Abuse and diversion of buprenorphine sublingual tablets and film

Severtson, Stevan G.; Martinez, Erin; Bucher-Bartelson, Becki; Lait, Marie-Claire Le; Green, Jody L.; Murrelle, Lenn; Cicero, Theodore J.; Kurtz, Steven P.; Rosenblum, Andrew; Surratt, Hilary L.; Dart, Richard C.

doi:10.1016/j.jsat.2014.02.003

Cited by 83 publications

(64 citation statements)

References 27 publications

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“…The value of this schedule for assessing abuse liability is that it can provide an empirical differentiation among drugs that function as positive reinforcers (49)(50)(51). Remifentanil and buprenorphine exhibit strong and mildto-moderate reinforcing strengths, respectively, in monkeys under the PR schedule, concordant with their abuse potential in humans (4,9).…”

Section: Discussionmentioning

confidence: 99%

“…However, buprenorphine is not devoid of reinforcing effects, the most devastating side effect of MOP receptor agonists. The abuse or misuse of buprenorphine has been documented, which limits its use worldwide (9)(10)(11). There has been a decades-long effort aimed at developing opioid analgesics with fewer side effects (12-15), but to date, safe opioid analgesics devoid of abuse potential remain undiscovered (16,17).…”

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confidence: 99%

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A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates

Ding

Czoty

Kiguchi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

102

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Despite the critical need, no previous research has substantiated safe opioid analgesics without abuse liability in primates. Recent advances in medicinal chemistry have led to the development of ligands with mixed mu opioid peptide (MOP)/nociceptin-orphanin FQ peptide (NOP) receptor agonist activity to achieve this objective. BU08028 is a novel orvinol analog that displays a similar binding profile to buprenorphine with improved affinity and efficacy at NOP receptors. The aim of this preclinical study was to establish the functional profile of BU08028 in monkeys using clinically used MOP receptor agonists for side-by-side comparisons in various wellhoned behavioral and physiological assays. Systemic BU08028 (0.001-0.01 mg/kg) produced potent long-lasting (i.e., >24 h) antinociceptive and antiallodynic effects, which were blocked by MOP or NOP receptor antagonists. More importantly, the reinforcing strength of BU08028 was significantly lower than that of cocaine, remifentanil, or buprenorphine in monkeys responding under a progressive-ratio schedule of drug self-administration. Unlike MOP receptor agonists, BU08028 at antinociceptive doses and ∼10-to 30-fold higher doses did not cause respiratory depression or cardiovascular adverse events as measured by telemetry devices. After repeated administration, the monkeys developed acute physical dependence on morphine, as manifested by precipitated withdrawal signs, such as increased respiratory rate, heart rate, and blood pressure. In contrast, monkeys did not show physical dependence on BU08028. These in vivo findings in primates not only document the efficacy and tolerability profile of bifunctional MOP/NOP receptor agonists, but also provide a means of translating such ligands into therapies as safe and potentially abusefree opioid analgesics.N/OFQ peptide receptor | respiratory depression | reinforcing effects | physical dependence | mu opioid peptide receptor P ain, a symptom of numerous clinical disorders, afflicts millions of people worldwide. Despite the remarkable advances in the identification of potential targets as analgesics in the last decade, mu opioid peptide (MOP) receptor agonists remain the most widely used analgesics for pain management (1). Several side effects associated with MOP receptor agonists have severely limited the value of opioid analgesics, however (2). Owing to the abuse liability and the high mortality rate caused by respiratory arrest, opioid abuse not only has dire consequences, but also leads to mounting medical and economic burdens in our society (3-5). There is a clear, unmet need for safe analgesics without abuse liability in the global community.Buprenorphine, a partial MOP receptor agonist, is considered a safe analgesic because of its ceiling effect on respiratory depression (6, 7). Buprenorphine is commonly used in both human and veterinary medicine to treat various pain conditions, including cancer pain and neuropathic pain (7,8). However, buprenorphine is not devoid of reinforcing effects, the most devastating side effect...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates

Ding

Czoty

Kiguchi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

102

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“…Although this age difference was not unanticipated (Turner et al, 2015), the proportion within both young adult men and women was not. Because of the frequent reference to buprenorphine products in the DAP and because an even cursory Internet search of substance user groups pulls up simple, detailed, and plausible directions on how to convert the buprenorphine/naloxone film strips into an injectable product (see also Cicero et al, 2014b;Lavonas et al, 2014), Suboxone film strips may offer less of a pronounced benefit over the generic Zubsolv tablets than is generally appreciated.…”

