A Brief History of the Opioid Epidemic and Strategies for Pain Medicine
A Brief History of the Opioid Epidemic and Strategies for Pain Medicine
Jatinder S. Gill . Thomas T. Simopoulos 0 1 2
0 A. D. Kaye Louisiana State University Health Science Center , New Orleans, LA , USA
1 J. Peck Johns Hopkins Medical Center, All Children's Hospital , St. Petersburg, FL , USA
2 M. R. Jones (&) O. Viswanath J. S. Gill T. T. Simopoulos Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA , USA
The opioid epidemic has resulted from myriad causes and will not be solved by any simple solution. Consequent to a staggering increase in opioid-related deaths in the USA, various governmental inputs and stakeholder strategies have been proposed and implemented with varying success. This article summarizes the history of opioid use and explores the causes for the present day epidemic. Recent trends in opioid-related data demonstrate an almost fourfold increase in overdose deaths from 1999 to 2008. Tragically, opioids claimed over 64,000 lives just last year. Some solutions have undergone legislation, including the limitation of numbers of opioids postsurgery, as well as growing national prevalence of enhanced recovery after surgery protocols which focus on reduced postoperative opioid consumption and shortened hospital stays. Stricter prescribing practices and prescription monitoring programs have been instituted in the recent past. Improvement in abuse deterrent strategies which is a major focus of the Food and Drug Administration (FDA) for all opioid preparations will likely play an important role by increasing the safety of these medications. Future potential strategies such as additional legislative policies, public awareness, and physician education are also detailed in this review.
Abuse deterrent formulations; Enhanced recovery after surgery; Non-opioid pain treatments; Opioid epidemic; Overdose
As of October 16, 2017, the US Government
declared the opioid epidemic a public health
emergency. The medical community, and
particularly pain medicine practitioners, have been
active participants and fully aware of the
development of the current state. Prescription
drug monitoring programs (PDMPs) and the
National All Schedules Prescription Electronic
Reporting Act (NASPER) have effectively
contributed to the reduction in opioid prescriptions
by 8% and prescription opioid overdose death
rates by 12% . Despite these substantial
reductions in opioid prescriptions in the USA,
deaths by opioid overdose continue to escalate
at alarming rates: 64,000 people died from drug
overdoses in 2016; over 42,000 of those were
opioid deaths [2, 3]. This represents a 20%
increase from the total of 52,000 drug overdose
fatalities in 2015. Overdoses related to illegally
manufactured fentanyl represent the greatest
contribution to the increase, accounting for
20,000 deaths in total; heroin accounted for
15,000 deaths; and prescription drugs for less
than 15,000. Figures 1 and 2 present the rates of
opioid prescriptions and the rate of
Many parties are responsible for the present
day epidemic. Well-intentioned efforts by
multiple industries, medical specialty associations,
and governmental oversight organizations have
resulted in our current climate. This manuscript
Fig. 2 Number of opioid overdose deaths by category,
1999–2016. Opioid-related deaths increase dramatically in
will describe a brief overview of the history of
opioid therapy as it relates to pain and forecast
in detail the ramifications for the practice of
pain medicine as an independent and
increasingly vital specialty.
Compliance with Ethics Guidelines
This article is based on previously conducted
studies and does not contain any studies with
human participants or animals performed by
any of the authors.
BRIEF TIMELINE OF OPIOID
Although a detailed description of pain
pathways and relevant medical interventions is
beyond the scope of this paper, it suffices to say
that much of our understanding of pain
pathophysiology is recent, and that the field
remains in infancy but rapidly evolving. Before
1800, clinicians regarded pain as an existential
phenomenon, a consequence of aging . There
was no regulation on the use of cocaine and
opioids, resulting in widespread marketing and
prescribing for many ailments ranging from
diarrhea to toothache . The Harrison Narcotic
Control Act of 1914, passed in response to the
sudden emergence of street heroin abuse as well
as iatrogenic morphine dependence, influenced
both physician and patient alike to avoid
opiates . Patients with unexplained pain in the
1920s were regarded as deluded, malingering, or
abusers, and cancer patients through the 1950s
were encouraged to wean themselves off opioids
until their lives ‘‘could be measured in weeks’’
This attitude persisted into the latter half of
the twentieth century; a general world-wide
‘‘opiophobia’’ is thoroughly detailed in
contemporary literature. Morgan in 1985 and Zenz
and Willweber-Strumpf in 1992 both describe a
state of under-reliance of opioid analgesics and
a resultant under-treatment of pain in Europe
and North America [
developments over this era served to increase awareness
of pain under-treatment. A 1973 manuscript
from Marks and Sachar in the Annals of Internal
Medicine described a failure to treat patients in
severe pain with adequate doses of opioid
analgesics . Two decades later, Max [
decried the same failure, invoking the
conventional wisdom of the day that ‘‘therapeutic use
of opiate analgesics rarely results in addiction.’’
