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17 Articles in Volume 19, Issue #4
Analgesics of the Future: Inside the Potential of Nerve Growth Factor Antagonists
Best Practices Are Still Largely Undefined in Task Force Report
Brief Behavioral Interventions for Chronic Pain
Cervicogenic Headache: Diagnosis and Management
Chronic Headache and Central Pain Conditions
Considering Comorbidities When Selecting Medications for Pain (Part 4)
For APPs: How to Contribute to Clinical Research
Gabapentin and Suicidal Ideation: Is There a Link?
Intranasal Ketamine for the Relief of Cluster Headache
Letters: Slipping Rib Syndrome; Burning Leg Pain; CGRP Complications
Pain Assessment Tools for Malingering in Patients with Chronic Pain
Refractory Chronic Migraine: Mild, Moderate, or Severe
Should Probuphine be considered for MAT?
Special Report: The Abuse Potential of Gabapentin & Pregabalin
Tension-Type Headache: Evidence for Trigger Points
Treatment Alternatives for Migraine
Trigeminal Neuralgia: Current Diagnosis and Treatment Options

Should Probuphine be considered for MAT?

June 2019 Ask the Expert - With addiction rising, demand for formulations such as buprenorphine to aid in medication-assisted treatment continues to grow.
Pages 17-19

Buprenorphine implant, branded as Probuphine, is the first long-acting dosage form of buprenorphine indicated by FDA for the maintenance treatment of opioid dependence.*1 Probuphine is a match-sized implant measuring 26 mm x 2.5 mm, made of ethylene vinyl acetate and manufactured by Braeburn Pharmaceuticals, Inc., in conjunction with Titan Pharmaceuticals, Inc.2 It is recommended for patients aged 16 to 65 that have achieved clinical stability with ≤8 mg per day of transmucosal buprenorphine. The initial insertion involves four rods placed subdermally into the upper arm in an outpatient setting for a duration of six months.1 Due to the recent public focus on opioid prescribing, use, and misuse, increasing access to medication-assisted treatment (MAT) options are a top priority for the US Department of Health and Human Services.3 Probuphine is one such option.

Original Trials

Efficacy of Probuphine was originally established through a randomized, double-blind, placebo-controlled trial from 2010 that evaluated buprenorphine implants versus placebo implants in 163 patients throughout 18 sites across the US.4 Patients had the option of using sublingual (SL) buprenorphine/naloxone tablets for withdrawal and cravings starting at 4 mg along with mandatory counseling at least weekly. The primary endpoint of the percentage of opioid-negative urine samples during the first 16 weeks was 40.4% (95% CI, 34.2% to 46.7%) in the buprenorphine implant group and 28.3% (95% CI, 20.3% to 36.3%) in the placebo group (P = 0.04). However, limitations to this trial were high attrition, inadequate power to examine subgroups, and short duration.

In 2013, a separate randomized, double-blind, placebo-controlled trial studied buprenorphine implants versus placebo implants versus open-label SL buprenorphine/naloxone in 287 patients throughout 20 sites in the US.5 All subjects were allowed to receive supplemental sublingual buprenorphine as needed. The primary efficacy endpoint was the percentage of opioid-negative urine samples over 24 weeks examined as a cumulative distribution function. Results showed statistically significant superiority in the buprenorphine implant group compared to placebo at all timepoints (P < 0.0001). Buprenorphine implants were also determined to be non-inferior to sublingual buprenorphine/naloxone when looking at the percentage of opioid-negative urine samples.

Managing opioid use disorder (OUD) continues to be a major public health concern as well as a clinical challenge. (Source: 123RF)

Following these trials, FDA denied the original request for new drug approval in April 2013. The response letter asked for additional data in regard to the opioid-blocking mechanism of the medication, the effects of higher doses equivalent to 12 to 16 mg per day of SL buprenorphine, and human factors testing of the insertion and removal training.6 Consequently, a third trial known as the PRO-814 study evaluated SL buprenorphine plus placebo implants versus SL placebo plus buprenorphine implants in 177 patients. The study included patients that were receiving daily SL buprenorphine ≤ 8 mg per day for six months and were opioid abstinent for at least 90 days prior to the trial initiation. Results showed 96.4% of the SL placebo plus buprenorphine implant group and 87.6% of the SL buprenorphine plus placebo implant group went at least four of six months without an opioid-positive urine test result (8.8% difference; CI, 0.009 to ∞; P < 0.001 for non-inferiority; P = 0.03 for superiority).7 Probuphine was later approved in May 2016.3

Patient Candidacy, Selection, and Risk

After a patient is diagnosed with opioid dependence* and becomes stabilized on transmucosal buprenorphine for at least five days, he/she may be considered as a candidate for Probuphine. Each buprenorphine implant contains 74.2 mg of buprenorphine equivalent to 80 mg of buprenorphine hydrochloride. Following insertion, the maximum plasma concentration of four implants is reached within approximately 12 hours. If cravings or withdrawal are still present, patients may be prescribed additional as-needed transmucosal buprenorphine. Steady-state concentrations are achieved by Week 4 and are maintained throughout the 24-week dosage period at average levels of 0.5 to 1 ng/mL.1 To prescribe and place implants, healthcare providers must be certified in a risk evaluation and mitigation strategy (REMS) program due to the Schedule III status of buprenorphine and the black-box warning associated with insertion and removal.1,8 Providers may be certified to prescribe only, perform procedures only, or both. Certification involves training, assessment, enrollment, and annual recertification.

