Writing in the January 2011 edition of the Journal of Pain and Symptom Management researchers retrospectively examined accumulated data from 5 clinical trials of patients taking daily opioids for chronic noncancer pain (≥60 mg/day oral morphine equivalent) and also prescribed immediate-release (IR) fentanyl buccal tablets (FBT) for breakthrough pain [Passik et al. 2011]. The studies, which were primarily to assess FBT safety and efficacy, incorporated up to 18 months of case-report data coded for abuse, overdose, and/or various aberrant behaviors. A total of 1,160 patients were evaluated; 57% women, 93% white, 94% aged ≤65 years. Aberrant behaviors were categorized as those involving FBT (such as, overuse, lost or stolen study drug, and others) and those not involving FBT (eg, patients seeking prescriptions from other sources, not returning for follow-up, etc.).
Only 10 patients (<1%) had an opioid abuse-related event, 18 (<2%) had a positive urine drug screening for a non-prescribed drug or illicit substance, and 12 (1%) had an event consistent with opioid overdose. Overall, 124 subjects (11%) had aberrant behaviors related to FBT, and 68 (6%) had aberrant behaviors that were unrelated to FBT. Aberrant behaviors were significantly more frequent in men and in patients ≤49 years of age.
The authors conclude that the incidences of drug-abuse events and aberrant drug-related behaviors were low, possibly due to adequate patient monitoring in the clinical trials. However, overall, this was a large-scale study and the minimal numbers of problematic events relating to opioid use may suggest that such problems are of a lesser magnitude and significance than is commonly believed. And, this questions whether the need for severe restrictions placed on the prescribing IR-fentanyl formulations and certain other opioids is warranted.
COMMENTARY: Considering the large total sample size of 1,160 patients, the low percentages of problematic events related to opioid use are remarkable; especially when taking into account that patients were managing both around-the-clock opioids for persistent pain and IR-fentanyl for breakthrough pain on a daily basis. There are a number of further points worth noting:
- Behaviors observed in this study as aberrant are probably overstated. The authors identify 40 different drug-related behaviors defined as “aberrant” in the literature, ranging from a missed doctor’s appointment to overdose and death. They concede that the meaning of aberrant behavior in clinical settings has not been well defined or validated, and such behaviors sometimes reflect uncontrolled pain or psychological stress. The authors relied on the “face validity” of behavioral factors that might predict abuse, addiction, or other deviance; however, this was not evidence-based and many so-called aberrant behaviors reflected possibly innocuous everyday occurrences. Similar difficulties in determining what is genuinely aberrant opioid-using behavior have been described by other authors [eg, Chou et al. 2009].
- Indeed, among the 124 aberrant behaviors associated with FBT use, the top 2 were overuse of the drug (79 events) and medication theft (45 events) — which may have explanations other than unqualified misbehavior by patients. Similarly, others categorized as aberrant included motor vehicle accident (7), fear of addiction (6), and loss of medication (5). There were only 6 events considered indicative of actual abuse/addiction and 8 consistent with overdose (although there were no deaths reported).
- Aberrant behaviors not involving FBT included 36 patients who were lost to followup (the largest percentage), 7 who took non-prescribed medications (unspecified and possibly justified), and only 4 cases (<1%) classified as abuse or addiction.
- In total, among the 1,160 patients studied and closely monitored for 18 months, there were only a total of 10 cases of substance abuse or addiction reported (0.8%), which is consistent with low numbers found in other studies [eg, see discussion in Pain-Topics e-Briefing here].
- Higher opioid doses were not associated with greater risks of aberrant behaviors and, of great importance, patients with a history of substance abuse more than 5 years prior to study enrollment were actually somewhat less likely to display aberrant behaviors than those without such a history. Furthermore, the risk of aberrant behavior onset was unrelated to how long the patient had been in treatment and taking opioids during the study.
- The authors describe this study as a “post hoc exploratory analysis”; elsewhere, such an approach has been described as “data mining” or “data dredging.” That is, taking evidence that was initially gathered for other purposes and culling the data for new outcomes of significance. The propriety and validity of this approach is sometimes questioned by authorities on evidence-based medicine.
- The fentanyl buccal tablet formulation under study (Fentora®) is FDA-approved strictly for adult patients who are opioid tolerant and being treated for cancer-related pain. However, the 5 clinical trials enrolled patients with noncancer pain: back pain (57%), osteoarthritis (6%), complex regional pain syndrome (RSDS, 5%), and “traumatic injury” (9%, which might imply acute rather than chronic pain). Therefore, publication of this article might be perceived as an endorsement of “off-label” prescribing of the product. On the other hand, the data do imply that there is no medical rationale for limiting use of the product to cancer pain.
- With the exception of the lead author, Steven Passik, PhD, the other 3 authors were employees of the manufacturer of Fentora®, and the study was sponsored and funded by the manufacturer. While the journal article is written in an objective manner, the potential biases favoring product promotion should be considered — and questioned.
For example, the U.S. FDA has just approved a new formulation of immediate-release (IR) transmucosal fentanyl for the treatment of breakthrough pain in opioid-tolerant adults specifically with cancer (Abstral®, announced 1/7/2011). This product is only available through a REMS (Risk Evaluation and Mitigation Strategy) program requiring distributors, pharmacists, and healthcare providers to be specially enrolled and patients must conform to a Patient-Prescriber Agreement. The FDA is recommending that all manufacturers of IR-fentanyl products adopt the same measures, which means this most likely will happen.
We have advocated for better education of prescribers and patients/caregivers on opioid analgesic safety, and good medical practices balancing the benefits/risks of these agents for better patient care. Further restrictions placed on opioid analgesics do not appear to be supported by much of the research evidence, including data reported in this present study. Unfortunately, the unintended consequences of added restrictions may mean that many patients with pain who would otherwise benefit might be denied access to essential opioid analgesics.
> Chou R, Fanciullo GJ, Fine PG, et al. Opioids for Chronic Noncancer Pain: Prediction and Identification of Aberrant Drug-Related Behaviors: A Review of the Evidence for an American Pain Society and American Academy of Pain Medicine Clinical Practice Guideline. J Pain. 2009;10(2):131-146.e5 [abstract here]
> Passik SD, Messina J, Golsorkhi A, Xie F. Aberrant Drug-Related Behavior Observed During Clinical Studies Involving Patients Taking Chronic Opioid Therapy for Persistent Pain and Fentanyl Buccal Tablet for Breakthrough Pain. J Pain Symptom Manag. 2011(Jan);41(1):116-125 [abstract here].