs of fatal opioid overdoses, illicit opioid use, and adjustment for underreporting of opioid-involved overdose deaths in its calculations, annual costs of the current epidemic were estimated to range from $80B (4) to more than $500B. This review will focus on potential individual and population health advantages of intermediate and long-acting formulations of buprenorphine that use novel delivery systems for treatment of opioid use disorder.

Methadone has a long track record of efficacy for treatment of OUD. However, its availability has been constrained to administration and dispensing at federally regulated opioid treatment programs (5), thus limiting its availability to the broader population of people who use opioids nonmedically and who meet criteria for OUD. Long-standing cultural stigmatization of methadone patients also dissuades potential recipients of treatment. Long-acting naltrexone binds the mu receptor with an antagonist, but limited availability, slow (but accelerating) implementation of prescription and administration by clinicians, and patient choice have thus far limited the broad penetration of this efficacious medication, which has been approved by the U.S. Food and Drug Administration (FDA).

Buprenorphine for Treatment of OUD

The Drug Addiction Treatment Act of 2000 extended medical treatment of OUD further into the community by allowing patients to be prescribed sublingual buprenorphine by physicians in their offices, as long as the office-based prescribers had received sufficient training (8 hours) to obtain a waiver from the Drug Enforcement Administration (DEA) to legally prescribe buprenorphine for addiction treatment. Sublingual buprenorphine is an inverse mu opioid receptor agonist and a Schedule III narcotic for the treatment of OUD (6). Since 2016, physician assistants and nurse practitioners may also obtain a DEA waiver to prescribe buprenorphine for treatment of OUD after completing the required 24 hours of training (7).

Benefits and Issues With Orally Administered Buprenorphine

Transmucosal formulations of buprenorphine for sublingual or buccal absorption have demonstrated efficacy for treatment of OUD versus placebo (8) and are generally superior to detoxification or psychosocial treatment alone (9–11). However, certain drawbacks affect both individual treatment and population health. The pharmacokinetics of transmucosally administered buprenorphine vary considerably between individuals, and partly because of differences in absorption, drug bioavailability may vary threefold or more between individuals (12). Because mucosally absorbed oral formulations are typically taken daily, there are peak and trough variations in plasma levels over a 24-hour period, most pronounced with once-daily dosing (13). In a substantial subpopulation, the fall-off in plasma levels from the daily peak is associated with subjective opioid withdrawal symptoms (14). Although is yet unclear whether this plasma variation adds significant risk of nonadherence, when dosing is under the patient’s direct control, self-administration can be disrupted by conditions that affect the decisional process among those with OUD, such as morning craving or dysphoric mood, that may result from decreased buprenorphine plasma levels.

Other issues may reduce adherence to the prescribed buprenorphine dosage, such as diversion, which may be accidental or intentional. Accidental diversion of buprenorphine may result from theft or accidental administration, as is seen in the most common drug overdose emergency department visits among children under age 6 (15, 16). Intentional diversion of buprenorphine is not uncommon; it is given or sold to another person, typically for use in staving off opioid withdrawal symptoms rather than for recreational use (17).

Adherence to OUD medications reduces relapse and overdose risk. Compared with psychosocial intervention alone or placebo, evidence-based pharmacological treatment of OUD reduces the frequency of nonmedical opioid use (18–21) and morbidity and mortality, as well as infectious disease transmission (22, 23). Detoxification from opioids carries significant risk of relapse (24). In addition, individuals with OUD who are not in specialty addiction treatment are at high mortality risk (25), but retention in OUD treatment with FDA-approved medications, such as methadone or buprenorphine, reduces both all-cause and overdose mortality (26), and patients who are adherent to medications for OUD use cumulatively fewer illicit opioids (27). Therefore, medication adherence is a critical factor in buprenorphine treatment outcomes. However, prescribed sublingual or buccal doses are under the patient’s control, and the decision for dosing each day is subject to changes in motivation, mood, and stress or to changes in medication access, in the case either of theft or of being distant from the place where one’s medications are stored. Although all prescribed transmucosal buprenorphine formulations are subject to potential diversion, a recent adhesive film formulation of buprenorphine/naloxone (Bunavail; BioDelivery Sciences International, Inc., Raleigh, NC) adheres strongly to the buccal mucosa and increases bioavailability while dissolving; compared with other transmucosal formulations, the adhesive film formulation reduces the likelihood of diversion—but only when directly administered under clinical supervision (28, 29).

