Kevin Chen

Rutgers University
4219 BPO Way
Piscataway. NJ 08854

April 28, 2014

Moriah Weissman, RPh, PharmD, CCD

President
New Jersey Pharmacists Association
760 Alexander Road
Princeton, New Jersey, 08543

Dear Dr. Moriah Weissman,

I am very thankful for your attendance at the presentation of my proposal to fix the problem of
prescription painkiller abuse. The following attachment explains the problem that created this
national epidemic, and the solutions that would ultimately stop and prevent the misuse of
prescription painkillers in our country. The use of new, non-addicting painkillers and appropriate
substitute drugs will negate the use of the current drugs that have a high potential for abuse and
physical harm. It is necessary for your further examination into this subject, as the solutions are
going to require the human resources of your company in order to be successfully implemented.
With your experience and expertise leading the New Jersey Pharmacists Association, the creation
and implementation of CR845 will be soon available to the general public

Prescription painkillers are especially hard to combat when it comes to misuse due to the nature
of the drug. These drugs are designed to negate pain, and cease to function when it is no longer
administered, which leads to positive feedback mechanism of even more pain. It is crucial for the
current generation of prescription drugs to be re-evaluated and eventually replaced by newer
drugs of safer nature and lower potential of abuse. Drugs such as CR845 and other drugs that do
not target the reward pathways in the brain will be successful in negating pain in patients while
preventing it from being used without context. This will prevent overdose, which is the biggest
cause of accidental death in the modern American society.

To solve the issue of prescription painkiller abuse, I seek to implement drugs that have shown
significant success in clinical trials and effectiveness in post-clinical trials to be commercially
available, so all pharmacies and medical practitioners can prescribe these medications as a
replacement of the traditional painkillers that plague our society. If you have any concerns about
this plan, or any questions regarding to this topic, please feel free to contact me through my
email (kmc408@rutgers.edu), or by phone (973-567-5727). Thank you for your time and
consideration into my proposal, I am looking forward to hearing from you soon.

Sincerely,

Kevin Chen
 Pharmacological Methods to Halt and Prevent Growth of Painkiller Abuse

Submitted by:
Kevin Chen

Submitted to:
Moriah Weissman, RPh, Phar.D., CCD
President
New Jersey Pharmacists Association
760 Alexander Road
Princeton, New Jersey, 08543

Date: April 28, 2014

Scientific and Technical Writing

Professor Nicole Reda

Abstract
Ever since the discovery of painkillers, its use by people has proved dramatic results in the
suppression and control of pain from various sources in all human body parts. This extreme
efficiency comes with a cost, however. Even after hundreds of years of clinical research and trial,
most painkillers still pose a serious threat to health when taken in high doses or when
administered incorrectly. Although painkillers are very effective at treating pain, the general
trend of higher effectiveness leading to higher lethal dosage is very prevalent. This is a red flag
for people who are poor at personal pain management, or people who are uninformed about the
negative side-effects of these drugs. It is a commonly known fact that illegal drug use is
detrimental to health, but much of the public remain unaware of the legality and danger of
prescription painkillers. Prescription painkillers are effective at a very low dose while having a
low lethal dose, which means that death by overdose is very prevalent.

There are ways to prevent and control this modern epidemic of painkiller abuse. For most
people addicted to painkillers, the reason for addiction is the high chance and high severity of
withdrawal symptoms. People are not able to wean off prescription painkillers even when they
have no pain because the Dopamine receptors in the brain are damaged from long term use of the
drugs, leading to a feedback mechanism of requiring more painkillers to achieve the same
effects. Clinical studies by Cara Therapeutics Inc. have shown the dramatic impact of anti-opioid
medications in controlling cravings and withdrawal symptoms of patients. The use of their drug
CR845 provides for an alternative opioid that does not lead to the dependency associated with
past-generation drugs such as Vicodin. Additionally, solutions of fixing benzodiazepine abuse
include the use of Flumazenil, which significantly impact the recovery rates of patients and aid
with halting withdrawal symptoms that are seen in many people who are addicted to
benzodiazepine type drugs. The plan is to introduce Flumazenil and CR845 to clinics across the
nation and aid with people who are hesitant to try other methods of recovery, such as support
groups.

