February 27, 2018
RADARS® System
Rocky Mountain Poison and Drug Center
Denver Health and Hospital Authority
777 Bannock Street, MC0180
Denver, Colorado 80204
(303) 389-1240
Response to Docket No. FDA-2017-P-5396
This document comments on the Citizen’s Petition requesting FDA should immediately seek
removal of oral and transmucosal ultrahigh dosage unit (UHDU) opioid analgesics from the
market.
We believe the petition should be denied because the scientific evidence upon which it relies is
incomplete and the existing information has been misrepresented in the petition. Many of these
concerns were identified and addressed by Coyle, et al.(1)
1. The petition does not distinguish between opioid abusers and legitimate patients
with pain. Studies to date alleging a dose threshold in mortality associated with
prescription opioids have simply examined the daily prescribed dose of an opioid
analgesic. They have not included other relevant features such as the motive of the person
receiving the prescription. This line of research is still evolving, but it is clear that
multiple groups exist (Green 2011, Kelly 2015): conflating these groups is likely to lead
to errors of misattribution. Published evidence reveals that there are multiple remarkably
different groups to consider:
a. The legitimate patient
i. The overwhelming majority of persons without risk factors who receive a
prescription opioid for treatment of pain will use the drug as directed.
ii. Substantial evidence and professional opinion indicates that this person is
highly likely to use their prescription as prescribed and rarely develops
substance abuse behaviors.
b. The innocent bystander
i. The innocent bystander refers to the person with few or no risk factors
who develops a substance use disorder when treated appropriately for
chronic pain. Less than 1% of legitimate patients who receive an opioid
analgesic for treatment for a chronic pain condition will develop substance
abuse behaviors (Fishbain 2008).
ii. These patients often have or have had a history of alcohol, stimulant or
other substance abuse problem before deciding to abuse an opioid.
Routine brief screening instruments typically alert these concerns to the
physician.
c. The imposter (established opioid abuser)

 i. A substantial portion of persons in this category are actually abusers
posing as a patient in pain in order to use the health care system as a
supplier of opioid analgesics for their abuse and dependence.
ii. These individuals masquerade as a legitimate patient, but never intended
to use the drug as labeled for use. They intend to sell the drug or use
themselves. By deceiving the prescriber, the use the health care system as
their “dealer”.
2. Limiting the size of prescription dosage units is unlikely to meaningfully benefit any
of these groups.
a. The legitimate patient
i. A small proportion of legitimate patients have a condition that requires
large daily doses. When this dosage is required, it should be administered
in the smallest number of doses possible and as infrequently as possible in
order to improve efficacy and reduce adverse events.
ii. If the size of a dosage unit is decreased, these true patients will have to
take many more tablets, which can be expected to cause increased rates of
drug errors, adverse drug events and potentially increase the number of
dosage units available for diversion. In addition, lowering available
dosage sizes increases costs to both the patient and the health care system.
b. The innocent bystander
i. These patients have real pain, which should be treated in the most
effective and safe manner.
ii. If tablet size is decreased, we can expect increased rates of treatment
failure, which could actually encourage the use of larger doses and the
inevitable safety issues inherent in managing multiple tablet doses.
iii. This group won’t benefit from smaller dosage units because the issue is
their desire to get high and the size of the dosage unit will not affect this
desire.
iv. Data indicate that the issue for this group is not the size of the dose, but
the duration of treatment.
c. The imposter (established opioid abuser)
i. The imposter is often experienced at manipulating the health care system
to obtain prescription opioids. The size of the dosage unit is less important
to them. Indeed, as they become aware that smaller tablets create less
suspicion, they will encourage prescribing of these dosage units so they
appear like a legitimate patient.
ii. Furthermore, if these individuals truly desire the drug, they can obtain
opioid from myriad other sources, including heroin and illicitly
manufactured fentanyl.
3. The petition misinterprets the research literature.
a. The petition states that there is increased risk of overdose and death at a threshold
of 90 morphine equivalents (MME)/day.
b. The apparent threshold at 90 MME/day is likely an artifact due to underpowered
analyses. In order to increase power, researchers have aggregated daily doses
above a specified threshold. Therefore, an overdose event at 200 MME, 300

