| Randomized Controlled Trials |
|---|
| Colucci, 201412 |
|---|
Drug Liking
Overall drug liking were highest after receiving oxycodone (vs. sOXN or placebo) Pairwise comparisons were all statistically significant : OXY vs. placebo, P<0.001; sOXN vs. OXY, P < 0.001; sOXN vs. placebo, P = 0.05
Take Drug Again
Scale of whether the patient would take the drug again were highest after oxycodone (compared with sOXN and placebo) Pairwise comparisons were all statistically significant: OXY vs. placebo, P ≤ 0.001; sOXN vs. OXY, P ≤ 0.001
Subjective Monetary Drug Value
Safety
Incidence of TEAE: 95.7% for OXY, 29.2% for sOXN, 20.8% for placebo. (Most common were euphoric mood, feeling hot, somnolence, and headache) Serious TEAE: 2 cases of ventricular tachycardia (one after sOXN and one after placebo)
|
The concentration of naloxone (0.035 mg/kg) in the sOXN was sufficient to decrease the degree of drug liking when compared with conventional oxycodone (administered intravenously) More data is needed to determine the abuse deterrent properties of sOXN in a real-world setting.
|
| Harris, 201413 |
|---|
Abuse Quotient
AQ 5 times higher in Oxy API (102.15 ng/mL/h) and original oxycodone (94.75 ng/mL/h) than finely (17.57 ng/mL/h) and coarsely crushed tamper resistant oxycodone (16.96 ng/mL/h). Differences in AQ for both finely and coarsely crushed tamper resistant oxycodone vs. OXY API and original oxycontin were statistically significant (P < 0.001)
Drug Liking
Highest drug liking occurred within 1 hour of administration For global measures of drug effect, both finely and coarsely ground reformulated oxycodone had lower Emax than the non-reformulated oxycodone powders (P ≤ 0.002).
Subjective Monetary Drug Value
Safety
No serious TEAEs, or serious AEs. Incidence of AEs: 96.4% for finely crushed oxycodone, 89.7% for Oxy API, 86.2% for finely crushed reformulated oxycodone, 75.0% for coarsely crushed reformulated oxycodone, 41.4% for placebo. Most common AEs were euphoric mood, somnolence, pruritus, and nasal congestion.
|
|
| Webster, 20129 |
|---|
Drug liking at 0 to 1 h, 0 to 2 h, and 0 to 3 h was less for both doses of oxycodone with niacin than for oxycodone and drug dislike was higher for oxycodone with niacin than without. (P < 0.0001 for most comparisons. P value statistically significant for all comparisons) Percentage of participants who disliked the drug at 30 min: 60% (40/240 mg), 64% (80/480 mg), 15% (40 mg/0), 4% (80 mg/0) Decreases in “take drug again” were statistically significant at all assessments (1, 2, and 8 h) comparing oxycodone + niacin with the respective oxycodone doses. Patients found oxycodone with niacin less desirable than oxycodone alone (55% at the 40/240 mg vs. 40 mg/0 dosing and 72% at the 80/480 mg vs. 80 mg/0 dosing)
Safety
The majority of TEAEs were mild to moderate Any TEAE (% patients): 77% 40 mg/0; 98% 80 mg/0; 98% 40/240 mg; 100% 80/480 mg; 13% placebo Most common TEAEs were pruritus, somnolence, and flushing.
|
The initial lower ‘drug liking’ of oxycodone with niacin compared with oxycodone supports the lower abuse potential of the combination, as those taking the drug recreationally expect a positive effect within the first hour. The relative aversive reaction to the niacin versus the oxycodone alone after 8 and 12 hours is promising in deterring abuse. The stronger dislike for the higher dose of oxycodone plus niacin may be a deterrent for abuse and may help prevent overdose.
|
| Webster, 201214 |
|---|
Drug liking
Drug liking was similar for 80 mg CR, 40 mg of IR, and 40 mg CR crushed oxycodone. When compared with 40 mg of IR, 40 mg CR of crushed oxycodone, and 80 mg CR oxycodone, drug liking was significantly less for 40 mg CR (P ≤ 0.05) For the intervals assessed, drug liking was similar for 40 mg IR and 40 mg crushed CR oxycodone.
