Opioid Use Disorder

Alexander M. Dydyk; Nitesh K. Jain; Mohit Gupta.

Author Information and Affiliations

Last Update: June 21, 2022.

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Continuing Education Activity

Opioid use disorder has a significant impact on the quality of life. It is an epidemic in the
United States. The persistent use of opioids should be diagnosed and treated promptly. This
activity reviews the evaluation and management of opioid use disorder and highlights the role
of the interprofessional team in improving care for patients with this condition.
Objectives:
 Identify the etiology of opioid use disorder medical conditions and emergencies.
 Outline the appropriate evaluation of opioid use disorder.
 Review the management options available for opioid use disorder.
 Describe interprofessional team strategies for improving care coordination and
communication to advance opioid use disorder and improve outcomes.
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Introduction
Opioid use disorder is the chronic use of opioids that causes clinically significant distress or
impairment. Opioid use disorders affect over 16 million people worldwide, over 2.1 million
in the United States, and there are over 120,000 deaths worldwide annually attributed to
opioids.[1] There are as many patients using opioids regularly as there are patients diagnosed
with obsessive-compulsive disorder, psoriatic arthritis, and epilepsy in the United States.
Opioid use disorder diagnosis is based on the American Psychiatric Association DSM-5 and
includes a desire to obtain and take opioids despite social and professional consequences.
Examples of opioids include heroin, morphine, codeine, fentanyl, and synthetic opioids such
as oxycodone. Opioid use disorder consists of an overpowering desire to use opioids,
increased opioid tolerance, and withdrawal syndrome when discontinued. Opioid use disorder
includes dependence and addiction with addiction representing the most severe form of the
disorder.[2] The disease is treated with opioid replacement therapy using buprenorphine or
methadone, which reduces the risk of morbidity and mortality. Naltrexone may be useful to
prevent relapse. Naloxone is used to treat opioid overdose.[3] Nonpharmacologic behavioral
therapy is also beneficial. Patients with opioid use disorder often benefit from twelve-step
programs, peer support, and mental health professionals, individual and group therapy.
[4] The significant prevalence of opioid use disorder stresses the importance of clinicians to
understand more about opioids and be able to refer patients to available treatment centers for
substance use disorders, as well as be weaned from prescription opioids due to their addictive
potential and significant side effect profile. The opioid-use disorder typically involves periods
of exacerbation and remission, but the vulnerability to relapse never disappears. The pattern
is similar to other chronic relapsing conditions; signs and symptoms can be severe, and long-
term adherence to treatment is often intermittent. Patients with opioid problems may have
extended periods of abstinence and usually do well. However, there is a chronic risk of
accidental overdose, trauma, suicide, and infectious diseases. The risk decreases with
abstinence from opioids.
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Etiology
The etiology of opiate use disorder is multifaceted. Dependence and substance abuse is a
product of biological, environmental, genetic, and psychosocial factors.[5] Opioids, including
prescription analgesics, derive from the poppy plant. Clinicians prescribe various opioids to
control pain, decrease cough, or relieve diarrhea. Opioid-use disorders occur in individuals
from all educational and socioeconomic backgrounds. There is a biological base of addiction.
Patients can be deficient in neurotransmitters such as dopamine, making them more likely to
seek external sources of endorphins. In an attempt to self-correct this deficit, some
individuals may turn to opioids. Separately, a patient with first-degree relatives who have a
substance abuse disorder is more likely to develop an opiate use disorder. There is an
estimated 50% heritability to opioid use disorder.[6] Patients diagnosed with opioid use
disorder exposed to an environment that includes opioid use may be more likely to develop
substance abuse disorder. Environmental influence on opioid use may be secondary to peer
relationships or be from a physician's prescription for a previous injury. Patients with a
history of depression, post-traumatic stress disorder (PTSD), or anxiety are more likely to
suffer from substance abuse, as well as patients with histories of childhood trauma and abuse.
[7] Opioid dependence includes physical or psychological dependence or both. The majority
of opioids in use are prescribed, but many are obtained illegally. According to the CDC, there
were more than 191 million opioid prescriptions prescribed from 2012 to 2017.
