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Buprenorphine implant for opioid addiction
Practice Points
Walter Ling* Implementing an innovative pharmacotherapy: Treating opioid-addicted patients can be challenging,
and the few approved medications are not optimally effective in many cases. If a new form of a proven medication offers benefits that outweigh potential risks, clinicians must be willing to consider such innovative developments. Induction issues: At induction, a Clinical Opiate Withdrawal Scale (COWS) score below 12 often reflects
insufficient time since last opioid use, whereas presence of significant withdrawal symptoms (and a higher COWS score) usually favors a better induction process and outcome. ‘Explant’ and discontinuation of buprenorphine: After removal of buprenorphine implants, the patient
must be tapered off the buprenorphine condition via sublingual tablet formulations. Some patients seem psychologically reliant on the presence of the medication, taking doses as small as 0.5 mg/day. Clinicians familiar with sublingual buprenorphine should be capable of managing the care of patients after removal of implant buprenorphine. Use in pain management: Buprenorphine is a powerful analgesic with a long history of use in treating
acute and chronic pain. The implant formulation may represent a potential advance in managing chronic pain. Additional data are needed to complement existing research findings. Potential for treating other addictions: Research by the NIDA Clinical Trials Network is examining
buprenorphine in sublingual form for its ability to reduce cocaine use in cocaine-dependent individuals. Possible issues. Patients treated with the implants could attempt to remove them for diversion, although
the implant rods contain only 80 mg buprenorphine per rod and there is not likely to be much of a market for it if it is removed.
SUMMARY
The buprenorphine implant (Probuphine™, Titan Pharmaceuticals, CA, USA) is a recently developed long-acting formulation of buprenorphine, which is a partial opioid agonist that is widely used in the marketed, sublingual, daily-dose form for managing opioid addiction. The new formulation uses a novel delivery system consisting of subcutaneously implanted solid matrix ‘rods’ made from a mixture of ethylene vinyl acetate and buprenorphine. The buprenorphine implant was developed to ensure medication compliance, eliminate *Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine at UCLA, 1640 S. Sepulveda Blvd, Suite 120, Los Angeles, CA 90025-7535, USA; [email protected]
10.2217/PMT.12.26 © 2012 Future Medicine Ltd
Pain Manage. (2012) 2(4), 345–350
part of
ISSN 1758-1869
345
Review Ling misuse and abuse from diversion of sublingual buprenorphine, and increase therapeutic benefit of the medication. The implant is not a ‘new’ drug, but an innovative means of delivering a medication proven effective for treating opioid addiction. The implant has not yet been approved by the US FDA. The information in this review has been gleaned from research reports, documentation in the literature, and from the author’s experience treating opioid-dependent patients, and involvement in clinical research examining sublingual buprenorphine and the buprenorphine implant. A discussion of the buprenorphine implant must begin with an initial understanding of bupren orphine, which in itself is arguably the most significant advance in the history of pharmaco therapy for opioid addiction, heralded by the introduction of methadone maintenance a half century ago. Beyond offering a safer and more easily delivered medication capable of being prescribed from a physician’s office, bupren orphine returns opioid addiction treatment in the USA for the first time in nearly a century to the hands of physicians, making it possible for them to treat their opioid-addicted patients in the same manner as all other patients. This was made possible as a result of the evolutionary changes in the societal attitude about addicts and addiction. The pharmacological character istics of buprenorphine, perceived as less addic tive and safer than methadone, contribute to its being more acceptable to society at large. But the formal approval of buprenorphine and its clinical acceptance would not have been pos sible without change in societal attitudes toward addiction itself, seeing it as a disease rather than a crime or moral failing. Forty years of treatment experience with methadone did not produce this societal change, as the treatment philosophy about methadone has been a reflection of the societal ambiva lence about addicts and their treatment. With less than a decade of approved use in the USA, buprenorphine is already well accepted by soci ety, as evident in the less stringent regulations compared with those applied to methadone [1] , perhaps largely because of its good safety profile and ease of administration [2,3] . Buprenorphine allows physicians to take a new perspective about addiction and about addicts, one that is akin to the relationship that clinicians have with their other patients with chronic disorders – since physicians are societal leaders, that perspective will filter to the rest of society. If physicians begin to view patients differently, speak to them about their illness differently, and speak to oth ers about them differently, eventually society may come to regard them differently.