This widespread belief was based upon two
small retrospective publications from the 1980s:
the first, published as a one paragraph letter to
the editor without detailing any scientific rigor,
described low (0.03%) addiction rates for
inpatients receiving opioids for acute pain; the
second, a retrospective review of 38 patients,
demonstrated that only 2 of 38 patients with
chronic pain developed misuse or abuse issues
when receiving opioids [
]. The scientific
background for the use of opioids for
non-malignant pain was therefore not based upon any
demonstrable outcomes or safety studies.
The World Health Organization addressed
the under-treatment of postoperative and
cancer pain in 1986 with their Cancer Pain
]. A rapid improvement in the
treatment of cancer pain soon unfurled in many
countries, though not entirely, as many
countries even today suffer from poor access to
]. This further prompted a number of
publications in the 1990s that questioned the
state of pain under-treatment. Notably, Ronald
Melzack in 1990 [
] published an article in
Scientific American that questioned why opioids
were reserved solely for cancer pain and avoided
entirely in chronic pain states. The newfound
interest bore misconceptions, drawn largely by
cancer pain specialists lacking expertise on
other chronic, non-cancer pain, that equated
the etiologies of malignant and non-malignant
]. This dangerous conflation disregards
the complex biopsychosocial phenomena that
is chronic pain, and despite many cautions to
this effect, opioids grew into the primary
modality of chronic non-cancer pain treatment
in the USA [
Alongside this opioid evolution, the
American Pain Society launched their influential
‘‘pain as the fifth vital sign’’ campaign in 1995,
with intent to encourage proper, standardized
evaluation and treatment of pain symptoms
]. The Veteran’s Health Administration lent
support to the campaign with their 1999
adoption of pain as the fifth vital sign initiative [
Solidifying the national response to the
aforementioned efforts, the Joint Commission
(TJC) published standards for pain management
in 2000, emphasizing the need for
organizations to conduct quantitative assessments of
pain as recommended by the Institute of
]. The Federation of State Medical
Boards and the Drug Enforcement Agency also
issued statements promising less regulatory
scrutiny over opioid prescribers, thereby
assuaging physician reluctance to prescribe
more liberal amounts of opioid analgesics [
The rapid institution of strict standards for
pain management in hospital systems
culminated in several unintended consequences.
Physicians were now mandated to provide
adequate pain control by the TJC, resulting in a
heavy reliance on opioid medications. The fear
among hospital administration was that if new
TJC benchmarks were not met, then they were
unlikely to receive federal healthcare funds.
