Opioid Abuse
Practice Essentials
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]
Signs and symptoms
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:
Autonomic symptoms - diarrhea, rhinorrhea, diaphoresis, lacrimation, shivering, nausea, emesis, piloerection
Central nervous system arousal - sleeplessness, restlessness, tremors
Pain - abdominal cramping, bone pains, and diffuse muscle aching
Craving - for the medication
History
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]
Taking larger amounts of opioids or taking opioids over a longer period than was intended
Experiencing a persistent desire for the opioid or engaging in unsuccessful efforts to cut down or control opioid use.
Spending a great deal of time in activities necessary to obtain, use, or recover from the effects of the opioid.
Craving, or a strong desire or urge to use opioids.
Using opioids in a fashion that results in a failure to fulfill major role obligations at work, school, or home.
Continuing to use opioids despite experiencing persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of opioids.
Giving up or reducing important social, occupational, or recreational activities because of opioid use.
Continuing to use opioids in situations in which it is physically hazardous.
Continuing to use opioids despite knowledge of having persistent or recurrent physical or psychological problems that are likely to have been caused or exacerbated by the substance.
Tolerance, as defined by either a need for markedly increased amounts of opioids to achieve intoxications or desired effect, or a markedly diminished effect with continued use of the same amount of an opioid.
Withdrawal, as manifested by either the characteristic opioid withdrawal syndrome, or taking opioids to relieve or avoid withdrawal symptoms.
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
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.
Withdrawal
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:
Autonomic symptoms - Diarrhea, rhinorrhea, diaphoresis, lacrimation, shivering, nausea, emesis, piloerection (the phrase stopping "cold turkey" refers to piloerection, or "gooseflesh")
Central nervous system arousal - Sleeplessness, restlessness, tremors
Pain - Abdominal cramping, bone pains, and diffuse muscle aching
Craving - For the medication
Addiction
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:
Drug craving
Compulsive use
Strong tendency to relapse after withdrawal
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.
Physical
Dependence
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.
Withdrawal
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.
Intoxication
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:
Respiratory depression (may occur while the patient maintains consciousness)
Alterations in temperature regulations
Hypovolemia (true as well as relative), leading to hypotension
Miosis
Needle marks or soft tissue infection
Increase sphincter tone (can lead to urinary retention)
Addiction
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.
Causes
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.
Pharmacological factors
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. [68] Its use in the United States has grown over the past decade and it is estimated that millions of people take it regularly. [69] 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. [70] 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. [71]
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). [72] 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. [73]
Studies in rodents suggest alkaloids in kratom bind to opioid receptors and elicit antinociceptive properties, but with less respiratory depression than typical opioids. [74]
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. [75]
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). [76]
Social factors
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.
Psychological factors
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. [27]
Genetic factors
Genetic epidemiologic studies suggest a high degree of heritable vulnerability for opioid dependence. [28] 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.
Diagnostic Considerations
Sepsis
Antisocial personality
Panic attack
Pontine infarct or hemorrhage
Depressed mood
Although GI symptoms of nausea, vomiting, and abdominal pain are predominant and common in opioid withdrawal, they may warrant consideration of gastroenteritis, pancreatitis, peptic ulcer disease, and intestinal obstruction.
Sympathetic overactivity must lead to consideration of panic attacks and CNS stimulants, such as amphetamines.
Because multi-drug abuse is common, investigate intoxication by drugs other than narcotics (benzodiazepines, barbiturates) in unconscious patients. A person who abuses opioids may conceal information about other abusive drugs. Because opioid intoxication generally does not cause tremulousness, delirium, and seizures, their presence should raise suspicion of alcohol and benzodiazepine dependence.
Small-sized pupils are observed in opioid intoxication, pontine lesions, and local cholinergic drops.
An antisocial personality may be mistaken as addictive behaviors (and vice versa), especially if confrontation with the law is involved.
Besides opioid-induced psychiatric disorders, a high prevalence of non–opioid-related psychiatric disorders exists. In Baltimore during the early 1990s, a study of people who were addicted and treated with methadone was performed, and the lifetime prevalence of comorbid mood and anxiety disorders was 19% and 8.2%, respectively. Lifetime rates of personality disorders in decreasing frequency were as follows:
Antisocial disorder (25.1%)
Avoidant disorder (5.2%)
Borderline disorder (5.2%)
Passive aggressive disorder (4.1%)
Paranoid disorder (3.2%)
In women, depression, anxiety disorders, and borderline personality disorder were considerably more common, and antisocial personality disorder was less common compared to males.
