A large study found that the frequency and type of aberrant behaviors associated with strong opioids prescribed for chronic pain were minimal and generally of minor consequence. While this is good news there are some limitations and biases of the study that should be taken into account.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.
REFERENCES:
> 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].
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9 comments:
From patients to pharmacists to physicians, the rate of addiction is repeatedly overestimated. This study reinforces other recent research revealing prescription abuse and addiction rates at or below 1%. When you account for patients who sell their opioid drugs (rather than abuse them), as well as other non-addiction behaviors, the addiction percentage among chronic pain patients is even lower. I read another such study last year that pegged addiction among chronic pain patients at 0.37%. These rates are far below public and professional estimates and this research shoots a huge hole into groups clamoring to make narcotic pain medications more difficult to access.
Research reports such as this one do not support efforts by governments and agencies to restrict access to opiate medications due to fear of addiction and abuse. In fact, they clearly reveal that addiction and prescription abuse rates are not pervasive societal problems and that further restriction of those medications will only result in needless suffering.
Dr. Leavitt, and other informed commenters, could you please explain to me why these fentanyl breakthrough products continue to be labeled for cancer breakthrough pain only, therefore inducing insurance companies not to cover them for other diseases with similar pain?
I have CRPS in all 4 quadrants of my body. Is there any medical or scientific evidence that my pain is different than cancer pain with CNS involvement? Or is simply a social or cultural bias: the public, and therefore the policy makers at the drug company and governmental level, see cancer patients as more deserving of relief?
My father has had melanoma and pancreatic cancer, my mother has had lymphoma (twice) and my brother has had lymphoma. They had almost NO pain, easily managed by tramadol or hydrocodone. The only cancer patient in my extended family whose pain reached the level that I experience is my grandmother who died of pancreatic cancer.
Please help me to understand the disconnect I am experiencing and trying to make sense of.
Linda Pedigo
West Lafayette, IN
In response to Ms. Pedigo above, we’re really not certain why immediate-release fentanyl products have not been approved for noncancer breakthrough pain. One possibility is that the manufacturers simply did not conduct and submit, as yet, the necessary clinical trials for FDA approval. Another, is that the existence and importance of breakthrough pain in noncancer conditions is still being debated in some circles. Finally, these strong opioids are perceived as being popular with those who would abuse them; hence, the severe restrictions are a reaction to such fears. Or, it may be combination of all three -- which is of no help at all to persons like you who would benefit from the added pain relief.
If you have to be weaned off a drug are you not addicted to it? I know some doctors will tell you are physically dependant on it but that is the nice way to say you are addicted to it.
Physical dependence is a natural occurrence with opioids and is NOT the same thing as addiction. Gradually reducing the opioid dose, or weaning, will help to prevent uncomfortable withdrawal symptoms; again, this has nothing at all to do with addiction. -- SBL
In this age when we have access to medications 80 times more powerful than morphine, no one should suffer from chronic pain. None of us should suffer severe pain for a moment longer, if only our physicians would provide the long-acting drugs that we need (Fentanyl Transdermal, Oxycontin, Kadian, etc.), plus the short-acting narcotics for breakthrough pain (Hydrocodone, Oxycodone, etc) and the off-label medications appropriate for our conditions (anti-depressants, anti-convulsants, anti-inflammatories, etc,).
Sadly, many physicians today are more motivated by fear of going on a DEA list than by adequately addressing the pain needs of their patients. Each day we read articles about the “horrors” of addiction. But the truth is that the percentage of chronic pain patients who become addicted to pain medications ranges from 1% to 3%. Don’t believe me? Here is the latest control group, double blind, algorism based research: http://www.ncbi.nlm.nih.gov/pubmed/20091598?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=1 and http://updates.pain-topics.org/2011/01/study-finds-low-risk-of-rx-opioid-use.html.
There is NO ADDICTION EPIDEMIC! Read for yourself.
We, the patients in chronic severe pain, are victims of a media campaign against the use of opiates for pain management. We, the patients in chronic pain, have become victims as a result of those who abuse and steal narcotics for their own use or to sell to others.
Again, please look at the research revealing the addiction rate at 1% to 3%. Or, conduct your own research. You will see that there IS NO EPIDEMIC OF ADDICTION among us – the chronic pain patients. The addiction epidemic, if there is one, is among drug abusers and those who steal medication in order to sell it to others. Please know that these groups are very separate and distinct.
Almost all of us who require opiates for pain will never sell a single pill, patch or injection. We need it to survive. The more that government makes it difficult for us to access pain medication; the more that people like us will perish from suicide or other conditions related to untreated chronic pain; or the more we will resort to purchasing our pain medications illegally. Thus, the new laws and dictates against the widespread administration of pain medications could backfire, sending innocent pain patients who have never committed a single crime in their lives into the streets to illegally purchase required pain drugs that our physicians were frightened from providing.
Thanks, Charles, for your comments immediately above. In the past, we have referenced that Noble et al. Cochrane review that you link to, which found an extremely low addiction rate. Some of the newer evidence points to a much higher rate (as high as 30%); however, this is a complex subject, and the research is inconsistent and often of questionable quality or validity. We are currently re-examining the evidence (as of May 2012) and hope to arrive at more realistic answers… or, at least be able to say that there is no definitive conclusion. --- SBL
i have recently been advised that i am being taken off the pain medications i have been on for years for my chronic lower back pain of oxycontin 30mg,2 times a day and percocets 10mg, 4 times aday, the reason cited was to save my internal organs from damage and to keep from damaging my liver.this is the first itme this has been mentioned to me in 9 years of since this injury happened. can these medications damage my internal organs as said and damage my liver ? someone please answer this question for me, please. thank you
According to the evidence that I have seen over the years, oxycodone at usual therapeutic dosages does not, in itself, cause permanent internal organ damage. Percocet contains acetaminophen, which at daily doses greater than 3,000 mg can be very harmful to the liver (or lower doses of acetaminophen in persons who regularly drink alcohol). There may be certain undesirable side effects of oxycodone when taken for long periods of time, as with most other opioids, but perhaps there was some misunderstanding of what your physician was trying to communicate. --SBL
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