Indeed, hospitals that invested more readily in
opioid therapy generally received better
satisfaction rates among their patient population
]. Pharmaceutical companies heavily pushed
the use of opioids as a humane treatment
option, often using paid physician consultants
to expound on the safety and benefits of opioids
use. Not prescribing opioids for a patient with
pain risked being labeled as inhumane, often
even to the extent of litigation for the
undertreatment of pain [
]. Trainees in pain
medicine as well as other medical specialties were
taught to rely more on opioids for pain
treatment. Concurrently, pharmaceutical companies
introduced new formulations, such as extended
release oxycodone (OxyContin), which were
frequently prescribed because of a presumed
lower likelihood of abuse, while in reality were
heavily abused. From 1997 to 2002, OxyContin
prescriptions increased from 670,000 to 6.2
]. Overall opioid consumption
continued to climb throughout the 2000s in the
USA, rising from 46,946 kg consumed in the
year 2000 to a peak of 165,525 kg in 2012 [
The initial response was favorable, and the
push for better pain control appeared
successful. One study found that the mean
consumption of opiates per patient in the postanesthesia
care unit (PACU) increased from 40.4 mg of
morphine equivalent to 46.6 mg from 2000 to
2002 with no associated increase in length of
stay, naloxone use, or nausea and vomiting
]. However, concerns soon began to surface
regarding overzealous opioid treatment. One
report found that the incidence of opioid
oversedation more than doubled from 11.0 to
24.5 per 100,000 inpatient hospital days with
the implementation of a new standardized,
numerical pain treatment algorithm [
Institute for Safe Medication Practices began to
establish a link between overaggressive pain
management and substantial increases in the
incidence of oversedation and associated fatal
respiratory depression. The culture change,
driven by intent to ensure access to pain relief, had
opened the floodgates to the current opioid
climate. In just the past 15 years, there has been
a proportionate quadrupling of prescription
opioid sales and mortality in both men and
women based on National Vital Statistics
System mortality statistics from the Centers for
Disease Control and Prevention [
Perplexingly, in addition to the increasing mortality,
no study to this date has established level I
evidence for the long-term safety and efficacy of
opioid therapy in reducing chronic pain
intensity and improving function. Instead, numerous
other ills arising from opioid medication, such
as hyperalgesia, increasing disability, and a host
of other formidable problems, including
endocrine and psychological co-morbidities, have
emerged in relation to chronic opioid use.
It must be noted that pharmaceutical
companies contributed significantly to the rise of
the opioid epidemic, receiving considerable
reprimands as a consequence. In 2007, as the
opioid epidemic began to inflict profound
damage, Purdue Pharma pleaded guilty to
federal charges related to the misbranding of
OxyContin. Purdue agreed to pay a total of
$634.5 million to resolve Justice Department
investigations, as well as a $19.5 million
settlement to 26 states and the District of Columbia
]. Allegations accuse Purdue of intentionally
downplaying the risk of addiction posed by
OxyContin and misleading both physicians and
the healthcare industry as a whole by
overstating the benefits of opioids for chronic pain. At
the time of this publication, at least 14 states
have submitted lawsuits against the privately
held Purdue, and the company has announced
that it will cut its sales force in half and stop
promoting opioids to physicians in a stark
reversal of policy from recent decades.
REACTION TO OPIOID EPIDEMIC
In response to the current epidemic, changes in
focus to the development of new abuse
deterrent opioid formulations at the US Food and
Drug Administration (FDA) as well as drafting of
new public standards for pain treatment were
created at TJC in 2017 [
]. Efforts to develop
and provide access to medications intended to
treat opioid dependence had begun some time
before, however. The Drug Addiction Treatment
Act of 2000 (DATA 2000) allowed physicians
with a waiver from the Center for Substance
Abuse and Mental Health Services
Administration to prescribe schedule III, IV, and V
medications to treat opioid dependence. The FDA
approval in 2002 of buprenorphine and
buprenorphine/naloxone formulations allowed
specially trained primary care physicians (PCPs)
access to these medications. The 2006
Reauthorization Act increased the allowable
maximum number of buprenorphine patients per
PCP from 30 to 100 patients. These efforts
greatly enhanced access to treatment for
In response to the opioid epidemic, FDA
public policy changes were announced in
February 2016. Among these new positions were
a re-examination of the risk–benefit paradigm
for opioids with strict emphasis on the large
public health ramifications; expanded access to
and encouraged development of
abuse-deterrent opioid formulations; expert advisory
committee assembly prior to new applications for
opioids lacking abuse-deterrent properties;
improved access to naloxone and other
treatment options for opioid use disorder; inclusion
of safety information and warnings on
immediate-release (IR) opioid labeling; and support
for alternative pain management modalities.
