Opioids are powerful pain killers that are highly addictive. Opioid dependence affects nearly 5 million people in the United States and leads to approximately 17,000 deaths annually.[1] According to the CDC, the death rate from overdoses tripled from 6.1 per 100,000 people in 1999 to 19.8 in 2016 and rose 20% from 2015 to 2016. The number of people fatally overdosing on fentanyl and other synthetic opiates more than doubled from 9,580 in 2015 to 19,413 in 2016.[2] Half of deaths due to drug overdose are related to prescription drugs, according to a report on the leading cause of deaths from injury in the United States.[3] In 2017, researchers announced that US life expectancy was down for a second straight year, the first 2-year decline since the early 1960s when flu deaths were likely to blame. The current culprit is the opioid overdose epidemic.[4]
Symptoms of opioid abuse can be categorized by physical state.
Intoxication state
Patients with opioid use disorders frequently relapse and present with intoxication. Symptoms vary according to level of intoxication. For mild to moderate intoxication, individuals may present with drowsiness, pupillary constriction, and slurred speech. For severe overdose, patients may experience respiratory depression, stupor, and coma. A severe overdose may be fatal.
Withdrawal state
Symptoms of withdrawal include the following:
See Clinical Presentation for more detail.
The Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition (DSM-5) defines opioid use disorder as a problematic pattern of opioid use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period:[5]
Tolerance and withdrawal criteria are not considered to be met for individuals taking opioids solely under appropriate medical supervision.
Opioid use disorder can be classified by severity as mild, moderate, or severe.
See Workup for more detail.
Current guidelines recommend comprehensive treatment with pharmacological agents such as methadone, buprenorphine, or buprenorphine combined with naloxone as well as psychosocial therapy.
The American Psychiatric Association (APA) guidelines identify the following treatment modalities as effective strategies for managing opioid dependence and withdrawal.[6]
The APA guidelines recommend the following evidence-based psychosocial treatments for opioid use disorder:[6]
See Treatment and Medication for more detail.
See Pain Management: Concepts, Evaluation, and Therapeutic Options, a Critical Images slideshow, to help assess pain and establish efficacious treatment plans.
Opioids are defined by their ability to bind to and influence opiate receptors on cell membranes. They can be divided into 3 classes:
The terms opiate and narcotic are generally used interchangeably with the term opioid.
Opioids act by binding to opioid receptors on neurons distributed throughout the nervous system and immune system. Four major types of opioid receptors have been identified: mu, kappa, delta, and the more recently identified OFQ/N.
These receptors are the binding sites for several families of endogenous peptides, including enkephalins, dynorphins, and endorphins. These endogenous peptides regulate and modulate several important functions, including the following:
Understanding the role of endogenous peptides allows us to understand why medications and drugs that bind to opioid receptors have such profound effects on so many organ systems and bodily functions.
More than 20 clinically available medications bind opioid receptors. Most of these are prototypical mu receptor full agonists (capable of producing a maximal response at mu receptor subtypes in opioid-sensitive systems), and are associated with the following constellation of effects:
Almost all abused opioids are prototypical mu agonists. The euphoria associated with mu receptor activation is often termed a high. Moreover, when opioids are injected or inhaled, levels in the brain rise rapidly, causing a rush or thrill. The rush is a brief, intense, usually pleasurable sensation, which is followed by a longer-lasting high. When opioids are used chronically, tolerance and physical dependence occur. Over time, those with physiologic dependence often try to avoid unpleasant withdrawal symptoms rather than seeking the pleasurable sensations associated with initial use of opioids.
Short-term opioid use has been associated with gray matter changes in patients with chronic pain. In a small, placebo-controlled study, long-term gray matter changes correlated with the dose of morphine after only one month of use, with some changes persisting when remeasured an average of 4.7 months later.[7]
Mu receptor agonists with rapid onset of action and short half-lives have the greatest potential for destructive addictive behaviors, as addicted individuals get immediate reward followed by noticeable withdrawal symptoms. For example, heroin typically produces the following destructive behavioral pattern:
Mu receptor agonists with delayed onset of action and longer half-lives, such as methadone, cause dependence without necessarily causing the same destructive cycle to occur. Methadone can be used once daily, and can be obtained legally. Once tolerance develops, methadone has little impact on mood, judgment, and psychomotor skills. Therefore, methadone can be used to replace drugs associated with more destructive lifestyles (maintenance therapy).
In 2014, the FDA announced that extended-release and long-acting (ER/LA) opioid pain relievers should be restricted for use only in the management of severe pain that requires daily, around-the-clock treatment because alternative treatments were inadequate. Labels added include warnings, which state that long-term maternal use of ER/LA opioid pain relievers could result in potentially fatal neonatal opioid withdrawal syndrome. One of the drugs approved in 2014 was hydrocodone bitartrate, an extended-release formulation with abuse-deterrent properties, designed to be hard to crush, break, dissolve, or prepare for injection.[8] These announcements were made in an effort to combat the epidemic of addiction and fatal overdoses associated with opioid abuse.[9]
In 2016, the CDC released final recommendations for prescribing opioids for chronic pain to combat the epidemic of prescription overdoses. The primary recommendation states that opioids should not be first-line treatment for chronic pain. Health care providers should first consider nonopioid pain relievers or nonpharmacological options. Other recommendations include conducting a urine test before opioid therapy, starting at the lowest dose possible and avoiding doses of 90 morphine milligram equivalents (MME) or more, prescribing immediate-release as opposed to longer-acting opioids, and limiting treatment for acute pain to usually no more than 7 days.[10]
Buprenorphine is a partial agonist at the mu receptor (it can only partially activate the receptor). Therefore the intensity of mood alteration induced by buprenorphine plateaus, and users do not generally feel the rush or intense high they feel when using other opioids. This has been termed a ceiling effect. Fortunately, buprenorphine’s partial agonism is sufficient to prevent cravings and withdrawal symptoms. Therefore, like methadone, buprenorphine can be used to replace other more destructive opioids via maintenance therapy.