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Pain Manage. (2012) 2(4)
The changes in attitudes and practices are borne out in the statistics; buprenorphine pre scriptions increased from 50,000 in 2002 to approximately 5.7 million in 2009, with more than 93% for treatment of opioid abuse or dependence for at least 330,000 patients with ‘opioid type dependence’ (code 304.0) [101] . Since its approval, buprenorphine has surpassed meth adone in the number of patients being treated at any time, estimated to be more than 340,000 on Suboxone® plus more than 50,000 on generic buprenorphine [Johnson E, Reckitt Benckiser, Pers. Comm.] compared with approximately 285,000 on methadone [Parrino M, AATOD, Pers. Comm.] . Many buprenorphine patients are attracted to the pharmacot herapy as an alternative to methadone [4] . However, the success of buprenorphine is not unqualified. With large numbers of patients hav ing large amounts of the medication on hand, street diversion has occurred. There is perhaps more of a market for diverted buprenorphine today because of the many prescription opioid addicts. Increasing use of diverted bupren orphine is an indicator of non-compliance with medication – the more successful buprenorphine treatment is, the bigger the problem with com pliance and diversion. Also of concern is the out come of improper or insecure storage, resulting in accidental poisoning, especially in children. While clinicians are generally satisfied with sublingual buprenorphine, many are also becom ing increasingly concerned about medication compliance and street diversion of the sublingual preparation. The magnitude of the problem is directly proportionate to the success of the sub lingual formulation, with an increasing number of patients seeking buprenorphine for opioid addiction treatment. While buprenorphine treatment should be recognized for its successes, a solution must be sought to overcome medica tion non-adherence and street diversion. The subcutaneous implant form of buprenorphine is a direct result of that search for a solution. Buprenorphine administered by subcutaneous implant with 6 months of sustained effects is
future science group
Buprenorphine implant for opioid addiction potentially a better way to deliver buprenorphine that eliminates the possibility of noncompliance and diversion. The implant is being examined in Phase III trials in the process of gaining US FDA approval. All of the pharmacological and logis tic advantages of sublingual buprenorphine are applicable to the implantable buprenorphine. The advantages of the buprenorphine implant are obvious: there is no medication to divert and compliance is built into the implant. It is also intuitively tempting to suggest that a nonfluctuating steady blood level may yet be another advantage, although this has not been prospec tively studied in a controlled clinical trial, and the total buprenorphine exposure is less than that of the sublingual formulations. Indications & usage Since the buprenorphine implant is simply an alternative method of delivering an effective dose of buprenorphine sustained for six months, the clinical indications and its usage would be expected to mirror those of sublingual buprenor phine. Given the extensive documentation of buprenorphine’s effectiveness for opioid addic tion, the confirmation of effectiveness for the implant form is not surprising [5] . Other indi cations for which the buprenorphine implant may be useful, depending on results of future research, may include management of chronic pain and treatment of other substance use disorders. Dosage & administration In clinical trials to date, treatment with implant buprenorphine consists of four to five matrix implants, each 2.5 mm by 26 mm, placed sub cutaneously in the inner upper arm in a brief, in-office procedure, with the implants removed in a similar manner at the end of the treatment period. Each rod contains the equivalent of 80 mg buprenorphine, released at a constant rate through diffusion into adjacent body tissues, providing assured dosing for 6 months. Before implant, an induction with sublingual buprenorphine is required to ensure patient sta bilization. Standard practices for induction onto sublingual buprenorphine are well described (e.g., see [6]), and only briefly recounted here. An important initial element in this process is an accurate assessment of the patient’s level of with drawal symptoms, based usually on the Clinical Opiate Withdrawal Scale (COWS; [7,8]); too low a COWS score, stemming from insufficient time
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since last opioid use, can result in a failed induc tion due to emergent withdrawal symptoms in response to the buprenorphine partial agonist activity. For the induction, the first dose of sub lingual buprenorphine varies from 2 to 8 mg, followed by clinical observation for up to several hours, with subsequent administration of addi tional doses as appropriate. The total dose for day 1 may be 8–16 mg, day 2 doses will range between 8 and 16 mg, and day 3 doses between 12–24 mg. Patients receive enough medication to continue dosing until the next office visit (3–5 days from first dose). Stabilization has occurred when objective and subjective measures indicate control of withdrawal symptoms and minimal opioid craving. At that point, based on clinician determination of patient stability, the buprenorphine rods can be implanted. Clinical pharmacology Mechanism of action
Buprenorphine is a partial agonist with strong affinity for the µ-opioid receptor and is an antagonist at the k-opioid receptor. The high affinity for and limited intrinsic activity at the mu receptor inhibits the reinforcing effect of exogenous opioids. Although buprenorphine is a partial opioid agonist, its tight binding char acteristic and slow rate of disassociation result in a prolonged clinical effect and limited physi cal dependence. Buprenorphine is metabolized via N-dealkylation and glucuronidation, with resulting norbuprenorphine conjugating with glucuronic acid [9] . Metabolites are excreted in the biliary system, with the major excretory route in feces and urine, regardless of route of administration. Acute administration results in small amounts of metabolite in plasma, while chronic dosing results in increased plasma levels of norbuprenorphine, the only biologically active metabolite [10] . The solid matrix of the buprenorphine implant releases buprenorphine slowly through diffusion. The ceiling on agonist activity of buprenorphine reduces potential for overdose and confers low toxicity even at high doses [11] . Buprenorphine can also block the effects of exogenous opioids [12] , thus reducing illicit opioid use. Pharmacodynamics & pharmacokinetics