The various modified opioids released over the
past 20 years, such as tamper-resistant
preparation, have had differing levels of success, and
are collectively referred to as Risk Evaluation
and Mitigation Strategies (REMS); these include
Targiniq (oxycodone and naloxone),
Suboxone (buprenorphine/naloxone), reformulated
OxyContin ER (extended release), among
]. Presently, fewer than one dozen
FDA-approved Abuse-Deterrent Formulations
(ADFs) exist, but further development and
improvements are ongoing [
The January 2017 release of new TJC
standards continued the focus on appropriate and
effective management of pain, including the
recommended inclusion of psychosocial risk
factors that may affect self-reporting pain in any
pain assessment; set realistic goals when
developing treatment plans with patients; emphasize
impairment of physical function during pain
assessment; emphasize diligent monitoring of
opioid prescribing patterns; and promote use of
non-pharmacologic pain treatments. In
addition, the draft suggests changes to pain
management designed to prevent diversion, such as
identification of high-risk patients, readily
available equipment for monitoring high-risk
patients, easy clinician access to prescription
monitoring programs databases, and educating
patients and families on the safe use, storage,
and disposal of opioid medications. Changes
have also been put in place at the state level,
including providing more limited and
standardized doses of opioids for acute pain
management and required continuing education for
all clinicians who prescribe opioid medications.
In this regard, a joint Food and Drug
Administration Advisory in 2016 voted unanimously to
require continuing education for all
opioidprescribing physicians, regardless of specialty,
and presently remains a common element of
quality improvement projects [
IMPLICATIONS FOR PAIN
With the evolution and manifestation of the
current opioid epidemic, opioid prescription
and use dependence have gained national
attention at the forefront of healthcare politics.
Related research and publications in
peer-reviewed journals have grown exponentially, and
government policy has adapted to meet
growing concerns surrounding opioids, including
greater scrutiny and laws limiting opioid doses
during the first week of acute pain management
]. Maintaining adequate pain control is still a
priority, but efforts to titrate opioid use and to
increase the use of multimodal pain regimens
and ADFs are underway. Enhanced recovery
after surgery techniques focus on regimens that
include nerve blocks, non-steroidals,
gabapentinoids, acetaminophen, and ketamine
to decrease postoperative opioid consumption
and reduce hospital stays.
As stated earlier, the conflation of cancer
pain with chronic non-malignant pain ignored
the biopsychosocial complexities underlying
the latter, leaving a multidisciplinary approach
to the wayside in favor of an overreliance on
opioids. Pain management as a specialty will
benefit from reinstitution of such
multidisciplinary involvement, with emphasis on
multimodal analgesia, interventional therapies, and
outcomes stressing improvement in physical
There is also a growing focus on preventing
opioid use disorder (OUD) and on offering
affected individuals accessible and effective
treatment. US government policy reflects these
changes and both the Affordable Care Act and
the Mental Health Parity and Addiction Equity
Act were major steps forward in treating opioid
addiction. The Affordable Care Act, which was
signed into law in 2010, with major provisions
coming into effect by 2014, dramatically
reduced the number of uninsured patients
within the USA by 2016 and ensured access to
essential health benefits including substance
use disorder services and rehabilitative services
]. This gave opioid-dependent individuals
more accessible and affordable routes to
treatment. Similarly, the Mental Health Parity and
Addictions Equity Act, which took effect in
2010, prevented insurers from placing greater
restrictions on mental health and substance
abuse disorder treatment benefits than benefits
for medical and surgical care [
initiatives reduce barriers to effective treatment.
Modern culture surrounding opioid use
disorder has also changed. Recent studies confirm
that treatment for OUD is most effective when
comprised of multimodal interventions that are
both pharmacological and psychosocial [
Therefore, peer-led support groups,
communitywide prevention strategies, and stigma-reducing
initiatives continue to develop and to
demonstrate varying degrees of success in response to
the opioid epidemic [
]. In this regard, one
recent publication also addressed the role of
local government in the opioid crisis and
stressed the importance of local public health
coalitions aimed at preventing overdoses and
promoting treatment options, as well as
citywide anti-stigma education .
Governmental and regulatory agencies’ new
legislation necessitates a shift in tactics by
medical specialty associations in order to
comply with and respond to the new perspective. It
is crucial that the response to the opioid
epidemic does not eradicate the significant strides
made over the past half century in our
understanding of pain and the enrichment of the
therapeutic arsenal at our disposal. This is
reflected by the 2010 Declaration of Montreal
released by the International Association for the
Study of Pain, wherein they maintain and
reemphasize the ideal that the relief of suffering
and pain is a moral duty of physicians, and that
access to pain treatment is a fundamental
human right [
]. Following this light, in order
to continue to curb opioid abuse and reduce
opioid deaths while maintaining adequate
access to pain relief, the American Society of
Interventional Pain Physicians (ASIPP) has
issued recommendations focused on two main
arenas: more effective legislative efforts while
maintaining appropriate access, and the
promotion of non-opioid modalities including
interventional techniques. These
recommendations are comprised in three separate tiers.