Genetics may also play a role in the development of opioid use disorder. Mu, delta, and
kappa are the three different principal receptors for opioids. Mu acts in the brain by
decreasing the release of neurotransmitters.[8]Research has demonstrated a genetic basis in
the treatment of pain for opioid use disorder. There are no specific pharmacogenomic dosing
recommendations, as there is no clear evidence connecting genotype to drug effect, toxicity,
or dependence.[9]
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Epidemiology
Over 16 million people worldwide are opioid-dependent and would meet the criteria for
opioid use disorder, three million in the USA. Opioid use disorder results in over 120000 and
47000 deaths per year worldwide and in the U.S., respectively.[10] Opioid-related death is
the most lethal drug epidemic in American history. According to the CDC, the age-adjusted
drug poisoning death rate involving opioid analgesics increased to 7.0 per 100000 in 2015.
[11][12] Substance abuse is widespread, with over 20 million suffering from substance use
disorder, including alcohol, methamphetamines, and opioids. Nearly 10% of the United
States population over the age of 12 has used an illicit drug in the prior month. Of the 20
million Americans with substance abuse, two million are using prescription opioid pain
medications, 500 thousand use heroin. Recreational use of opioids was at its highest in 2010
and has gradually decreased as the opioid epidemic has gained attention in the United States.
Up to 50% of patients on chronic opioid therapy meet the criteria for opioid use disorder.[13]
The prevalence of opioid use and dependency varies by age and gender. Men are more likely
to use opioids, become dependent on various opioids, and they account for the majority of
opioid-related overdoses. Women have prescribed opioids more often than men for analgesia.
Deaths due to opioid use tend to skew at older ages with overdoses from opioids highest
among individuals between the ages of 40 and 50. Yet, heroin overdoses peak between the
ages of 20 and 30. The peak age of treatment for opioid use disorder is between 20 to 35-year
olds.[14] Patients diagnosed with an opioid-use disorder who encounter legal problems
related to their drug use are more likely in persons with previous criminal records and high
impulsivity.[15]
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History and Physical

To make the diagnosis of the opioid-use disorder, the patient must meet the diagnostic criteria
via the DSM-5:[16][17]
The opioid-use disorder is defined as opioid use and the repeated occurrence within 12
months of two or more of eleven problems. The problems include opioid withdrawal with
stopping opioid use, giving up essential life events for opioid use, and excessive time using
opioids. The individual also has significant impairment or distress as a result of opioid use.
Six or more items on the diagnostic criteria indicate a severe condition.
The signs and symptoms of opioid use disorder include drug-seeking behavior, legal or social
ramifications due to opioid use, and multiple opioid prescriptions from different clinicians.
Furthermore, various medical complications from the use of opioids, opioid cravings,
increased opioid usage over time, and symptoms of opioid withdrawal with stopping opioids.
A list of the eleven problems is given below:
 Continued use despite worsening physical or psychological health
 Continued use leading to social and interpersonal consequences
 Decreased social or recreational activities
 Difficulty fulfilling professional duties at school or work
 Excessive time to obtain opioids, or recover from taking them
 More taken than intended
 The individual has cravings
 The individual is unable to decrease the amount used
 Tolerance
 Using despite it being physically dangerous settings
 Withdrawal
A full social history and mental health history should be a part of the history for a patient
meeting the criteria of an opioid use disorder. Furthermore, the patient's previous injury
history should be recorded.
Opioid withdrawal symptoms include abdominal cramps, craving, agitation, diarrhea, pupil
dilation, anxiety, elevated blood pressure, sneezing, sweating, elevated heart rate, tearing,
shakiness, muscle pain, rhinorrhea, goosebumps, and insomnia.
Opioid intoxication symptoms include confusion, miosis, hypersomnia, nausea, euphoria,
constipation, and decreased pain perception.
For suspected opioid overdose, on a physical exam, there are pinpoint pupils. The patient can
be hypothermic or bradycardic, with limited responsiveness or unconsciousness.
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Evaluation
The basis for the diagnosis of opioid use disorder is primarily on history or physical.
