Faculty Perspectives in Chronic Pain, Part 3 of 5

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In Vitro and Clinical Assessments of Abuse-Deterrent Formulations for Chronic Pain

Sabeeha Muneer, PhD

Chronic noncancer pain is now considered a global epidemic and a public health problem in the United States, partly owing to its prevalence, underdiagnosis, and undertreatment.1 The resultant and unprecedented increase in the use of opioids has become a national concern because of parallel increases in the misuse, abuse, and diversion of these medications.1 According to the 2015 US Food and Drug Administration (FDA) report Guidance for Industry: Abuse-Deterrent Opioids—Evaluation and Labeling, abuse is defined as “the intentional, non-therapeutic use of a drug product or substance, even once, to achieve a desirable psychological or physiological effect,” and misuse is defined as “intentional therapeutic use of a drug product in an inappropriate way.”2 Diversion, broadly defined, is when the legal supply chain of opioids is broken, and these drugs are transferred from a licit to an illicit channel of distribution or use.

A 10-fold increase in opioid prescriptions was reported since 1990, and US manufacture of 2 commonly used opioids was estimated at 99% and 83% of the global totals, respectively, in 2010.3,4 To aid ingestion, some patients and/or caregivers may unknowingly administer opioids by nonprescribed means such as crushing tablets instead of swallowing them intact, which can inadvertently deliver excessive, unsafe doses. Furthermore, in 2013, 4.5 million Americans aged ≥12 years were current nonmedical users of prescription pain relievers.5

In addition to potential for misuse and deliberate abuse of opioids, overdose is an epidemic problem.6,7 According to the Centers for Disease Control and Prevention, 44 individuals in the United States die every day from overdose of prescription painkillers, and many more become addicted.6 These compelling data illustrate the magnitude of the current prescription drug abuse issue in the United States, underscoring the need for concerted efforts to control this public health problem. Achieving a balance between ensuring patient access to legitimate opioid medications and minimizing the burden of prescription opioid abuse, misuse, and diversion poses a significant challenge for all stakeholders, including prescribers, manufacturers, and regulatory authorities.1

Oral abuse is the preferred route of administration of opioids, with available evidence indicating that 72% to 97% of opioid abusers use this route,8 followed by intranasal and intravenous (IV) administration.2 Nonoral routes of administration are commonly adopted due to the appeal of enhanced drug delivery. Unfortunately, for this same reason, extended-release (ER) opioids, which were developed to provide long-acting, stable levels of medication for continuous treatment of pain, are particularly attractive to prescription drug abusers because of their relatively high opioid content and rapid onset of effect when manipulated, similar to the immediate-release (IR) formulation.8 Although ER opioids are hypothesized to have a slower onset and lower peak concentration compared with IR formulations, drug abuse by crushing for insufflation, injection, or inhalation confers rapid rates of onset since the manipulation overrides the ER mechanism and reverts it to an IR modality.2,8

In 2011, the US Office of National Drug Control Policy proposed a national strategy that stressed the development of abuse-deterrent formulations (ADFs) of opioids designed to impede or deter attempts for manipulation.9 In response to this call for action, pharmaceutical manufacturers have developed ADFs that introduce some impediment intended to mitigate either inadvertent or deliberate attempts at manipulation. ADFs can be classified into 7 categories: (1) physical or chemical barriers; (2) agonist/antagonist combinations; (3) aversion; (4) delivery systems; and (5) new molecular entities and prodrugs that can offer resistance to abuse; (6) combination therapy; and (7) novel approaches (Table).2



Opioid ADFs: Physical or Mechanical Barriers


The opioid ADF approach that employs physical or mechanical barriers is designed to render a tablet resistant to abuse methods such as chewing, crushing, milling, or dissolution, making it difficult to prepare for insufflation or injection.10-12 Additional formulation strategies may impart viscosity when the drug is exposed to water, making it difficult to draw into a syringe and thereby thwarting efforts to inject it. An exclusively mechanical approach may reduce the drug’s attractiveness for abuse without exposing legitimate patients to adverse events associated with opioid antagonists or aversive compounds. In vitro, clinical, and epidemiological assessments have been conducted to determine whether such tablets are able to withstand the efforts of experienced IV and intranasal drug abusers.