Drug high
All oxycodone formulations resulted in greater ratings of “do you feel high” than placebo. The maximum high was similar for 40 mg IR, 40 mg crushed CR, and 80 mg CR oxycodone. These were all significantly higher than for 40 mg CR oxycodone (P < 0.05) For each time interval assessed after the first hour, the mean assessment of drug high was similar for the 40 mg IR oxycodone, 40 mg crushed oxycodone CR, and 80 mg oxycodone CR, which were all greater than 40 mg oxycodone CR. Mean time to maximum drug high was shorter for 40 mg IR (1.5 h) than for 40 mg CR (2.4 h) (P < 0.05); no other comparisons were significant.
Safety
TEAEs were mild to moderate Most common TEAEs were pruritus, nausea, headache, and decreased oxygen saturation.
|
Intact CR oxycodone tablets have reduced abuse potential relative to IR formulation. When CR formulation was crushed, the reduced abuse potential was defeated. Oxycodone CR resulted in lower subjective scores of drug liking and high than IR oxycodone. Further, a twofold difference between doses of oxycodone CR and IR oxycodone that yielded comparable subjective effects was observed.
|
| Setnik, 201115 |
|---|
Drug Liking
Remoxy 40 mg (whole and chewed, both on ‘fed’ stomachs) was associated with statistically significantly lower scores of drug liking when compared with Oxycodone IR 40 mg (fasting) and Oxycodone ER 40 mg (crushed, fasting). (P ≤ 0.0461) Time to drug liking was significantly delayed for Remoxy (both whole and chewed) when compared with oxycodone IR and ER crushed (P ≤ 0.0193)
TEAEs:
All were mild to moderate, most common were pruritus, dizziness, somnolence, nausea, and vomiting.
|
|
| Observational Studies |
|---|
| Cicero, 201516 |
|---|
45% of patients entering drug treatment from January to June 2009 (prior to the introduction of the ADF), used OxyContin for non-medical use in the 30 days before entering treatment. After the introduction of ADF OxyContin, 26.0% used OxyContin for non-medical use in the 30 days before entering treatment. (95% CI, 23.6% to 28.4% in July to December 2012; χ2 = 230.83; P < .001) This decrease remained consistent – from January to June 2014, 26.7% used OxyContin prior to seeking treatment (95% CI, 23.7% to 29.6%). 33.3% of RAPID respondents indicated that the ADF had no effect on drug selection and continued to abuse OxyContin; a separate 33.3% indicated that they replaced OxyContin with other drugs as a result of the ADF. 3.3% of respondents indicated that the ADF influenced their decision to stop taking drugs. Of the patients who switched drugs after the introduction of ADF OxyContin, 70% of respondents switched to heroin. Comments from patients included that they had to learn how to make the ADF injectable and that they were able to search the internet for information on how to inject or take the ADF.
|
|
| Degenhardt, 20158 |
|---|
Following the introduction of reformulated OxyContin, there was a lower demand for safe injection equipment. Following introduction of reformulated OxyContin, the reformulated OxyContin was the opioid least injected among users at safe injection sites The number of visits to safe injection sites decreased overall after the introduction of reformulated OxyContin. Prior to the introduction of reformulated OxyContin, 56% of interviewed opioid users had used OxyContin 80 mg in the previous month; following the introduction, 8% had used OxyContin 80 mg in the previous 30 days. There was a low level of Targin use both pre- and post-introduction of reformulated OxyContin (2%, and 0.4% had used in the last month respectively). No clear increase in the use of other drugs.
|
Short term data suggest that the introduction of reformulated OxyContin resulted in reductions in the use of injected OxyContin in Australia. Reformulated OxyContin did not appear to be as attractive for injection drug users.
|
| Larochelle, 201517 |
|---|
Dispensing rates of ER oxycodone products increased from 22.9 to 27.7 mg MED between 2003 and 2010. Immediately following the release of abuse deterrent oxycodone, the prescribing rate dropped by 4.56 mg MED per member per quarter (95% CI −5.91 to −3.21). 2 years after the formulation change, the dispensing rate for ER oxycodone decreased 39% Following the reformulation, no change was detected with respect to the out of pocket cost of OxyContin. Prescription opioid overdose decreased following the reformulation of OxyContin, however, data specific to oxycodone was not presented.
|
Opioid prescription patterns and rates of overdose decreased after the introduction of abuse deterrent oxycodone and the removal of propoxyphene from the market. Market interventions may be helpful in reducing opioid abuse.