Urine drug tests are necessary before starting and while maintaining methadone or
buprenorphine.[18]
If the patients have a history of IV drug abuse, tests for HIV, hepatitis B, and C should be
ordered.[19][20][21] A patient who is unconscious or obtunded secondary to opioid
intoxication or overdose may require a non-contrast CT of the head for possible hemorrhage
or a chest X-ray for possible aspiration pneumonia. Furthermore, IV opioid users with
bacteremia will require an echocardiogram to rule out endocarditis.Neuroimaging and
neuropsychological studies demonstrate dysregulation of the circuits associated with emotion,
impulsivity, and stress. Neuroimaging shows both functional and structural brain alterations
for patients in patients with a substance use disorder.[22]
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Treatment / Management
There are a variety of approaches to rehabilitation and maintenance of patients with opioid
use. Rehabilitation begins with a cognitive-behavioral approach similar to that used in the
treatment of other chronic conditions. Maintenance programs should include psychological
support. Patients are encouraged and motivated to change through education, reward
cooperation, and medications. The goal of therapy is to minimize drug use relapse. Patients
with substance-use disorders are encouraged to participate in self-help programs such as
Alcoholics Anonymous and Narcotics Anonymous. The combination of education,
motivational enhancement, and self-help groups helps patients change how they think about
the ways that opioids affect their lives.[23][24][23] A 12-step program is similar to the
alcoholics anonymous program. The program supports behavioral modification through self-
help and peer-support programs. The program enforces the idea that addicts must surrender to
the fact that they have a chronic addiction that will never go away. Group therapy helps
maintain self-control and restraint for patients with substance abuse disorder.[25] Group
therapy is cost-effective in comparison to individualized therapy in the treatment of substance
abuse.[26]
Together various forms of rehabilitation help patients recognize that change is possible, and
there is a need to decrease behaviors that perpetuate illicit-drug use while developing new
behaviors that diminish drug-related problems.[27] The goal is to limit opioid use to the
minimum level needed to provide pain relief. Usually, drugs and physical therapy provide a
long-term solution to pain management and minimization of the use of opioids. The treatment
of opioid use disorders improves physical and psychological conditions, reduces risks, and
criminal behavior.[28][29] Cognitive-behavioral therapy is most effective if combined with
medications; however, there are mixed results on its effectiveness.[17][30] Education about
dealing with pain syndromes and minimizing opioid use can help build rapport and create
realistic treatment goals. There is also the need to warn patients to avoid misuse of other
drugs, which enhance the effects of opioids such as benzodiazepines to help prevent
overdose.
Opioid replacement, maintenance, or substitution therapy involves replacing an opioid with a
longer-acting but less euphoric and addicting opioid. The commonly used drugs are
buprenorphine and methadone prescribed and given under medical supervision. The
combination of buprenorphine and naloxone is the most widely used. Opioid maintenance
drugs help the patient experience reduced symptoms of drug withdrawal, reduced cravings,
and little or no euphoria. Almost half of the patients can maintain abstinence from additional
opioids while receiving replacement therapy.[31] Opioid dependence includes a reluctance to
or an inability to discontinue opioids. Patients often want to improve their health and quality
of life. Maintenance goals include improving health, avoiding the risks of developing HIV, or
hepatitis B or C infection. Other goals include improving interpersonal relationships,
decreasing craving, and diminishing crimes committed to pay for illicit drugs.
Methadone, an oral mu agonist, is commonly used in opioid replacement. It has been widely
used and studied worldwide, and methadone maintenance is a well-established approach. In
the U.S., methadone is offered only for specially monitored clinics. Patients with an opioid-
use disorder with physiologic features or who are likely to relapse would be eligible for a
methadone clinic. The advantages of methadone treatment include blocking euphoric effects,
decreasing narcotic craving, and reducing transmission of infectious diseases. Methadone
maintenance is non-sedating and is medically safe, provided there is no concomitant use of
other prescription or illicit drugs. The maintenance phase begins approximately six weeks
after the initiation of therapy. The length of the maintenance phase can last years to an entire
lifetime. Tapering off methadone can take weeks or months, depending on the patient's opioid
dependence.[32][33]
An alternative oral, long-acting opioid is buprenorphine for maintenance therapy.