Rationale for Extended-Release OUD Medications

Because an important drawback of the daily buprenorphine dosing strategy is the opportunity for intentional or unintentional diversion, altering the drug delivery system to one that provides weekly, monthly, or semiannual clinician-administered dosing provides clinical and public health advantages, such as primary prevention of altered self-administration or dose escalation, and reduces the likelihood of diversion or accidental ingestion. A greater interval of exposure to opioid agonist treatment is associated with better outcomes (27, 30, 31), and it is reasonable to expect that average cumulative exposure to a medication would be increased when the dosing frequency is extended beyond daily to weekly, monthly, or biannually. In addition, a significant percentage of fatal opioid overdoses are intentional (32), and thus consistently binding the mu opioid receptor with a medication such as buprenorphine that has high affinity (12) and slow receptor association-dissociation kinetics (33) should reduce the likelihood of a fatal outcome to an impulsive opioid overdose. Because the evidence base and FDA approval of multiple sublingual formulations of buprenorphine support the efficacy of buprenorphine in the treatment of OUD, if novel delivery systems are effective and supply a predictable dose over time, then one would expect that the formulations will also have efficacy in OUD treatment.

Intermediate-Range Buprenorphine Formulations

Two different depot buprenorphine formulations have been developed for subcutaneous administration. One long-acting buprenorphine preparation for monthly injection, RBP-6000 (Sublocade; Indivior, Richmond, VA), was FDA-approved in November 2017, and the other, CAM2038 (approved as Buvidal, Camurus AB, Lund, Sweden, by Australia, and the European Commission; Brixadi, Braeburn Pharmaceuticals, Inc., Princeton, NJ), has two subcutaneous doses, one each for weekly and monthly administration, and has tentative FDA approval as of December 2018 (34). Both formulations create a stationary mass on contact with the body’s aqueous phase at the site of injection and do not accelerate release of the medication, which should have a significant deterrent effect on those contemplating use of the preparations intravenously. Because each formulation is clinician administered, there is significant potential for reduction in diversion and accidental exposure, and with fewer dosing episodes and more time to adjust for dosing delays, there is more consistent dosing than with daily sublingual strategies.

RBP-6000

RBP-6000 (Sublocade) is a biocompatible solvent containing biodegradable poly lactide-coglycolide microcapsules containing buprenorphine, which solidifies on its surface contact with the subcutaneous space and elutes buprenorphine through diffusion and degradation of the polymer at a predictable rate for 1 month. It was approved in 2017 for monthly subcutaneous injections of 300 mg or 100 mg of buprenorphine in the abdomen for patients with moderate to severe DSM-5 OUD who are clinically stabilized for at least 7 days on transmucosal buprenorphine to suppress opioid withdrawal symptoms (buprenorphine insert 2017). Repeat-dosing studies have demonstrated that 300-mg injections achieved rapid, effective, and sustained buprenorphine exposure that blocked the agonist effects of a hydromorphone challenge (35), thus providing some protection from overdose resulting from use of illicit opioids, and during a 2-week simulated drug holiday, the agent still maintained efficacy, with ≥70%−80% mu receptor occupancy, which is comparable to buprenorphine plasma levels of ≥2 ng/mL and is associated with both clinically meaningful withdrawal suppression and opioid blockade (36).

