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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.

C
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

Anterior
Insula cingulate cortex
Thalamus (pain) (pain)
(pain)

Ventral
tegmental area
(reward)

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

Spinal Cord

Dorsal horn

Anterior horn

Peripheral Terminal

E PIDE RM IS

DE RMIS

Small Intestine
C fiber
A-delta
fiber

A DIPO C YT E S

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
Patient-related
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
Acetaminophen
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
Biofeedback
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.

References
1. Institute of Medicine. Relieving pain JA, Dworkin RH. The prevalence of chron- 2014 (http://www.cdc.gov/nchs/fastats/drug
in America: a blueprint for transforming ic pain in United States adults: results of -use-therapeutic.htm).
prevention, care, education and research. an Internet-based survey. J Pain 2010;11: 4. Levy B, Paulozzi L, Mack KA, Jones
Washington, DC:National Academies 1230-9. CM. Trends in opioid analgesic-prescrib-
Press, 2011. 3. Centers for Disease Control and Pre- ing rates by specialty, U.S., 2007-2012.
2. Johannes CB, Le TK, Zhou X, Johnston vention. FastStats. Therapeutic drug use. Am J Prev Med 2015;49:409-13.

1260 n engl j med 374;13nejm.org March 31, 2016

The New England Journal of Medicine


Downloaded from nejm.org by LUCAS KOLOTELO VELTRINI on April 14, 2016. For personal use only. No other uses without permission.
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Opioid Abuse in Chronic Pain