Animal studies with the buprenorphine implant produced no effects on the CNS or other functions different from those of sublingual
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Review Ling buprenorphine. Animal studies have shown the buprenorphine implant to exhibit pharmaco kinetic consistency, with release from the implants occurring dose proportionally. In a small Phase I and Phase II human trial of the buprenorphine implant [13] , plasma con centrations (Cmax) of buprenorphine were pre dictably consistent. Six participants received two rods of 90 mg each, and six received four rods. The Cmax for the lower dose was 2.00 ng/ml (±0.41), reached 17.3 h post-implant (±5 h), and Cmax for the high dose was 3.23 ng/ml (±0.48), reached at 16 h after implant (±4.9 h). Plateau plasma concentrations occurred 21–28 days after implant, sustained through 6 months; average plasma concentration from 21 days through six months was 0.37 ng/ml for the two-rod group, and 0.72 ng/ml for the participants with four rods. Clinical evidence: overview of clinical trials Although the buprenorphine implant is simply another method to deliver buprenorphine, cer tain clinical trials are required by the regulatory agencies in some countries as a part of medication development toward approval. Specifically, there is a need to show that the product is clinically superior to placebo and at least ‘non-inferior’ to the established treatment. A recently reported 18-site randomized, double-blind, placebo-controlled trial of the buprenorphine implant included 163 male and female patients aged 18–65 years meet ing DSM-IV criteria for opioid dependence. Participants were first inducted on sublingual buprenorphine at 12–16 mg/day and after being stabilized on 12–16 mg/day for 3 consecutive days, then were randomized to either buprenor phine implant condition or placebo implant in a 2:1 ratio. Throughout the study, patients assigned to the active implant compared with those assigned to placebo had less illicit opioid use, better retention, fewer withdrawal symp toms, lower craving scores, and better global clinical improvement by investigator and patient assessments. The overall conclusion was that the 6‑month buprenorphine implant was more effective than placebo and was well tolerated, suggesting that, upon approval, this pharmaco therapy may be a practicable treatment option for patients with opioid dependence in a com munity-based setting. Post-implant sublingual buprenorphine to control cravings was permit ted; however, participants were removed from
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the study as ‘treatment failures’ if they received 3 or more days per week of supplemental sub lingual buprenorphine for 2 weeks in a row or a total of 8 or more days over 4 weeks in a row after receiving an additional implant rod. A more recent three-armed study with a ‘noninferiority’ component compared the implant buprenorphine to the sublingual formulation [102] . Over the 6-month trial, 31% of buprenor phine implant participants had negative urine samples compared with 33% of those on sub lingual buprenorphine, thus demonstrating the non-inferiority of the implant versus the sublingual formulation. Adverse reactions The active medication delivered by the implant is buprenorphine and therefore one would expect that the adverse reactions other than those related to the implant insertion and removal process would be similar to those of sublingual buprenorphine. The most common side effects of buprenorphine, apart from those related to opioid withdrawal (e.g., yawning, rhinitis, tearing and goose bumps) are head ache, constipation, difficulty sleeping, drow siness, nausea, anxiety and depression. Less common side effects include abdominal pain, dyspnea, weakness, weight gain, irregular men struation, decreased libido, dental problems, sweating, skin rash and itching. Possible side effects from the implant procedure include pain, swelling, bruising, bleeding, pressure, itching, scarring, and infection. After 163 ran domized subjects in one study, events related to the implant insertion procedure occurred at sim ilar rates in both groups, with greater percentages of active implant patients versus placebo implant patients experiencing itching (25 vs 14%) and pain (22 vs 11%) [5] . In the few cases of break age, the broken pieces were successfully removed without residual adverse events. Drug interactions Drug interaction studies specific to the bupren orphine implant have not been conducted, but interactions between the buprenorphine implant and other drugs are likely to approximate those involving sublingual buprenorphine, although at doses typically higher than the plasma lev els conferred by the implant formulation. Deaths have occurred when buprenorphine was combined with alcohol or other opioids. Combining buprenorphine with alcohol or
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Buprenorphine implant for opioid addiction other sedating medications is dangerous. The combination of buprenorphine with benzodi azepines (e.g., Valium®, Librium®, Ativan®, Xanax® and Klonopin®) has resulted in deaths. Other interactions may occur with monoam ine oxidase inhibitors and medications affecting the cytochrome system, specifically, CYP3A4 medications that could either increase or inhibit buprenorphine metabolism (e.g., protease inhib itors, macrolide antibiotics, antifungals and anticonvulsants) [14] . Although buprenorphine alone does not prolong the QT interval, in the presence of anti-retrovirals buprenorphine does prolong QT but without apparent clinically significant effects (i.e., QT interval less than 450 ms in 100% of buprenorphine patients, whereas 49% of methadone patients exhibited QT intervals greater than 450 ms) [15,16] . Use in specific populations HIV-infected populations
Research findings from cohorts of HIV-infected patients indicate that buprenorphine treat ment is associated with increased adherence to antiretroviral therapy and that patients experi ence appropriate increases in CD4 + cell count and reductions in viral load [17,18] . The use of buprenorphine, whether delivered sublingually or as implant, in the presence of HIV medica tions has not posed a problem, given the mini mal drug–drug interactions compared with those with methadone. Adolescents
