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Review Article

DanL. Longo, M.D., Editor

Opioid Abuse in Chronic Pain

Misconceptions and Mitigation Strategies
NoraD. Volkow, M.D., and A.Thomas McLellan, Ph.D.

hronic pain not caused by cancer is among the most prevalent From the National Institute on Drug
and debilitating medical conditions but also among the most controversial Abuse, National Institutes of Health,
Bethesda, MD (N.D.V.); and the Treat
and complex to manage. The urgency of patients needs, the demonstrated ment Research Institute, Philadelphia
effectiveness of opioid analgesics for the management of acute pain, and the limited (A.T.M.). Address reprint requests to
therapeutic alternatives for chronic pain have combined to produce an overreliance Dr. Volkow at the National Institute on
Drug Abuse, National Institutes of Health,
on opioid medications in the United States, with associated alarming increases 6001 Executive Blvd., Bethesda, MD 20892,
in diversion, overdose, and addiction. Given the lack of clinical consensus and or at nvolkow@nida.nih.gov.
research-supported guidance, physicians understandably have questions about N Engl J Med 2016;374:1253-63.
whether, when, and how to prescribe opioid analgesics for chronic pain without DOI: 10.1056/NEJMra1507771
increasing public health risks. Here, we draw on recent research to address com- Copyright 2016 Massachusetts Medical Society.

mon misconceptions regarding the abuse-related risks of opioid analgesics and

highlight strategies to minimize those risks.

Source of the Opioid Epidemic

More than 30% of Americans have some form of acute or chronic pain.1,2 Among
older adults, the prevalence of chronic pain is more than 40%.2 Given the preva-
lence of chronic pain and its often disabling effects, it is not surprising that opioid
analgesics are now the most commonly prescribed class of medications in the
United States.3 In 2014 alone, U.S. retail pharmacies dispensed 245 million pre-
scriptions for opioid pain relievers.4,5 Of these prescriptions, 65% were for short-
term therapy (<3 weeks),6 but 3 to 4% of the adult population (9.6 million to 11.5
million persons) were prescribed longer-term opioid therapy.7 Although opioid
analgesics rapidly relieve many types of acute pain and improve function, the
benefits of opioids when prescribed for chronic pain are much more questionable.8
However, two major facts can no longer be questioned. First, opioid analgesics
are widely diverted and improperly used, and the widespread use of the drugs has
resulted in a national epidemic of opioid overdose deaths and addictions. More
than a third (37%) of the 44,000 drug-overdose deaths that were reported in 2013
(the most recent year for which estimates are available) were attributable to pharma-
ceutical opioids; heroin accounted for an additional 19%. At the same time, there
has been a parallel increase in the rate of opioid addiction, affecting approxi-
mately 2.5 million adults in 2014.9 Second, the major source of diverted opioids is
physician prescriptions.10,11 For these reasons, physicians and medical associations
have begun questioning prescribing practices for opioids, particularly as they re-
late to the management of chronic pain. Moreover, many physicians admit that
they are not confident about how to prescribe opioids safely,12 how to detect abuse
or emerging addiction, or even how to discuss these issues with their patients.13
This review is not intended as clinical instruction in chronic pain management;

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Table 1. Misconceptions Regarding Opioids and Addiction.*