Some semisynthetic opioids used for chronic pain (especially ER formulations) are preferred among abusers, justifying the development of formulations with abuse-deterrent properties.13,14 The ER form of one of these agents has now been reformulated with a polymer matrix that confers resistance to breaking and crushing in addition to turning into a viscous gel when combined with fluids.10-12 Preapproval evidence demonstrated the bioequivalence of the reformulated agent with the original formulation when ingested orally in either the fasted or fed state across different doses.10

Cone and colleagues developed a model for in vitro laboratory assessment of the abuse-deterrent properties of a reformulated opioid; they evaluated the agent incrementally and with iterative changes that allowed objective testing in lieu of exhaustive and impractical testing of all potential abuse methods.15 This model applied standardized physical and chemical procedures that related to real-world scenarios to demonstrate the relative difficulty of manipulation of the reformulated ER version compared with the original IV formulation, and assessed the quantity and purity of the recovered active opioid. It was concluded that manipulating the reformulated version to yield small particles required more time as well as effort/resources in terms of sophisticated mechanical means compared with the original formulation, which could be reduced to a fine powder with a spoon or a credit card. Extraction studies conducted to assess the solubility in different household solvents, and at different temperatures (room temperature and near-boiling temperature), particle sizes, and times of extraction (10 min to >18 h), also demonstrated that the reformulated version was considerably more difficult to extract and even retained some controlled-release properties. In addition, the hydrogelling characteristics of the reformulated drug resulted in high viscosity of the fluid, impaired syringeability, and impaired injectability. Dose dumping was also not an issue for the reformulated product, either intact or physically manipulated, when coingested with ethanol.

To confirm these laboratory-based results in human subjects, clinical studies have evaluated the pharmacokinetics, attractiveness, and abuse potential of the reformulated ER version in comparison to the original formulation.16-18 A randomized, single-blind, single-dose, crossover study that evaluated the pharmacokinetics, tolerability, and safety of the reformulated version administered intranasally (both finely crushed and coarsely crushed) compared with the original formulation (finely crushed) in 83 healthy adults showed that the reformulated version had a lower intranasal abuse potential.16 The reformulated version was associated with reduced peak plasma concentration (Cmax) and increased time to peak plasma concentration (Tmax), which corresponded to lower abuse quotient scores compared with control.16 In addition, the reformulated version was associated with greater nasal discomfort and stuffiness compared with control.

A randomized, double-blind, positive- and placebo-­controlled crossover study evaluated a reformulated opioid versus an original formulation versus placebo for abuse potential, pharmacokinetics, pharmacodynamics, and safety in 27 recreational opioid users with a recent history of intranasal drug abuse.17 The reformulated version (crushed) was associated with reduced Cmax and increased Tmax versus the 2 positive controls. Moreover, subjects’ ratings of overall drug liking, likelihood of taking the drug again, the “high” produced, and monetary drug value were significantly lower with the reformulated drug than with the 2 positive controls.

In a noninterventional study, 30 medically healthy recreational opioid users underwent interviews and manipulation sessions to assess preferences in terms of abuse methods and utility of commonly available supplies for manipulation, overall tampering potential, and preferences for a reformulated drug relative to placebo.18 The surveyed participants considered the reformulated version to be the “least attractive, least valuable, least desirable, and least likely to be tampered with” drug among all opioids studied in direct contrast to the original formulation.

Taken together, these data indicate that a reformulated ER opioid was associated with lower and delayed peak plasma concentrations, decreased drug-liking, decreased intranasal tolerability, and decreased willingness of recreational users to pay, suggesting that it has a reduced potential for abuse.

