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17 Articles in Volume 19, Issue #7
Analgesics of the Future: Inside the Potential of 3 Drug Delivery Systems
Balancing Pain Care - and Opioids - in the Aging Adult
Book Review: A Useful Guide for New Pain Practitioners
Correspondence: Opioid Tapering & Discontinuation
Effective Interventions for Post-Stroke Shoulder Subluxation and Pain
Family: Their Role and Impact on Pain Management
Introducing the "Phoenix Sign:" Improved Vascular Perfusion of the Dorsalis Pedis Artery after a Subanesthetic Dose of Lidocaine
Medication Management of Chronic Pain in Patients with Comorbid Cardiovascular Disease
Multisite Pain May Be Associated with Fractures in the Elderly
Reconciling the New HHS Opioid Tapering Guideline with CDC and State Policies
Research Insights: Impaired Motor Imagery in Chronic Pain Conditions
Tapentadol: A Real-World Look at Misuse, Abuse, and Diversion
Temporomandibular Disorders in Performance Artists (Part 2)
Thoracic Outlet Syndrome Presenting as an Acute Stroke Mimic
Untangling Chronic Pain and Hyperarousal with Heart Rate Variability: A Case Report
What topicals exist for post-herpetic neuralgia pain?
When to Keep Your License: Older Physicians and Boundary Issues

Tapentadol: A Real-World Look at Misuse, Abuse, and Diversion

This Schedule II opioid may offer clinicians an alternative to other opioid analgesics for managing pain in appropriate patients.

This article is appearing online in December 2019, in advance of print in the January/February 2020 issue of Practical Pain Management.

 

The Continued Need for Analgesic Alternatives

Abuse of prescription opioids is a widely recognized public health problem in the United States and is associated with substantial morbidity and mortality in addition to the social and legal consequences of substance abuse and addiction.1,2 Although prescription opioids are an important treatment option for relief of acute and chronic pain in appropriate patients,3,4 pain relief is the most common reason for prescription opioid misuse.5,6 Thus, provision of adequate pain management presents a challenge in this era of opioid analgesic abuse, because less attention has been paid to the potentially devastating consequences of dose limitations (or discontinuation) and rapid tapering of opioid analgesics in patients with a legitimate need.7-9 A recent guide from the US Department of Health and Human Services on opioid analgesic dosage reduction or discontinuation notes that the need for appropriate access to opioid therapy must be weighed against the potential risks, including opioid misuse and abuse.10

Current strategies to mitigate the opioid crisis and manage chronic pain focus on new products that treat pain effectively with lower potential for abuse and addiction.11 Although traditional opioids primarily interact with the mu-opioid receptor, large differences in potencies, pharmacokinetic characteristics, and propensity for abuse and addiction are seen between the pharmacological opioid classes.11,12

A Schedule II centrally acting opioid analgesic, tapentadol has two proposed mechanisms of action—mu-opioid agonist activity and norepinephrine reuptake inhibition. Tapentadol modulates pain signals in both ascending and descending neural pathways.13,14 The drug has been available in the United States in immediate-release (IR) and extended-release (ER) formulations since 2008 and 2011, respectively,15,16 but its use is lower than that of other opioid formulations. The IR formulation is indicated for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate;15 ER indications are for pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate, including for neuropathic pain associated with diabetic peripheral neuropathy.16

Although chronic opioid therapy has been shown to increase the potential for drug dependence,17 dependence was not reported in pre-marketing studies of tapentadol IR15 and occurred in less than 1% of patients treated with tapentadol ER in 10 Phase 2 and 3 clinical studies.16 The purpose of this review is to analyze available post-marketing data to provide clinicians with insights into the potential for abuse, addiction, dependence, diversion, or misuse of tapentadol in clinical experience beyond randomized controlled clinical trials.

Methods

PubMed searches were conducted in August 2019 to identify English-language publications using the terms “tapentadol” and “abuse” (OR “addiction” OR “dependence” OR “diversion” OR “misuse”) without date limits. Articles related to tapentadol post-marketing information were selected for inclusion, and the bibliographies of selected articles were reviewed to identify additional sources. In addition, digital congress abstract archives from January 2017 through August 2019 were accessed for scientific meetings of pain medicine (eg, American Academy of Pain Medicine, PAINWeek). A total of 14 publications (12 journal articles, one US federal government report, and one congress presentation) have been included in this review.