|
| Cassidy, 201418 |
|---|
|
|
|
| Havens, 201419 |
|---|
In the month prior to the introduction of ADF oxycodone: 74% reported ER oxycodone abuse, 74% reported IR oxycodone abuse. In the 30 days preceding the interview, the prevalence of use ADF oxycodone was 33%, IR oxycodone (not available in ADF) was 96% Abuse of ADF oxycodone was significantly lower than IR oxycodone for all time periods. (RR = 0.34, 95%CI 0.28 to 0.42). Prevalence of injecting (5%) and snorting (1%) ADF oxycodone was low. Heroin abuse not common in the study population.
|
Following its release, ADF ER oxycodone abuse was infrequent and remained infrequent throughout the study period. Abuse of ER oxycodone did not replace abuse of original ER oxycodone, especially for those who chose injection or intranasal routes of administration. There was some shift from ER to IR oxycodone use following the ADF ER introduction.
|
| Michna, 20147 |
|---|
Abuse rates among patients who switched from ER oxycodone to a non-abuse deterrent formulation following the introduction of the ADF were higher than in those who switched to the ADF. (6.7% vs. 3.5%, relative risk 1.9, P < 0.001) ER oxycodone patients who discontinued ER opioid treatment following the introduction of reformulated ER oxycodone had a higher rate of diagnosed opioid abuse compared with patients who switched to reformulated ER oxycodone (10.9% vs. 3.5%, relative risk 3.1, P < 0.001)
|
31% of ER oxycodone users avoided switching to the abuse-deterrent formulation. Opioid abusers may seek out formulations that are more easily abusable and some may switch from legal to illegal substances.
|
| Rossiter, 201420 |
|---|
In the 6 months following the reformulation of ER oxycodone, rates of diagnosed abuse decreased by 22.7% in commercially insured and 18.0% in Medicaid patients. Change rate was not significantly different from the pre-study period among Medicare-eligible patients. 1
|
|
| Sessler, 201421 |
|---|
A reduced number of ER oxycodone-related fatalities were reported following the introduction of the ADF. This decrease began the first year following the introduction of ADF and became more pronounced the subsequent years. Fatalities involving ER oxycodone decreased 82% (95% CI −89% to −73%) (from 32.8 to 5.8 per quarter) between the year prior to the reformulation and the third year following reformulation. ER oxycodone overdose-related fatalities decreased by 87% (95% CI −93% to −78%) (from 26.0 to 3.3 reports per quarter) between the year prior to the reformulation and the third year following reformulation.
|
The number of spontaneous reports of death that involved ER oxycodone decreased after the introduction of an abuse deterrent formulation. In context with the findings of previously reported studies, authors suggest that there are fewer fatalities associated with the misuse or abuse of ADF ER oxycodone.
|
| Butler, 201322 |
|---|
In the pre-ADF period, 24.0% of opioid abusers reported ER oxycodone abuse in the past 30 days. In the post ADF period, 12.1% of opioid abusers reported ADF oxycodone abuse. A significant difference was not found between the abuse of oxycodone pre and post-ADF formulation (P = 0.06). When authors controlled for the time period when both ER non-reformulated and ADF oxycodone were both available, a significant difference was found (P = 0.003) 33% decline in prescription-adjusted past-30-day abuse of ADF compared with ER oxycodone prior to the reformulation. Frequency of ER oxycodone abuse decreased 30% following the introduction of ADF. 95% CI −34.90 to −25.68, P <0.0001 Reduction in other opioid abuse was not seen during the same study period.
