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.
The etiology of opiate use disorder is multifaceted. Dependence and substance abuse is a product of biologic, 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]
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 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 tends 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 is more likely in persons with previous criminal records and high impulsivity.[15]
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 listed below.
A full social history and mental health history should be apart of the history for a patient meeting 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.
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, 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]
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 the 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 euphoric. 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 reduction of 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 treat 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 therapy is 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.
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 disorder, and various chronic injuries and diseases should be apart of the differential for opioid use disorder. Evaluation and treatment of the underlying medical condition responsible for opioid use are of the utmost importance.
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 decrease drug-related crimes, illicit drug use, improved social interactions, and increased rates of retention in rehabilitation programs.[48][49][50]
Over 90% of patients who go through opioid withdrawal, then relapse one month later.[47]
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 maybe 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]
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.
While the 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 the 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:
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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