1
Table of Contents
Abstract.......................................................................................................................................................i
Table of Contents.......................................................................................................................................ii
Table of Figures.........................................................................................................................................ii
Introduction...............................................................................................................................................1

History of Painkiller Abuse.....................................................................................................................1

Different categories of prescription painkillers.......................................................................................3

Causes of Opioid Addiction.....................................................................................................................3

Origins of Benzodiazepine Addiction......................................................................................................5

Literature Review......................................................................................................................................6

Use of alternative painkillers and opioids...............................................................................................6

Flumazenil research and use in Italy.......................................................................................................8

Plan Details................................................................................................................................................9

Integrating CR845 as the standard Opiate painkiller..............................................................................9

Popularizing Flumazenil in the domestic market..................................................................................10

Budget.......................................................................................................................................................10

Justifications..........................................................................................................................................11
Discussion.................................................................................................................................................12
References................................................................................................................................................13

Table of Figures
Figure 1: Prescription Opioids largest contributor to drug-induced deaths 1
Figure 2: Nonmedical use of medications and drugs in 12th graders (in the past year) 2
Figure 3: Increase in Unintentional Overdose Deaths Involving Opioid Analgesics, 1999-2008 3
Figure 4: Death rate from overdoses caused by a single prescription painkiller 4
Figure 5: Estimated number in ER visits involving Benzodiazepines 5
Figure 6: Number of deaths from benzodiazepines 6
Figure 7: Pain intensity in patients who have taken CR845 vs. Placebo 7
Figure 8: Incidence of Opioid-related Adverse Events over 24 hours 7
Figure 9: Reversal of midazolam sedation by flumazenil vs. placebo 8
Figure 10: Sum ( SEM) of changes in self-rated aggression seen in flumazenil use vs. placebo 9
Figure 11: Timeline for Drug Evaluation 11

2
Introduction
History of Painkiller Abuse
Ever since the beginnings of civilization, mankind has been in an endless search for the ultimate
painkiller that would remedy all ailments and discomforts caused by the natural world. The
discovery of alcohol has shown a dramatic impact in temporarily numbing pain in its users;
however it often causes debilitation and proved to be very addictive due to its nature. The further
discovery of the medicinal benefits of opium, refined from the poppy plant, marked a dramatic
new era in the use of painkillers. Opium is extremely effective in subduing acute pain; early
examples are often mixed with alcohol to create the remedy Laudanum. However, Laudanum
proved to be very addicting and highly lethal at even low doses, so alternatives are researched to
replace it (Narconon International, 2015). The synthesis of morphine, a much more stable and
effective compound than opium, proved to a milestone in the invention of modern painkillers.
Government regulations of morphine and its derivatives such as heroin are very lax in the early
nineteenth century. It wasnt until the Harrison Narcotic Tax Act of 1916 where opiates such as
morphine are put under the control of doctors, requiring a prescription in order to acquire these
potent medications (Narconon International, 2015). In modern times, many different classes and
trade names of opiates are synthesized for prescription use only. These contemporary opiates
include hydrocodone (Vicodin), oxycodone (OxyContin/Percocet), and codeine (cough syrup)
(National Institute on Drug Abuse, 2014). These modern opioids are significantly more effective
than NSAIDs (Aleve, Advil, etc.) in treating chronic pain, due to the fact that opioids directly
affect the central nervous system by binding to opioid receptors and nulling pain signals, while
NSAIDs act in the peripheral nervous system and only work on body tissues that are directly
injured by reducing inflammation (Pasternak, 1993). In recent times, prescription painkillers
have shown a dramatic increase in use and overdose-related deaths, as illustrated by Figure 1.

Figure 1:

Source: Addressing Opioid Dependence in the Primary Care Setting (Brigham and
Womens, 2012)

1
Drug abuse and overdose is very prevalent in cities, where both the affluent and the extremely
poor dabble in painkillers. According to the Center of Disease Control (CDC), Prescription drug
overdose is the leading cause of injury death in the United States, killing 43,982 people in 2013
(Centers for Disease Control, 2015). Also in 2013, 81.1% of drug overdoses were unintentional,
while only 12.4% have suicidal intent. More than half of these overdoses were caused by
pharmaceuticals, medications that are prescribed by doctors to help their patients (2015). A major
cause of drug overdose is the addictive nature of the drugs, causing the users to develop
dependences that require more substances to achieve the same painkilling effect. Mistakes in
dosing due to dependence are the leading cause of overdose (2015). Additionally, the rise of
abusing painkillers is also seen in teenagers and young adults, many stealing the prescribed
medications from parents with chronic pain issues (Figure 2).