With increasing numbers of children younger than 18 years involved in opioid misuse, clini cians and parents are struggling to find effec tive treatment approaches. Anecdotal reports of buprenorphine therapy for opioid-addicted teens is also increasing. While parents and cli nicians are encouraged by the availability of a medication to reduce illicit use of opioids, the potential for misuse and diversion of the sub lingual form hinders wider implementation of buprenorphine for opioid-addicted children. Implant buprenorphine may be advantageous, given its non-divertible, assured delivery, but research in patients younger than 18 years has not been conducted. Pregnant & parenting women
Opioid-using women do become pregnant and the standard recourse for these patients has been methadone maintenance, although the literature
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would suggest that the newborns of patients treated with buprenorphine during pregnancy may actually suffer less neonatal withdrawal [19,20] . A distinct advantage of implant bupren orphine would be to eliminate the need for daily clinical contact required of methadone. One can conjecture that the steady-state blood level of the buprenorphine implant may bode well for the pregnant mother and her child, but pertinent clinical data are lacking [21] . Conclusion Development of the buprenorphine implant is compelling testimony to the success of sublin gual buprenorphine, as well as a result of recog nizing problems inherent with the sublingual formulation. All of the clinical advantages and some of the disadvantages of sublingual buprenorphine are applicable to the implant. The most direct benefits of the implant are obvi ous – medication adherence and prevention of street diversion. Other benefits are perhaps less clear. It is possible that patients may benefit from steady rather than fluctuating blood levels, and the total buprenorphine exposure for the patient in treatment is less with the implant. Perhaps less appreciated but apparent once pointed out is the relief felt by patients who regard the implant as a means of freeing themselves from the daily preoccupation with logistic problems involved in obtaining their medication, as is the case with methadone. In terms of logistics and other concerns, clinicians should consider the following points, based primarily on the author’s experience in clinical practice and in conducting research studies with hundreds of patients treated with sublingual and implant buprenorphine, as well as with naltrexone, levoa-acetylmethadol and methadone. Like sublingual buprenorphine, the implant form should also be viewed as a means of bring ing in a new treatment philosophy and a more humane approach. The basic tenets of opioid addiction treatment must go beyond what medi cation can do physiologically and extend to the possibility of life changes. Recovery has now been defined as a lifestyle characterized by sustained abstinence, improved health, personal responsi bility and citizenship. These are goals that clini cians should strive to help patients achieve, and to do so might require a change in attitude and belief systems of the caretakers. Every patient is a broken life story. The physician’s role is to help the patient make the story whole.
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Review Ling Financial & competing interests disclosure W Ling has received unrestricted education grants from Reckitt/Benckiser, and research support from Reckitt/ Benckiser and Hythiam Inc. He has also served as an occasional consultant to Reckitt/Benckiser, Titan Pharmaceuticals, US World Med, Alkermes and DemeRx. The author has no
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Fiellin DA. The first three years of buprenorphine in the United States: experience to date and future directions. J. Addict. Med. 1(2), 62–67 (2007).
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Ducharme S, Fraser R, Gill K. Update on the clinical use of buprenorphine: In opioidrelated disorders. Can. Fam. Physician 58(1), 37–41 (2012).
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Kraus ML, Alford DP, Kotz MM et al. Statement of the American Society of Addiction Medicine Consensus Panel on the use of buprenorphine in office-based treatment of opioid addiction. J. Addict. Med. 5(4), 254–263 (2011).
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Sullivan LE, Chawarski M, O’Connor PG, Schottenfeld RS, Fiellin DA. The practice of office-based buprenorphine treatment of opioid dependence: is it associated with new patients entering into treatment? Drug Alcohol Depend. 79(1), 113–116 (2005). Ling W, Casadonte P, Bigelow G et al. Buprenorphine implants for treatment of opioid dependence: a randomized controlled trial. JAMA 304(14), 1576–1583 (2010). Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) Series 40. DHHS Publication No. (SMA) 043939. Substance Abuse and Mental Health Services Administration, MD, USA (2004).
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Chiang CN, Hawks RL. Pharmacokinetics of the combination tablet of buprenorphine and naloxone. Drug Alcohol Depend. 70(Suppl.), S39–S47 (2003).
10
Kuhlman JJ Jr, Levine B, Johnson RE, Fudala PJ, Cone EJ. Relationship of plasma buprenorphine and norbuprenorphine to withdrawal symptoms during dose induction, maintenance and withdrawal from sublingual buprenorphine. Addiction 93(4), 549–559 (1998).
11
Umbricht A, Huestis MA, Cone EJ, Preston KL. Effects of high-dose intravenous buprenorphine in experienced opioid abusers J. Clin. Psychopharmacol. 24(5), 479–487 (2004).
17
Carrieri MP, Vlahov D, Dellamonica P et al. Use of buprenorphine in HIV-infected injection drug users: negligible impact on virologic response to HAART. The Manif-2000 Study Group. Drug Alcohol Depend. 60(1), 51–54 (2000).
18
Moatti JP, Carrieri MP, Spire B, Gastaut J, Cassuto JP, Moreau J. Adherence to HAART in French HIV-infected injecting drug users: the contribution of buprenorphine drug maintenance treatment. AIDS 14(2), 151–155 (2000).
19
Kraft WK, Dysart K, Greenspan JS, Gibson E, Kaltenbach K, Ehrlich ME. Revised dose schema of sublingual buprenorphine in the treatment of the neonatal opioid abstinence syndrome. Addiction 106, 574–580 (2011).