Buprenorphine also binds extremely tightly to the mu receptor. This tight binding prevents other opioids from accessing the mu receptor, in turn preventing a user from getting high on other opioids. Moreover, buprenorphine’s binding is so strong that it displaces other opioids from mu receptors. Therefore, if buprenorphine is taken while a patient has significant serum levels of another opioid, the patient will rapidly experience withdrawal symptoms as the other opioid is displaced from receptors. The Substance Abuse and Mental Health Services Administration (SAMHSA) recommends the induction phase of buprenorphine be preceded by 12 to 24 hours of opioid abstinence in order to avoid the acute withdrawal symptoms caused by the displacement of opioid agonists from mu receptors.[11]
Mechanisms of tolerance and withdrawal include but are not limited to the following:
One of the most insidious features of opioid addiction is the tendency to relapse on the drug even weeks, months, or years after those addicted stop using and withdrawal symptoms disappear. The mechanism for this type of relapse is being studied intensely. Animal studies suggest 3 distinct conditions that reliably induce relapse:
There is evidence that long-term administration of opioids can permanently alter the density of dendritic spines in certain neurons, and these permanent changes may contribute to long-lasting vulnerability to relapse.
Since the 1990s, opioid use and abuse have risen markedly in the United States. The increased abuse has coincided with the availability of high-purity heroin, which allows users to begin use by snorting or smoking rather than by IV administration. Moreover, increased opioid abuse has coincided with a controversial US campaign against undertreatment of pain that has caused an enormous increase in opioid prescriptions; the growth of prescription opioid abuse has been particularly explosive. The following statistics dramatically illustrate this problem:
An analysis from the US Centers for Disease Control and Prevention (CDC) of 2012 prescribing data collected from US retail pharmacies showed that healthcare providers wrote 259 million prescriptions for opioid painkillers that year and that 46 individuals died each day in the United States from an overdose of prescription painkillers.[13, 14, 15] The distribution of opioid painkiller prescriptions varied widely among states; healthcare providers in the highest-prescribing state (Alabama) wrote almost three times as many prescriptions per person as those in the lowest-prescribing state (Hawaii).
The 2014 National Survey on Drug Use and Health (NSDUH), sponsored by the Substance Abuse and Mental Health Services Administration (SAMHSA), also provided data graphically illustrating the increase in prescription opioid abuse. In 2014, 10,337 persons aged 12 or older had used pain relievers illicitly in the last year; 4,325 persons aged 12 or older used pain relievers illicitly in the last month.[16]
Prescription opioids have been suggested to be an important gateway drug, and the fact that they are prescribed by doctors lulls users into believing they are safe. In 2016, the CDC released final recommendations for prescribing opioids for chronic pain to combat the epidemic of prescription overdoses. The primary recommendation states that opioids should not be first-line treatment for chronic pain. Health care providers should first consider nonopioid pain relievers or nonpharmacological options.[10]
The great majority of illicitly used prescription opioids are obtained from 1 physician, not from drug dealers.
In 2015, among persons aged 12 and older who had misused prescription pain relievers in the past 12 months, the following sources were reported for the most recent misuse:
Strikingly, these data suggest that drug dealers are a relatively small source of illicitly used prescription opioids. Diversion through family and friends is now the greatest source of illicit opioids. The majority of opioids are obtained by prescription from 1 physician, not from "doctor shopping."[17]
The progression from illicitly using opioids to opioid dependence has dire consequences, including a yearly mortality rate of approximately 2%. Moreover, sustained remission from opioid dependence is difficult to achieve.
Since 1990, data from numerous US jurisdictions have reported dramatic increases in mortality related to drug poisonings. This increase has been due primarily to unintentional drug poisonings attributed either to opioid pain relievers or unspecified drugs.
According to the CDC, the death rate from overdoses tripled from 6.1 per 100,000 people in 1999 to 19.8 in 2016 and rose 20% from 2015 to 2016. The number of people fatally overdosing on fentanyl and other synthetic opiates more than doubled from 9,580 in 2015 to 19,413 in 2016.[2] In 2017, researchers announced that US life expectancy was down for a second straight year, the first 2-year decline since the early 1960s when flu deaths were likely to blame. The current culprit is the opioid overdose epidemic.[4]
The American Pain Society has published guidelines intended to improve the safety of methadone treatment.[19, 20]
Increases in accidental heroin overdoses are postulated to stem in part from a combination of decreasing cost and increasing purity. According to the DEA, average heroin purity increased from 7% in 1980, to 48% in 2000, to 70% in 2003. This allows first-time users to get high by snorting or smoking heroin, and eventually advance to IV use when tolerance develops, making initial heroin use more palatable to some addicts. Increased purity also makes mistakes in dosing potentially more lethal.
Additionally, many users believe that risk of overdose is minimal when snorting or smoking heroin. In reality, the risk of overdose remains substantial regardless of route of administration.
Mortality rates are substantially reduced when patients are treated with methadone or buprenorphine maintenance therapy.
Opioid use and dependence are associated with significant medical and psychiatric morbidities, as well as adverse social, familial, vocational, and legal consequences. The risk of criminal activity and legal consequences becomes greater as dependence becomes more severe. Intravenous injection of opioids is associated with increased risk of blood-borne infections such as hepatitis B and C and HIV.
Many of these morbidities are reduced by substitution therapies as confirmed in a 12-month, open-label, randomized controlled trial from various German centers that examined more than 1,000 patients who were severely opioid dependent and were treated with supervised oral methadone or intravenous heroin.[21]
A large study of veterans identified 3 key factors in reducing opioid-related deaths. They are quarterly physician visits, psychosocial care, and no opioid or benzodiazepine prescribing. These factors may help reduce deaths by nearly one third in individuals with opioid use disorder (OUD).[22, 23]
While females were more likely to use prescription pain relievers than males in 2015 (38.8% female vs. 33.9% male), males were more likely to misuse prescription pain relievers than females (5.3% male vs. 4% female).[17]
In a Polish study published in 1996, the direct mortality rate of people who use IV drugs was 25.7 deaths per 1000 person-years for men and 14.3 deaths per 1000 person-years for women. Compared with the general population, the risk of death was 11 times higher among males who used drugs and 20 times higher among females who used drugs.
Illicit use of opioids usually begins in late adolescence or early adulthood. Experimentation with cigarettes, alcohol, and other drugs generally precedes experimentation with opioids. The period of time from initial use to dependency is extremely variable, ranging from a few weeks to several years.