Researchers have also formulated a semisynthetic ER opioid that incorporates a polyethylene oxide matrix, providing high mechanical strength that confers abuse-resistant properties in terms of crushing and preparation for abuse and misuse.10-12,19 In vitro studies have shown that these reformulated tablets resisted crushing by a variety of commonly used tools such as spoons, pill crushers, and hammers, in addition to resisting extraction in a range of solvents, and turn gel-like and viscous when combined with fluid.19

Three open-label, randomized studies have demonstrated bioequivalence between the reformulated and original formulations of this drug in healthy adults under fasted conditions (Study 1, 5-mg dose; Study 2, 40-mg dose) or after a high-fat meal (Study 3, 40-mg doses), showing similarities in plasma concentration over time, mean plasma concentration, and systemic plasma exposure.20 In addition, 2 open-label, randomized crossover studies evaluated the effects of ethanol on the in vitro dissolution and in vivo pharmacokinetics of the original and reformulated versions in fasted healthy volunteers.21 The results suggest that the integrity of both formulations was retained with ethanol exposure. Concurrent administration of the reformulated version with a 240-mL solution containing 20% or 40% ethanol had no effect on area under the curve, although it increased Cmax and decreased Tmax.

Two postmarketing 1-day studies of current prescription opioid abusers examined the mechanical stability of the reformulated version of this ER drug.22 The goals were to determine whether experienced abusers were able to convert the reformulated tablets into forms that were amenable to intranasal (Study 1) or IV (Study 2) drug administration in comparison with original ER tablets formulated with the polysaccharide hydrogel TimeRx® matrix. The primary outcomes of Study 1 and Study 2 were particle size distribution and percent yield of active drug in the extracts, respectively. The study findings showed that the manipulated reformulated tablet particles prepared for abuse were large and angular, and 90.2% were larger than 1.705 mm, whereas the original tablet particles could be easily crushed to a fine powder, with 97.7% of particles smaller than 1.705 mm, suggesting that the reformulated tablet was more difficult to crush into particles suitable for insufflation or injection. The majority of study participants reported unwillingness to insufflate (92%) or inject (84%) the manipulated product, largely due to the powder/tablet consistency, the anticipated nasal effects of the particles (in Study 1), and the viscosity of the solution (Study 2). Percent yield of active drug in extracts was similar between the 2 formulations.22

Another opioid, characterized as a μ-opioid receptor agonist and norepinephrine reuptake inhibitor,23 was formulated for the treatment of chronic pain with an INTAC™ matrix to provide abuse resistance. Two randomized studies conducted in the outpatient setting examined whether ADFs of this drug at 50 mg (TAP50) and 250 mg (TAP250) could be converted into forms amenable to intranasal (Study 1) or IV abuse (Study 2); participants included 25 experienced healthy oxycodone ER abusers.24 The primary outcomes of Study 1 and Study 2 were the number of subjects willing to snort the manipulated tablets and percent yield of active drug in the extracts, respectively. Study findings showed that the reformulated version was less liked than the original (nonabuse-­resistant) formulation of another commonly used opioid. In Study 1, all 25 participants were willing to snort the nonabuse-resistant tablets, but only 24% of participants indicated willingness to snort TAP50, and only 16% were willing to snort TAP250 (P <.001). In Study 2, only 3.5% of active drug was extracted from the TAP50 tablet, compared with 37% from the nonabuse-resistant tablet (P = .008), and no samples from the TAP250 tablet contained analyzable solutions of the drug.23,24

Opioid ADFs: Inclusion of Sequestered Antagonists


Combining an opioid with a low-dose antagonist is another effective abuse-resistant strategy that has been employed.10-12 Opioid receptor antagonists have been used clinically to treat opioid dependence, and they have been combined with opioids at low doses to reduce adverse events such as constipation. In the context of abuse deterrence, they are sequestered in opioid analgesics at higher doses and are released, only upon product manipulation, to block the euphoric effects of opioids.12

One of these combinations is available as a sublingual film and a tablet.11,12 The film is difficult to crush into a powder for intranasal abuse. Upon manipulation and injection of either formulation, the antagonist component is designed to reduce the effects of the opioid and may result in withdrawal in opioid-dependent individuals.12 Although this formulation is approved for the treatment of opioid dependence, it is commonly used off-label for pain relief.25 These newer tablets have been shown to have reduced abuse liability compared with original tablets comprised solely of the opioid.26