Tier 1 stresses aggressive public education to
explicitly address the dangers of illicit drugs
(heroin and fentanyl); the adverse
consequences of opioid abuse along with the
increased risk of opioids combined with
benzodiazepines; mandatory 4 h of continuing
physician education per year for all prescribers
of any amount of opioid or benzodiazepine; and
mandatory patient education associated with
the first prescription of any amount of opioid.
According to a recent survey published in the
New England Journal of Medicine, a significant
percentage of the public blame the opioid
epidemic on doctors who inappropriately
prescribe medication (46%), with only 28%
allocating blame to people who illegally sell
prescription pain killers, and 13% blaming
pharmaceutical companies [
]. In this same
survey, the public believes public awareness and
education programs are effective and should be
ASIPP’s tier 2 recommendations emphasize
ease of access along with lower or no copayments
for directed modalities based on non-opioid pain
therapy including physical therapy and
interventional techniques. Interestingly, evidence
demonstrates a direct correlation between the
decline in the utilization of interventional
techniques since 2010 secondary to decreasing
reimbursements and the ultimate escalation in opioid
deaths over the same period [
]. Until prior
authorizations for non-opioid treatment
modalities are eliminated, and prior authorizations for
opioid treatments increased, the arsenal of
nonopioid therapies available to pain medicine
clinicians will be limited, and the reliance on opioids
will continue. Another strategy emphasized in
tier 2 is the expansion of low-threshold access to
buprenorphine for opioid use disorder, which,
after implementation in France, effectively
decreased opioid overdose deaths by 79% over a
6-year period . Lastly, tier 2 recommendations
include the establishment of prescription drug
monitoring programs (PDMP) that are capable of
interstate communication, as well as mandatory
provider review of PDMP data prior to prescribing.
The third tier of ASIPP’s approach focuses on
buprenorphine and methadone. ASIPP
recommends that buprenorphine be changed to a
schedule II substance, and be made mandatorily
available for chronic pain management in
addition to medication-assisted treatment. Finally,
ASIPP recommends in tier 3 that methadone be
removed from the formulary, as it is responsible
for over 3000 deaths per year despite comprising
in total only 1% of prescribed opioids.
The opioid epidemic has arisen in part from a
complex history of well-intentioned efforts by
multiple industries to balance adequate and
vital treatment of pain against the misuse and
abuse of opioid medications. The presumption
that opioids are safe and effective for chronic
pain over the previous decade led to the
overreliance on opioids and a significant reduction
in the number of multidisciplinary pain centers
across the USA that were proven effective for
this condition. A reduction in reimbursement
for such multispecialty centers further shifted
management in the direction of
pharmacotherapy. Nevertheless, the current state of
rampant abuse and consequential fatal
overdoses afflicting the USA is unacceptable and
deserving of a profound response. There is a
clear need to end the focus on blaming
responsible parties and shift to implementing
solutions. To that end, governmental regulatory
agencies and specialty-specific physician
associations have released multiple regulatory
measures and societal recommendations that
together have contributed to a decrease in the
amount of opioid prescriptions over recent
years. Concerted efforts from multiple
disciplines, including physicians, legislators,
pharmaceutical companies, educators, and the
general public are required to ensure that the
epidemic does not continue into the future.
Funding. No funding or sponsorship was received for this study or publication of this article.
Authorship. All named authors meet the
International Committee of Medical Journal
Editors (ICMJE) criteria for authorship for this
article, take responsibility for the integrity of
the work as a whole, and have given their
approval for this version to be published.
Disclosures. Mark R. Jones, Omar Viswa
nath, Jacquelin Peck, Jatinder S. Gill, and
Thomas T. Simopoulos have nothing to disclose.
Alan D. Kaye is on the Speakers Bureau for
Depomed, Inc. and Merck, and has served on
the FDA Advisory Board on Analgesics,
Anesthetics, and Addiction Medicine since 2012.
Compliance with Ethics Guidelines. This
article is based on previously conducted studies
and does not contain any studies with human
participants or animals performed by any of the
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