Figure 2:
Nonmedical use of medications and drugs in 12th graders (in the past year)

Source: University of Michigan, 2011 Monitoring the Future Study

While some efforts are used to combat the addiction rate of drugs, they continue to be ineffective
with fixing the problem as a whole (Manchikanti, 2006). Due to the effective nature of
prescription painkillers, physicians often liberally prescribe these medications to patients in
regards to a number of ailment. These over-prescriptions frequently cause overdose because of
the high feeling the patients get when the medicine is taken. Americans seeking treatment for
the addiction of opioids increased by 900% since 1997 (Brandeis University, 2015). According to
the Brandeis study, the prevalence of this starting addiction is due to the long-term prescription
of opioids that are very addicting, a practice that is encouraged by many opioid manufacturers
(2015).

Another class of potent painkillers are barbiturates. Barbiturates are a class of potent sedatives
that are prescribed to combat neuroses and psychoses, which are effective in certain doses

2
(Lopez-Munoz et al 2005). Popular in the 1930s and 40s, barbiturates were eventually phased
out due to the high toxicity and high frequency of suicidal self-poisoning in its users (Aitken &
Proudfoot, 1970). Benzodiazepines took over as the premier anxiolytic medication that filled the
roles that barbiturates did. The use and dangers of Benzodiazepines will be further discussed in
this proposal.

Different categories of prescription painkillers

There are many classes of painkillers that are prescribed, which target different parts of the
human body for specific purposes. The two main classes of prescription painkillers that are the
causes of this national epidemic are opiates and benzodiazepines (BZD). These two classes of
drugs have different mechanisms of action, toxicity, and anatomical targets, but they are similar
in that they are often abused due to the rewarding high that they make the users feel. Due to
the chemical and mechanical differences of these two categories of drugs, different strategies
must be used to combat the addition rates and overdose caused by them. The mechanisms of
action taken by these two categories of drugs will be elaborated in the next two sections.

Causes of Opioid Addiction

Opioids are a class of drugs that resembles opiates in its chemical effects on the body. These
drugs bind to opioid receptors, which are found primarily in the central nervous system (CNS)
that includes the brain and spinal cord. Long term use of opioids leads to tolerance, or
neuroadaptations resulting in reduced drug effects for the same amount of drugs taken. This
means that as a patient progresses with taking the opioids prescribed to them, they may find
themselves needing more active drugs to achieve the same painkilling effect (Pradhan, et al.,
2010). This often leads to dangerously high levels of opioid intake, which results in overdose
leading into death. The world health organization estimates that 69,000 people die every year
from this opioid overdose, and an estimated 15 million people suffer from opioid dependence
(addiction). The bigger problem stated by the organization is that while there are effective
treatments for opioid dependence, only 10% of people who need it are receiving it (World Health
Organization, 2014). Recent data has shown dramatic increases in opioid overdose deaths, as
seen in Figure 3.
Figure 3:
Increase in Unintentional Overdose Deaths Involving Opioid Analgesics, 1999-2008

3
 Source: Centers for Disease Control and Prevention, accessed through CDC Wonder
Online Database, 2011
Currently, there are effective treatments to opioid addiction. A prominent example of these
treatments include methadone and buprenorphine. Both of these medications are opioid agonists,
they target the opioid receptors in the central nervous system and disrupts them so that it would
not take up the prescription opiate painkillers (Veilleux, Colvin, Anderson, York, & Heinz, 2010).
However, problems exist in both the administration of methadone and buprenorphine.
Methadone is, ironically, still an opiate. What sets methadone apart from other opiates is that it
has a potential for delayed toxicity, meaning that the symptoms of overdose could appear much
later than traditional overdose symptoms would (Wolff, 2002). Many people who overdose from
methadone resulted from taking methadone to cure an existing opiate overdose, only to overdose
on methadone much later. Figure 4 shows the rate of overdose from people taking different
opioids. It is important to note that this figure accounts for overdose from a single painkiller, not
a conjunction of different opioids. The combinations of methadone and other opiates such as
oxycodone may lead to even higher overdose numbers.