A similar combination combines an opioid and an opioid receptor antagonist in a 2:1 ratio to deter abuse. This product, which is administered intravenously, was recently approved by the FDA for the treatment of severe pain that requires continuous long-term opioid treatment and is inadequately treated by alternative therapies.27,28 Data from in vitro and human abuse liability studies have demonstrated adequate abuse-resistant properties and lower abuse potential with this combination compared with an opioid alone.29,30 Two of these were double-blind, randomized, crossover studies that evaluated the abuse potential, pharmacokinetics, and safety of this product following intranasal and IV routes of administration in experienced opioid drug users.29,30 The results showed significant attenuation of opioid effects and significant reductions in pharmacodynamic outcomes relating to drug-liking compared with an opioid alone. Separately, a noninterventional study conducted in current recreational opioid users who had experience in manipulating and administering prescription formulations by alternative routes of administration compared the relative effectiveness of this product with that of other opioid formulations.31 The study participants judged the combination as the least attractive of the products, and they ranked it the lowest for “overall desirability and estimated street value.”

Opioid ADFs: Incorporation of Aversive Agents

A novel abuse-deterrent approach is to combine the opioid with aversive products that produce noxious adverse events upon abuse.10-12 One IR opioid has now been reformulated with sodium lauryl sulfate as the aversive agent that serves to irritate the nasal passage as a means to deter insufflation, in addition to conferring gel-like properties when exposed to water to deter IV use.32 The bioequivalence of this IR reformulation to the original IR formulation has been demonstrated, with comparable times to peak exposure and terminal elimination half-life.33 A double-blind study showed that this ADF with aversion technology was associated with reduced ability to insufflate tablets within the prescribed time.34 In addition, decrease in drug likeability was reported, as evidenced by 30% of the participants in the reformulated group expressing that they would not insufflate the product again compared with only 5% in the comparator group. Participants in the reformulated group also experienced a higher incidence of nasopharyngeal and facial adverse events.

Abuse-Deterrent Technologies in Development


Several new opioid ADFs are currently under investigation for the management of pain, including a 12-hour, ER formulation of an opioid.35 In a nasal human abuse liability study, abuse potential for the crushed intranasal form of this drug was significantly lower than for an original formulation among nondependent, recreational opioid users.35 Researchers are also studying an opioid–polymer conjugate that is designed to be slowly absorbed through the blood–brain barrier, thereby limiting the potential of rapid high-dose central nervous system exposure and attenuating euphoric effects.36 In a human abuse liability study, this novel ADF was associated with drug-liking scores that were significantly lower than those for a standard opioid (P <.0001 at most doses).36 Another innovative technology, which involves the encapsulation of abuse-resistant opioid-containing beads,37 has been designed to provide ER drug delivery while safeguarding against common methods of manipulaton, including crushing, chewing, heating and injecting, and smoking.38

Conclusions

Although there are several potential benefits to the use of opioid analgesics in patients with chronic noncancer pain, there is also an alarming rise in the incidence of abuse, misuse, and diversion of these medications. Clearly, there is an urgent need to reduce opioid manipulation and subsequent abuse without creating barriers to safe, effective, legitimate management of pain. In response to this need, ADFs of various opioids continue to be developed and approved. It is hoped that further progress on this path will lead to a reduction in prescription drug-related overdoses and deaths while providing patients with the chronic pain relief they need.