In the same study, comorbid dependence was also observed for cocaine (64.7%), cannabis (50.8%), alcohol (50%), and sedatives (46.6%).
Differential Diagnoses
Influenza
Laboratory Studies
Abuse and dependence
See the list below:
Urine drug screen
Detection of drugs in sweat and hair is a recent addition to drug abuse detection technology. However, it is not used widely.
Withdrawal
See the list below:
Electrolytes
CBC count
Urine drug screen is rarely useful.
Intoxication
See the list below:
Comprehensive urine drug testing is performed when the drug abuse habit of the patient is unknown but suspected. Some labs use the inexpensive thin-layer chromatography (TLC) procedure. This test has low sensitivity for commonly used drugs. TLC cannot detect fentanyl.
Enzyme immunoassay and radioimmunoassay are more sensitive than TLC, but they are less specific because molecules with similar functional groups cross-react with antibodies. These are relatively inexpensive tests.
Gas-liquid chromatography (GLC) and gas chromatography-mass spectrometry (GC-MS) are very sensitive and specific tests, but they are time consuming, labor intensive, and expensive.
In drug abuse detection, knowing the half-life of the drug, the biotransformation of the drug, and the excretion route of the drug are important.
Screening and confirmation cut-off concentration for heroin, methadone, morphine, and codeine is 300 ng/mL and are detected in urine within 1-4 days.
False-negative results occur more easily than false positives, simply because once a test is screened negative, it is not tested further. The federal government requires that the results of the drug testing programs go directly to medical review offices to prevent improper interpretation of drug testing data.
Blood alcohol levels also may be tested.
Addiction
In case of historical or clinical evidence of IV drug abuse, perform the following:
LFT
Rapid plasma reagent (RPR)
Hepatitis viral testing
HIV testing
Blood cultures (in appropriate clinical setting)
Imaging Studies
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.
Other Tests
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.
A positive test is indicative of physical dependence and consists of typical withdrawal symptoms and signs. These symptoms and signs usually last for 30-60 minutes.
This test is found to be very helpful before starting opiate antagonists for maintenance therapy. Starting opioid antagonists, such as naltrexone, soon after detoxification may cause withdrawal symptoms and discourage patients from further treatment.
Medical Care
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.
Opioid intoxication
General supportive measures for opioid intoxication are as follows:
Assess patient to clear airway.
Provide support ventilation, if needed.
Assess and support cardiac function.
Provide IV fluids.
Frequently monitor the vital signs and cardiopulmonary status until the patient has cleared opioids from the system.
Give IV naloxone if necessary. Naloxone is a specific opiate antagonist with no agonist or euphoriant properties. When administered intravenously or subcutaneously, it rapidly reverses the respiratory depression and sedation caused by heroin intoxication.
Opioid overdose
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. [29, 30]
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. [31, 32]
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. [33]
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.
Opioid maintenance therapy
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 [34] (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. [35]
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 [36] 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. [37, 38]
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. [39] 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. [40] 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. [41] 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. [42]
Office-based treatment of opioid addiction is now possible with BMT. [43] 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. [44]
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. [45]
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. [46]
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. [47]
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. [48] 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. [49]
Preventing opioid dependence relapse
A randomized, placebo-controlled trial suggested that an injectable, sustained-release form of naltrexone (Depotrex) increased retention of patients in treatment for opioid abuse. [50] 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. [51]
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. [52] 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. [53]
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). [54]
Treatment with catechol-O -methyltransferase (COMT) inhibitors may improve adherence to buprenorphine maintenance treatment for opioid addiction. [55] 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. [55] 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. [56]
Because decision-making deficits are common, individuals with more prominent deficits may particularly benefit from treatment in a residential setting. [57]
Opiate withdrawal
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. [84, 85]
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. [58]
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. [86]
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, [59] 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. [60, 61] 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. [62]
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. [63]
Psychotherapies and support groups: Detoxification alone, without ongoing treatment, is not adequate to manage patients. [64]
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:
Relapse prevention: Based on the work of Marlatt and Gordon, important relapse prevention concepts and techniques include identification and avoidance of high-risk situations, understanding the chain of decisions leading to drug use, and changing one's lifestyle.
Cognitive therapy of substance abuse: Developed by Beck and colleagues, cognitive therapy of substance abuse is based on the concept that drug abusers engage in complex behaviors and thought processes, such as positive and negative drug-related beliefs and spontaneous flashes related to drug use before giving in to the actual drug use
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. [65]
Pain management
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. [66]
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. [67]
Common misconceptions include the following:
OAT provides analgesia: Maintenance methadone or buprenorphine does not provide sustained analgesia. Although methadone and buprenorphine are potent analgesics, the analgesic properties last only 4-8 hours, while the medications are dosed every 24-48 hours.