A study that examined 30-year trajectories of heroin among men and women who were in methadone maintenance treatment in California in the late 1970s found that more school problems and earlier age at onset of heroin use and first arrest were associated with more persistent heroin use.[24]
In 2017, researchers, using data from the Nationwide Emergency Department Sample, looked at patients who entered the ED for any reason and selected all patients up to 21 years old who had opioid dependence and abuse codes. Total number of visits meeting the criteria was 257,165. Findings show that 88.3% of ED visits were made by individuals aged 18 to 21 years and 8.4% were made by teens aged 16 to 17 years.[25]
The Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition (DSM-5) defines opioid use disorder as a problematic pattern of opioid use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period:[5]
Tolerance and withdrawal criteria are not considered to be met for individuals taking opioids solely under appropriate medical supervision.
Opioid use disorder can be classified by severity as mild, moderate, or severe.
Tolerance is the need for increasing doses of medication to achieve the initial effect of the drug. Tolerance to the analgesic and euphoriant effects and unwanted adverse effects, such as respiratory depression, sedation, and nausea, may develop. However, little tolerance develops to constipation and meiosis. Opioid tolerance usually does not develop in patients with cancer who are being treated for pain; the need for increasing doses in those patients typically is due to an increasing level of pain. No consistent relationship between intrinsic efficacy and tolerance exists.
Continuous administration of opioids leads to physical dependence, the emergence of withdrawal symptoms during abstinence. Physical dependence is expected after 2-10 days of continuous use when the drug is stopped abruptly. The onset and duration of withdrawal varies with the drug used. For example, meperidine withdrawal symptoms peak in 8-12 hours and last for 4-5 days. Heroin withdrawal symptoms usually peak within 36-72 hours and may last for 7-14 days. Symptoms of opioid withdrawal include the following:
The phenomenon of addiction is seen in a variable number of patients using drugs. Addiction is characterized as a psychological and behavioral syndrome in which the following features are observed:
Addiction must be defined by the observation of maladaptive behaviors, such as adverse consequences due to drug use, loss of control over drug use, and preoccupation with obtaining opioids, rather than pharmacological phenomenon of physiologic dependence, tolerance, and dose escalation. Do not use the term addiction to describe patients who are merely physically dependent. Also, keep in mind that undertreatment in patients with pain may result in a pseudoaddiction, and opioid-seeking behavior may be mistaken for addiction.
Long-acting medications, such as methadone and sustained-release morphine, tend to have slower onset of action, and the rush or high experienced with more rapid-onset medications is not as prominent. Thus, the longer-acting opioids are less likely to be abused.
Mental status effects include depression with any or all of its symptoms, such as sleep disturbances, lack of interest, selflessness, suicidal ideation, and poor coping skills.
Physiological effects: Because tolerance to many of the actions of the opioids develops, it is not likely for even a careful observer to notice the effects of opioids. Small-sized pupils may be the only observation because only very mild tolerance develops for miosis. Inflamed nasal mucosa may be seen if heroin is snorted.
Mental status effects include purposive behaviors, such as complaints and manipulations directed at getting more drugs, or anxiety.
Physiologic effects include autonomic signs (eg, tachycardia, high blood pressure, fever, piloerection [goose flesh], mydriasis, and lacrimation, CNS arousal (irritability), and yawning.
In milder abstinence syndrome, clinical features may be limited to dysphoria, craving, yawning, lacrimation, rhinorrhea, and restlessness. In moderate-to-severe cases, piloerection, mydriasis, increased BP and pulse, and GI symptoms are seen as well.
Mental status effects include euphoria, sedation, decreased anxiety, a sense of tranquility, and indifference to pain produced by mild-to-moderate intoxication. Severe intoxication can lead to delirium and coma.
Physiological effects include the following:
The physical examination provides little information to add in the diagnosis of addiction. However, symptoms of opioid withdrawal or track marks are often suggestive of addiction.
Constipation is a common occurrence due to almost continuous use of narcotics.
Opioid dependence is considered a biopsychosocial disorder. Pharmacological, social, genetic, and psychodynamic factors interact to influence abuse behaviors associated with drugs. However, pharmacological factors can be especially prominent, more so than in other types of drug use disorders.
Opioids are strongly reinforcing agents because of the euphoric effects and reported ability to reduce anxiety, increase self esteem, and help coping with daily problems. Most opioids associated with abuse and dependence are mu-agonists, such as heroin, morphine, hydrocodone, oxycodone, and meperidine. Some partial mu-agonists, such as buprenorphine, or some that have no mu-agonism, such as pentazocine, also can possess reinforcing properties. Rapid development of physical dependence and a protracted abstinence syndrome are unique to opioid use and can make abstinence difficult.
Of note, more than half of persons taking 90 days of opioid therapy over a 6-month period remain on opioids years later. Opioid continuation was strongly associated with prior opioid exposure, daily opioid doses of 120 mg or more of morphine equivalent per day, and possible misuse; however the data from which these associations did not include clinical measures of pain or disease severity.[26]
Kratom
Kratom (Mitragyna speciosa) is a psychoactive plant in the coffee family native to Southeast Asia.[27] Its use in the United States has grown over the past decade and it is estimated that millions of people take it regularly.[28] Controversy exists regarding whether kratom has any acceptable medicinal use and its safety.