|
The ‘real-world’ results of this post-marketing surveillance study are consistent with the results of controlled trials. The reduction in the use of ER oxycodone following the introduction of the ADF was likely not the result of a trend toward less opioid abuse, as the abuse of oxymorphone and morphine increased, or remained consistent. The study was conducted early after the introduction of the ADF and patterns may change once users learn to use the new formulation. Substantially lower rates of ADF abuse were seen when compared with historical use of ER oxycodone
|
| Coplan, 2013,23 |
|---|
Change in intentional exposures following introduction of ADF:
Abuse: 36% reduction (95% CI −40 to −23, P < 0.0001) Suspected Suicide: 21% reduction (95% CI −26 to −10, P < 0.0001) Misuse: 21% reduction (95% CI −29 to 2, P = 0.0076)
Change in unintentional exposures following introduction of ADF:
Misuse: 26% reduction (95% CI −58 to 37, P = 0.2826) General: 39% reduction (95% CI −49 to −29, P < 0.0001) Therapeutic errors: 20% reduction (95% CI −26 to −9, P < 0.0001)
Change in:
Adverse reactions: 34% reduction (95% CI −50 to −17, P = 0.0005) Withdrawal: 67% reduction (95% CI −74 to −37, P < 0.0001)
Rates of change of other agents (oxymorphone, heroin) were not reduced (mostly increased). |
With respect to events that were reported to poison centres, abuse, therapeutic errors affecting patients, and accidental exposures decreased following the introduction of ADF ER oxycodone. Physiochemical barriers can likely decrease abuse of oxycodone, however may not decrease abuse of opioids in general.
|
| Severston, 2013,24 |
|---|
Mentions of abuse for ADF ER oxycodone decreased progressively each quarter throughout the time period of the study. (Reduction of 38% post-ADF introduction; 95% CI 31 to 45, P < 0.001) Abuse rates of other opioids following the introduction of ADF ER oxycodone were not significantly different. There was a reduction in the number of prescribing errors after the introduction of ADF ER oxycodone. Street cost of ADF ER oxycodone was 22% lower than that of ER oxycodone prior to the reformulation (95% CI: 9 to 33, P = .002 Fewer unintentional therapeutic errors were observed following the introduction of ADF ER oxycodone. The decline was larger for ADF ER oxycodone than for other opioids (P < 0.001)
|
Tamper resistant products may be an important component of abuse reduction programs. Due to the ease of switching, it is difficult to determine the public health implications of ADF ER oxycodone unless other opioids also have tamper resistant formulations.
|
| Butler, 201125 |
|---|
IR oxycodone:
ER oxycodone:
Abuse risk: 0.374 Abuse risk per 100,000 prescriptions: 0.0320 Prescription adjusted Relative Risk of abuse vs. IR oxycodone: 5.821 (P < 0.0001)
|
|
| Rintoul, 201126 |
|---|
From 2003 to 2009 320 deaths were oxycodone-related 172 deaths were attributed to oxycodone toxicity alone. Highest number of drug toxicity deaths occurred in areas with the lowest socioeconomic status (55.2%). 19.9% of all narcotic use was oxycodone use. Oxycodone supply to the area had increased from 7.5 mg to 67.5 mg per capita from 2000 to 2009
|
|
| Roxburgh, 20112 |
|---|
Outpatient treatment for problematic oxycodone use doubled between 2002 and 2008 (0.01 per 1000 people in 2002–03 to 0.02 per 1000 population in 2007–08) 465 oxycodone-related deaths between 2001 and 2009 (largest number in 2007) 10% of deaths were due to oxycodone-only toxicity. Median age of death due to oxycodone: 41 years. 57% were male. The 40 to 49 years age group had the highest incidence of oxycodone related death (31%). Oxycodone
|
Prescriptions for oxycodone increased in Australia, some of which likely reflected proper pain management prescribing. Deaths due to oxycodone had not reached the proportions seen in the United States.
|
| Qualitative Study |
|---|
| Buer, 2014,27 USA |
|---|
Since the formulation change in August 2010, respondents said that OxyContin had become unpopular. They indicated that this was due to not being able to inject or snort the new formulation. Those who used ADF OxyContin orally or claimed to be able to snort (n = 6) or inject (n = 3) the formulation indicated that they did not find the ADF to be ‘as strong’ as the previous formulation. Respondents said that people were willing to pay less for the ADF and therefore were asking for prescriptions for IR formulation, as they were able to sell it for more. They indicated that ADF was therefore, more difficult to find on the black market. Those who did claim to have injected or snorted the ADF did not like the experience. All participants claimed that single ingredient IR oxycodone hydrochloride had replaced OxyContin as the most misused prescription drug.
|
It appeared that reformulating OxyContin had successfully deterred misuse and abuse of the drug in Appalachia. However, the reformulation did not decrease overall opioid misuse or abuse, as use of other opioid (particularly IR oxycodone) formulations increased. The results provide strong support for the development of further reformulations in order to deter intranasal and intravenous administration of prescription opioids.
|