Mu-opioid receptors are densely concentrated in
brain regions that regulate pain perception (peri-
Addiction is the same as physical dependence and tolerance. This miscon aqueductal gray, thalamus, cingulate cortex, and
ception leads some clinicians to avoid prescribing opioids to patients who
would benefit from them and many patients to be afraid of taking opioids
insula), including pain-induced emotional re-
as prescribed. sponses (amygdala), and in brain reward regions
Addiction is simply a set of bad choices. This misconception contributes to the (ventral tegmental area and nucleus accumbens)
discrimination against patients with addiction and to the willful ignorance that underlie the perception of pleasure and
by many in the health care system about modern treatment methods. It also well-being. This explains why opioid medications
promotes mistrust of patients by clinicians and prevents affected patients
from seeking help for their addiction. can produce both analgesia and euphoria. Mu-
opioid receptors in other brain regions and in
Pain protects patients from addiction to their opioid medications. This mis
conception can lead to overconfidence and overprescribing among clini peripheral organs account for other common
cians as well as failure to monitor and recognize addictive behaviors or to opioid effects. In particular, mu-opioid receptors
intervene properly when they emerge. Research has shown that patients in the brain stem are mainly responsible for the
who are prescribed opioid medications for pain can become addicted to
them even when the drugs are taken as prescribed. respiratory depression associated with opioid-
Only long-term use of certain opioids produces addiction. The misconception overdose incidents and deaths21,22 (Fig.1).
that addiction is simply the property of certain opioid drugs promotes over Opioids not only directly activate these brain
prescribing of certain types of opioids that may be as risky as types that analgesia and reward regions but also concur-
are well known to be associated with addiction. An improved prescribing
practice in the management of acute pain is a necessary step in the control rently mediate a learned association between
of opioid diversion and overdose, since the overprescription of opioids for receipt of the drug and the physiological and
acute pain is the main source of drug diversion. perceptual effects of the drug a type of Pav-
Only patients with certain characteristics are vulnerable to addiction. Certain lovian conditioning.23 Repeated receipt of opioids
conditions do increase the vulnerability to addiction. These include sub strengthens these learned associations and over
stance-use disorder (including abuse of alcohol, nicotine, and illicit drugs),
developmental stage (adolescents are more vulnerable than adults), and time becomes part of the desire (craving) for the
certain mental illnesses (e.g., attention deficithyperactivity disorder and drugs effects analgesic or pleasurable.24 For
major depressive disorder). Although some patients are more vulnerable a patient in chronic pain, even mild levels of
than others, no patient is immune to addiction.
pain can trigger the learned associations be-
Medication-assisted therapies are just substitutes for heroin or opioids. The
use of opioid-agonist medications such as methadone and buprenorphine
tween pain and drug relief, which are mani-
for opioid addiction has led to the misconception that such drugs are just fested as an urge for relief. Such a conditioned
substitutes for the opioid being abused. Although these medications are urge for relief from even mild pain can lead to
opioid agonists, their slower brain pharmacokinetics along with their more
stable concentrations help to stabilize physiologic processes that are dis
the early, inappropriate use of an opioid outside
rupted by intermittent abuse of opioids. The use of these drugs also pro prescribed scheduling.
tects against risks associated with opioid abuse while facilitating recovery.18-20 Opioid medications vary with respect to their
affinity and selectivity for the mu-opioid recep-
* These misconceptions were drawn directly from questions submitted by physi
cians to two major websites for pain-management specialists (the American tor, since some also bind to kappa- or delta-
Academy of Pain Management and the American Pain Society). opioid receptors or to other neurotransmitter
receptors and transporters. There is also consid-
erable variation among the drugs with respect to
for that, we suggest recent clinical guidelines.14-17 their pharmacokinetics and bioavailability. When
Instead, this review focuses on the pharmaco- combined, these pharmacologic properties af-
logic properties of opioids that underlie both fect the rapidity of onset, potency, and duration
their therapeutic effects and their abuse-produc- of both the analgesic and pleasurable effects of
ing effects and on the ways in which these opioids.
properties should inform us in correcting com- The effects of opioids particularly their
mon clinical misconceptions that interfere with rewarding effects are accentuated most when
the proper prescription and monitoring of opioids the drugs are delivered rapidly into the brain.25
in the management of chronic pain (Table1). This is why diverted opioids that are taken for
their rewarding effects are frequently injected.
This also explains why the Food and Drug Ad-
W h y Opioid Medic at ions
A r e Di v er ted a nd A bused ministration has encouraged and approved abuse-
deterrent formulations that are designed to pre-
Opioid medications exert their analgesic effects vent the injection of pharmaceutical opioids26
predominantly by binding to mu-opioid receptors. (Table2).

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Opioid Abuse in Chronic Pain

Brain and Brain Stem

Insula cingulate cortex
Thalamus (pain) (pain)

tegmental area

Nucleus accumbens
Brain stem (reward)
(breathing) Amygdala
(reactivity to pain)
Periaqueductal gray

Spinal Cord

Dorsal horn

Anterior horn

Peripheral Terminal



Small Intestine
C fiber


Figure 1. Location of Mu-Opioid Receptors.