The ongoing debate in the United States regarding kratom and its growing use originates from reports of kratom-related deaths, seizures, liver failure, psychosis, and concern of its addictive properties.[29] Proponents of kratom describe the botanical product and its history of being sold as a dietary supplement in Southeast Asia to manage pain, boost energy, and as a method to avoid opioid use and relieve opioid withdrawal symptoms. Recently, recreational use of kratom has been described.[30]
In 2016, the DEA announced its intention to designate kratom as a Schedule 1 controlled substance (ie, a substance with high potential for abuse and no currently accepted medical use).[31] Criticism of the DEA’s announcement came from those using kratom. Researchers also expressed concern regarding expensive and time-consuming regulations required to obtain Schedule I substances. Instead, the DEA withdrew the scheduling, and announced they would gather further scientific evidence. Kratom is currently listed as a "drug of concern" within the DEA’s Drugs of Abuse resource guide 2017 edition.[32]
Studies in rodents suggest alkaloids in kratom bind to opioid receptors and elicit antinociceptive properties, but with less respiratory depression than typical opioids.[33]
FDA scientists analyzed the chemical structures of the 25 most common compounds in kratom utilizing a computational model. Their conclusion was that all of the compounds share structural characteristics with controlled opioid analgesics, such as morphine derivatives. Additionally, the FDA found the compounds in kratom bind strongly to mu-opioid receptors, comparable to opioid drugs.[34]
At the time of this writing, a handful of states (ie, Alabama, Arkansas, Indiana, Tennessee, Vermont, Wisconsin) and several cities (ie, Denver, San Diego, Sarasota, and Washington DC) have banned or limited kratom sales. Legislation is being considered in other states (eg, Illinois).[35]
Easy drug availability and acceptable social attitudes make experimentation easy. A high rate of drug use is seen in areas of the city with poor parental functioning and higher crime and unemployment rates. Except for the association between higher exposure to the drug and higher rates of addiction, the precise role of social factors in creating dependent and addictive behaviors is uncertain.
Ego defects in certain patients are postulated to form the basis of drug use. Opioids are theorized to help the ego in managing painful effects such as anxiety, guilt, and anger. Behavioral theory postulates that basic reward-punishment mechanisms perpetuate addictive behavior.
Preexisting mental health diagnoses appear to increase the risk for long-term use of opioids among adolescents and young adults with chronic pain.[36]
Genetic epidemiologic studies suggest a high degree of heritable vulnerability for opioid dependence.[37] Gene polymorphisms for dopamine receptors/transporters, opioid receptors, serotonin receptors/transporters, proenkephalin, and catechol-O-methyltransferase (COMT) all appear to be associated with vulnerability to opioid dependence. Future interventions for opioid dependence may include medications identified through genetic research.
See the list below:
See the list below:
See the list below:
In case of historical or clinical evidence of IV drug abuse, perform the following:
For addiction, in case of historical or clinical evidence of IV drug abuse, perform an x-ray of the lungs (eg, history of injecting drugs contaminated with microcrystalline talc) to search for evidence of pulmonary fibrosis.
Naloxone challenge test: This test is performed to assess physical dependence. As an intramuscular injection or IV, 0.2-0.8 mg of naloxone is administered.
Acute opioid-related disorders that require medical management include opioid intoxication, opioid overdose, and opioid withdrawal. Issues pertaining to treatment of chronic opioid abuse include opioid agonist therapy (OAT), psychotherapy, and treatment of acute pain in patients already on maintenance therapy.
General supportive measures for opioid intoxication are as follows:
In November 2015, intranasal naloxone was approved by the FDA after fast track designation and priority review. It is indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression. The ready-to-use single-dose sprayer delivers a 4-mg dose by intranasal administration. Approval was based on pharmacokinetic studies that compared IM and intranasal dosage forms. The National Institute on Drug Abuse also was crucial to the approval by forming a public-private partnership by designing and conducting the clinical trials required to determine that the intranasal formulation delivered naloxone as quickly and as effectively as an injection.[38, 39]
In April 2014, the FDA approved naloxone (Evzio) as an autoinjector dosage form for home use by family members or caregivers. The product delivers 0.4 mg that may be administered either IM or SC in the anterolateral aspect of the thigh. The device includes visual and voice instruction, including directions to seek emergency medical care immediately after use.[40, 41]
In 1996, community-based programs began offering naloxone and other opioid overdose prevention services to persons who abuse opioids, their families, and friends, and service providers (eg, homeless shelters). Since their inception, the programs have distributed naloxone to over 53,000 persons who abuse drugs. Naloxone is effective in treating acute overdose and is first-line treatment.[42]
Because overdoses usually occur in the presence of other people and because medical care is often not sought or is sought too late, at-home naloxone programs have been piloted in several countries. This is a controversial treatment that raises concerns about condoning heroin use, discouraging medical care, and producing side effects that cannot be managed at home. However, the efficacy of these pilot programs should be carefully monitored, as the potential for reducing mortality is high.
Pharmacologic therapy for heroin addiction has focused on ameliorating withdrawal symptoms and reducing cravings. By replacing heroin with legally obtained opioid agonists, many risk factors of the drug-abusing lifestyle can be mitigated.
Methadone maintenance therapy[43] (MMT) has been the standard of care for more than 30 years. However, the recent advent of buprenorphine maintenance therapy (BMT) is changing the landscape of treatment for opioid-dependent patients.[44]
Methadone, a long-acting synthetic opioid agonist, can be dosed once daily and replaces the necessity for multiple daily heroin doses. As such, it stabilizes the drug-abusing lifestyle, reducing criminal behaviors, and also reducing needle sharing and promiscuous behaviors leading to transmission of HIV and other diseases.
Methadone is a highly regulated Schedule II medication, only available at specialized methadone maintenance clinics. It is estimated that established methadone clinics can accommodate only 15-20% of US heroin addicts.
Methadone clinics often generate controversy in communities fearful of addicts in various stages of recovery. In addition, some patients are unable to travel to clinics, and others will not enter MMT because of fear of stigmatization. Clearly other options would be beneficial for treatment of chronic opioid abuse.
Buprenorphine is a mu-opioid partial agonist that, like methadone, suppresses withdrawal and cravings. However, the property of partial agonism confers a "ceiling effect," at which higher doses of buprenorphine cause no additional effects. This ceiling effect affords a wider margin of safety than methadone, which can be lethal in overdose. The increased safety of buprenorphine has allowed it to become available by prescription as a Schedule III medication.
Buprenorphine has been combined with naloxone[45] in a 4:1 ratio (Suboxone, Zubsolv) or a 6-7:1 ratio (Bunavail) in order to alleviate concerns that the sublingual tablet would be dissolved and injected by addicts. Naloxone is an opioid antagonist that is poorly absorbed sublingually and orally but is well-absorbed intravenously. As a result, an opioid-dependent patient injecting buprenorphine/naloxone will suffer a withdrawal syndrome secondary to naloxone's occupation of mu-opioid receptors.