 MME/day or even higher counts the same as an event at 90 MME/day. This
produces the illusion of a dose threshold.
c. It is currently unknown whether a threshold exists. If such a threshold does exist,
it is likely well above 90 MME/day because 90 MME/day is the lowest daily
dosage typically included in the published analyses. However, the data are also
consistent with much higher thresholds.
d. The biologic plausibility of a threshold seems unlikely. While it is logical to
speculate that a higher daily dosage of an opioid would produce a higher rate of
adverse events, this does not infer that a threshold exists. One would expect a
legitimate patient to take their medication as prescribed. If their dose is increased,
it is increased in a stepwise manner and the patient develops tolerance. One would
not expect a sudden catastrophic event when an opioid is administered in this
manner.
e. In contrast, sudden catastrophic events are expected among abusers of
prescription opioids. In these cases, an abuser may take an unexpected amount of
drug or, more likely, combine with other known or unknown toxic substances,
including benzodiazepines, heroin and other drugs.
f. The multidrug use context of many substance use disorders and catastrophic
events suggest that evidence is lacking for a prescription opioid threshold, and
would be nearly impossible to detect because of the myriad doses and potential
interactions between multiple substances, not to mention aberrant routes of
administration like snorting and injecting, which lead to dramatic changes in
absorption and toxicity.
g. The petition is also logically inconsistent in that it ignores transdermal
formulations. The labeled dose of several fentanyl products are above the artificial
threshold suggested. There is no justification presented for why transmucosal and
solid oral formulations would be subject to the alleged dose threshold
phenomenon when some of the citations also included fentanyl patches.
h. Coyle, et al., stated “The results of several reviewed studies show an increasing
risk of misuse, overdose, and death with increasing opioid analgesic dose.
However, these studies do not indicate that there is a specific dose that should not
be exceeded for safe use, or that any dose below a specified threshold is safe. The
available data support the conclusion that all opioid analgesic doses carry some
level of risk, and that this risk increases continuously over a wide dose range.”
4. Conclusion
a. Like many well intended but misguided interventions, the UHDU petition would
penalize the legitimate patient and have little or no effect on abusers of the drug.
The legitimate patient would experience more complicated and more expensive
regimens to treat their pain. Increased complexity inevitably lead to therapeutic
failure in some patients and increases the rate of adverse events.
b. In contrast, there are essentially no benefits to the other groups – the abusers the
ultimately are simply trying to obtain an opioid drug. These individuals do not
care if they get a smaller dosage unit as witnessed by the switch for OxyContin 80
mg dosage units to Roxicodone 30 mg dosage units after OxyContin was
reformulated.

 c. Improved opioid prescribing for pain is an important goal that has life-altering
implications for both chronic pain patients and substance abusers. Restrictions
based on poor science have serious negative effects, including death.

Richard C. Dart, MD, PhD
Rocky Mountain Poison and Drug Center
Denver Health and Hospital Authority
777 Bannock Street, Mailcode 0180
Denver, CO 80204
Richard.Dart@rmpdc.org
303-389-1240 (o)
303-389-1443 (f)
Nabarun Dasgupta, PhD
Rocky Mountain Poison and Drug Center
Denver Health and Hospital Authority, Denver, Colorado
Janetta Iwanicki, MD
Rocky Mountain Poison and Drug Center
Denver Health and Hospital Authority
Sidney Schnoll, MD, PhD
Vice President, Pharmaceutical Risk Management Services
Pinney Associates, Bethesda, MD
Theodore J. Cicero, PhD
Professor, Department of Psychiatry
Washington University School of Medicine, St Louis, MO
Steven Kurtz, PhD
Mark W. Parrino, MPA
American Association for the Treatment of Opioid Dependence, New York, NY
George Woody, MD
Professor of Psychiatry
Perelman School of Medicine
University of Pennsylvania, Philadelphia, Pennsylvania
John Burke
President, Pharmaceutical Diversion Education, Inc.
Bethel, Ohio 45106

 References
Coyle DT, Pratt CY, Ocran-Appiah J, Secora A, Kornegay C, Staffa J. Opioid analgesic dose and
the risk of misuse, overdose, and death: A narrative review. Pharmacoepidemiol Drug Saf. 2017
Dec 15. doi: 10.1002/pds.4366.
Fishbain DA, Cole B, Lewis J, et al. What Percentage of Chronic Nonmalignant Pain Patients
Exposed to Chronic Opioid Analgesic Therapy Develop Abuse/Addiction and/or Aberrant DrugRelated Behaviors? A Structured Evidence-Based Review. Pain Med 2008; 9:
doi:10.1111/j.1526-4637.2007.00370.x
Green TC, Black R, Grimes Serrano JM, Budman SH, Butler SF. Typologies of prescription
opioid use in a large sample of adults assessed for substance abuse treatment. PLoS One. 2011;
6(11): e27244. doi: 10.1371/journal.pone.0027244
Kelly, BC, Rendina HJ, Vuolo M, Wells BE, Parsons JT. et al. A typology of prescription drug
misuse: A latent lass approach to differences and harms. Drug Alcohol Rev. 2015 Mar; 34(2):
211–220.