Shown are the locations of muopioid receptors in the human brain, with high concentration in the thalamus, peri
aqueductal gray, insula, and anterior cingulate (regions involved with pain perception), in the ventral tegmental area
and nucleus accumbens (regions involved with reward), in the amygdala (a region involved with emotional reactivity
to pain), and in the brain stem (nuclei that regulate breathing). In the spinal cord, a high concentration of muopioid
receptors is located in the dorsal horn. Muopioid receptors in peripheral terminals modulate the perception of pain,
and receptors in the small intestine regulate gut motility.

Opioid -Induced T ol er a nce between physical dependence and addiction. The

a nd Ph ysic a l Dependence repeated administration of any opioid almost
inevitably results in the development of tolerance
There is lingering misunderstanding among and physical dependence. These predictable
some physicians about the important differences phenomena reflect counter-adaptations in opioid

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Table 2. Formulations for Deterrence of Abuse.

analgesia up to 10 times the original dose.30
Similarly, tolerance with respect to the reward-
When opioids are diverted because of their rewarding effects, they are typically ing effects of opioids leads to the characteristic
taken at higher doses than were originally prescribed. In other cases, the
pills are crushed so that the drug can be snorted, smoked, or injected. These
dose escalation seen in opioid addiction, which
routes of administration result in faster drug delivery into the brain, which can result in daily doses of up to 800 morphine
in turn is associated with a rapid and more intense drug effect. Thus, strat milligram equivalents (MME, the conversion fac-
egies for abuse-deterrent formulations have been developed to minimize
the likelihood that the opioids will be injected or snorted or taken at higher
tor used to facilitate comparison of potency
doses than prescribed.27,28 These strategies include the following: among opioids).31
Combining the opioid agonist with an antagonist. Mixing the opioid with nal Some opioid effects show tolerance after a
oxone or naltrexone will interfere with the opioid effects if the drug is in single dose,32 whereas for others, tolerance oc-
jected but not if it is taken orally or sublingually. Examples include Embeda curs more slowly.29 In particular, tolerance to the
(morphine sulfate plus naltrexone hydrochloride) and Targiniq ER (oxyco
done plus naloxone). analgesic and euphoric effects of opioids devel-
ops quickly, whereas tolerance to respiratory
Delivering the opioid in a form that cannot be crushed and extracted.
Examples of such drug-delivery technologies include opioids approved by depression develops more slowly,33,34 which ex-
Food and Drug Administration (FDA) in abuse-deterrent formulations plains why increases in dose by the prescriber or
such as Hysingla (hydrocodone) and the new formulation of OxyContin patient to maintain analgesia (or reward) can
(oxycodone), as well as opioids not approved as abuse-deterrent formu
lations, including Exalgo (hydromorphone), Nucynta ER (tapentadol), markedly increase the risk of overdose.
Opana ER (oxymorphone), Oxecta (oxycodone), and Xartemis (oxycodone Physical dependence underlies the physiologi-
and acetaminophen). cal adaptations that are responsible for the emer-
Combining the opioid with a substance that triggers an adverse response. If gence of withdrawal symptoms on the abrupt
the drug is tampered with or used at a higher dose than indicated, such
formulations are designed to produce adverse results. Examples include discontinuation of opioids. Withdrawal symp-
Lomotil (diphenoxylate hydrochloride plus atropine) and Acurox (oxyco toms (e.g., piloerection, chills, insomnia, diar-
done plus niacin). rhea, nausea, vomiting, and muscle aches) vary
Developing prodrugs that require enzymatic activation. Such formulations appreciably in severity (from not noticeable to
could provide a chemical barrier to in vitro conversion into the active opi quite uncomfortable) and duration (1 to 14 days)
oid. There are currently no abuse-deterrent formulations approved by the
FDA that use this strategy. Examples being developed include prodrugs on the basis of the type, dose, and duration of
for hydrocodone, oxycodone, and hydromorphone that require molecular opioid prescribed.35,36
cleavage by trypsin in the digestive system to release the parent opioid. In the context of chronic pain management,
the discontinuation of opioids requires dose ta-
pering in order to prevent the emergence of such
receptors and their intracellular signaling cas- withdrawal symptoms. In some patients, the re-
cades.29 These short-term results of repeated peated use of opioids can also lead to hyperalge-
opioid administration resolve rapidly after dis- sia, which is a state of heightened pain sensitiv-
continuation of the opioid (i.e., in a few days to ity.37,38 In the clinical context, hyperalgesia can
a few weeks, depending on the duration of expo- lead to inappropriate increases in opioid doses,
sure, type of opioid, and dose). In contrast, ad- which further exacerbate rather than ameliorate
diction will occur in only a small percentage of pain.39 In the case of hyperalgesia, dose tapering
patients exposed to opioids. Addiction develops or tapering to discontinuation is a better pain-
slowly, usually only after months of exposure, relief strategy.40
but once addiction develops, it is a separate, of- Unlike tolerance and physical dependence,
ten chronic medical illness that will typically not addiction is not a predictable result of opioid
remit simply with opioid discontinuation and prescribing. Addiction occurs in only a small per-
will carry a high risk of relapse for years without centage of persons who are exposed to opioids
proper treatment. The molecular processes re- even among those with preexisting vulnera-
sponsible for addiction are also distinct from bilities (Table3). Older medical texts and several
those underlying tolerance and physical depen- versions of the Diagnostic and Statistical Manual of
dence, and so are the clinical consequences. Mental Disorders (DSM) either overemphasized the
Tolerance leads to a decrease in opioid po- role of tolerance and physical dependence in the
tency with repeated administration. Thus, pre- definition of addiction or equated these pro-
scribing opioids long-term for their analgesic cesses (DSM-III and DSM-IV). However, more
effects will typically require increasingly higher recent studies have shown that the molecular
doses in order to maintain the initial level of mechanisms underlying addiction are distinct