One study found that a 4-week buprenorphine taper combined with naltrexone maintenance treatment boosted abstinence rates.[46, 47]
A randomized clinical trial found that patients with prescription opioid dependence whose buprenorphine therapy was tapered were less likely to abstain from illicit opioid use during the 14-week study period than were those who received maintenance therapy.[48] Patients in the taper group reported engaging in a mean of 1.27 days of opioid abuse after the taper, compared with 0.47 days in the maintenance group, and there was a mean of 2.7 consecutive weeks of opioid abstinence in the taper group, compared with 5.2 in the maintenance group.
The FDA approved buprenorphine/naloxone (Zubsolv) sublingual tablets in July 2013 for the maintenance treatment of opioid dependence. The new formulation has high bioavailability, a fast dissolve time, a small tablet size, and a menthol flavor to encourage patient adherence with treatment.[49] Zubsolv’s indication was expanded to include induction dosing for patients dependent on short-acting opioids (eg, heroin) in August 2015. For patients dependent on long-acting opioids (eg, methadone), buprenorphine monotherapy is recommended for induction.
In June 2014, the FDA approved a buccal form of buprenorphine/naloxone (Bunavail) for opioid dependence maintenance therapy. Approval was based on a phase III, 12-week, clinical trial of 249 patients that were converted to the buccal film from the sublingual tablet (Suboxone). The film was shown to be safe and effective with less constipation than with Suboxone.[50] Suboxone sublingual tablets have been replaced on the market with a Suboxone sublingual film.
In August 2015, in a randomized double-blinded placebo-controlled clinical trial, 118 participants maintained on buprenorphine were treated with clonidine or placebo for 14 weeks. Those given clonidine maintained initial abstinence for longer periods than the placebo group, suggesting that clonidine could be a useful adjunctive maintenance treatment alongside buprenorphine by decoupling daily-life stress from increases in drug craving.[51]
Office-based treatment of opioid addiction is now possible with BMT.[52] Physicians wishing to prescribe buprenorphine must meet several criteria, including requirements outlined in the Drug Abuse Treatment Act of 2000. However, physicians who do not meet these criteria can take an 8-hour training course to become certified to prescribe buprenorphine. Currently, physicians are limited to 30 buprenorphine patients for 1 year, and may apply for a waiver after the first year for 100 patients. In 2016, this limit was raised to 275 patients for providers who held a 100-patient waiver for 1 year and held additional credentialing or practiced in a qualified practice setting.[53]
In 2016, the FDA approved the first buprenorphine implant (Probuphine) for opioid dependence. The implant, which is comprised of four, one-inch-long rods that are implanted under the skin on the inside of the upper arm, provides a constant, low-level dose of buprenorphine for six months. Each rod contains approximately 80 mg of the drug for a total of 320 mg implanted at once. The implant is designed for use in patients who are already stable on a low dose of the drug. Because it must be inserted and removed surgically, only health care providers who have completed the training and become certified through a restricted program called the Probuphine Risk Evaluation and Mitigation Strategy (REMS) program should insert and remove the implants.[54]
Persons with opioid dependence often experience difficulty following current existing pharmacologic treatments designed to reduce or eliminate opioid use. Ling et al studied the efficacy of buprenorphine implants over a 6-month period in patients with opioid dependence. Initial induction with sublingual buprenorphine-naloxone tablets preceded implant placement. Less opioid use was observed (as assessed by urine samples) in patients using the buprenorphine implants compared with placebo implants.[55]
In 2017, the FDA approved a once-monthly SC injection (Sublocade) for opioid use disorder (OUD). When injected, it forms a solid mass upon contact with body fluids from the Atrigel delivery mechanism. The drug must be administered in a healthcare setting to avoid inadvertent IV administration that could result in death. It is indicated for treatment of moderate-to-severe OUD in adults who have initiated treatment with a transmucosal buprenorphine-containing product and have been on a stable dose of transmucosal buprenorphine treatment for ≥7 days.[56]
Historically, l-alpha-acetylmethadol (LAAM) has also been used for opioid-dependence maintenance pharmacotherapy. However, LAAM is associated with prolonged QT interval, and several cases of cardiac arrhythmia and death have been reported. Therefore, LAAM was recently removed from the market in the European Union and was given a black box label by the FDA.
Several Cochrane Database Systematic Reviews about the efficacy of opioid agonist therapy have been published in recent years. While all of these reviews stress the need for larger, multicenter, randomized clinical trials of longer duration, some conclusions can be drawn from existing data.
A review of Cochrane reviews found that high-dose MMT (60-109 mg/d) is more effective in retaining patients in treatment than low-dose MMT (1-59 mg/d). Moreover, methadone at flexible doses was more effective in retaining patients in treatment (RR, 1.23) than buprenorphine. A second systematic review of databases found that low-dose methadone (20 mg/d) was less effective than buprenorphine (2-8 mg/d) and that high-dose methadone (>50-65 mg/d) was more effective than buprenorphine (2-8 mg/d).
Another Cochrane review found that oral substitution treatment was associated with significant reductions in heroin injection and needle sharing, as well as a decrease in patients with multiple sexual partners and a reduction in exchanges of sex for drugs or money.[57] Importantly, these changes were correlated with reductions in cases of HIV infection.
Although pain is common among opioid-dependent patients, pharmacologic approaches are limited. Tsui et al found that treatment with escitalopram, a selective serotonin reuptake inhibitor, was associated with clinically meaningful reductions in pain severity and pain interference during the initial 3 months of treatment.[58]
A randomized, placebo-controlled trial suggested that an injectable, sustained-release form of naltrexone (Depotrex) increased retention of patients in treatment for opioid abuse.[59] Further studies are necessary to evaluate the efficacy of this treatment modality.
FDA approval of extended-release IM naltrexone for the prevention of relapse to opioid dependence was based on data from a 6-month, multicenter, randomized, phase 3 study, which met its primary efficacy endpoint and all secondary efficacy endpoints. Once monthly treatment with extended-release IM naltrexone showed statistically significant higher rates of opioid-free urine screens compared with placebo (P< .0002).