Post-Marketing Data on Abuse, Misuse, and Diversion of Tapentadol

Both tapentadol IR and ER formulations have been tracked across multiple outcomes for potential signals of abuse liability since the IR release in 2008. Broader post-marketing data sources, including surveillance results from nationwide programs dedicated to studying and preventing addiction, pharmacy and medical claims databases, and online discussion forums have become available over the past decade as well.15,16,18-31 See Figure 1 and Table I below for a chronological summary of post-marketing data.

Nationwide Surveillance Programs

The RADARS System

The Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System, a proactive surveillance program, utilizes a multifaceted combination of programs to monitor opioid abuse and diversion across all phases of the drug abuse pathway throughout the US.32 An analysis of RADARS programs (Poison Center, Drug Diversion, Opioid Treatment, and SKIP programs) for the first 24 months of tapentadol IR availability (July 2009 through June 2011) was performed to assess the potential for its misuse.18 Findings showed that the overall population-based rates (per 100,0000 population) of abuse and diversion for tapentadol IR were lower compared with those of oxycodone and hydrocodone and were stable over time across all four datasets. When abuse and diversion rates were analyzed per 1,000 unique recipients of dispensed drugs (URDD), greater variability by program was observed for tapentadol IR, which may be related to varying degrees of market penetration of tapentadol IR across different geographic regions and experimentation by abusers with a newly available opioid. In addition, intentional exposure rates for tapentadol IR were low, ranging from 0.003 to 0.02 cases per 100,000 population (0.3 to 0.33 per 1,000 URDD) over the time evaluated.

Rates of nonmedical use of tapentadol IR among college students also were reported to be low during this period based on the College Survey program (another RADARS System program), an internet-based survey of self-identified US undergraduate college students.19 Of the 13,514 eligible respondents, 1626 (12%) reported nonmedical use of prescription opioids within the prior 90 days compared with 101 (0.7%) students who reported nonmedical use of tapentadol IR. Also, following peak use of tapentadol IR (0.013 per 100,000 population in fourth quarter 2009) shortly after its introduction, subsequent use decreased (0.004 per 100,000 population in third quarter 2011).

Subsequent analysis of data from October 2011 to September 2014 from two RADARS System programs (Drug Diversion and StreetRx programs) investigating abuse of tapentadol IR and ER formulations relative to other Schedule II opioid tablets (ie, oxycodone, hydromorphone, oxymorphone, morphine, methadone) showed that tapentadol ER was rarely sold illicitly and, when sold illicitly, had a low street price.20 The average quarterly diversion rate was 0.003 per 100,000 population for tapentadol IR, 0.001 per 100,000 population for tapentadol ER, and 1.495 per 100,000 population for other Schedule II IR and ER opioid tablets; the rate for tapentadol ER was significantly lower than that for other Schedule II IR and ER opioids (adjusted P < 0.001) and tapentadol IR (adjusted P = 0.004). Although analysis showed diversion rates per 1,000 prescriptions dispensed, rates were similar for tapentadol ER (0.016) compared with tapentadol IR (0.030, P = 0.408); the rate with tapentadol ER was significantly lower than the rate for other Schedule II IR and ER opioids (0.172, P < 0.001). In addition, median street prices per milligram for tapentadol ER and IR were similar ($0.10 and $0.18, respectively), and both were significantly lower (adjusted P < 0.0001) than the median price per milligram for other Schedule II IR and ER opioids ($1.00).

Abuse liability of the tapentadol active pharmaceutical ingredient (API; includes data for both IR and ER formulations) was assessed during the time when both formulations were available in the market (October 2011 to June 2016).21 Tapentadol API abuse liability was compared with products containing oxycodone, hydrocodone, oxymorphone, hydromorphone, morphine, or tramadol using data from three RADARS System programs (Poison Center, Drug Diversion, and Opioid Treatment). Tapentadol API was associated with quarterly event rates of abuse and diversion significantly lower than all other opioids compared (< 0.5 cases per 1,000,000 population for tapentadol API across all data streams). In addition, when adjusted for drug utilization, rates of tapentadol abuse liability were still lower compared with most opioids but were not the lowest (see Figure 2).21

NAVIPPRO ASI-MV

The National Addictions Vigilance Intervention and Prevention Program (NAVIPPRO) provides post-marketing surveillance using the Addiction Severity Index-Multimedia Version (ASI-MV) Connect, a national data stream that captures data of individuals assessed for substance use problems for clinical treatment planning and triage purposes.33 ASI-MV is a structured, self-administered computerized interview that measures the severity of a range of problem areas typically associated with drug and alcohol abuse, medical and psychiatric status, family/social relationships, legal status, and employment.