Buprenorphine treatment reduces morbidity and mortality. The recommended for
buprenorphine is the minimum treatment of 12 months, although, as with methadone, risks of
relapse and overdose increase following discontinuation of buprenorphine. Reliable and
consistent data support the effectiveness of buprenorphine maintenance. Initiating
buprenorphine maintenance as soon as possible can enhance efficacy. Oral buprenorphine is
processed in the liver but absorbed as a sublingual tablet or buccal film. It demonstrates a
reduction in opioid withdrawal symptoms and partially blocks intoxication from other
opioids. Office-based maintenance with buprenorphine can prescribe for up to 275 patients as
of 2016. Buprenorphine effects last for 24 to 36 hours. The induction phase of buprenorphine
lasts approximately seven days in patients who are misusing a short-acting opioid such as
heroin. The stabilization phase begins when there is a marked reduction in craving; opioid
misuse is diminished or absent, and withdrawal symptoms are absent. It typically takes eight
weeks to reach maintenance status. Buprenorphine does not precipitate withdrawal unless it is
in its intravenous form. In this case, the withdrawal symptoms can be sudden and severe.[34]
[35]
Patient selection criteria for buprenorphine maintenance resemble that of methadone
maintenance. Considerations of buprenorphine compared to methadone include the cost, the
availability of methadone clinics, as well as access to physicians licensed to prescribe
buprenorphine. Comparing methadone and buprenorphine, they both improve outcomes.
Methadone maintenance is associated with higher rates of patient retention. Moreover,
buprenorphine is more expensive than methadone. The cost of buprenorphine might be more
than going to a methadone clinic. Buprenorphine is safer than methadone during the
induction of labor, and its administration can take place in offices. Buprenorphine is
associated with less respiratory depression compared to methadone. There is no universal
agreement on who should receive what therapy.[36] Some clinicians attempt to discontinue
their medications after approximately one year. Others emphasize relapse and overdose
deaths after leaving these programs and suggest that treatment should be open-ended and
potentially lifelong. Patients considering stopping opioid replacement therapy should be
tapered off the drug. The dose should be decreased slowly while being monitored and
adjusted according to observing for withdrawal symptoms.[37][38][39]
Naltrexone works by blocking opioid effects and helps maintain abstinence from opioids by
being a mu-receptor agonist. The initiation of naltrexone treatment is only when the patient is
free of physiological opioid dependence. Seven days without acute withdrawal symptoms is a
requirement before starting the medication. Both oral and intramuscular naltrexone is
superior to placebo in maintaining abstinence from opioids, but other studies have shown
them to be ineffective.[40] Naltrexone is used for the treatment of opioid addiction as it
blocks the euphoric, physiological effects of opioids. The intramuscular injection has better
compliance due to monthly dosing. Monthly naltrexone intramuscular injections are FDA
approved for opioid dependence in opioid users.[41] Naltrexone administered alongside
buprenorphine has shown to be an effective treatment [42]. Available in daily tablets,
naltrexone's effects last between 24 to 36 hours.
Clonidine or lofexidine treats the signs and symptoms of withdrawal as an adjunctive therapy.
In some countries, not including the United States, long-term injecting drug users who fail
methadone are treated with pure injectable diamorphine. Dihydrocodeine in both extended-
release and immediate-release forms are useful in the maintenance treatment as an alternative
to methadone or buprenorphine.[43] Clonidine or tizanidine are helpful to decrease anxiety
associated with opioid withdrawal. They also cause piloerection and other signs and
symptoms of autonomic overactivity. The treatment of anxiety and insomnia associated with
opioid withdrawal is with benzodiazepines or other sedating drugs. Diarrhea, nausea, and
vomiting are treated with loperamide. Prochlorperazine, along with sports drinks or
intravenous fluids, is also helpful. Pain mitigation is through the use of nonsteroidal anti-
inflammatory agents such as naproxen. Combination therapies are superior to placebo for
symptomatic relief.