A study of 150 opioid-dependent individuals examined the efficacy of two methods of outpatient opioid detoxification for induction to extended-release naltrexone – .naltrexone-assisted detoxification and a buprenorphine taper. The trial demonstrated that naltrexone-assisted detoxification increased the likelihood of a successful transition to extended-release injection naltrexone (XR-naltrexone) by almost threefold compared with those given a buprenorphine taper. Study findings support the development of a detoxification regimen of ascending doses of oral naltrexone for transitioning opioid-dependent patients seeking induction onto XR-naltrexone for the prevention of relapse.[60]
In a double-blind, placebo-controlled, randomized, 24-week trial, 250 patients with opiate dependence were given monthly injections of an extended-release formulation of 380 mg of naltrexone or placebo.[61] The study found substantial benefit in the actively treated group, with abstinence rates of 90% compared with 35%. Other measures confirmed this benefit, with a median retention of 168 days in the naltrexone group compared with 96 days in the placebo group, and reduced craving in the naltrexone group. Given the poor therapeutic efficacy of oral naltrexone in most opioid-dependent populations, this intramuscular formulation may be a valuable addition to the methods of treating opioid dependence if its value is verified in subsequent studies over longer therapeutic time periods in diverse groups of patients.
The use of naltrexone was shown to be effective in fostering sobriety in heroin- and amphetamine-dependent outpatients in a 10-week randomized, double-blind, placebo-controlled trial. Naltrexone implants resulted in higher retention in the study (52% of patients with naltrexone implants versus 28% in the control group), decreased heroin and amphetamine use (drug-free urine samples were 38% for the naltrexone group versus 16% placebo), and improved clinical conditions for the patients.[62]
A long-acting buprenorphine subdermal implant (Probuphine) was approved by the FDA in May 2016 for use in opioid tolerant patients who have achieved and sustained prolonged clinical stability on low-to-moderate doses of a transmucosal buprenorphine-containing product (ie, doses ≤8 mg/day of Subutex or Suboxone sublingual tablet equivalent or generic equivalent). Four implants (80 mg/implant of buprenorphine HCl) are inserted in the upper arm for 6 months of treatment and removed by the end of the sixth month. In addition to improved adherence, other benefits of buprenorphine implant include a reduced risk of diversion, abuse, misuse, and accidental exposure.
Efficacy of noninferiority was assessed for buprenorphine implant in clinically-stable patients on maintenance treatment by comparing the implant with daily doses of buprenorphine/naloxone SL of 8 mg or less. Results of primary and secondary endpoint analyses showed buprenorphine implant met the criteria for noninferiority with a 95% CI of (0.009, 0.167).[63]
Treatment with catechol-O -methyltransferase (COMT) inhibitors may improve adherence to buprenorphine maintenance treatment for opioid addiction.[64] In a study of 253 opiate-dependent patients who had failed to comply with initial buprenorphine maintenance treatment, 186 (73.5%) remained abstinent for longer than 6 months when they received the COMT inhibitor entacapone (200-1000 mg/day) in addition to buprenorphine. Another 61 patients (24.1%) remained abstinent for 12- to 24 months and 41 (16.2%) remained abstinent for 24- to 30 months. Forty-one (16.2%) patients were able to achieve abstinence using long-acting naltrexone.[64] This is the first study of its kind to demonstrate COMT-inhibitors' anticraving effects.
Stress has been associated with impaired decision making and increased risk for relapse, even after long periods of abstinence. In a double-blind, placebo-controlled, randomized protocol, the negative effects of stress on performance were prevented by the beta-adrenoceptor antagonist propranolol as early as after 30 days and as late as 24 months after abstinence began, suggesting a potential role for beta-blockers in decreasing the risk for relapse.[65]
Because decision-making deficits are common, individuals with more prominent deficits may particularly benefit from treatment in a residential setting.[66]
Opiate withdrawal is generally considered less likely to produce severe morbidity or mortality compared with barbiturates and benzodiazepines. Safe withdrawal from opioids is termed detoxification and can be performed as outpatient or inpatient therapy, depending upon presence of comorbid medical and psychiatric problems, availability of social support, and polydrug abuse.
Lofexidine (Lucemyra) is an oral centrally-acting alpha2 agonist approved by the FDA in May 2018 for mitigation of opioid withdrawal symptoms in adults. Approval was supported by 2 randomized, double-blind, placebo-controlled clinical trials, an open-label study, and clinical pharmacology studies with concomitant administration of either methadone, buprenorphine, or naltrexone. Data show that compared to placebo, participants treated with lofexidine experienced less severe withdrawal symptoms and were significantly more likely to complete a 7-day opioid discontinuation treatment.[67, 68]
In 2017, the FDA approved the first device designed to reduce the symptoms of opioid withdrawal. The NSS-2 Bridge device is placed behind the patient's ear and emits electrical pulses to stimulate branches of certain cranial nerves. The device can be used for up to 5 days during the acute phase of opioid withdrawal. Approval was based on a single-arm study of 73 patients undergoing physical withdrawal from opioids. Within 30 minutes of using the device, all patients showed a reduction in Clinical Opiate Withdrawal Scale (COWS) score of almost 31%. The device is available by prescription only.[69]
The FDA approved another wearable device for the treatment of opioid withdrawal symptoms in 2018. The device is an auricular neurostimulator that emits electrical pulses to ear-fitted needles, much like the first device approved. Continuous treatment from the wearable device can be provided for up to 5 days, but there have been reports of reductions in symptoms of opioid withdrawal within 30 to 60 minutes after treatment starts, according to the manufacturer.[70]
Methadone, buprenorphine, and alpha-2 agonists, such as clonidine and lofexidine, are commonly used pharmacologic methods of detoxification. The use of methadone and buprenorphine is based on the principle of cross-tolerance in which one opioid is replaced with another and then slowly withdrawn. Alpha-2 agonists appear to be most effective in suppressing autonomically mediated signs and symptoms of abstinence,[71] but they are less effective for subjective symptoms.
Two Cochrane reviews compared the efficacy of alpha-2 adrenergic agonists to methadone or buprenorphine for management of withdrawal.[72, 73] Patients experienced decreased side effects and stayed in treatment longer using tapered methadone compared to the alpha-2 agonists, clonidine or lofexidine.
Buprenorphine was associated with fewer adverse effects than clonidine, and patients were more likely to complete withdrawal with buprenorphine compared with clonidine. Moreover, a second multicenter randomized trial demonstrated that buprenorphine-naloxone was more effective than clonidine for opioid detoxification. Buprenorphine was equally effective as methadone for withdrawal completion, but withdrawal symptoms appeared to resolve more quickly with buprenorphine.