In a study evaluating self-reports of past 30-day abuse of tapentadol IR, tapentadol ER, and 16 other opioid formulations (eg, oxycodone, oxymorphone, hydrocodone, hydromorphone, morphine, fentanyl, tramadol, buprenorphine) among 113,914 individuals assessed for substance abuse between January 2011 and September 2012, tapentadol abuse was reported significantly less often than all comparator opioids (P < 0.001).22 The unadjusted prevalence of tapentadol IR abuse in the past 30 days was significantly lower than that of comparator IR opioids (P < 0.001) except for fentanyl, whereas the abuse prevalence of tapentadol ER was lower than ER opioid comparators (P < 0.001) except hydromorphone ER. In addition, the prescription-adjusted risk for abuse (per 10,000 prescriptions) of tapentadol was significantly lower for tapentadol IR (P < 0.001) compared with all comparators except for tramadol IR, and the relative risk for tapentadol ER was significantly lower than all comparator ER opioids (P < 0.05) except hydromorphone ER.

When the abuse profile of tapentadol ER was compared with corresponding profiles for other ER opioids with FDA–approved labeling for abuse deterrence (ie, abuse-deterrent formulations, ADFs) and with non‒ADF ER opioids in a sample of 205,189 adults assessed for substance abuse from January 2014 through December 2017, annual rates of past 30-day abuse and rates adjusted for prescription volume (1,000,000 tablets dispensed) with tapentadol ER were lower than with comparator ADF and non‒ADF ER opioids (see Figure 3).23 Furthermore, tapentadol ER was associated with less frequent use of nonoral, alternative routes of administration than other ER opioids evaluated.

Other Nationwide Databases

In a 2017 annual report from the National Forensic Laboratory Information System (NFLIS), which collects results of chemical analyses of drugs seized by law enforcement, tapentadol was not listed among the nine narcotics included in the top 25 drugs reported: fentanyl, oxycodone, hydrocodone, buprenorphine, tramadol, carfentanil, morphine, furanyl fentanyl, and codeine; in addition, tapentadol was not included in the list of opioids with ≥ 0.81% of all opioid analgesic reports.24

A retrospective analysis of calls to the National Poison Data System (NPDS) over a 6-year period (November 2008 to December 2013) showed that tapentadol exposures in children and adolescents were uncommon relative to other prescription opioids.25 Of the 104 calls concerning tapentadol exposure reported to NPDS, 93 cases were determined to be unintentional exposures, of which three involved ingestion of tapentadol to abuse it; two other cases involved intentional misuse for a reason other than to achieve a psychotropic effect; three other cases were determined to be suicide attempts.25 In contrast to the number of exposures reported for tapentadol, NPDS received 54,026 and 33,184 prescription opioid exposure reports in children and adolescents from 2000 to 2015 for hydrocodone and oxycodone, respectively.34

Another retrospective study of calls to the NPDS (June 2009 to December 2011), compared differences in reporting of toxicities of tapentadol and tramadol; there were 217 and 8566 individual cases of reported sole ingestion of tapentadol and tramadol, respectively.26 Most common reasons for reported exposures with tapentadol in patients older than 19 years of age were suspected suicide (31.6%) and therapeutic error (24.9%); with tramadol, the most common reasons were suspected suicide (43.4%) and intentional misuse (16.4%). Although reasons for the differences in toxicities are not fully understood, tramadol, unlike tapentadol, has active metabolites and is known to inhibit serotonin reuptake, which together may increase the risk for drug–drug interactions and serotonin syndrome, and other resulting toxicities.35

In summary, results from national post-marketing surveillance programs indicate that the risk of abuse for both the IR and ER tapentadol formulations, including the API, was low compared with other Schedule II opioids, including FDA-approved ADF and non-ADF opioids.

Population-Based Cohort Studies Based on Data from a Claims Database

The IMS LRx is a nationwide longitudinal claims database that captures information on prescribers, all retail pharmacies, and all drugs dispensed, including method of payment (ie, cash versus insurance).27 Using this database, a retrospective cohort study was conducted to compare the risk of opioid doctor shopping behavior (ie, obtaining opioid prescriptions from multiple prescribers) for tapentadol IR compared with oxycodone IR in opioid-naive patients (ie, no opioid prescription within the prior 3 months) who were exposed to these opioids between July 2009 and December 2010.27 In patients followed for 1 year, doctor shopping behavior was observed in a small percentage of patients in the tapentadol IR and oxycodone IR groups (0.20% and 0.86%, respectively); however, when adjusted for gender and benzodiazepine use, risk of shopping behavior was 3.5 times higher with oxycodone IR compared with tapentadol IR.