A methadone taper stabilizes a patient to prevent withdrawal but does not oversedate. Doses
are decreased, 10% to 20% every one to two days over two to three weeks or longer. The
taper can occur over approximately one week for hospitalized inpatients. In a methadone
reduction program, the patient receives enough methadone to avoid withdrawal symptoms.
Then after a period of stability, the dose is tapered until methadone can be discontinued or
switch to an opiate with a more relaxed withdrawal profile, such as buprenorphine.
Buprenorphine should be given 12 to 18 hours after the last dose of methadone. This delayed
administration reduces the change of withdrawal in patients who are receiving long-acting
drugs such as methadone. After the patient’s condition stabilizes for three to five days, the
dose decreases over two or more weeks.
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Differential Diagnosis
The differential diagnosis of opioid use disorder includes many of the comorbid conditions
that lead to chronic opioid use. Moreover, the differential diagnosis includes malingering and
substance abuse disorder. The clinician must determine if the patient is using opioids for
secondary gain, or are they using illegal controlled substances, prescription opioids, or street
drugs. Chronic pain disorders, mental health disorders, substance abuse disorders, and
various chronic injuries and diseases should be a part of the differential for opioid use
disorder. Evaluation and treatment of the underlying medical condition responsible for opioid
use are of the utmost importance.
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Prognosis
The diagnosis of opioid use disorder helps modify clinicians prescribing practices to
recognize patients taking chronic opioids. Clinicians should offer all patients with the opioid-
use disorder naloxone, a mu-opioid receptor antagonist. It saves lives.[44][45] Patients are at
the highest risk of death in the first four weeks of opioid dependence treatment and then in
the next four weeks after treatment ends.[46]
During and after tapering off methadone, close contact with the patient should be maintained
because discontinuation of maintenance carries high risks of relapse to the use of illicit drugs
and overdoses that may lead to death.[47] The mortality during induction with buprenorphine
is lower than that during induction with methadone.[48] The advantage of buprenorphine and
methadone therapy is a reduction in morbidity and mortality. Opioid replacement therapy
reduces the incidence of long-term opioid addiction while decreasing illegal opiate use and
decreasing mortality. The cost to society with opioid replacement is lessened, including
crimes associated with drugs and the expense of dealing with HIV, sepsis, and other medical
complications. Opioid replacement therapy has the support of most national and international
organizations as a cost-effective method of reducing injection infections and lowering
HIV/AIDS exposure. Methadone treatment for opioid use disorder is associated with a 50%
reduction in all-cause mortality, as well as a 50% reduction in the incidence of hepatitis C.
Methadone also decreases drug-related crimes, illicit drug use, improved social interactions,
and increased rates of retention in rehabilitation programs.[48][49][50]
Over 90% of patients go through opioid withdrawal and relapse one month later.[47]
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Complications
Addiction is a subset of opioid use disorder and is present in the most severe form. Addiction
is continued drug use despite adverse consequences or events. Addiction to opioids occurs by
sensitizing the drug reward system and amplifying compulsive drug-seeking. Primarily the
effects of chronic opioids are in the orbitofrontal area, which is essential for regulating
anxiety, emotional responses, and reward-related behaviors. The socioeconomic impact of
opioid use disorder affects every aspect of a patient's life. Legal action, loss of impact,
personal relationships, and significant morbidity and mortality are all consequences of long-
term opioid use.[46]
Dependence is associated with withdrawal syndrome that occurs upon cessation of repeated
exposure to a drug stimulus. Providers must advise patients not to stop chronic opioids
without tapering their medication dosage. Dependence is also a subset of a substance use
disorder, manifesting as physical or psychological dependence or both. Opioid withdrawal
onset varies with the type of opioid used but correlates with dependence. Withdrawal is a
significant complication associated with opioid use disorder. Heroin withdrawal begins in as
little as five hours, whereas methadone may be two to three days following the last dosage.