A multisite, randomized, controlled 24-week safety-efficacy study (N=504) tested two dose regimens, RBP-6000 300 mg × 6 doses (300/300 mg) and RBP-6000 300 mg × 2 doses followed by 100 mg × 4 doses (300/100 mg) against placebo for treatment-seeking participants first induced and dose adjusted on 8–24 mg of sublingual buprenorphine over 2 weeks until clinically stable. Percentages of opioid-negative urine samples with no self-reported opioid use during study months 2 through 6, assessed by cumulative distribution function, were significantly increased in both active treatment groups (p<0.001). There were no unexpected safety findings, and overall the medication was well tolerated, but there were anticipated mild to moderate injection site reactions in the active medication groups. The 300 mg × 6 doses group experienced more drug discontinuations as a result of adverse events; frequent adverse events leading to drug discontinuation included elevated liver enzymes, injection site reactions, sedation, constipation, somnolence, lethargy, and drug withdrawal syndrome (37). The indication suggests that after the first two dosages of 300 mg, the maintenance dosage should be reduced to 100 mg monthly. The product labeling carries a boxed warning because of the risk of serious harm or death that could result from intravenous self-administration, such as occlusion, local tissue damage, and thromboembolic events, including life-threatening pulmonary emboli (37). It is thus required that the medication be distributed through a Risk Evaluation and Mitigation Strategy (REMS) program, and participating pharmacies and care delivery settings must have REMS-certification and demonstrate compliance (38).

CAM2038

CAM2038 (Brixadi) is buprenorphine in low-viscosity, two-lipid medium that self-assembles into a liquid crystal nanoparticle gel in contact with bodily fluids and is delivered through a small needle from a prefilled syringe for weekly (50 mg/mL) or monthly (356 mg/mL) subcutaneous injection (39–41). After subcutaneous injection, the resulting gel releases buprenorphine at a predictable rate as the depot biodegrades. A multisite, double-blind, double-dummy, 24-week randomized clinical trial (N=428) compared daily sublingual placebo and 12 weeks of weekly subcutaneous buprenorphine injections followed by 12 weeks of monthly subcutaneous buprenorphine, with 24 weeks of daily sublingual buprenorphine and placebo subcutaneous weekly injections for 12 weeks, followed by monthly subcutaneous placebo for 12 weeks (41). Primary outcomes in this noninferiority trial were the proportion of urine samples negative for illicit opioids for 24 weeks and the response rate, defined as no illicit opioid use for at least eight of ten prespecified points during weeks 9 to 24, with 2 points at week 12 and during weeks 21 to 24.

Both primary outcomes met noninferiority thresholds. The responder rate was 14.4% in the sublingual buprenorphine group and 17.4% in the subcutaneous buprenorphine group (p<0.001). When the the percentage of opioid-negative urine samples was compared, subcutaneous buprenorphine was noninferior to sublingual buprenorphine during the first 12 weeks and met statistical superiority from weeks 13 to 24 (p<0.02). There were no between-group differences in opioid craving and opioid withdrawal symptoms, and study retention in the CAM2038 group was noninferior. Of clinical interest, study physicians not only clinically titrated each participant’s daily sublingual buprenorphine-naloxone dose but were apparently able to individualize the weekly and monthly injection dose (41). This potential dosing flexibility holds promise for matching equivalent doses to sublingual buprenorphine in office-based practice and titrating subcutaneous doses in patients with OUD who are new to medication treatment without first inducting them to sublingual buprenorphine. The 2017 submission to the FDA proposed an indication for subcutaneous injection in multiple sites, including upper arm, buttock, thigh, and abdomen (42).

Long-Acting Buprenorphine Formulation

An FDA-approved long-acting buprenorphine implant (Probuphine; Titan Pharmaceuticals, San Francisco) is indicated for patients with OUD who have sustained clinical stability on a transmucosal formulation of buprenorphine (43). Four matchstick-sized ethylene vinyl acetate polymer rods, each containing 80 mg of buprenorphine hydrochloride, are implanted in a fan-shaped configuration from a single insertion point into the subdermal space of the inner upper forearm. The implants elute buprenorphine in a relatively linear fashion over 6 months prior to when the implants are to be removed and may be replaced with another 6-month dose inserted in the contralateral arm. Two placebo-controlled, randomized, safety-efficacy multisite trials were conducted over 24 weeks with patients who had DSM-IV opioid dependence and who were first inducted and stabilized clinically within 2 weeks onto 12–16 mg daily of sublingual buprenorphine and then given active versus placebo implants at a ratio of 2:1 (44, 45).