12 Walsh SL, Preston KL, Bigelow GE,
Stitzer ML. Acute administration of buprenorphine in humans: partial agonist and blockade effects. J. Pharmacol. Exp. Ther. 274(1), 361–372 (1995).
20 Unger A, Jagsch R, Jones H et al.
Randomized controlled trials in pregnancy: scientific and ethical aspects. Exposure to different opioid medications during pregnancy in an intra-individual comparison. Addiction 106(7), 1355–1362 (2011).
13 White J, Bell J, Saunders JB et al. Open-label
dose-finding trial of buprenorphine implants (Probuphine) for treatment of heroin dependence. Drug Alcohol Depend. 103(1–2), 37–43 (2009). 14
15
Wesson DR, Ling W. The clinical opiate withdrawal scale (COWS). J. Psychoactive Drugs 35(2), 253–259 (2003). Tompkins DA, Bigelow GE, Harrison JA, Johnson RE, Fudala PJ, Strain EC. Concurrent validation of the Clinical Opiate Withdrawal Scale (COWS) and single-item indices against the Clinical Institute Narcotic Assessment (CINA) opioid withdrawal instrument. Drug Alcohol Depend. 105(1–2), 154–159 (2009).
other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
16
McCance-Katz EF, Moody DE, Morse GD et al. Interactions between buprenorphine and antiretrovirals. I. The nonnucleoside reverse-transcriptase inhibitors efavirenz and delavirdine. Clin. Infect. Dis. 43(Suppl. 4), S224–S234 (2006). Anchersen K, Clausen T, Gossop M, Hansteen V, Waal H. Prevalence and clinical relevance of corrected QT interval prolongation during methadone and buprenorphine treatment: a mortality assessment study. Addiction 104(6), 993–999 (2009). Baker JR, Best AM, Pade PA, McCanceKatz EF. Effect of buprenorphine and antiretroviral agents on the QT interval in opioid-dependent patients. Ann. Pharmacother. 40(3), 392–396 (2006).
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Jones HE, Kaltenbach K, Heil SH et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N. Engl. J. Med. 363(24), 2320–2331 (2010).
Websites
101 Green P. Outpatient drug utilization trends for
buprenorphine years 2002–2010. http://buprenorphine.samhsa.gov/bwns/2010_ presentations_pdf/09_Greene_508.pdf 102 Titan Pharmaceuticals Press Release. Titan
Pharmaceuticals provides additional positive results in confirmatory Phase 3 trial of probuphine data to be presented in plenary session at ISAM 2011 September. CA, USA (2011). www.titanpharm.com/press/2012/120420press-rel-titan-asam-presentation.htm
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Buprenorphine implant for opioid addiction
Practice Points
Walter Ling* Implementing an innovative pharmacotherapy: Treating opioid-addicted patients can be challenging,
and the few approved medications are not optimally effective in many cases. If a new form of a proven medication offers benefits that outweigh potential risks, clinicians must be willing to consider such innovative developments. Induction issues: At induction, a Clinical Opiate Withdrawal Scale (COWS) score below 12 often reflects
insufficient time since last opioid use, whereas presence of significant withdrawal symptoms (and a higher COWS score) usually favors a better induction process and outcome. ‘Explant’ and discontinuation of buprenorphine: After removal of buprenorphine implants, the patient
must be tapered off the buprenorphine condition via sublingual tablet formulations. Some patients seem psychologically reliant on the presence of the medication, taking doses as small as 0.5 mg/day. Clinicians familiar with sublingual buprenorphine should be capable of managing the care of patients after removal of implant buprenorphine. Use in pain management: Buprenorphine is a powerful analgesic with a long history of use in treating
acute and chronic pain. The implant formulation may represent a potential advance in managing chronic pain. Additional data are needed to complement existing research findings. Potential for treating other addictions: Research by the NIDA Clinical Trials Network is examining
buprenorphine in sublingual form for its ability to reduce cocaine use in cocaine-dependent individuals. Possible issues. Patients treated with the implants could attempt to remove them for diversion, although
the implant rods contain only 80 mg buprenorphine per rod and there is not likely to be much of a market for it if it is removed.