Withdrawal symptoms may last days to weeks known as protracted abstinence syndrome.[51]
The side effects of naltrexone include gastrointestinal upset, fatigue, and insomnia, as well as
elevated levels on liver-function tests at higher doses. However, naltrexone is relatively safe
in persons who consume large amounts of alcohol and those with hepatitis C or HIV
infection.
If the methadone dosage increases too quickly during opioid replacement, it is associated
with cardiac arrhythmias, including prolonged QT syndrome.
The mortality rate of patients on chronic opioids is ten times as high as the average
population.[52]
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Deterrence and Patient Education

There is an international effort to decrease the morbidity and mortality associated with opiate
prescriptions. One of the most common reasons for death is acute respiratory depression and
resulting in death by asphyxiation.
The various side effects of chronic opioids merit discussion, and the educational materials
provided.
If the patient is an IV drug user, communicable diseases should be ruled out, such as HIV or
hepatitis B or C.
Methadone and buprenorphine save lives and should be considered for patients on chronic
opioids to minimize the risk of death.
Naloxone is used in the acute treatment of an opiate overdose and can be given subcutaneous,
IM, IV, intranasal, or inhalation. Naloxone rapidly displaces opioids from opioid receptors
and prevents the activation of these receptors by opioids. It is reasonable to prescribe to any
patient taking chronic opioids.
Naloxone kits are a recommendation for individuals that may witness or be the initial
responder to an opioid overdose. It should be available in drug or substance abuse programs.
[53][54]
An addiction medicine or pain medicine specialist may be a valuable member of the patient's
care team, depending on the patient's goals and needs.
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Enhancing Healthcare Team Outcomes

While opioid use disorder is on the rise across the world and has transformed into an
epidemic in the U.S., it needs a better understanding from healthcare professionals and
government intervention along with resources and a team-based approach to managing these
patients. It requires an interprofessional approach where the cognitive and behavior therapies
need to be supported by medical intervention to reduce the chances of withdrawal and
relapse. Medications are available to use in pregnancy and have shown better neonatal
outcomes, as well as improve morbidity and mortality in the adult population.
The primary care physician is responsible for coordinating the care, which includes the
following:
 Consensus expert opinion suggests screening for all adult patients for opioid use
disorder.
 The primary care provider diagnoses opioid use disorder. They are also responsible
for coordinating care and management associated with opioid use.
 When assessing a patient on chronic opioids, the recommendation is to order a urine
drug screen.
 For opioid intoxication, signs, and symptoms of respiratory depression, constipation,
reduced consciousness, and cardiac arrhythmias require monitoring.
 Treatment of the underlying comorbid condition associated with opioid use disorder is
necessary— for example, cognitive behavioral therapy and antidepressants for major
depressive disorder.
 Discussion of the diagnosis of opioid use disorder with the patient and the long term
and immediate effect of opioids on their morbidity and mortality
 Prescribed naltrexone for an emergency overdose of opioid analgesia for any patient
on chronic opioids
 If the patient is using IV drugs, the clinician should order various labs to rule out
potential HIV, hepatitis B, and C.
 Referral to an addiction medicine specialist or methadone clinic for the patient on
high-dose opioids, if the primary care provider is uncomfortable managing opioid use
disorder.
 Discuss a rehabilitation program for the patient who has the means for detoxification.
 A referral to a pain medicine specialist if the patient continues to require opioid
analgesia or desires interventional procedures as an alternative to treat their pain.
Furthermore, the possibility of addiction, dependence and withdrawal symptoms must merit
consideration when treating opioid use disorder. An interprofessional team working together
can reduce the morbidity and mortality of chronic opioid use and overdose. Naloxone can be
a life-saving treatment for a patient on chronic opioids. The long-term outcomes for
detoxification and drug rehabilitation are promising.
Specialty trained nurses in addiction and pain medicine are involved in care. They monitor
patients, provide education, and facilitate communication between team members.
Pharmacists review opioid treatment, check for contraindications and interactions, as well as,
providing education to patients and their families. They can often be the first to notice opioid
misuse by the filling of prescriptions from multiple providers, early refill requests, etc., and
should contact the prescriber(s0 in such instances. These interprofessional interventions can
drive better outcomes for patients with this disorder. [Level V]
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