The first trial (N=162) demonstrated that the experimental group with four 80-mg buprenorphine implants completed the study at more than twice the rate as those who were given dummy implant (65.7% versus 30.9%) (p<0.001) and had significantly more illicit opioid–free urine samples over weeks 1–16 (p=0.04), lower subjective symptoms of withdrawal and craving, and lower clinician-rated opioid severity and withdrawal symptoms (44). The second trial (buprenorphine, N=114; placebo, N=54) added a third, open-label arm (N=119) in which study participants were continued on their postinduction dose of sublingual buprenorphine so that the arm could be used as the comparison group in a noninferiority study against the group with active implants (45). The active-implants group had a significantly higher cumulative percentage of urine samples free of illicit opioids over the 24 study weeks (p<0.001); the study also replicated the first study’s higher rate of study completion, with participants experiencing higher global improvement and lower withdrawal symptoms on clinician ratings and participants’ ratings of less withdrawal and craving. In addition, the group with buprenorphine implants was noninferior to the sublingual buprenorphine group with respect to urine samples negative for illicit opioids over the 24 weeks of the study (45).

A third multisite study was conducted as a double-blind, double-dummy, head-to-head noninferiority comparison of buprenorphine implants versus sublingual buprenorphine among participants who had been treated for at least 6 months with sublingual buprenorphine and deemed clinically stable without evidence of illicit opioid use at a stable dose of ≤8 mg for 3 months prior to randomization (46). The responder rate, defined as ≥4 of 6 months without a positive opioid urine test or self-report, was 96.4% in the buprenorphine implant group and 87.6% in the sublingual buprenorphine group, which confirmed noninferiority (p<.001) and allowed an analysis demonstrating superiority (p=0.03). In addition, abstinence from illicit or nonmedically used prescription opioids was significantly greater in the implant group after the third study month and maintained through month 6, with cumulative abstinence over the 6-month study in 85.7% of the implant group and 71.9% of those receiving continued sublingual buprenorphine (p=0.03) (46).

Of interest, although the third study selected a subpopulation that differed from that seen in traditional medication trials in OUD, in which medication-naïve participants with heroin use disorder are inducted onto study medications, the subpopulation may match more closely the demographic characteristics of those affected by the current opioid epidemic: participants were predominantly white and employed, with a high school education or higher, and a large majority were diagnosed as having prescription opioid use disorder. Studies of medication treatment for OUD have demonstrated that participants with only nonmedical use of prescription opioids tend to have better treatment retention and better treatment outcomes than those who inject heroin or those who use prescription opioids and inject heroin (47, 48).

In the target population of patients with OUD clinically stabilized on ≤8 mg, switching to buprenorphine implants was not clinically destabilizing with respect to exacerbation of craving, subjective need or desire to use opioids, or withdrawal symptoms (46). The rate of implant-related adverse events was low, and complications seen more frequently in earlier studies, such as hematoma or implant fracture, were largely reduced because of improvements in insertion and removal technique, such as a 24-hour pressure dressing postinsertion and use of a custom removal forceps with an extraction point at the midline of the implant (49). A recent case report about buprenorphine implants that were removed 7 years after insertion demonstrated neither fibrotic infiltration nor significant structural deterioration, allowing for a standard and uncomplicated removal (50).

As with any buprenorphine formulation for treatment of OUD, prescribers must have a DEA waiver. Prescribers of the long-acting implant must also participate in a REMS program because of FDA concerns that the implant can protrude, be expelled, or migrate and the insertion procedure can cause nerve damage and other complications (Probuphine prescribing information). Clinicians who propose to administer the implants to patients must be certified by the manufacturer after a live training in the insertion and removal techniques (51).

Conclusion

Extended-release buprenorphine formulations for treatment of OUD offer significant advantages over traditional sublingual and buccal routes of administration. Comparative advantages for individual patient treatment include more consistent pharmacokinetics and predictable range of plasma levels; prolonged exposure to steady-state treatment, with decreased relapse and opioid overdose risk; elimination of direct patient control that reduces nonadherence; and a wider interval over which to safely bridge treatment continuation. Population-level advantages include reduction in risk of diversion and in accidental exposure and poisoning; also, because buprenorphine treatment reduces all-cause and overdose mortality, improved length of exposure to buprenorphine treatment may reduce transitions from use of prescription pain medication to use of illicit opioids (52).