SUMMARY
The buprenorphine implant (Probuphine™, Titan Pharmaceuticals, CA, USA) is a recently developed long-acting formulation of buprenorphine, which is a partial opioid agonist that is widely used in the marketed, sublingual, daily-dose form for managing opioid addiction. The new formulation uses a novel delivery system consisting of subcutaneously implanted solid matrix ‘rods’ made from a mixture of ethylene vinyl acetate and buprenorphine. The buprenorphine implant was developed to ensure medication compliance, eliminate *Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine at UCLA, 1640 S. Sepulveda Blvd, Suite 120, Los Angeles, CA 90025-7535, USA; [email protected]
10.2217/PMT.12.26 © 2012 Future Medicine Ltd
Pain Manage. (2012) 2(4), 345–350
part of
ISSN 1758-1869
345
Review Ling misuse and abuse from diversion of sublingual buprenorphine, and increase therapeutic benefit of the medication. The implant is not a ‘new’ drug, but an innovative means of delivering a medication proven effective for treating opioid addiction. The implant has not yet been approved by the US FDA. The information in this review has been gleaned from research reports, documentation in the literature, and from the author’s experience treating opioid-dependent patients, and involvement in clinical research examining sublingual buprenorphine and the buprenorphine implant. A discussion of the buprenorphine implant must begin with an initial understanding of bupren orphine, which in itself is arguably the most significant advance in the history of pharmaco therapy for opioid addiction, heralded by the introduction of methadone maintenance a half century ago. Beyond offering a safer and more easily delivered medication capable of being prescribed from a physician’s office, bupren orphine returns opioid addiction treatment in the USA for the first time in nearly a century to the hands of physicians, making it possible for them to treat their opioid-addicted patients in the same manner as all other patients. This was made possible as a result of the evolutionary changes in the societal attitude about addicts and addiction. The pharmacological character istics of buprenorphine, perceived as less addic tive and safer than methadone, contribute to its being more acceptable to society at large. But the formal approval of buprenorphine and its clinical acceptance would not have been pos sible without change in societal attitudes toward addiction itself, seeing it as a disease rather than a crime or moral failing. Forty years of treatment experience with methadone did not produce this societal change, as the treatment philosophy about methadone has been a reflection of the societal ambiva lence about addicts and their treatment. With less than a decade of approved use in the USA, buprenorphine is already well accepted by soci ety, as evident in the less stringent regulations compared with those applied to methadone [1] , perhaps largely because of its good safety profile and ease of administration [2,3] . Buprenorphine allows physicians to take a new perspective about addiction and about addicts, one that is akin to the relationship that clinicians have with their other patients with chronic disorders – since physicians are societal leaders, that perspective will filter to the rest of society. If physicians begin to view patients differently, speak to them about their illness differently, and speak to oth ers about them differently, eventually society may come to regard them differently.
346
Pain Manage. (2012) 2(4)
The changes in attitudes and practices are borne out in the statistics; buprenorphine pre scriptions increased from 50,000 in 2002 to approximately 5.7 million in 2009, with more than 93% for treatment of opioid abuse or dependence for at least 330,000 patients with ‘opioid type dependence’ (code 304.0) [101] . Since its approval, buprenorphine has surpassed meth adone in the number of patients being treated at any time, estimated to be more than 340,000 on Suboxone® plus more than 50,000 on generic buprenorphine [Johnson E, Reckitt Benckiser, Pers. Comm.] compared with approximately 285,000 on methadone [Parrino M, AATOD, Pers. Comm.] . Many buprenorphine patients are attracted to the pharmacot herapy as an alternative to methadone [4] . However, the success of buprenorphine is not unqualified. With large numbers of patients hav ing large amounts of the medication on hand, street diversion has occurred. There is perhaps more of a market for diverted buprenorphine today because of the many prescription opioid addicts. Increasing use of diverted bupren orphine is an indicator of non-compliance with medication – the more successful buprenorphine treatment is, the bigger the problem with com pliance and diversion. Also of concern is the out come of improper or insecure storage, resulting in accidental poisoning, especially in children. While clinicians are generally satisfied with sublingual buprenorphine, many are also becom ing increasingly concerned about medication compliance and street diversion of the sublingual preparation. The magnitude of the problem is directly proportionate to the success of the sub lingual formulation, with an increasing number of patients seeking buprenorphine for opioid addiction treatment. While buprenorphine treatment should be recognized for its successes, a solution must be sought to overcome medica tion non-adherence and street diversion. The subcutaneous implant form of buprenorphine is a direct result of that search for a solution. Buprenorphine administered by subcutaneous implant with 6 months of sustained effects is
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Buprenorphine implant for opioid addiction potentially a better way to deliver buprenorphine that eliminates the possibility of noncompliance and diversion. The implant is being examined in Phase III trials in the process of gaining US FDA approval. All of the pharmacological and logis tic advantages of sublingual buprenorphine are applicable to the implantable buprenorphine. The advantages of the buprenorphine implant are obvious: there is no medication to divert and compliance is built into the implant. It is also intuitively tempting to suggest that a nonfluctuating steady blood level may yet be another advantage, although this has not been prospec tively studied in a controlled clinical trial, and the total buprenorphine exposure is less than that of the sublingual formulations. Indications & usage Since the buprenorphine implant is simply an alternative method of delivering an effective dose of buprenorphine sustained for six months, the clinical indications and its usage would be expected to mirror those of sublingual buprenor phine. Given the extensive documentation of buprenorphine’s effectiveness for opioid addic tion, the confirmation of effectiveness for the implant form is not surprising [5] . Other indi cations