5. National Institute on Drug Abuse. S, et al. Methadone and buprenorphine 34. Ling GS, Paul D, Simantov R, Paster-
The latest prescription trends for con- for the management of opioid dependence: nak GW. Differential development of
trolled prescription drugs. 2015 (http:// a systematic review and economic evalua- acute tolerance to analgesia, respiratory
www.drugabuse.gov/news-events/meetings tion. Health Technol Assess 2007;11:1-171. depression, gastrointestinal transit and
-events/2015/09/latest-prescription-trends 19. Kreek MJ. Methadone-related opioid hormone release in a morphine infusion
-controlled-prescription-drugs). agonist pharmacotherapy for heroin ad- model. Life Sci 1989;45:1627-36.
6. Volkow ND, McLellan TA, Cotto JH, diction: history, recent molecular and 35. Argoff C, Turk D, Benzon H. Major
Karithanom M, Weiss SR. Characteristics neurochemical research and future in opioids and chronic opioid therapy. Phila-
of opioid prescriptions in 2009. JAMA mainstream medicine. Ann N Y Acad Sci delphia:Mosby Elsevier, 2008.
2011;305:1299-301. 2000;909:186-216. 36. Wax P, Ruha A. Withdrawal syn-
7. Boudreau D, Von Korff M, Rutter CM, 20. Nutt DJ. Considerations on the role of dromes: opioid withdrawal. In:Irwin RS,
et al. Trends in long-term opioid therapy buprenorphine in recovery from heroin ad- Rippe JM, eds. Irwin & Rippes intensive
for chronic non-cancer pain. Pharmaco- diction from a UK perspective. J Psycho- care medicine. Philadelphia:Lippincott
epidemiol Drug Saf 2009;18:1166-75. pharmacol 2015;29:43-9. Williams & Wilkins, 2003.
8. Chou R, Deyo R, Devine B, Hansen R, 21. Akil H, Watson SJ, Young E, Lewis ME, 37. Arout CA, Edens E, Petrakis IL, Sofuo-
Sullivan S, Jarvik J. The effectiveness and Khachaturian H, Walker JM. Endogenous glu M. Targeting opioid-induced hyper-
risks of long-term opioid treatment of opioids: biology and function. Annu Rev algesia in clinical treatment: neurobio-
chronic pain:Evidence Report/Technology Neurosci 1984;7:223-55. logical considerations. CNS Drugs 2015;
Assessment. Rockville, MD:Agency for 22. Pattinson KT. Opioids and the control 29:465-86.
Healthcare Research and Quality, 2014. of respiration. Br J Anaesth 2008;100:747- 38. Kim SH, Stoicea N, Soghomonyan S,
No. 218 (AHRQ publication no. 14-E005- 58. Bergese SD. Intraoperative use of remi-
EF). 23. Miguez G, Laborda MA, Miller RR. fentanil and opioid induced hyperalgesia/
9. Results from the 2013 National Sur- Classical conditioning and pain: condi- acute opioid tolerance: systematic review.
vey on Drug Use and Health: summary of tioned analgesia and hyperalgesia. Acta Front Pharmacol 2014;5:108.
national findings. NSDUH series H-48. Psychol (Amst) 2014;145:10-20. 39. Chen L, Sein M, Vo T, et al. Clinical
Rockville, MD:Substance Abuse and Men- 24. Ewan EE, Martin TJ. Analgesics as interpretation of opioid tolerance versus
tal Health Services Administration, 2014. reinforcers with chronic pain: evidence opioid-induced hyperalgesia. J Opioid
HHS publication no. (SMA) 14-4863. from operant studies. Neurosci Lett 2013; Manag 2014;10:383-93.
10. Compton WM, Boyle M, Wargo E. 557 Pt A:60-4. 40. Lee M, Silverman SM, Hansen H, Patel
Prescription opioid abuse: problems and 25. Butler SF, Black RA, Cassidy TA, Dai- VB, Manchikanti L. A comprehensive re-
responses. Prev Med 2015;80:5-9. ley TM, Budman SH. Abuse risks and view of opioid-induced hyperalgesia. Pain
11. Shei A, Rice JB, Kirson NY, et al. routes of administration of different pre- Physician 2011;14:145-61.
Sources of prescription opioids among scription opioid compounds and formula- 41. Lev R, Petro S, Lee A, et al. Methadone
diagnosed opioid abusers. Curr Med Res tions. Harm Reduct J 2011;8:29. related deaths compared to all prescrip-