Figure 4:
Death rate from overdoses caused by a single prescription painkiller

Source: Substance Abuse and Mental health Services Administration, Center for
Behavioral Statistics and Quality, Drug Abuse Warning Network Medical Examiner
Component, 2009

As figure 4 suggests, Methadone has the highest rate of overdoses when compared to other
opiates. The second drug discussed before for use in anti-overdose measures is Buprenorphine,
which is also included in Figure 4. Buprenorphine is a newer alternative developed in more
recent times, and has generally replaced methadone in most major health institutions (Whelan &
Remski 2012). It has a much lower overdose rate, the lowest overall in fact, but it does have its
faults. The problem with buprenorphine is its cost and availability. Buprenorphine is much less
liberally prescribed to patients than other opiates. For example, Oxycontin, a potent opiate
painkiller, is featured in the 100 most prescribed branded drugs in a Medscape Medical News
journal. Oxycontin is prescribed 5,505,961 times in September 2014 alone, it is the 26th most
prescribed drug. On the other hand, Buprenorphine is not even mentioned on that (Brown, 2014).

4
Additionally, Buprenorphine is by no means cheap. Patients without health insurance can expect
to pay more than 500 dollars a month for anti-opioid medication, which would put an even
greater economic burden after they have already spent large amounts of money on other
painkillers (Bup Practice, 2015). A 20 tablet supply of Oxycontin can cost from 100-300 dollars,
depending on the concentration of the tablet, this means that a patient seeking to stop opiate
withdrawal can easily spend up to 1000 dollars a month on medications (Drugs.com, 2015).

Origins of Benzodiazepine Addiction

Benzodiazepines (BZD) are a class of drugs that are used to treat anxiety, sleeplessness,
paranoia, and other mental disorders. It works by enhancing GABA receptors, which result in
sedative, anxiolytic (anti-anxiety), hypnotic, and muscle relaxing properties. However, high
doses of benzodiazepines may cause amnesia and dissociation (Page, Michael, Sutter, Walker, &
BB, 2002). Short term BZD use is generally viewed as safe and effective, but long term use is
controversial. This is due to concerns about its side effects, which include decreased
effectiveness, physical dependence, and withdrawal (Saas & Gallarda, 2007). This poses as a
danger to people taking BZD to treat anxiety, as BZD is prescribed to be taken as a long term
medication for anti-anxiety treatment (Dikeos, Theleritis, & Soldatos, 2008). The most common
side effects of BZD are aggression and violence, but more important long term effects are shown
to be severe cognitive impairment (2008). Patients stopping long term use of BZD may suffer
from Benzodiazepine Withdrawal Syndrome, which includes sleep disturbances, increased
anxiety, panic attacks, and cognitive impairment. The very symptoms that BZD are designed to
treat are the same as the withdrawal symptoms (Petursson, 1994). Additionally, recent studies
have shown a rising trend with emergency room visits correlated with the use of BZD, and in
conjunction with other drugs, as seen in Figure 5. There has also been an increasing trend in
deaths related to BZD use, see Figure 6.

Figure 5:
Estimated number in ER visits involving Benzodiazepines alone and in conjunction with
other drugs

5
Source: 2005 to 2010 SAMHSA Drug Abuse Warning Network (Substance Abuse and Mental
Heakth Services Administration, 2014)

Figure 6:

Source: National Center for Health Statistics, CDC Wonder (National Institute on Drug
Abuse, 2015)