Section: Discussionmentioning

confidence: 99%

Use and Misuse of Opioids in Maine: Results From Pharmacists, the Prescription Monitoring, and the Diversion Alert Programs

Piper

Desrosiers²,

Lipovsky³

et al. 2016

J. Stud. Alcohol Drugs

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ABSTRACT. Objective: Although opioids have substantial efficacy for acute pain management, escalation to opioid misuse and abuse is a persistent concern. This report assesses the current status of the opioid epidemic in Maine using three complementary data sets. Method: A representative sample of pharmacists (N = 275) completed an online survey regarding the extent that opioids affected their practice. A countylevel analysis of opioid prescriptions (N = 1.22 million) reported to the Maine Prescription Monitoring Program (M-PMP) in 2014 and the agents implicated in arrests as reported to the Maine Diversion Alert Program (DAP, N = 2,700) in 2014/15 also was completed. Results: A significantly greater number of pharmacists agreed that opioid misuse (85.9%), rather than diversion (76.8%) or access (54.2%), was a concern. Only half (56.2%) reported use of the M-PMP. Opioids were dispensed to 22.4% of residents (37.7% of women in their 80s). This was enough to supply everyone in Maine with a 16.1-day supply. Buprenorphine accounted for almost half of opioid prescriptions to young adults (46.3% women, 49.3% men). Arrests increased by 13.3% from 2014 to 2015, and the proportion of arrests that involved prescription opioids decreased while those involving stimulants and heroin were elevated. Conclusions: Pharmacists are very aware of the potential for opioid misuse, but many do not consistently use the M-PMP. There continues to be substantial legitimate use, as well as criminal activity, involving oxycodone and other prescription opioids. Continued vigilance and use of tools like the PMP and DAP are necessary to minimize nonmedical use of opioids in Maine. (J. Stud. Alcohol Drugs, 77, 556-565, 2016)

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“…[60,[62][63][64] However, differences in routes of abuse have been reported between different buprenorphine formulations. [65,66] Both overall rates of abuse and rates of abuse by non-oral routes of administration appear lower with buprenorphine/naloxone film than with buprenorphine or buprenorphine/naloxone tablets. [65,66] …”

Section: Differences In Routes Of Abuse Between Formulationsmentioning

confidence: 99%

“…[65,66] Both overall rates of abuse and rates of abuse by non-oral routes of administration appear lower with buprenorphine/naloxone film than with buprenorphine or buprenorphine/naloxone tablets. [65,66] …”

Section: Differences In Routes Of Abuse Between Formulationsmentioning

confidence: 99%

Routes of abuse of prescription opioid analgesics: a review and assessment of the potential impact of abuse-deterrent formulations

Gąsior

Bond

Malamut

2015

Postgraduate Medicine

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Prescription opioid analgesics are an important treatment option for patients with chronic pain; however, misuse, abuse and diversion of these medications are a major global public health concern. Prescription opioid analgesics can be abused via intended and non-intended routes of administration, both intact or after manipulation of the original formulation to alter the drug-delivery characteristics. Available data indicate that ingestion (with or without manipulation of the prescribed formulation) is the most prevalent route of abuse, followed by inhalation (snorting, smoking and vaping) and injection. However, reported routes of abuse vary considerably between different formulations. A number of factors have been identified that appear to be associated with non-oral routes of abuse, including a longer duration of abuse, younger age, male sex and a rural or socially deprived location. The development of abuse-deterrent formulations of prescription opioid analgesics is an important step toward reducing abuse of these medications. Available abuse-deterrent formulations aim to hinder extraction of the active ingredient, prevent administration through alternative routes and/or make abuse of the manipulated product less attractive, less rewarding or even aversive. There are currently five opioid analgesics with a Food and Drug Administration abuse-deterrent label, and a number of other products are under review. A growing body of evidence suggests that introduction of abuse-deterrent opioid analgesics in the USA has been associated with decreased rates of abuse of these formulations. The availability of abuse-deterrent formulations therefore appears to represent an important step toward curbing the epidemic of abuse of prescription opioid analgesics, while ensuring the availability of effective pain medications for patients with legitimate medical need.

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Abuse and diversion of buprenorphine sublingual tablets and film

Cited by 83 publications

References 27 publications

A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates

A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates

Use and Misuse of Opioids in Maine: Results From Pharmacists, the Prescription Monitoring, and the Diversion Alert Programs

Routes of abuse of prescription opioid analgesics: a review and assessment of the potential impact of abuse-deterrent formulations

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