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Opioid Abuse in Chronic Pain

from those responsible for tolerance and physi- Table 3. Factors Associated with the Risk of Opioid Overdose or Addiction.
cal dependence, in that they evolve much more
slowly, last much longer, and disrupt multiple Factor Risk
brain processes.57 Medication-related
Cardinal features of addiction include a pro- Daily dose >100 MME* Overdose,8 addiction8
nounced craving for the drug, obsessive think-
Long-acting or extended-release formulation Overdose14,41
ing about the drug, erosion of inhibitory control (e.g., methadone, fentanyl patch)
over efforts to refrain from drug use, and com- Combination of opioids with benzodiazepines Overdose42
pulsive drug taking (DSM-5). These behavioral
Long-term opioid use (>3 mo) Overdose,43 addiction44
changes in turn are associated with structural
and functional changes in the reward, inhibitory, Period shortly after initiation of long-acting or Overdose45
extended-release formulation (<2 wk)
and emotional circuits of the brain.58,59 Clinical
studies have also shown that the ability of opi-
oids to produce addiction is genetically modu- Age >65 yr Overdose46
lated, with heritability rates similar to those of Sleep-disordered breathing Overdose47
diabetes, asthma, and hypertension.60,61 For these Renal or hepatic impairment Overdose48
reasons, we do not know the total dose or the Depression Overdose, addiction49
duration of opioid administration that will reli- Substance-use disorder (including alcohol) Overdose,50 addiction49
ably produce addiction. However, we do know
History of overdose Overdose51
that the risk of opioid addiction varies substan-
Adolescence Addiction52
tially among persons, that genetic vulnerability
accounts for at least 35 to 40% of the risk as- * The risk of opioid overdose increases in a doseresponse manner at opioid
sociated with addiction,62-64 and that adolescents doses of more than 20 morphine milligram equivalents (MME).
are at increased risk because of the enhanced Although addiction is associated with long-term but not short-term opioid use,
the prescription of a higher quantity of opioids than is needed for acute pain
neuroplasticity of their brains and their under- contributes substantially to the availability of opioids for diversion and abuse.
developed frontal cortex, which is necessary for Sleep-disordered breathing refers to conditions that manifest as abnormal
self-control.52,62 Hence, in adolescents, the risks breathing patterns during sleep and includes obstructive sleep apnea and cen
tral sleep apnea.53
and benefits of prescribing opioids for pain Patients with these disorders are at increased risk because the disposition of
management need to be even more carefully various opioid drugs is affected by hepatic and renal impairments, which re
weighed than in adults. duce drug clearance and increase bioavailability.54-56
In a person with an opioid addiction, discon-
tinuation of the opioid will rapidly reverse the
tolerance and physical dependence within days verity of these risks are largely independent and
or a couple of weeks. In contrast, the underlyinggoverned by different factors. All these risks are
changes that are associated with addiction will present to some degree with all opioids and with
persist for months and even years after the dis- all pain diagnoses. This means that no single or
continuation of opioids.65 This finding is clini-simple change in prescribing behavior can be
cally relevant, because after abstinence from expected to alleviate all risks while properly
opioids, addicted patients are particularly vul- managing pain. For example, these risks cannot
nerable to overdosing: their intense drive to take
be mitigated simply by restricting prescribing to
the drug persists, but the tolerance that previ- a particular type of opioid or by avoiding the
ously protected them from overdosing is no prescription of opioids to a particular type of
longer present. These effects explain the high patient. However, there are common strategies
risk of overdosing among persons with an opioid that can help mitigate all risks, including limit-
addiction after they have been released from ing the prescribed opioid to the lowest effective
prison or from a detoxification program.66,67 dose for the shortest effective duration (for both
acute and chronic pain) without compromising
effective analgesia. Regular monitoring and re-
Mi t ig at ion S t r ategie s
assessment provide opportunities to minimize
The rewarding effects of opioids play a major the risks associated with long-term opioid use by
role in the risks of opioid diversion, overdose, allowing for the tapering and discontinuing of
and addiction. However, the likelihood and se- opioids among patients who are not receiving a