Opin 2015;31:779-84. 26. Department of Health and Human tion related deaths. Forensic Sci Int 2015;
12. Keller CE, Ashrafioun L, Neumann Services. Guidance for industry:abuse- 257:347-52.
AM, Van Klein J, Fox CH, Blondell RD. deterrent opioids:evaluation and labeling. 42. Paulozzi LJ. Prescription drug over-
Practices, perceptions, and concerns of April 2015 (http://www.fda.gov/downloads/ doses: a review. J Safety Res 2012;43:283-9.
primary care physicians about opioid de- Drugs/GuidanceComplianceRegulatory 43. Paulozzi LJ, Zhang K, Jones CM, Mack
pendence associated with the treatment of Information/Guidances/UCM334743.pdf). KA. Risk of adverse health outcomes with
chronic pain. Subst Abus 2012;33:103-13. 27. Mastropietro DJ, Omidian H. Abuse- increasing duration and regularity of opi-
13. Hagemeier NE, Gray JA, Pack RP. Pre- deterrent formulations: part 2: commer- oid therapy. J Am Board Fam Med 2014;
scription drug abuse: a comparison of cial products and proprietary technolo- 27:329-38.
prescriber and pharmacist perspectives. gies. Expert Opin Pharmacother 2015;16: 44. Edlund MJ, Martin BC, Russo JE,
Subst Use Misuse 2013;48:761-8. 305-23. DeVries A, Braden JB, Sullivan MD. The
14. Nuckols TK, Anderson L, Popescu I, 28. Raffa RB, Pergolizzi JV Jr. Opioid for- role of opioid prescription in incident
et al. Opioid prescribing: a systematic re- mulations designed to resist/deter abuse. opioid abuse and dependence among in-
view and critical appraisal of guidelines Drugs 2010;70:1657-75. dividuals with chronic noncancer pain:
for chronic pain. Ann Intern Med 2014; 29. Williams JT, Christie MJ, Manzoni O. the role of opioid prescription. Clin J Pain
160:38-47. Cellular and synaptic adaptations mediat- 2014;30:557-64.
15. American Pain Society, American Acad- ing opioid dependence. Physiol Rev 2001; 45. Miller M, Barber CW, Leatherman S,
emy of Pain Medicine Opioids Guidelines 81:299-343. et al. Prescription opioid duration of ac-
Panel. Guideline for the use of chronic 30. Buntin-Mushock C, Phillip L, Mori- tion and the risk of unintentional over-
opioid therapy in chronic noncancer pain: yama K, Palmer PP. Age-dependent opioid dose among patients receiving opioid ther-
evidence review (http://americanpainsociety escalation in chronic pain patients. Anesth apy. JAMA Intern Med 2015;175:608-15.
.org/uploads/education/guidelines/chronic Analg 2005;100:1740-5. 46. Pergolizzi J, Bger RH, Budd K, et al.
-opioid-therapy-cncp.pdf). 31. Eder H, Jagsch R, Kraigher D, Pri- Opioids and the management of chronic
16. The Management of Opioid Therapy morac A, Ebner N, Fischer G. Comparative severe pain in the elderly: consensus
for Chronic Pain Working Group. VA/DoD study of the effectiveness of slow-release statement of an International Expert
clinical practice guideline for manage- morphine and methadone for opioid main- Panel with focus on the six clinically
ment of opioid therapy for chronic pain. tenance therapy. Addiction 2005; 100: most often used World Health Organiza-
Washington, DC:Department of Veterans 1101-9. tion Step III opioids (buprenorphine, fen-
Affairs, Department of Defense, 2010. 32. Kornetsky C, Bain G. Morphine: single- tanyl, hydromorphone, methadone, mor-
17. Dowell D, Haegerich TM, Chou R. dose tolerance. Science 1968;162:1011-2. phine, oxycodone). Pain Pract 2008; 8:
CDC guideline for prescribing opioids 33. Hill R, Lyndon A, Withey S, et al. 287-313.
for chronic pain United States, 2016. Ethanol reversal of tolerance to the respi- 47. Cheatle MD, Webster LR. Opioid ther-
MMWR Recomm Rep 2016;65(No. RR-1): ratory depressant effects of morphine. apy and sleep disorders: risks and mitiga-
1-49. Neuropsychopharmacology 2016;41:762- tion strategies. Pain Med 2015;16:Suppl 1:
18. Connock M, Juarez-Garcia A, Jowett 73. S22-6.