References

  1. The use of opioids for the treatment of chronic pain: a consensus statement from the American Academy of Pain Medicine and the American Pain Society. Clin J Pain. 1997;13:6-8.
  2. US Food and Drug Administration. Guidance for Industry: Abuse-Deterrent Opioids—Evaluation and Labeling. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM334743.pdf. Accessed August 20, 2015.
  3. Office of the Director, Centers for Disease Control and Prevention. Public health grand rounds: prescription drug overdoses—an American epidemic [slide presentation]. www.cdc.gov/cdcgrandrounds/pdf/phgrrx17feb2011.pdf. Accessed March 5, 2015.
  4. International Narcotics Control Board. Narcotic Drugs Report 2011. Part four: Statistical information on narcotic drugs. www.incb.org/documents/Narcotic-Drugs/Technical-Publications/2011/Part_FOUR_Comments_NAR-Report-2011_English.pdf. Accessed March 5, 2015.
  5. Substance Abuse and Mental Health Services Administration. Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings. www.samhsa.gov/data/sites/default/files/NSDUHresultsPDFWHTML2013/Web/NSDUHresults2013.pdf. Accessed April 6, 2015.
  6. Centers for Disease Control and Prevention. Prescription drug overdose: what the public needs to know about the epidemic. www.cdc.gov/drugoverdose/epidemic/public.html. Accessed April 6, 2015.
  7. Centers for Disease Control and Prevention. CDC grand rounds: prescription drug overdoses—a U.S. epidemic. MMWR Morb Mortal Wkly Rep. 2012;61:10-13.
  8. Kirsh K, Peppin J, Coleman J. Characterization of prescription opioid abuse in the United States: focus on route of administration. J Pain Palliat Care Pharmacother. 2012;26:348-361.
  9. Office of National Drug Control Policy. Epidemic: responding to America’s prescription drug abuse crisis. www.whitehouse.gov/sites/default/files/ondcp/issues-content/prescription-drugs/rx_abuse_plan.pdf. Accessed January 14, 2015.
  10. Schaeffer T. Abuse-deterrent formulations, an evolving technology against the abuse and misuse of opioid analgesics. J Med Toxicol. 2012;8:400-407.
  11. Alexander L, Mannion RO, Weingarten B, et al. Development and impact of prescription opioid abuse deterrent formulation technologies. Drug Alcohol Depend. 2014;138:1-6.
  12. Stanos SP, Bruckenthal P, Barkin RL. Strategies to reduce the tampering and subsequent abuse of long-acting opioids: potential risks and benefits of formulations with physical or pharmacologic deterrents to tampering. Mayo Clin Proc. 2012;87:683-694.
  13. Young AM, Havens JR, Leukefeld CG. Route of administration for illicit prescription opioids: a comparison of rural and urban drug users. Harm Reduct J. 2010;7:24.
  14. Cicero TJ, Ellis MS, Surratt HL, et al. Factors influencing the selection of hydrocodone and oxycodone as primary opioids in substance abusers seeking treatment in the United States. Pain. 2013;154:2639-2648.
  15. Cone EJ, Giordano J, Weingarten B. An iterative model for in vitro laboratory assessment of tamper deterrent formulations. Drug Alcohol Depend. 2013;131:100-105.
  16. Perrino PJ, Colucci SV, Apseloff G, et al. Pharmacokinetics, tolerability, and safety of intranasal administration of reformulated OxyContin® tablets compared with original OxyContin® tablets in healthy adults. Clin Drug Investig. 2013;33:441-449.
  17. Harris SC, Perrino PJ, Smith I, et al. Abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered crushed oxycodone HCl abuse-deterrent controlled-release tablets in recreational opioid users. J Clin Pharmacol. 2014;54:468-477.
  18. Sellers EM, Perrino PJ, Colucci SV, et al. Attractiveness of reformulated OxyContin® tablets: assessing comparative preferences and tampering potential. J Psychopharmacol. 2013;27:808-816.
  19. Bartholomaeus JH, Arkenau-Maric E, Galia E. Opioid extended-release tablets with improved tamper-resistant properties. Expert Opin Drug Deliv. 2012;9:879-891.
  20. Benedek IH, Jobes J, Xiang Q, et al. Bioequivalence of oxymorphone extended release and crush-resistant oxymorphone extended release. Drug Des Devel Ther. 2011;5:455-463.
  21. Fiske WD, Jobes J, Xiang Q, et al. The effects of ethanol on the bioavailability of oxymorphone extended-release tablets and oxymorphone crush-resistant extended-release tablets. J Pain. 2012;13:90-99.
  22. Vosburg SK, Jones JD, Manubay JM, et al. Assessment of a formulation designed to be crush-resistant in prescription opioid abusers. Drug Alcohol Depend. 2012;126:206-215.