Literature Review
Models

Use of alternative painkillers and opioids

A breakthrough drug named CR845 developed by Cara Therapeutics Inc. has recently undergone
phase 2 trial and even been featured in applications in Japan. CR845 is an opiate, but it does not
produce the high effect that traditional opiates do when acted on the opioid receptors in the
central nervous system (Cara Therapeutics, 2015). The way CR845 works is that it agonizes the
kappa opioid receptors that exist in the central nervous system. This means that the receptors
would be more available to take in more peptides. Kappa opioid receptors are proved by a study
to create dysphoric feelings, which counter the euphoric high feelings that traditional opiates
give (Land, et al., 2008). Traditional opiates such as oxycodone do not act on the kappa opioid
receptors that exist in the CNS, which means that the feelings of euphoria are unrestrained and
open to abuse by patients (Pradhan 2010). By acting on the kappa receptors, and instead targeting
the peripheral nervous system, CR845 subdues pain in site-specific areas such as the knees or the
back (Cara Therapeutics 2015). The main purpose of CR845 is to subdue pain, whether it be
acute or chronic, just like any other traditional opiate. Figure 7 showcases the effectiveness of
CR845 when compared to a placebo in pain management. The collected numbers are based on

6
patients who took CR845 and patients who took a placebo medication immediately after
laparoscopic surgery, and the data is recorded over the period of two days.

Figure 7:
Pain intensity in patients who have taken CR845 vs. Placebo

Source: Phase 2 Clinical Trial of CR845 Administration for Hysterectomy Surgery

conducted by the U.S. National Institutes of Health (U.S National Institutes of Health, 2014)

Additionally, in the same trial conducted by the US National Institutes of Health, CR845 is
shown to exhibit minimal side effects reported by patients. Patients taking the placebo actually
reported higher amounts of nausea and vomiting, along with other side effects, when compared
to those who took CR845, as seen in Figure 8.

Figure 8:
Incidence of Opioid-related Adverse Events over 24 hours

Source: Phase 2 Clinical Trial of CR845 Administration for Hysterectomy Surgery

conducted by the U.S. National Institutes of Health

7
CR845 has recently been taken up by Maruishi Pharmaceutical Company, Ltd. To produce orally
administered medications. CR845 is projected to be approved by the FDA in 2016, and
introduced to the general public shortly after (usatoday.com 2014).

Flumazenil research and use in Italy

Flumazenil is a GABA receptor antagonist, a drug that reverses the effect of benzodiazepine
overdose and dependence much like an antidote. It works by competitive inhibition of the GABA
receptor site that also takes in benzodiazepine, effectively blocking it out of the system
(Goldfrank, 2002). It is currently the only GABA receptor antagonist available, which makes it
very valuable and desired in the treatment of benzodiazepine dependence.

In Italy, the treatment of BZD dependency is the administration of 8-10 days of low dose
flumazenil (Lugoboni, et al., 2011). One addiction treatment center in Italy has used this to treat
over 300 patients who are dependent on benzodiazepine (Lugoboni & Leone, 2012). Flumazenil
has also been tested against placebo in studies of benzodiazepine withdrawal, and the results
show that flumazenil is significantly more effective in stopping withdrawal symptoms, as seen in
Figure 9.

Figure 9:
Reversal of midazolam sedation by flumazenil vs. placebo

Source: Reversal of central benzodiazepine effects by intravenous flumazenil

In another study, flumazenil has shown to be effective in curbing hostility and aggression seen in
people dependent on benzodiazepine. Twenty patient are tested, ten treated with flumazenil and
ten control (Saxon et. al 2010). The study shows that the patients treated with flumazenil exhibit
improvement in aggression when compared to the placebo, as shown in Figure 10.

8
 Figure 10:
Sum ( SEM) of changes in self-rated aggression seen in flumazenil use vs. placebo

Source: Reduction of aggression during benzodiazepine withdrawal: Effects of flumazenil

The Italian model along with contemporary studies show the efficiency of flumazenil in treating
benzodiazepine overdose and dependence, however the use of flumazenil in clinical settings are
currently confined to Italy. An introduction of flumazenil to the United States as the primary
treatment for benzodiazepine related health issues will prove to be extremely beneficial to our
patients.