n engl j med 374;13nejm.org March 31, 2016 1261


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Downloaded from nejm.org by LUCAS KOLOTELO VELTRINI on April 14, 2016. For personal use only. No other uses without permission.
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The n e w e ng l a n d j o u r na l of m e dic i n e

48. Beaudoin FL, Merchant RC, Janicki A, DC, Samaan Z. Genetics of opioid depen- ber 2014 (https://prevention.nih.gov/docs/
McKaig DM, Babu KM. Preventing iatro- dence: a review of the genetic contribu- programs/p2p/ODPPainPanelStatement
genic overdose: a review of in-emergency tion to opioid dependence. Curr Psychia- Final_10-02-14.pdf).
department opioid-related adverse drug try Rev 2014;10:156-67. 77. Jones T, Moore T, Levy JL, et al. A com-
events and medication errors. Ann Emerg 63. Tsuang MT, Lyons MJ, Meyer JM, et al. parison of various risk screening methods
Med 2015;65:423-31. Co-occurrence of abuse of different drugs in predicting discharge from opioid treat-
49. Boscarino JA, Rukstalis M, Hoffman in men: the role of drug-specific and ment. Clin J Pain 2012;28:93-100.
SN, et al. Risk factors for drug depen- shared vulnerabilities. Arch Gen Psychia- 78. Wang J, Christo PJ. The influence of
dence among out-patients on opioid ther- try 1998;55:967-72. prescription monitoring programs on
apy in a large US health-care system. Ad- 64. Xian H, Chantarujikapong SI, Scherrer chronic pain management. Pain Physi-
diction 2010;105:1776-82. JF, et al. Genetic and environmental influ- cian 2009;12:507-15.
50. Alcohol involvement in opioid pain ences on posttraumatic stress disorder, 79. Delcher C, Wagenaar AC, Goldberger
reliever and benzodiazepine drug abuse- alcohol and drug dependence in twin BA, Cook RL, Maldonado-Molina MM.
related emergency department visits and pairs. Drug Alcohol Depend 2000;61:95- Abrupt decline in oxycodone-caused mor-
drug-related deaths United States, 2010. 102. tality after implementation of Floridas
MMWR Morb Mortal Wkly Rep 2014;63: 65. Public policy statement on rapid and Prescription Drug Monitoring Program.
881-5. ultra rapid opioid detoxification. Chevy Drug Alcohol Depend 2015;150:63-8.
51. Hasegawa K, Brown DF, Tsugawa Y, Chase, MD:American Society of Addic- 80. Paulozzi LJ, Kilbourne EM, Desai HA.
Camargo CA Jr. Epidemiology of emer- tion Medicine, 2005. Prescription drug monitoring programs
gency department visits for opioid over- 66. Seaman SR, Brettle RP, Gore SM. and death rates from drug overdose. Pain
dose: a population-based study. Mayo Clin Mortality from overdose among injecting Med 2011;12:747-54.
Proc 2014;89:462-71. drug users recently released from prison: 81. Surratt HL, OGrady C, Kurtz SP, et al.
52. Chambers RA, Taylor JR, Potenza MN. database linkage study. BMJ 1998; 316: Reductions in prescription opioid diver-
Developmental neurocircuitry of motiva- 426-8. sion following recent legislative interven-
tion in adolescence: a critical period of 67. Wines JD Jr, Saitz R, Horton NJ, tions in Florida. Pharmacoepidemiol Drug
addiction vulnerability. Am J Psychiatry Lloyd-Travaglini C, Samet JH. Overdose Saf 2014;23:314-20.
2003;160:1041-52. after detoxification: a prospective study. 82. Deyo RA, Irvine JM, Hallvik SE, et al.
53. Callop N, Cassel DK. Snoring and Drug Alcohol Depend 2007;89:161-9. Leading a horse to water: facilitating reg-
sleep disordered breathing. In:Lee-Chiong 68. Common elements in guidelines for istration and use of a prescription drug
T Jr, Sateia M, Carskadon M, eds. Sleep prescribing opioids for chronic pain. At- monitoring program. Clin J Pain 2014 No-
medicine. Philadelphia:Hanley & Belfus, lanta:Centers for Disease Control and vember 7 (Epub ahead of print).
2002. Prevention, 2015. 83. Hildebran C, Cohen DJ, Irvine JM,
54. Bosilkovska M, Walder B, Besson M, 69. McCabe SE, Cranford JA, Boyd CJ, et al. How clinicians use prescription drug