  23. Tzschentke TM, Jahnel U, Kogel B, et al. Tapentadol hydrochloride: a next-generation, centrally acting analgesic with two mechanisms of action in a single molecule. Drugs Today (Barc). 2009;45:483-496.
  24. Vosburg SK, Jones JD, Manubay JM, et al. A comparison among tapentadol tamper-resistant formulations (TRF) and OxyContin® (non-TRF) in prescription opioid abusers. Addiction. 2013;108:1095-1106.
  25. Barry DT, Savant JD, Beitel M, et al. Pain and associated substance use among opioid dependent individuals seeking office-based treatment with buprenorphine-­naloxone: a needs assessment study. Am J Addict. 2013;22:212-217.
  26. Comer SD, Sullivan MA, Vosburg SK, et al. Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine-maintained intravenous heroin abusers. Addiction. 2010;105:709-718.
  27. US Food and Drug Administration. FDA approves new extended-release oxycodone with abuse-deterrent properties [news release]. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm406407.htm. Accessed January 19, 2015.
  28. DePriest AZ, Miller K. Oxycodone/naloxone: role in chronic pain management, opioid-induced constipation, and abuse deterrence. Pain Ther. 2014;3:1-15.
  29. Colucci S, Perrino P, Shram M, et al. Abuse potential of oxycodone/naloxone solution administered intravenously in nondependent recreational drug users with moderate opioid experience [abstract]. Paper presented at PAINWeek, September 2013. http://conference.painweek.org/media/mediafile_attachments/00/650-painweek2013acceptedabstracts.pdf. Accessed January 19, 2015.
  30. Harris S, Perrino P, Shram M, et al. Abuse potential of oxycodone/naloxone (OXN) tablets administered intranasally in nondependent recreational drug users with moderate opioid experience [abstract]. Paper presented at PAINWeek, September 2013. http://conference.painweek.org/media/mediafile_attachments/00/650painweek2013acceptedabstracts.pdf. Accessed January 19, 2015.
  31. Perrino P, Colucci S, Shram M, et al. Relative attractiveness of oxycodone/naloxone (OXN): comparative assessment of tampering potential and recreational drug user preferences for different opioid formulations [abstract]. Paper presented at PAINWeek, September 2013. http://conference.painweek.org/media/mediafile_attachments/00/650painweek2013acceptedabstracts.pdf. Accessed January 19, 2015.
  32. Johnson F, Setnik B. Morphine sulfate and naltrexone hydrochloride extended-release capsules: naltrexone release, pharmacodynamics, and tolerability. Pain Physician. 2011;14:391-406.
  33. Leibowitz MT, Zamora CA, Brzeczko AW, et al. A single-dose, 3-way crossover pharmacokinetic comparison between immediate-release oxycodone hydrochloride with aversion technology (IRO-A, Oxecta), IRO-A with niacin, and oxycodone hydrochloride (Roxicodone) in healthy adults under fasting conditions. Am J Ther. 2014;21:99-105.
  34. Oxecta (oxycodone HCI, USP) Tablets for oral use only-CII [prescribing information]. New York, NY: Pfizer Inc; January 2014.
  35. Teva Pharmaceutical Industries. Teva announces initiation of new drug application and positive results from second human abuse liability study for CEP-33237 (hydrocodone bitartrate) extended-release tablets [news release]. www.tevapharm.com/Media/News/Pages/2014/1975252.aspx. October 8, 2014. Accessed February 17, 2015.
  36. Schnoll S. Findings from a NKTR-181 human abuse liability study. Slide presentation at a press conference during the 75th Annual Meeting of the College on Problems of Drug Dependence, June 19, 2013. www.nektar.com/pdf/pipeline/NKTR-181/CPDD_NKTR-181_Hal_Study_Presentation.pdf. Accessed February 17, 2015.
  37. Collegium Pharmaceutical. Collegium Pharmaceutical Inc. announces successful Type A meeting with FDA for tamper-resistant, extended release opioid. www.businesswire.com/news/home/20110926005190/en/Collegium-Pharmaceutical-Announces-Successful-Type-Meeting-FDA#.VSL8TvnF9Eg. September 26, 2011. Accessed April 6, 2015.
  38. Collegium Pharmaceutical website. DETERx® technology platform. www.collegiumpharma.com/technology-platform/overview. Accessed April 6, 2015.
Uncategorized - January 5, 2016

The Tip of the Iceberg

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Uncategorized - January 5, 2016

In Vitro and Clinical Assessments of Abuse-Deterrent Formulations in the Management of Chronic Pain

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