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Table 4. Mitigation Strategies against Opioid Diversion and Misuse.

scale or procedure was effective.8 Risks of diver-
sion through doctor shopping are best mitigated
Several mitigation strategies for risk assessment of opioid misuse have been by the full participation of all prescribers in Pre-
proposed.74 These include the following:
scription Drug Monitoring Programs (PDMPs).
Screening tools to identify patients with a substance-use disorder. Such tools
include the Opioid Risk Tool; the Screener and Opioid Assessment for
PDMPs are statewide electronic databases that
Patients with Pain (SOAPP), version 1.0; SOAPP-Revised; and the Brief collect information on prescription and dispens-
Risk Interview; or the use of a simple question such as How many times ing of controlled prescription drugs (including
in the past year have you used an illegal drug or used a prescription medi
cation for nonmedical reasons? since patients who score above a certain
opioid drugs) and were designed to monitor in-
threshold (e.g., 1 to the sample question) may be at increased risk for formation pertaining to suspected abuse or diver-
opioid abuse.75 sion.78 Although these data have been shown to
Use of data from the Prescription Drug Monitoring Program. Such data can be help health care professionals reduce doctor
used to identify doctor shopping, which is frequently an indication of drug shopping and overdoses,79-81 their use by health
misuse or diversion.
care providers is inconsistent.82-84 This in part re-
Use of urine drug screening. Such screening, which can be performed before
prescription of opioids and periodically as part of regular follow-up, can
flects the fact that PDMPs are voluntary programs
provide information on drug use not reported by patients and may help in in many states. Although 25 states and the Dis-
identifying patients who are not taking their prescribed opioids and might trict of Columbia update their databases daily, as
be diverting them.
of this writing, only Oklahoma provides real-
Doctorpatient agreement on adherence. Such personal contracts can help time reporting.85 In addition, only 22 of 49 PDMPs
doctors in monitoring a patients adherence to prescribed opioid medica
tions. share information across states.86 Another ob-
stacle is that access to PDMP data requires a
However, a recent review of the evidence showed that only limited data are
available regarding the efficacy of any of these strategies.76 computer that is separate from that used to ac-
cess electronic health records. However, imple-
mentation and consistent use will be facilitated
clear benefit or among those who are engaging by rapid changes in laws to require mandatory
in practices that increase the risk of overdose consultation of a PDMP before prescribing, ad-
(e.g., consumption of high doses of alcohol, vances in electronic technologies to deliver PDMP
concurrent use of benzodiazepines, and poor information in real time, better integration of
adherence to opiate medications).68 PDMPs with electronic health records, and access
of PDMP data across state lines.87
Preventing Drug Diversion
The most common form of diversion is the Reducing Risk of Overdose
transfer of opioid analgesics by patients who The rate of death from opioid overdose has quad
have received legitimately prescribed opioids to rupled during the past 15 years in the United
family members or friends who are usually try- States.88 Researchers at the Centers for Disease
ing to self-medicate a generic pain.69 This type Control and Prevention have estimated that
of diversion applies to prescriptions given for the 28,647 drug overdose deaths (61%) in 2014 in
management of either chronic or acute pain and the United States involved some type of opioid,
would be best managed by educating patients on including heroin.89 Even more prevalent are non-
the dangers of sharing their medications and fatal opioid overdoses that require medical care
on the importance of safe storage and disposal.70 in a hospital or emergency department. Such
Approximately 7 to 10% of diversion occurs events have increased by a factor of six in the
among patients who feign pain to acquire pre- past 15 years.90
scribed opioids,71 usually with the goal of main- The contributing factors associated with over-
taining their addiction, and who will often at- dose can be divided into those associated with
tempt to acquire opioids from multiple physicians the opioid itself (type, dose, potency, and dura-
(doctor shopping).71-73 Physicians have attempted tion of action) and those associated with critical
to identify dissembling or addicted patients features of the patient (Table3). Although the
through screening instruments or through de- use of any opioid can lead to overdose, research
tection of so-called aberrant behaviors that are suggests that exposure to higher doses of all
thought to be indicative of addiction (Table4).77 opioids increases the risk of overdose. Opioid
However, the most recent review of patient doses of more than 100 MME91,92 are dispropor-
screening efforts showed no evidence that any tionately associated with overdose-related hospital