Daali Y, Desmeules J. Analgesics in pa- Teter CJ. Motives, diversion and routes of monitoring programs: a qualitative in-
tients with hepatic impairment: pharma- administration associated with nonmed- quiry. Pain Med 2014;15:1179-86.
cology and clinical implications. Drugs ical use of prescription opioids. Addict 84. Irvine JM, Hallvik SE, Hildebran C,
2012;72:1645-69. Behav 2007;32:562-75. Marino M, Beran T, Deyo RA. Who uses
55. Verbeeck RK. Pharmacokinetics and 70. Chou R, Fanciullo GJ, Fine PG, et al. a prescription drug monitoring program
dosage adjustment in patients with he- Clinical guidelines for the use of chronic and how? Insights from a statewide sur-
patic dysfunction. Eur J Clin Pharmacol opioid therapy in chronic noncancer pain. vey of Oregon clinicians. J Pain 2014;15:
2008;64:1147-61. J Pain 2009;10:113-30. 747-55.
56. Mercadante S, Arcuri E. Opioids and 71. Gwira Baumblatt JA, Wiedeman C, 85. Prescription Drug Monitoring Program
renal function. J Pain 2004;5:2-19. Dunn JR, Schaffner W, Paulozzi LJ, Jones Training and Technical Assistance Cen-
57. Christie MJ. Cellular neuroadaptations TF. High-risk use by patients prescribed ter. State profiles reports. Waltham, MA:
to chronic opioids: tolerance, withdrawal opioids for pain and its role in overdose Brandeis University (http://www.pdmpassist
and addiction. Br J Pharmacol 2008;154: deaths. JAMA Intern Med 2014;174:796- .org/pdf/Collection_Frequency.pdf).
384-96. 801. 86. Model Alcohol and Other Drug Abuse
58. Kalivas PW, Volkow ND. The neural 72. Manchikanti L, Helm S II, Fellows B, Policy and Planning Coordination Act.
basis of addiction: a pathology of motiva- et al. Opioid epidemic in the United States. Charlottesville, VA:National Alliance for
tion and choice. Am J Psychiatry 2005; Pain Physician 2012;15:Suppl:ES9-38. Model State Drug Laws (http://www
162:1403-13. 73. McDonald DC, Carlson KE. Estimat- .namsdl.org/library/).
59. Volkow ND, Morales M. The brain on ing the prevalence of opioid diversion by 87. Perrone J, Nelson LS. Medication rec-
drugs: from reward to addiction. Cell doctor shoppers in the United States. onciliation for controlled substances
2015;162:712-25. PLoS One 2013;8(7):e69241. an ideal prescription-drug monitoring
60. Uhl GR, Drgo T. Genetic contribu- 74. Chou R, Turner JA, Devine EB, et al. program. N Engl J Med 2012;366:2341-3.
tions to individual differences in vulner- The effectiveness and risks of long-term 88. Calcaterra S, Glanz J, Binswanger IA.
ability to addiction and abilities to quit. opioid therapy for chronic pain: a system- National trends in pharmaceutical opioid
In: Verster JC, Brady K, Galanter M, Con- atic review for a National Institutes of related overdose deaths compared to
rad P, eds. Drug abuse and addiction in Health Pathways to Prevention Workshop. other substance related overdose deaths:
medical illness: causes, consequences and Ann Intern Med 2015;162:276-86. 1999-2009. Drug Alcohol Depend 2013;
treatment. New York:Springer, 2012:95- 75. Smith PC, Schmidt SM, Allensworth- 131:263-70.
105. Davies D, Saitz R. A single-question 89. Rudd RA, Aleshire N, Zibbell JE,
61. Hall FS, Drgonova J, Jain S, Uhl GR. screening test for drug use in primary Gladden RM. Increases in drug and opi-
Implications of genome wide association care. Arch Intern Med 2010;170:1155-60. oid overdose deaths United States,
studies for addiction: are our a priori as- 76. Executive summary. Pathways to pre- 20002014. MMWR Morb Mortal Wkly
sumptions all wrong? Pharmacol Ther vention workshop:the role of opioids in Rep 2016;64:1378-82.
2013;140:267-79. the treatment of chronic pain. Bethesda, 90. Knowlton A, Weir BW, Hazzard F,
62. Mistry CJ, Bawor M, Desai D, Marsh MD:National Institutes of Health, Septem- et al. EMS runs for suspected opioid over-