In summary, data to date suggest that buprenorphine and methadone are more effective than alpha-2 agonists, such as clonidine, for opioid detoxification, with buprenorphine associated with a shorter duration of withdrawal symptoms. However, all of these medications are effective, and the choice may depend in part on availability.
Kunoe et al described use of an investigational naltrexone implant in 56 abstinence-oriented patients who completed inpatient treatment for opioid dependence compared with patients who received usual care instead of the implant. The implant group had an average 45 days less heroin use and 60 days less opioid use than the usual care group over a 6-month period (P < 0.05). The naltrexone implant significantly reduced opioid use compared with usual care.[74]
Hulse et al compared daily oral naltrexone with a sustained-release naltrexone implant in 70 patients with DSM-IV heroin dependence. Study participants were randomized to receive either daily oral naltrexone (50 mg/d, plus placebo implants) or naltrexone implant (2.3 g, plus placebo tablets). More patients in the oral group had naltrexone serum concentrations less than 2 mg/mL at month 1 (P< 0.001) and month 2 (P< 0.01) compared with the implant group. Return to regular heroin use was observed more in the oral group by 6 months (P =0.003) and at an earlier stage (median 115 d vs 158 d) compared with the implant group. The authors concluded that naltrexone implant is effective in reducing relapse to regular heroin use compared with oral naltrexone.[75]
Psychotherapies and support groups: Detoxification alone, without ongoing treatment, is not adequate to manage patients.[76]
Patients in methadone programs often benefit from cognitive behavioral, supportive, or analytical-oriented psychotherapies if they are added to standard drug counseling.
Cognitive behavior psychotherapy primarily focuses on the patient's thoughts and behaviors. Cognitive behavior–based models are widely used in drug rehabilitation programs. Cognitive behavior theories were aimed at substance abuse beginning in the mid-1980s. The techniques used help patients acquire specific skills for resisting substance use and teach coping skills to reduce problems related to drug use. Two major cognitive behavior theories of substance abuse are the following:
Dynamic psychotherapy is based on the concept that all symptoms arise from underlying unconscious psychological conflicts. The major goal of this therapy is to help the patient become aware of these conflicts and develop more adaptive coping mechanisms and healthier methods of resolving intrapsychic conflict.
Group therapy is argued to be especially effective because it can target the social stigma attached to having lost the ability to control one's self with regard to the use of a substance. The presence of other group members who acknowledge having similar problems can provide support and be therapeutic in developing alternative methods of maintaining abstinence.
Aversion therapy involves pairing aversive stimuli to cognitive images of opioid use and conversely conjuring images of socially appropriate behaviors such as employment, education, and nondrug behavior.
Narcotics Anonymous (NA): In 1947, NA was formed in Lexington, Ky. NA is based on principles similar to those of Alcoholics Anonymous (AA), including progression through 12 steps of recovery. Some patients have difficulty engaging in the AA-NA approach to recovery; however, these programs do help some people and can provide much needed support for those attempting abstinence.
Although psychosocial therapy is likely to be beneficial in the treatment of opiate withdrawal, the specific type of psychosocial therapy may not be important. A Cochrane review assessed 11 studies involving 1592 patients and explored the effectiveness of any psychosocial intervention combined with any pharmacological intervention versus any pharmacological intervention alone for opioid detoxification treatment. Five different psychosocial interventions (including behavioral, counseling, and family therapies) were added to treatment with either methadone or buprenorphine. The addition of the psychosocial intervention (regardless of the specific psychosocial approach) to the pharmacological treatment significantly reduced dropouts, use of opioids during treatment, use of opioids during follow up, and clinical absences during treatment.[77]
A recent systematic review found that patients with chronic pain (noncancer) who had comorbid substance use disorders are more likely to be prescribed opioids and higher doses of opioid medications compared with patients who do not have a history of substance use disorders despite similar pain outcomes.[78]
As more patients with opioid addiction receive OAT, physicians will encounter OAT patients with acute pain syndromes. Acute pain must be adequately treated in these patients.[79]
Common misconceptions include the following:
Recommendations include the following:
Several options are possible, and the most effective approach will be determined with increasing clinical experience:
In March 2020, the Substance Abuse and Mental Health Services Administration (SAMHSA) released considerations for the care and treatment of mental and substance use disorders in the COVID-19 pandemic.[80, 81, 82]
SAMHSA advises that outpatient treatment options be used to the greatest extent possible. Inpatient facilities should be reserved for those for whom outpatient measures are not considered an adequate clinical option. SAMHSA strongly recommends the use of telehealth and/or telephonic services to provide evaluation and treatment of patients.
States may request blanket exceptions for all stable patients in an opioid treatment program (OTP) to receive 28 days of Take-Home doses of the patient’s medication for opioid use disorder (OUD). States may request up to 14 days of Take-Home medication for those patients who are less stable but who the OTP believes can safely handle this level of Take-Home medication.
In response to the COVID-19 pandemic, the American Society of Addiction Medicine (ASAM) released a focused update to its National Practice Guideline for the Treatment of Opioid Use Disorder (NPG).[83] New recommendations include the following:
The goals of pharmacotherapy are to treat the addiction of the chemical substances that cause them.
Clinical Context: Inhibits ascending pain pathways, diminishing the perception of and response to pain. There are inpatient facilities and a few, specialized, licensed, outpatient, drug treatment programs that provide opioid detoxification using methadone. Also a preferred agent for opioid agonist maintenance. Some experts feel that laboratory measures of plasma levels should be used to adjust the dose and that 400 ng/mL seems sufficient to stop craving and drug hunger.
Benefits include good treatment retention, psychosocial adjustment, and reduced criminal activity.
Two uses for opioid analgesics are as follows: (1) Oral substitution therapy or maintenance therapy or opioid agonist therapy (OAT) refers to substitution of an oral opioid for injected heroin, with the goal of reducing harmful behaviors associated with heroin use. (2) Detoxification, or controlled withdrawal with the goal of abstinence, is based on the principle of cross-tolerance in which one opioid is replaced with another and then slowly withdrawn.