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Opioid Abuse in Chronic Pain

admissions and deaths45 (Table S1 in the Supple- proved this belief. Although published estimates
mentary Appendix, available with the full text of of iatrogenic addiction vary substantially from
this article at NEJM.org). The use of long-acting less than 1% to more than 26% of cases,100 part
opioids, such as methadone and oxycodone, has of this variability is due to confusion in defini-
also been associated with an increased risk of tion. Rates of carefully diagnosed addiction have
overdose.45 averaged less than 8% in published studies,
Several identifiable characteristics among pa- whereas rates of misuse, abuse, and addiction-
tients have been reliably associated with an ele- related aberrant behaviors have ranged from 15
vated risk of opioid overdose (Table3). Included to 26%.101-103 A small (estimated at 4%) but grow-
among these factors are a history of overdose,51,93 ing percentage of persons who are addicted to
a history of addiction to any substance (but par- prescription opioids transition to heroin,1 main-
ticularly alcohol, benzodiazepines, or opioids),93 ly because heroin is typically cheaper and in
and health problems associated with respiratory some instances easier to obtain than opioids.
depression or concurrent prescription of any Clinical efforts to prevent the emergence of
medication that has a depressive effect on the addiction can be initiated in primary care set-
respiratory system, such as benzodiazepines and tings. Assessment of addiction risks before opi-
sedative hypnotics.88 The presence of renal or ates are prescribed is recommended as a miti-
hepatic dysfunction also increases the risk of over- gation strategy (Table3). Emerging signs of
dose, since in patients with either of these con- addiction can be identified and managed through
ditions, the clearance of many opioid drugs is regular monitoring, including urine drug testing
impaired, which leads to higher and longer- before every prescription is written, to assess for
lasting drug levels in blood.54,55 Finally, because the presence of other opioids or drugs of abuse.
some cases of overdose may be purposeful sui- Responsible physicians should be prepared to
cide attempts,94,95 a history of suicidal thoughts make a referral for specialty addiction treatment
or attempts and a diagnosis of major depression when indicated. Although addiction is a serious
are also markers for an elevated risk of overdose. chronic condition, recovery is a predictable re-
Recommended mitigation strategies include sult of comprehensive, continuing care and mon-
an overdose risk assessment (Table3) and urine itoring.104 In particular, the use of medication-
drug screening before prescription or represcrip- assisted therapy in managing opioid addiction
tion of opioids (to verify absence of drugs of among patients with co-occurring pain signifi-
abuse). The identification of these risks does not cantly improves outcomes.105
automatically rule out opioids as part of effective On the basis of research and clinical evi-
pain management. However, these risks do indi- dence, the Department of Health and Human
cate the needs for much greater education of the Services recently launched an initiative to reduce
patient (and the patients family) about overdose opioid overdoses and addiction that focuses on
risks, the use of an opioid treatment agree- improving opioid prescribing practices to reduce
ment,96 increased caution in prescribing high opioid-use disorders and overdoses, expanding
opioid doses or long-acting opioids, more fre- the use of naloxone to prevent overdoses, and
quent clinical follow-up, and, potentially, a pre- extending the use of medication-assisted treat-
scription for and instruction in the use of nal- ment to reduce opioid-use disorders and over-
oxone, an opioid antagonist that can reverse an doses.106
opioid-induced overdose. Indeed, expanding ac-
cess to naloxone has been shown to significantly C onclusions
reduce the rate of death from opioid overdoses.97
It is no longer possible to simply continue previ-
Minimizing the Risk of Addiction ous practices with respect to the management of
For many years, it was believed that pain pro- chronic pain. The associated risks of opioid di-
tected against the development of addiction to version, overdose, and addiction demand change.
opioid medications. However, epidemiologic stud- Although there are no simple solutions, we rec-
ies of opioid addiction among patients in pain, ommend three practice and policy changes that
as well as preclinical studies of addiction in can reduce abuse-related risks and improve the
animal models of chronic pain,24,98,99 have dis- treatment of chronic pain.