1262 n engl j med 374;13nejm.org March 31, 2016

The New England Journal of Medicine


Downloaded from nejm.org by LUCAS KOLOTELO VELTRINI on April 14, 2016. For personal use only. No other uses without permission.
Copyright 2016 Massachusetts Medical Society. All rights reserved.
Opioid Abuse in Chronic Pain

dose: implications for surveillance and evidence-based review. Pain Med 2008;9: osteoarthritis of the hip. Cochrane Data-
prevention. Prehosp Emerg Care 2013;17: 444-59. base Syst Rev 2014;4:CD007912.
317-29. 102. Martell BA, OConnor PG, Kerns RD, 113. Hayden JA, van Tulder MW, Malmi-
91. Centers for Medicare and Medicaid et al. Systematic review: opioid treatment vaara A, Koes BW. Exercise therapy for
Services. Opioid morphine equivalent for chronic back pain: prevalence, efficacy, treatment of non-specific low back pain.
conversion factors (https://w ww.cms.gov/ and association with addiction. Ann In- Cochrane Database Syst Rev 2005; 3:
Medicare/Prescription-Drug-Coverage/ tern Med 2007;146:116-27. CD000335.
PrescriptionDrugCovContra/Downloads/ 103. Vowles KE, McEntee ML, Julnes PS, 114. Simpson CA. Complementary medi-
Opioid-Morphine-EQ-Conversion-Factors Frohe T, Ney JP, van der Goes DN. Rates cine in chronic pain treatment. Phys Med
-March-2015.pdf). of opioid misuse, abuse, and addiction in Rehabil Clin N Am 2015;26:321-47.
92. Von Korff M, Saunders K, Thomas chronic pain: a systematic review and 115. Zhang W, Doherty M, Arden N, et al.
Ray G, et al. De facto long-term opioid data synthesis. Pain 2015;156:569-76. EULAR evidence based recommendations
therapy for noncancer pain. Clin J Pain 104. McLellan AT, Skipper GS, Campbell for the management of hip osteoarthritis:
2008;24:521-7. M, DuPont RL. Five year outcomes in a report of a task force of the EULAR Stand-
93. Hall AJ, Logan JE, Toblin RL, et al. cohort study of physicians treated for sub- ing Committee for International Clinical
Patterns of abuse among unintentional stance use disorders in the United States. Studies Including Therapeutics (ESCISIT).
pharmaceutical overdose fatalities. JAMA BMJ 2008;337:a2038. Ann Rheum Dis 2005;64:669-81.
2008;300:2613-20. 105. Weiss RD, Potter JS, Griffin ML, et al. 116. Chou R, Qaseem A, Snow V, et al.
94. Madadi P, Persaud N. Suicide by means Long-term outcomes from the National Diagnosis and treatment of low back
of opioid overdose in patients with chron- Drug Abuse Treatment Clinical Trials pain: a joint clinical practice guideline
ic pain. Curr Pain Headache Rep 2014;18: Network Prescription Opioid Addiction from the American College of Physicians
460. Treatment Study. Drug Alcohol Depend and the American Pain Society. Ann In-
95. Cheatle MD. Depression, chronic pain, 2015;150:112-9. tern Med 2007;147:478-91.
and suicide by overdose: on the edge. Pain 106. Office of the Assistant Secretary for 117. Boccard SG, Pereira EA, Aziz TZ.
Med 2011;12:Suppl 2:S43-8. Planning and Evaluation. Opioid abuse Deep brain stimulation for chronic pain.
96. Starrels JL, Wu B, Peyser D, et al. It in the U.S. and HHS actions to address J Clin Neurosci 2015;22:1537-43.
made my life a little easier: primary care opioid-drug related overdoses and deaths. 118. Krames ES. The dorsal root ganglion
providers beliefs and attitudes about us- Washington, DC:Department of Health in chronic pain and as a target for neuro-