Clinical Context: Partial opioid agonist and potent antagonist, is a potent analgesic that can be administered once a day to block withdrawal symptoms. The agonist effect is limited by a ceiling effect (ie, higher doses [>12-16 mg] do not produce more analgesia). The sublingual tablet is used for initial detoxification treatment of opioid addiction. It is administered in a stepwise regimen over 4-5 days before switching to maintenance treatment with buprenorphine/naloxone. Stabilization with buprenorphine transmucosal also precedes maintenance with a long-acting buprenorphine product (eg, once monthly SC injection, every 6 month subdermal implant).
Clinical Context: Semisynthetic narcotic mixed agonist-antagonist analgesic; exerts partial agonistic effects at the mu opioid receptor in the CNS and antagonistic effects at the kappa opioid receptor. The implant is indicated for the maintenance treatment of opioid dependence in patients who have achieved and sustained prolonged clinical stability on low-to-moderate doses of a transmucosal buprenorphine-containing product. The implants are inserted in the upper arm and provide 6 months of continuous buprenorphine.
Clinical Context: Once monthly SC injection that forms a solid mass upon contact with body fluids from the Atrigel delivery mechanism. Must be administered in a healthcare setting to avoid inadvertent IV administration that could result in death. The half-life is 43-60 days. It is indicated for treatment of moderate-to-severe opioid use disorder (OUD) in adults who have initiated treatment with a transmucosal buprenorphine-containing product and have been on a stable dose of transmucosal buprenorphine treatment for ≥7 days.
The sublingual product is used predominantly for induction dosing followed by maintenance with buprenorphine/naloxone SL. The buprenorphine subdermal implant may be considered for maintenance therapy of opioid addiction in patients who have achieved prolonged clinical stability on low-to-moderate buprenorphine/naloxone doses. Additionally, a once-monthly SC injection is also an option.
Clinical Context: Buprenorphine is a semisynthetic narcotic mixed agonist-antagonist analgesic. Naloxone is a potent antagonist at the mu opioid receptors and produces opioid withdrawal signs and symptoms in individuals physically dependent on full opioid agonists when administered parenterally.
This combination is used predominantly for maintenance dosing following initial induction dosing with buprenorphine SL. The sublingual tablet or film (Suboxone, Zubsolv) or the buccal film (Bunavail) may be used for induction for short-acting opioids (eg, heroin) but NOT for patients dependent on long-acting opioids (eg, methadone) because of risk for abrupt withdrawal symptoms.
Clinical Context: Pure opioid antagonist. Used to reverse opioid intoxication.
If patients do not respond to multiple doses of naloxone, consider alternative causes of unconsciousness. Need of ongoing substance abuse treatment should be established while caring for overdose. The injectable solution is available in vials and syringes (0.4 mg/mL, 1 mg/mL) for IV/IM/SC administration by healthcare providers. It is also available as an autoinjector (delivers 0.4 mg IM/SC) for home use by family or caregivers.
Clinical Context: Competitive opioid antagonist that antagonizes opioid effects by competing for the same receptor sites. The intranasal form is indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression.
Clinical Context: Used in combination with clonidine for rapid (4-5 d) detoxification.
Very effective long-acting opioid antagonist that was thought to be an ideal maintenance agent because it blocks receptor sites and, hence, opioid reinforcing properties. However, clinical results are not very promising when compared with methadone maintenance. Craving may continue during naltrexone maintenance. For groups of patients such as health care professionals or business executives for whom external incentives to stay away from drugs are important, naltrexone therapy has been very effective.
Indicated for prevention of relapse to opioid dependence following opioid detoxification.
Clinical Context: Central alpha-2 adrenergic agonist that binds to receptors on adrenergic neurons, resulting in reduced release of norepinephrine and decreased sympathetic tone. This action suppresses autonomic-mediated signs and symptoms of withdrawal. Indicated for short-term mitigation of withdrawal symptoms to facilitate abrupt opioid discontinuation in adults.
Clinical Context: May reduce norepinephrine release. In opioid withdrawal, seems to be most effective in suppressing autonomically mediated signs and symptoms of abstinence but less effective for subjective symptoms.
Used in higher doses for detoxification than for treating hypertension. Benzodiazepines may be beneficial as adjuvant therapy for muscle cramps and insomnia. Clonidine in combination with naltrexone, which is a potent long-acting narcotic antagonist, also is referred to as rapid detoxification. Treatment is initiated after confirmation of physical dependence by the naloxone challenge test. This drug combination is designed to shorten the time of withdrawal to 5 d.
Clonidine may also be beneficial in prolonging the duration of abstinence in patients concurrently receiving buprenorphine for maintenance therapy. Daily life stress may also be partially decoupled from opioid craving in patients receiving clonidine. However, although clonidine may prolong the time to relapse, it may not prevent it entirely. Clonidine alone and in combination has been demonstrated to be feasible in primary care settings as an outpatient treatment.
Used for mitigation of withdrawal symptoms to facilitate abrupt opioid discontinuation.
Opioid abuse treatment also is influenced by managed care, and it is changing rapidly.
Treatment in outpatient and inpatient settings is equally effective, but significant cost differences exist.
The ideal program should be comprehensive enough to target individual patient needs and the severity of the illness.
In general, the following complications may be observed.
Catalino et al found that opioid treatment relapse rates vary from 25-97%. Cigarette smokers have higher rates of relapse than nonsmokers.
Success is measured as improvement in following areas:
The prognosis varies according to the type of agent abused and other variables, such as medical care, employment, legal situation, family, and psychological difficulties.
In general, the success rate is much better in people who abuse opioids and are professionals than in individuals with a poor education level and low job prospects.
Understanding the nature of the disease helps formulate a strategy to fight against it. Although information may be provided in a single session, generally it is continuous process that begins at the identification of the problem. Statistical evidence may be provided if needed to facilitate the patient's understanding of the disease. The education must cover the following areas:
Contrary to the earlier beliefs, most substance abusers are closely tied to their families. In 1972, Levy provided evidence that at 5 years, patients who succeeded in overcoming narcotic abuse most often had family support. Educated family members are likely to provide positive influence without getting frustrated. The following issues must be addressed.
For patient education resources, see the Mental Health Center. Also, see the patient education articles Barbiturate Abuse, Drug Dependence and Abuse, Narcotic Abuse, and Substance Abuse.