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Table 5. Alternative Treatments for Chronic Pain.*

showed that more than 50% of opioid prescrip-
tions were for doses higher than 90 MME and
Nonpharmacologic for periods of more than 6 months.107 Better re-
Cognitive-behavioral therapy109 sults can be obtained by using the most contem-
Exercise therapy110-113 porary guidelines for pain management.14
Complementary medicine114 (e.g., yoga, meditation, acupuncture)
Increased Medical School Training on Pain
Nonopioid analgesics and Addiction
Very few medical schools offer adequate training
Nonselective nonsteroidal antiinflammatory drugs; recommended as first-line in pain management, and still fewer offer even
pharmacotherapy for osteoarthritis115 and low back pain116 in multiple
guidelines one course in addiction. The result is that even
experienced clinicians are unsure about how to
Cyclooxygenase-2 inhibitors
deal with fundamental and omnipresent clinical
Anticonvulsants (gabapentin or pregabalin)
issues in their practices. Many motivated, well-
Antidepressants (tricyclics and serotonin and norepinephrine reuptake inhibitors) intentioned physicians do not know whether to
Interventional and neural-stimulation therapies prescribe opioids for pain management and, if so,
Epidural injection; may provide short-term improvement for certain pain- which ones and for how long. Still fewer under-
associated conditions (e.g., lumbar radiculopathy)1 stand the pharmacologic or clinical relationships
Brain, spinal cord, and nerve stimulation, including transcranial magnetic among tolerance, physical dependence, and ad-
stimulation, transcranial direct current stimulation, electrical deep-brain diction.108 This education is particularly critical
stimulation, and stimulation devices for peripheral nerves or tissues117-120
for primary care practitioners, who prescribe
more than 70% of opioid analgesics.
Electromyography to help patients learn to control muscle tension and electro
encephalography to help patients learn to influence brain electrical signals
in order to modulate pain; may be beneficial in treatment of headaches,
Increased Research on Pain
some forms of chronic back pain, and other pain disorders121 At a recent workshop at the National Institutes of
Neurofeedback with the use of functional magnetic resonance imaging as a Health on the role of opioids in the treatment
supplemental approach for chronic pain management122 of chronic pain, attendants recommended several
areas of research that are needed for improved
* Evidence of efficacy varies for these strategies, and research is ongoing to as
sess their value in the management of chronic pain. clinical practice guidelines. These areas included
Multiple guidelines recommend the use of antidepressant and anticonvulsant how to differentiate the unique properties of
medications as either first-line or second-line treatment for neuropathic pain.123 acute and chronic pain and how to describe the
process by which acute pain transitions into
chronic pain.8 Discovery-oriented research was
Increased Use of Science-Supported also recommended to identify new, potent non
Prescribing and Management Practices opioid analgesics and other pain-treatment strat-
The extended prescription of opioids (>8 weeks) egies (Table5). Access to biomarkers of pain and
for the treatment of chronic pain has question- analgesia that take advantage of neuroimaging
able benefits for individual patients and presents technologies or genetic analyses would acceler-
substantial public health risks.8 The risks of ate the development of new medications and
overdose and addiction from this prescribing allow for more personalized clinical interven-
practice both among patients with chronic tions for pain management.
pain and the public at large increase with Dr. McLellan reports receiving fees for serving on the board
higher doses (>100 MME), longer duration of of directors of Indivior Pharmaceuticals. No other potential
conflict of interest relevant to this article was reported.
prescribing, and perhaps the use of long-acting Disclosure forms provided by the authors are available with
opioids. Despite these facts, a Medicaid study the full text of this article at NEJM.org.

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Opioid Abuse in Chronic Pain

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