for which the buprenorphine implant may be useful, depending on results of future research, may include management of chronic pain and treatment of other substance use disorders. Dosage & administration In clinical trials to date, treatment with implant buprenorphine consists of four to five matrix implants, each 2.5 mm by 26 mm, placed sub cutaneously in the inner upper arm in a brief, in-office procedure, with the implants removed in a similar manner at the end of the treatment period. Each rod contains the equivalent of 80 mg buprenorphine, released at a constant rate through diffusion into adjacent body tissues, providing assured dosing for 6 months. Before implant, an induction with sublingual buprenorphine is required to ensure patient sta bilization. Standard practices for induction onto sublingual buprenorphine are well described (e.g., see [6]), and only briefly recounted here. An important initial element in this process is an accurate assessment of the patient’s level of with drawal symptoms, based usually on the Clinical Opiate Withdrawal Scale (COWS; [7,8]); too low a COWS score, stemming from insufficient time
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since last opioid use, can result in a failed induc tion due to emergent withdrawal symptoms in response to the buprenorphine partial agonist activity. For the induction, the first dose of sub lingual buprenorphine varies from 2 to 8 mg, followed by clinical observation for up to several hours, with subsequent administration of addi tional doses as appropriate. The total dose for day 1 may be 8–16 mg, day 2 doses will range between 8 and 16 mg, and day 3 doses between 12–24 mg. Patients receive enough medication to continue dosing until the next office visit (3–5 days from first dose). Stabilization has occurred when objective and subjective measures indicate control of withdrawal symptoms and minimal opioid craving. At that point, based on clinician determination of patient stability, the buprenorphine rods can be implanted. Clinical pharmacology Mechanism of action
Buprenorphine is a partial agonist with strong affinity for the µ-opioid receptor and is an antagonist at the k-opioid receptor. The high affinity for and limited intrinsic activity at the mu receptor inhibits the reinforcing effect of exogenous opioids. Although buprenorphine is a partial opioid agonist, its tight binding char acteristic and slow rate of disassociation result in a prolonged clinical effect and limited physi cal dependence. Buprenorphine is metabolized via N-dealkylation and glucuronidation, with resulting norbuprenorphine conjugating with glucuronic acid [9] . Metabolites are excreted in the biliary system, with the major excretory route in feces and urine, regardless of route of administration. Acute administration results in small amounts of metabolite in plasma, while chronic dosing results in increased plasma levels of norbuprenorphine, the only biologically active metabolite [10] . The solid matrix of the buprenorphine implant releases buprenorphine slowly through diffusion. The ceiling on agonist activity of buprenorphine reduces potential for overdose and confers low toxicity even at high doses [11] . Buprenorphine can also block the effects of exogenous opioids [12] , thus reducing illicit opioid use. Pharmacodynamics & pharmacokinetics
Animal studies with the buprenorphine implant produced no effects on the CNS or other functions different from those of sublingual
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Review Ling buprenorphine. Animal studies have shown the buprenorphine implant to exhibit pharmaco kinetic consistency, with release from the implants occurring dose proportionally. In a small Phase I and Phase II human trial of the buprenorphine implant [13] , plasma con centrations (Cmax) of buprenorphine were pre dictably consistent. Six participants received two rods of 90 mg each, and six received four rods. The Cmax for the lower dose was 2.00 ng/ml (±0.41), reached 17.3 h post-implant (±5 h), and Cmax for the high dose was 3.23 ng/ml (±0.48), reached at 16 h after implant (±4.9 h). Plateau plasma concentrations occurred 21–28 days after implant, sustained through 6 months; average plasma concentration from 21 days through six months was 0.37 ng/ml for the two-rod group, and 0.72 ng/ml for the participants with four rods. Clinical evidence: overview of clinical trials Although the buprenorphine implant is simply another method to deliver buprenorphine, cer tain clinical trials are required by the regulatory agencies in some countries as a part of medication development toward approval. Specifically, there is a need to show that the product is clinically superior to placebo and at least ‘non-inferior’ to the established treatment. A recently reported 18-site randomized, double-blind, placebo-controlled trial of the buprenorphine implant included 163 male and female patients aged 18–65 years meet ing DSM-IV criteria for opioid dependence. Participants were first inducted on sublingual buprenorphine at 12–16 mg/day and after being stabilized on 12–16 mg/day for 3 consecutive days, then were randomized to either buprenor phine implant condition or placebo implant in a 2:1 ratio. Throughout the study, patients assigned to the active implant compared with those assigned to placebo had less illicit opioid use, better retention, fewer withdrawal symp toms, lower craving scores, and better global clinical improvement by investigator and patient assessments. The overall conclusion was that the 6‑month buprenorphine implant was more effective than placebo and was well tolerated, suggesting that, upon approval, this pharmaco therapy may be a practicable treatment option for patients with opioid dependence in a com munity-based setting. Post-implant sublingual buprenorphine to control cravings was permit ted; however, participants were removed from