Plan Details
Integrating CR845 as the standard Opiate painkiller

As proven by clinical trials and the acceptance by pharmaceutical manufacturers, CR845

represents the new generation of opiates designed to be extremely functional, potent, and
effective while being non-addictive and less abusive than current opiates. By implementing
CR845 as the premier opiate used to treat chronic pain, opiate addiction and the resulting
overdoses would be reduced significantly. A staggering 60% of people reported the use of
hydrocodone in a recreational, non-medicinal manner in the year of 2012 (Volkow, 2014). The
implementation of CR845 to replace hydrocodone and other opiates will significantly cut down
this statistic due to the non-addicting and abuse-free nature of the drug. Pharmaceutical
companies in the United States have not taken up CR845 in production yet, the current producers
of CR845 is in Japan. With your expertise and leadership in the New Jersey Pharmacists
Association, the process of manufacturing and sale of this medication will take up in the
pharmaceutical companies domestically. New Jersey is home to many headquarters and research
facilities of pharmaceutical companies; such as Merck, Pfizer, Johnson & Johnson, and Ortho-
McNeil. The close proximity and availability of these research companies presents an

9
opportunity for the creation and distribution of CR845 in the domestic market. Currently, the
Japanese market has been opened up through the adaptation of the drug by companies such as the
Maruishi Pharmaceutical Company. We will follow the steps taken by Maruishi and integrate
CR845 as the staple opiate for pain treatment, and ultimately solve the current crisis of
prescription opiate abuse and dependence.

Popularizing Flumazenil in the domestic market

As stated before in the literature review, flumazenil has been proven to be very effective in the
treatment of people undergoing benzodiazepine addiction and withdrawal. The efficacy of
flumazenil has been proven in both clinical trials and in general applications in Italy, and it
shows a promising trend of reducing aggression and increasing alertness in people influenced by
BZD. An introduction of flumazenil to the American market would not only dramatically
decrease the number of BZD overdoses and addiction rates, but it would also open up to new
drugs that would eventually replace benzodiazepines as the leading anxiolytic medication.
Currently, flumazenil is the only kind of medication designed to treat benzodiazepine overdose,
so its introduction and manufacture in the United States would pave way to other competitors
and even better medication for the treatment of drug overdose (Lugoboni 2011). The current
models that show success in Italy can be recreated in the domestic setting, and eventually
eradicate the prevalence of prescription BZD overdose and dependence. With the help of the
NJPhA, your influence will greatly help spread awareness and incentive to popularize flumazenil
to the American market. It is stated in the mission of the NJPhA to increase advocacy for
pharmaceuticals. The work of your organization in increasing awareness for the use of
Flumazenil will have dramatic results in making the drug more readily prescribed.

Budget
The process of getting a new drug into the US commercial market is complex and extend many
years once submitted to the US Food and Drug Administration (FDA). According to the World
Health Organization, recent estimates of having a drug approved by the FDA is $802 million
dollars (Sauer & Sauer, 2005). However, due to market drug approval, the cost of introducing
CR845 and Flumazenil will be decreased. Additionally, pharmaceutical companies are expected
to earn 1 to 5 billion dollars in revenue at the peak of the drug sales cycle (Targum & Milbauer
2008).

With the influence of the NJPhA, pharmaceutical companies would take up this opportunity to
introduce CR845 to the FDA and earn the corresponding profit when it finally hits market. By
encouraging the incentive of profit to pharmaceutical companies, the introduction of CR845 will
save millions of lives over the course of the next couple of decades. Figure 11 shows the
estimated timeline for drug evaluation. CR845 has completed Phase 2 trials and are currently
undergoing phase 3 trials, which would put it around 4 years away from full availability to the
market. By encouraging pharmaceutical companies, this process could potentially be shortened
through more resources dedicated to research and development (Targum & Milauer 2008).

10
 Figure 11:

Source: Graph created based on information provided in Scientific American article,

"Faster Evaluation of Vital Drugs"

Flumazenil has already been FDA approved in 1991, and has been taken off patent in 2008. This
means that no funds would need to be appropriated for FDA approval. The primary costs to
popularize flumazenil would be through the advocation of pharmacists and other medical
professionals. The cost of advocating for the use of flumazenil is dependent on the support and
representation from members of the NJPhA. These costs would be negligible due to the fact that
the NJPhA is a political action committee that consists of volunteers. Any operating costs would
be covered through donations made by sponsors and supporters.