Another retrospective cohort study analyzed risks of opioid abuse, addiction, and dependence in opioid-naive patients starting tapentadol IR or oxycodone IR in 2010 based on two US claims databases (Optum, MarketScan), with patients followed for 1 year.28 In both databases, tapentadol IR was associated with fewer diagnoses of opioid abuse compared with oxycodone IR.

In a population-based, cohort study, the risks of opioid doctor shopping and abuse among opioid-naive patients prescribed tapentadol IR or oxycodone IR were assessed concurrently based on linked prescription (IMS LRx) and diagnosis (IMS DX) databases (January 2010 to July 2011), with patients followed for 1 year.29 Incidence of opioid doctor shopping was lower in the tapentadol IR group compared with the oxycodone IR group (0.25% vs 0.66%, respectively; adjusted odds ratio: 0.45 [95% CI, 0.36-0.55]); incidence of abuse was also lower in the tapentadol IR group compared with the oxycodone IR group (0.28% vs 0.83%, respectively; adjusted OR: 0.44 [95% confidence interval, 0.37-0.54]). Overall, the risk of doctor shopping and abuse was reported to be lower for tapentadol IR compared with oxycodone IR in these claims database analyses.

Internet Discussions and Surveys

Internet forums discussing prescription drug abuse by recreational drug users capture uncensored information on the trends and preferences of nonmedical use of opioids in real time among prescription drug abusers, thus providing a unique data source for evaluating abuse liability of opioids. In a survey capturing just under 2,000,000 messages posted by recreational drug abusers in online forums between January 1, 2011, and September 30, 2012, the proportion of posts discussing tapentadol (0.0003) was the lowest of the nine compounds compared. It was significantly lower than the proportion for each of the other comparators (oxycodone, oxymorphone, hydromorphone, hydrocodone, morphine, buprenorphine, tramadol, and fentanyl; P < 0.001).30 In addition, the proportion of unique authors posting discussions of tapentadol was also significantly lower (P < 0.001). However, adjustment for prescription volume had essentially no effect on the relative proportions, suggesting that recreational drug abusers may be less interested in tapentadol compared with other opioids.

To characterize motivation, behaviors, and consequences of tapentadol nonmedical use, direct feedback was obtained from a web-based survey completed by recreational drug abusers accessing an online harm-reduction forum from January to May of 2017, followed by an online interview.31 Among 78 adults who completed the survey, levels of tapentadol diversion were low and the main sources were friends, family, and acquaintances; similar sources of diversion were reported for nonmedical use of other prescription opioids.36 Survey results also demonstrated that tapentadol IR and ER formulations were typically used via oral routes of administration (especially “swallowing whole”), and tampering was more common with the ER formulation than the IR formulation. However, median desirability ratings of tapentadol IR or ER were low (41 and 37, respectively, on a scale of 1 to 100, with 100 indicating “best drug imaginable for nonmedical use”) compared with other Schedule II prescription opioids (eg, oxymorphone IR [96], oxymorphone ER [86], oxycodone ER [80], and fentanyl [62]).31 Similarity of median desirability ratings for tapentadol ER and IR formulations potentially indicates that the low desirability is related to the tapentadol molecule and not the formulation. Overall, results from internet discussions and surveys suggest that recreational drug abusers are less interested in both tapentadol formulations relative to other opioid compounds.

Discussion

Based on an array of real-world post-marketing data, including nationwide surveillance studies, clinical/pharmacy databases, and online forums among participants who self-identified as opioid abusers, tapentadol IR and ER appear to have a low potential for unintended consequences compared with most other full agonist prescription opioid alternatives and tramadol. Abuse rates were consistently low at the population level when tapentadol IR was introduced, but variable when adjusted for drug availability. Although ER formulations of prescription opioids have long been identified as desirable for tampering and nonmedical use, abuse and diversion of tapentadol ER have been found to be relatively low. Furthermore, lower rates of abuse were reported for tapentadol ER compared with ADF ER and non‒ADF ER opioid comparators, both at a population level and when adjusted for drug utilization.

As noted in the introduction, a key public health concern is to provide adequate pain management and reduce the risk for nonmedical use and abuse of opioid medications.9 At the same time, existing CDC guidelines for treating patients with chronic pain may place added pressure on prescribers to taper or discontinue opioid therapy, which may have the unintended consequence of motivating patients to seek out illicit opioids for pain control, thereby increasing the risk for abuse/misuse of these medications.9 Thus, the lower risk of unintended consequences reported for tapentadol IR and ER suggests that these formulations may provide an important treatment option for the management of chronic pain.