Use of opioid analgesia may cause addiction relapse: No evidence indicates that exposure to opioid analgesics during acute pain increases relapse rates. In fact, evidence suggests that the stress of unrelieved pain can trigger relapse.
The combination of OAT and other opioids may cause respiratory depression: This is a theoretical risk that is not supported by clinical or empirical experience. Tolerance to respiratory and CNS depressant effects occurs rapidly and reliably.
Recommendations include the following:
Reassure patients that their addiction histories will not prevent adequate pain management, and discuss plans in a nonjudgmental manner.
Verify methadone and buprenorphine doses with clinics or prescribing physicians, and inform these physicians of any benzodiazepines or opioids given that may be detected on urine drug screening.
Aggressively treat pain with conventional opioid analgesics. Opioid cross-tolerance often necessitates higher opioid analgesic doses at shorter intervals.
Use continuous scheduled dosing orders rather than as-needed orders.
For patients receiving methadone maintenance therapy: Continue methadone maintenance dose and add short-acting opioid analgesics.
For patients receiving buprenorphine maintenance therapy: Pain management with opioids is complicated by the high affinity of buprenorphine for the mu receptor. This affinity may cause buprenorphine to compete with opioid analgesics at mu receptors. As buprenorphine's rate of dissociation from mu receptors is highly variable, naloxone should be available, and consciousness and respiration should be closely monitored.
Several options are possible, and the most effective approach will be determined with increasing clinical experience:
Continue BMT and titrate a short-acting opioid analgesic to effect.
Divide buprenorphine dose to 6-8 hours to take advantage of its short-acting analgesic properties.
Discontinue BMT, implement opioid analgesia, and restart BMT when opioid analgesia is no longer necessary.
In the hospitalized patient, discontinue BMT, initiate MMT, and add short-acting opioids to treat pain. Have naloxone at bedside. Convert back to BMT prior to discharge from hospital.
Medication Summary
The goals of pharmacotherapy are to treat the addiction of the chemical substances that cause them.
Opioid analgesics
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.
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.
Analgesics, Opioid Partial Agonist
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.
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).
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.
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.
Opioid Partial Agonist/Opioid Antagonist
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.
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.
Opioid Antagonists
Reverses opioid effects by inhibiting opioid agonists at receptor sites.
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.
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.
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.
Alpha 2 adrenergic agonists
Used for mitigation of withdrawal symptoms to facilitate abrupt opioid discontinuation.
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.
Clonidine (Catapres)
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.
Further Outpatient Care
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.
Complications
In general, the following complications may be observed.
Opioid dependence: Constipation, noncardiac pulmonary edema (usually with heroin), and heroin-induced glomerulonephritis may occur. Combination products may lead to acetaminophen or aspirin toxicity. Related to IV drug use, multifocal leukoencephalopathy and myelopathy, which may be related to the parenteral route of administration rather than opioids; HIV; viral hepatitis; and bacteremia may occur. Right-sided endocarditis and valvular damage also may occur.
Intoxication: Sedation, respiratory depression, and death
Prognosis
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:
Social functions
Reduction of illicit drug use
Performance at work and school
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.
Patient Education
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:
Inform the patient in no unclear terms about their inability to use the substance in a controlled fashion.
Treatment alone is hardly ever successful, and rehabilitation is almost always needed for recovery.
Will power is not enough to beat the disease, and the role of Narcotics Anonymous must be emphasized.
Recovery is possible, and a significant number of people are successful.
After a relapse, the patient must be encouraged and informed that it is not unusual and that a slip could be a valuable experience.
Dysphoric effects after abstinence are the main reason of relapse. Patients should be ready and equip themselves with a coping strategy.
Tell patient to value recovery and avoid high-risk situations of active drug use.
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.
Inform the patient about the concept of enabling so that such behaviors may be identified and replaced with assertive but compassionate behaviors.
Inform the patient and the family of ways of healthy intrafamily conflict resolution.
Keep the expectations reasonable. Relapses may occur often, and it does not mean the patient has to start from zero again.
Understand that a patient who abuses opioids and is trying to start life without opioids may develop unacceptable and unfamiliar behaviors, which may be quite painful for family members who are expecting a nice premorbid personality.
Inform patients about the availability of family support groups such as spouse support groups.
Place emphasis on encouraging patients to attend NA.
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.
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