Probuphine has a black-box warning due to risk of implant migration, protrusion, and expulsion associated with insertion and removal. Hypersensitivity reactions and infection at the implantation site are also associated risks. The treatment of acute pain may be of greater concern with the medication compared to other formulations of buprenorphine due to the half-life being 24 to 48 hours. Patients that require a dose reduction due to hepatic impairment are not candidates for treatment with Probuphine since it is hepatically metabolized. The drug has not been studied in pregnant women, geriatric patients, or for renal impairment, so caution is advised in these populations. Probuphine comes with the same warnings, precautions, and drug interactions related to all formulations of buprenorphine. Currently, no case reports or post-marketing studies are available for Probuphine specifically.

Safety and Adherence

Certain clinical aspects should be weighed when determining whether a patient may be an appropriate candidate for Probuphine treatment. Safety concerns associated with transmucosal buprenorphine, such as accidental ingestion by children or overdose, should be considered, for instance.1,2,9 Among 11,275 cases of children exposed to buprenorphine reported to US Poison Control Centers between 2007 and 2016, 86.1% were less than 6 years old, with 89.2% being unintentional.10 Probuphine prevents direct access to the drug product making overdose less likely. Probuphine may be considered preferential for patients with poor adherence as well. The implant omits non-adherence due to forgetfulness, misplacement, or diversion and increases convenience for patients. Those that travel frequently or live in rural areas may require less appointment scheduling.2,9,11 Fewer physician visits may be ideal for some while others may require constant follow-up care to stay focused on recovery.2 Probuphine could feasibly aid recovery through less fluctuation in plasma levels compared to daily administration of transmucosal buprenorphine.11 Patients who require frequent dose changes or are more susceptible to acute pain that require treatment with opioids may not be good candidates for Probuphine.1,11

Cost and Access

A disadvantage of Probuphine is its cost. Fortunately, the manufacturer provides patient assistance programs, depending on patient insurance status, that may be acquired if cost is of concern.12 Currently, Probuphine is only FDA approved for a total treatment duration of one year which limits long-term MAT.1 The medication is not unavailable from community pharmacies; it has to be ordered, stored, and distributed by the ordering physician’s office. Interdisciplinary communication is important between physicians and pharmacists with mutual patients due to potential drug interactions with Probuphine.13 Communication should also occur between physicians who are REMS certified for prescription or placement of the implant only to clarify who will be following up with the patient.1,9,11 The website Probuphinerems.com may be used as a resource to find training programs and/or trained providers.8

Conclusion

As the incidence of opioid addiction rises, the demand for long-acting formulations of MAT options will increase. As an implant, Probuphine offers a practical option for stabilized patients in recovery. Patient characteristics should be reviewed to assure the benefits outweigh the risks and that he/she is an appropriate candidate. Since Probuphine is the first of these to be marketed, efficacy, and safety data will continue to emerge as more patients initiate therapy. The medication has potential for clinicians working in addiction medicine and beyond as an advantageous, extended duration formulation to help enhance adherence, abstinence, and convenience while maintaining efficacy.

More on this topic in our addiction medicine and relapse prevention literature review series.

 

*Editor’s note: Opioid physical dependence and opioid addiction are distinct conditions. Opioid physical dependence, in general, refers to the way in which bodies adapt to the effects of opioids, including by developing rapid tolerance to sedation, nausea, respiratory depression, along with other changes. Individuals with physical dependence often experience withdrawal when opioids are stopped even though they may not be addicted. Opioid addiction, on the other hand, refers to the psychological phenomenon consisting of loss of control, continuation of use despite significant adverse consequences, and preoccupation or obsession with the drug. In 1994, the DSM-IV replaced the word “addiction” with “dependence,” and then in 2013, with the DSM-5, again changed the terminology to call opioid addiction “Opioid Use Disorder” (OUD). Thus, the confusion and the continued widespread use of the term “dependence” as a synonym for “addiction.” In this particular case, FDA indicated Prophubine using the term “opioid dependence” even though the use/meaning for the drug is aimed at treating those with addiction/OUD. This article uses the term “dependence” to align with the indication terminology.

Last updated on: June 21, 2019
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FDA Approves Buprenorphine Implant for Opioid Addiction
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