The pharmacologic properties of tapentadol and finite upper dose limitations may explain the low potential for abuse and misuse of this drug observed in post-marketing studies, but the exact reason remains unknown.15,16 Tapentadol does not have clinically significant cytochrome P450 drug interactions because it undergoes phase II metabolism almost exclusively.15 For the same reason, tapentadol is not affected by cytochrome P450 phenotypical outliers, such as poor or extensive isoenzyme metabolizers, which makes for a simpler conversion when transitioning from other opioids that similarly avoid the phase I metabolism pathway (eg, morphine, oxymorphone, and hydromorphone) and may avoid potential mathematical errors when transitioning to tapentadol from those opioids that do require the phase I metabolism pathway (eg, hydrocodone and oxycodone), especially for extreme phenotypic outliers.37-39

In addition, tapentadol has low or no effect on serotonin reuptake blockade, which minimizes potential for drug interactions and side effects related to serotonin agonist activity and serotonin withdrawal upon discontinuation.37 Moreover, in contrast to tramadol, tapentadol has a high binding affinity to mu receptors, is a full agonist opioid (as opposed to partial agonist), is not a prodrug, and has inactive metabolites only.37,40 When used as directed, tapentadol has been shown to be effective and well-tolerated in patients with chronic pain, with a lower incidence of gastrointestinal adverse events than other strong opioids.41

Limitations

This review presents with several limitations, consisting mainly of a reliance on real-world data, which are not obtained in as carefully controlled or structured a manner as data obtained in randomized controlled trials; uncertainties around drug doses and exposure in analyses conducted by medical examiners; limited availability of data on children and adolescents; and coding issues within the databases assessed. Moreover, the reasons for the comparatively low rates of nonmedical use of tapentadol are not well understood.

Conclusions

Healthcare providers need improved education about options for the management of acute and chronic pain. Post-marketing data show that tapentadol ER and IR are associated with low rates of nonmedical use, diversion, abuse, and endorsement for abuse compared with other prescription opioids, suggesting the public health burden related to tapentadol may be lower compared with that for other Schedule II analgesics. Additional data collection may be expected to provide periodic updates on the experience with tapentadol and other Schedule II medications in support of ongoing efforts to reduce the societal impact of abuse, addiction, dependence, diversion, or misuse related to these agents. 

 

Author Bio and Disclosures

Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP, FFSMB, is a clinical pharmacy specialist in pain management at the Stratton VA Medical Center in Albany, New York, and the CEO and founder of Remitigate, LLC, a software development company with a focus on opioid safety. He serves as an adjunct associate professor at Western New England University College of Pharmacy, and at the Albany College of Pharmacy and Health Sciences. A diplomate of the Academy of Integrative Pain Management, and a fellow of the American College of Clinical Pharmacy (ACCP), the American Society of Health-system Pharmacists, and the Federation of State Medical Boards, Dr. Fudin has been a staunch advocate for patients with chronic pain and an educator to providers for appropriately monitoring and interpreting opioid risks. He founded the ACCP Pain Pharmacy Practice Network group, and as a peer reviewer, helped to establish several clinical practice guidelines, including for arthritis, fibromyalgia, and chronic non-cancer pain, as well as for urine drug monitoring and opioid-induced constipation. Dr. Fudin serves as PPM’s Co-Editor-at-Large and helped to develop the brand’s online Opioid Conversion Calculator.

The content herein is the opinion of the author and does not reflect opinions of the federal government or any affiliations listed.

Dr. Fudin discloses that he serves as a speaker for Acutis Diagnostics, Inc, Daiichi Sankyo, and Astra Zeneca; as an advisory board member for AcelRx Pharmaceuticals, Daiichi Sankyo, GlaxoSmithKline, Quest Diagnostics, Salix Pharmaceuticals, and SCILEX Pharmaceuticals; and as a consultant for Bio- Delivery Sciences International and Firstox Laboratories. Dr. Fudin would like to acknowledge technical editorial and medical writing assistance provided by Pratibha Hebbar, PhD, and Craig Albright, PhD, of Synchrony Medical Communications, LLC, West Chester, PA, under the direction of the author. Funding for this support was provided by Collegium Pharmaceutical, Inc, Stoughton, MA. No funding was provided to Dr. Fudin.

 

 

Last updated on: December 9, 2019
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