Completing CR845 FDA approval $802,000,000

Cost of Flumazenil advocation $0

Total $802,000,000

Justifications

CR845 requires full FDA approval, which is estimated to be 802 million dollars as of
2015. The cost of getting pharmaceuticals FDA approved is steadily increasing, which
means that the sooner the funds are appropriated and created, the more potential profits
pharmaceutical companies can expect to make, and the more lives that the new drug
would save.
Flumazenil advocation would be enacted purely through volunteer support from the
members of NJPhA, there would be no costs associated other than the base operating
costs of the organization itself.

11
Discussion
The problem of prescription painkiller abuse and overdose is increasingly prevalent, and needs to
be dealt with as soon as possible. The two main categories of involved painkillers discussed are
opiates and benzodiazepines, and the plans to lessen the overdose and abuse rates will effectively
lower the startling statistics. The method to deal with opiate abuse and withdrawal symptoms is
to replace traditional opiates with CR845, a non-addictive, non-abusing medication currently
under phase 2 of clinical trials. The solution to the increasing numbers of benzodiazepine
dependence is to advocate for the use of flumazenil, an antidote that effectively halts all negative
effects of benzodiazepine overdose.

The costs of approving CR845 may seem staggering at first, but the profits generated by
pharmaceutical companies who take up the new drug will effectively negate the developmental
costs required. As shown in statistics, profits generated by big pharmaceutical companies are
very significant, and the incentive to create a drug that will solve the modern epidemic while
generating profits is very high.

By replacing addicting painkillers with non-addicting equivalents, and implementing

pharmacological strategies to cure overdoses in cases of emergency, negative prescription
painkiller related statistics will dramatically lower, and the people of the United States would
live healthier, more painless lives than it is ever possible.

12
References
Aitken, R., & Proudfoot, A. (1970). Dangers of Barbiturates. Br Med J, 295-295.

Brandeis University. (2015, Februrary 4). Opioid and heroin crisis triggered by doctors

overprescribing painkillers. Retrieved from ScienceDaily:

www.sciencedaily.com/releases/2015/02/150204125945.htm

Brigham and Womens. (2012, Fall). Addressing Opioid Dependence in the Primary Care Setting.

Retrieved from Department of Psychiatry Update:

http://www.brighamandwomens.org/Medical_Professionals/education/publications/Psych

iatryUpdate/images/Psychiatry-Update-Fall2012.pdf

Brown, T. (2014, November 03). 100 Most Prescribed, Best-Selling Branded Drugs Through

September. Retrieved from Medscape: http://www.medscape.com/viewarticle/834273

Bup Practice. (2015, April 27). Cost of Buprenorphine Treatment to Patients. Retrieved from

Bup Practice: http://www.buppractice.com/node/12321

Cara Therapeutics. (2015). CR845. Retrieved from Cara Therapeutics:

http://www.caratherapeutics.com/dimerscreen-technology.shtml

Centers for Disease Control. (2015, April 3). Injury Prevention & Control: Prescription Drug

Overdose. Retrieved from Centers for Disease Control and Prevention:

http://www.cdc.gov/drugoverdose/epidemic/index.html

Dikeos, D., Theleritis, C., & Soldatos, C. (2008). Benzodiazepines: effects on sleep. In S. Pandi-

Perumal, J. Verster, J. Monti, M. Lader, & S. Langer, Sleep Disorders: Diagnosis and

Therapeutics (pp. 220-222). Informa Healthcare.

Drugs.com. (2015, April 27). OxyContin Prices, Coupons and Patient Assistance Programs.

Retrieved from Drugs.com: http://www.drugs.com/price-guide/oxycontin

13
Goldfrank, L. R. (2002). Goldfrank's toxicologic emergencies. New York: McGraw-Hill Medical

Publ. Division.

Land, B., Bruchas, M., Lemos, J., Xu, M., Melief, E., & Chavkin. (2008, January). The

dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid

system. J. Neurosci, 28(2), 407-414.

Lpez-Muoz, F., Ucha-Udabe, R., & Alamo, C. (2005). The history of barbiturates a century

after their clinical introduction. Neuropsychiatric Disease and Treatment, 1(4), 329343.

Lugoboni, F., & Leone, R. (2012, July). Addiction, 107(7), 1359.

Lugoboni, F., Faccini, M., Quaglio, G., Casari, R., Albiero, A., & Pajusco, B. (2011). Agonist

substitution for high-dose benzodiazepine-dependent patients: let us not forget the

importance of flumazenil. Addiction, 853-853.