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the study as ‘treatment failures’ if they received 3 or more days per week of supplemental sub lingual buprenorphine for 2 weeks in a row or a total of 8 or more days over 4 weeks in a row after receiving an additional implant rod. A more recent three-armed study with a ‘noninferiority’ component compared the implant buprenorphine to the sublingual formulation [102] . Over the 6-month trial, 31% of buprenor phine implant participants had negative urine samples compared with 33% of those on sub lingual buprenorphine, thus demonstrating the non-inferiority of the implant versus the sublingual formulation. Adverse reactions The active medication delivered by the implant is buprenorphine and therefore one would expect that the adverse reactions other than those related to the implant insertion and removal process would be similar to those of sublingual buprenorphine. The most common side effects of buprenorphine, apart from those related to opioid withdrawal (e.g., yawning, rhinitis, tearing and goose bumps) are head ache, constipation, difficulty sleeping, drow siness, nausea, anxiety and depression. Less common side effects include abdominal pain, dyspnea, weakness, weight gain, irregular men struation, decreased libido, dental problems, sweating, skin rash and itching. Possible side effects from the implant procedure include pain, swelling, bruising, bleeding, pressure, itching, scarring, and infection. After 163 ran domized subjects in one study, events related to the implant insertion procedure occurred at sim ilar rates in both groups, with greater percentages of active implant patients versus placebo implant patients experiencing itching (25 vs 14%) and pain (22 vs 11%) [5] . In the few cases of break age, the broken pieces were successfully removed without residual adverse events. Drug interactions Drug interaction studies specific to the bupren orphine implant have not been conducted, but interactions between the buprenorphine implant and other drugs are likely to approximate those involving sublingual buprenorphine, although at doses typically higher than the plasma lev els conferred by the implant formulation. Deaths have occurred when buprenorphine was combined with alcohol or other opioids. Combining buprenorphine with alcohol or
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Buprenorphine implant for opioid addiction other sedating medications is dangerous. The combination of buprenorphine with benzodi azepines (e.g., Valium®, Librium®, Ativan®, Xanax® and Klonopin®) has resulted in deaths. Other interactions may occur with monoam ine oxidase inhibitors and medications affecting the cytochrome system, specifically, CYP3A4 medications that could either increase or inhibit buprenorphine metabolism (e.g., protease inhib itors, macrolide antibiotics, antifungals and anticonvulsants) [14] . Although buprenorphine alone does not prolong the QT interval, in the presence of anti-retrovirals buprenorphine does prolong QT but without apparent clinically significant effects (i.e., QT interval less than 450 ms in 100% of buprenorphine patients, whereas 49% of methadone patients exhibited QT intervals greater than 450 ms) [15,16] . Use in specific populations HIV-infected populations
Research findings from cohorts of HIV-infected patients indicate that buprenorphine treat ment is associated with increased adherence to antiretroviral therapy and that patients experi ence appropriate increases in CD4 + cell count and reductions in viral load [17,18] . The use of buprenorphine, whether delivered sublingually or as implant, in the presence of HIV medica tions has not posed a problem, given the mini mal drug–drug interactions compared with those with methadone. Adolescents
With increasing numbers of children younger than 18 years involved in opioid misuse, clini cians and parents are struggling to find effec tive treatment approaches. Anecdotal reports of buprenorphine therapy for opioid-addicted teens is also increasing. While parents and cli nicians are encouraged by the availability of a medication to reduce illicit use of opioids, the potential for misuse and diversion of the sub lingual form hinders wider implementation of buprenorphine for opioid-addicted children. Implant buprenorphine may be advantageous, given its non-divertible, assured delivery, but research in patients younger than 18 years has not been conducted. Pregnant & parenting women
Opioid-using women do become pregnant and the standard recourse for these patients has been methadone maintenance, although the literature
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would suggest that the newborns of patients treated with buprenorphine during pregnancy may actually suffer less neonatal withdrawal [19,20] . A distinct advantage of implant bupren orphine would be to eliminate the need for daily clinical contact required of methadone. One can conjecture that the steady-state blood level of the buprenorphine implant may bode well for the pregnant mother and her child, but pertinent clinical data are lacking [21] . Conclusion Development of the buprenorphine implant is compelling testimony to the success of sublin gual buprenorphine, as well as a result of recog nizing problems inherent with the sublingual formulation. All of the clinical advantages and some of the disadvantages of sublingual buprenorphine are applicable to the implant. The most direct benefits of the implant are obvi ous – medication adherence and prevention of street diversion. Other benefits are perhaps less clear. It is possible that patients may benefit from steady rather than fluctuating blood levels, and the total buprenorphine exposure for the patient in treatment is less with the implant. Perhaps less appreciated but apparent once pointed out is the relief felt by patients who regard the implant as a means of freeing themselves from the daily preoccupation with logistic problems involved in obtaining their medication, as is the case with methadone. In terms of logistics and other concerns, clinicians should consider the following points, based primarily on the author’s experience in clinical practice and in conducting research studies with hundreds of patients treated with sublingual and implant buprenorphine, as well as with naltrexone, levoa-acetylmethadol and methadone. Like sublingual buprenorphine, the implant form should also be viewed as a means of bring ing in a new treatment philosophy and a more humane approach. The basic tenets of opioid addiction treatment must go beyond what medi cation can do physiologically and extend to the possibility of life changes. Recovery has now been defined as a lifestyle characterized by sustained abstinence, improved health, personal responsi bility and citizenship. These are goals that clini cians should strive to help patients achieve, and to do so might require a change in attitude and belief systems of the caretakers. Every patient is a broken life story. The physician’s role is to help the patient make the story whole.
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Review Ling Financial & competing interests disclosure W Ling has received unrestricted education grants from Reckitt/Benckiser, and research support from Reckitt/ Benckiser and Hythiam Inc. He has also served as an occasional consultant to Reckitt/Benckiser, Titan Pharmaceuticals, US World Med, Alkermes and DemeRx. The author has no
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other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
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Pharmaceuticals provides additional positive results in confirmatory Phase 3 trial of probuphine data to be presented in plenary session at ISAM 2011 September. CA, USA (2011). www.titanpharm.com/press/2012/120420press-rel-titan-asam-presentation.htm
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