ing opioid treatment agreements. J Opioid and Human Services, March 26, 2015 modulation: a review. Neuromodulation
Manag 2014;10:95-102. (https://aspe.hhs.gov/basic-report/opioid 2015;18:24-32.
97. Opioid overdose prevention pro- -abuse-us-and-hhs-actions-address-opioid 119. Moreno-Duarte I, Morse LR, Alam M,
grams providing naloxone to laypersons -drug-related-overdoses-and-deaths). Bikson M, Zafonte R, Fregni F. Targeted
United States, 2014. MMWR Morb 107. Sullivan MD, Edlund MJ, Fan MY, therapies using electrical and magnetic
Mortal Wkly Rep 2015;64:631-5. Devries A, Brennan Braden J, Martin BC. neural stimulation for the treatment of
98. Hou YY, Cai YQ, Pan ZZ. Persistent Trends in use of opioids for non-cancer chronic pain in spinal cord injury. Neuro-
pain maintains morphine-seeking behav- pain conditions 2000-2005 in commer- image 2014;85:1003-13.
ior after morphine withdrawal through cial and Medicaid insurance plans: the 120. Treister R, Lang M, Klein MM, Oak-
reduced MeCP2 repression of GluA1 in rat TROUP study. Pain 2008;138:440-9. lander AL. Non-invasive transcranial mag-
central amygdala. J Neurosci 2015; 35: 108. Volkow ND, McLellan TA. Curtailing netic stimulation (TMS) of the motor cor-
3689-700. diversion and abuse of opioid analgesics tex for neuropathic pain at the tipping
99. Zhang Z, Tao W, Hou YY, Wang W, Lu without jeopardizing pain treatment. point? Rambam Maimonides Med J 2013;
YG, Pan ZZ. Persistent pain facilitates re- JAMA 2011;305:1346-7. 4(4):e0023.
sponse to morphine reward by downreg 109. Williams AC, Eccleston C, Morley S. 121. Glombiewski JA, Bernardy K, Hauser
ulation of central amygdala GABAergic Psychological therapies for the manage- W. Efficacy of EMG- and EEG-biofeedback
function. Neuropsychopharmacology 2014; ment of chronic pain (excluding head- in fibromyalgia syndrome: a meta-analy-
39:2263-71. ache) in adults. Cochrane Database Syst sis and a systematic review of randomized
100. Banta-Green CJ, Merrill JO, Doyle Rev 2012;11:CD007407. controlled trials. Evid Based Complement
SR, Boudreau DM, Calsyn DA. Opioid use 110. Busch AJ, Barber KA, Overend TJ, Alternat Med 2013;2013:962741.
behaviors, mental health and pain de- Peloso PM, Schachter CL. Exercise for
122. Guan M, Ma L, Li L, et al. Self-reg-
velopment of a typology of chronic pain treating fibromyalgia syndrome. Cochrane ulation of brain activity in patients with
patients. Drug Alcohol Depend 2009;104: Database Syst Rev 2007;4:CD003786. postherpetic neuralgia: a double-blind ran-
34-42. 111. Fransen M, McConnell S, Harmer domized study using real-time FMRI neu-
101. Fishbain DA, Cole B, Lewis J, Roso- AR, Van der Esch M, Simic M, Bennell KL. rofeedback. PLoS One 2015;10(4):e0123675.
moff HL, Rosomoff RS. What percentage Exercise for osteoarthritis of the knee. 123. OConnor AB, Dworkin RH. Treat-
of chronic nonmalignant pain patients Cochrane Database Syst Rev 2015; 1: ment of neuropathic pain: an overview of
exposed to chronic opioid analgesic ther CD004376. recent guidelines. Am J Med 2009;122:
apy develop abuse/addiction and/or aber- 112. Fransen M, McConnell S, Hernandez- Suppl:S22-32.
rant drug-related behaviors? A structured Molina G, Reichenbach S. Exercise for Copyright 2016 Massachusetts Medical Society.

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