Manchikanti, L. (2006). Prescription Drug Abuse: What is Being Done to Address This New

Drug Epidemic? Testimony Before the Subcommitee on Criminal Justice, Drug Policy

and Human Resources. Pain Physican, 287-321.

Narconon International. (2015). Prescription Drug Abuse History. Retrieved from Narconon:

http://www.narconon.org/drug-abuse/prescription-drug-history.html

National Institute on Drug Abuse. (2014, November). How do opioids affect the brain and body?

Retrieved from drugabuse.gov: http://www.drugabuse.gov/publications/research-

reports/prescription-drugs/opioids/how-do-opioids-affect-brain-body

National Institute on Drug Abuse. (2015, February). Overdose Death Rates. Retrieved from

Drugabuse.gov: http://www.drugabuse.gov/related-topics/trends-statistics/overdose-

death-rates

14
Page, C., Michael, C., Sutter, M., Walker, M., & BB, H. (2002). Integrated Pharmacology (2nd.

Edition). C.V. Mosby.

Pasternak, G. (1993). Pharmacological mechanisms of opioid analgesics. Clin Neuropharmacol,

1-18.

Petursson, H. (1994). The benzodiazepine withdrawal syndrome. Addiction, 89(11), 1455-1459.

Pradhan, A., Walwyn, W., Filliol, D., Erbs, E., Matifas, A., Evans, C., & Kieffer, B. L. (2010).

Ligand-Directed Trafficking of the -Opioid Receptor In Vivo: Two Paths Toward

Analgesic Tolerance. The Journal of Neuroscience, 30-49.

Saas, T., & Gallarda, T. (2007). Paradoxical aggressive reactions to benzodiazepine use: a

review. Encephale, 34(4), 330-336.

Sauer, C., & Sauer, R. M. (2005). Reducing barriers to the development of high quality, low cost

medicines. Retrieved from World Health Organization:

http://www.who.int/intellectualproperty/submissions/en/Sauerbarriers.pdf

Substance Abuse and Mental Heakth Services Administration. (2014, December 18).

Benzodiazepines in Combination with Opioid Pain Relievers or Alcohol: Greater Risk of

More Serious ED Visit Outcomes. Retrieved from The DAWN Report:

http://www.samhsa.gov/data/sites/default/files/DAWN-SR192-BenzoCombos-

2014/DAWN-SR192-BenzoCombos-2014.htm

Targum, S. D., & Milbauer, A. J. (2008). The Process of Getting New Drugs to

Market. Psychiatry (Edgmont), 5(8), 5760.

U.S National Institutes of Health. (2014, May 20). Study to Evaluate Analgesic Effect of IV

Administration of Kappa Agonist CR845 For Hysterectomy Surgery. Retrieved from

Clinicaltrials.gov: https://clinicaltrials.gov/ct2/show/NCT01361568

15
Veilleux, J. C., Colvin, P. J., Anderson, J., York, C., & Heinz, A. (2010, March). A review of

opioid dependence treatment: Pharmacological and psychosocial interventions to treat

opioid addiction. Clinical Psychology Review, 30(2), 155-166.

Volkow, N. D. (2014, April 29). Prescription Opioid and Heroin Abuse. Retrieved from

drugabuse.gov: http://www.drugabuse.gov/about-nida/legislative-activities/testimony-to-

congress/2014/prescription-opioid-heroin-abuse

Whelan PJ, Remski K. Buprenorphine vs. methadone treatment: A review of evidence in both

developed and developing worlds. Journal of Neurosciences in Rural Practice. 2012;

3(1):45-50. doi:10.4103/0976-3147.91934.

Wolff, K. (2002, August). Characterization of Methadone Overdose: Clinical Considerations and

the Scientific Evidence. Therapeutic Drug Monitoring, 24(4), 457-470. Retrieved from

http://journals.lww.com/drug-

monitoring/Abstract/2002/08000/Characterization_of_Methadone_Overdose__Clinical.1.

aspx

World Health Organization. (2014, November). Information sheet on opioid overdose. Retrieved

from World Health Organization Web site:

http://www.who.int/substance_abuse/information-sheet/en/

16