Thomas R. Kosten
Opiate analgesics are some of the oldest and most common medications in clinical practice, but have also been abused since at least 300 B.C. Nepenthe (Greek “free from sorrow”) helped the hero of the Odyssey, but widespread opium smoking in China and the Near East has caused harm for centuries. Since the first chemical isolation of opium and codeine 200 years ago, a wide range of synthetic opioids have been developed, and endogenous opioid peptides were discovered in 1995. Two of the most important adverse effects of all these agents are overdose and dependence. The 0.14% annual prevalence of heroin dependence in the United States is only about one-third the rate of prescription opiate abuse and is substantially lower than the 2% rate of morphine dependence in Southeast and Southwest Asia. While these rates are low relative to other abused substances, their disease burden is substantial, with high rates of morbidity and mortality; disease transmission; increased health care, crime, and law enforcement costs; and less tangible costs of family distress and lost productivity.
The diagnosis of opiate dependence in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) requires the repeated use of the drug while producing problems in three or more areas in a 12-month period. The areas include tolerance, withdrawal, use of greater amounts of opiates than intended, and use despite adverse consequences. The abuse diagnosis is related to legal problems, inability to meet obligations, use in hazardous situations, and continued use despite problems. The most striking aspect of opiate abuse has been its marked increase as the gateway to illicit drugs in the United States. Since 2007, prescription opiates have surpassed marijuana as the most common illicit drug that adolescents initially abuse.
The most commonly abused opiates are diverted prescriptions for oxycodone, followed by heroin and morphine, and—among health professionals—meperidine and fentanyl. Two opiate maintenance treatment agents—methadone and buprenorphine—are also abused, but at substantially lower rates, and the partial opiate agonists such as butorphanol, tramadol, and pentazocine are infrequently abused. The chemistry and general pharmacology of these agents are covered in major pharmacology texts, and this chapter focuses on the neurobiology and pharmacology relevant to abuse, dependence, and their treatments.
During the past 30 years, substantial progress has been made in elucidating the neurobiology of opiates and their effects not only on the three types of opiate receptors (mu, kappa, and delta) but also on the cascade of second, third, and fourth intracellular messenger systems and on neuronal action potentials. The different functional activities of these three receptors are summarized in Table 57-1, and abuse liability is primarily associated with the mu receptor. A fourth type of opiate receptor, the orphanin receptor, also modulates pain but is not affected by opiate drugs. These opiate receptors are all G protein–linked and coupled to the cyclic adenosine monophosphate (cyclic AMP) second messenger system and to potassium channels. Opiates are inhibitory and block the potassium channels from opening and depolarizing the neuron, which would produce an action potential. Thus, opiates acutely inhibit neuronal activity. Analgesia and sedation are induced through this inhibition of specific brain pathways, while the “high” from opiates involves an indirect activation of a different brain pathway—the mesolimbic dopamine pathway.
ACTIONS OF OPIOID RECEPTORS
The various effects of opiates are related to the specific neuroanatomic locations of mu receptors. Reinforcing and euphoric effects of opiates occur in the dopaminegic pathway from the ventral tegmental area (VTA) to the nucleus accumbens, where opiates increase synaptic levels of dopamine. This increase is due to inhibition of GABAergic neurons that inhibit both the VTA and nucleus accumbens activity. However, the “high” only occurs when the rate of change in dopamine is fast. Large, rapidly administered doses of opiates block GABA inhibition and produce a burst of nucleus accumbens activity that is associated with “high” in all abused drugs. Therefore, routes of administration that slowly increase opiate blood and brain levels, such as oral and transdermal routes, are effective for analgesia and sedation but do not produce an opiate “high” that follows smoking and intravenous routes. Other acute effects such as analgesia and respiratory depression leading to overdose are due to stimulation of opiate receptors located in other areas such as the locus coeruleus.
Opiate dependence and withdrawal are chronic effects related to the cyclic AMP system. This second messenger phosphorylates various intracellular proteins and produces a cascade of changes reaching into the nucleus and DNA. Immediate early gene products such as c-fos and c-jun are activated followed by regulation of other genes with more sustained protein transcription such as delta c-fos. With these sustained gene activations, several receptor-level changes occur, including downregulation of receptor numbers, reduced neuronal cell-surface receptor trafficking, uncoupling of G proteins from the mu opiate receptors, and upregulation of cyclic AMP second messenger systems. These effects are also reflective of genetic risk factors for drug dependence, with estimates of up to 50% of the risk for dependence due to polygenic inheritance. Specific functional genetic polymorphisms in the mu opiate receptor gene appear associated with this risk for opiate abuse, including one producing a threefold increase in this receptor’s affinity for opiates and the endogenous ligand beta endorphin. Epigenetic methylation changes also occur on the DNA of the mu receptor gene of opiate addicts. DNA methylation inhibits gene transcription.
This molecular cascade links acute intoxication and sedation to chronic opiate dependence and withdrawal within the specific neuroanatomic structure of the locus coeruleus. The locus coeruleus is the brain’s largest concentration of noradrenergic neurons and is responsible for a large proportion of brain cortical activation. When large opiate doses saturate and activate all of its mu receptors, its steady rate of action potentials can cease due to the inactivation of potassium channels. When this direct inhibitory effect is sustained over weeks and months of opiate use, a secondary set of regulatory effects take place in the cyclic AMP system that leads to tolerance, dependence, and withdrawal symptoms.
Opiate withdrawal symptoms reflect overactivity of adrenergic neurons that are located in the locus ceruleus. Opiates suppress the activity of these neurons, and when this suppression continues chronically from daily opiate use, a secondary upregulation occurs in adenyl cyclase enzyme capacity and the production of cyclic AMP from ATP. This upregulation is a homeo-static response to the chronic opiate suppression, but when that suppression is terminated by discontinuing the opiate, this enhanced adenyl cyclase activity leads to a marked increase in cyclic AMP. The now very high levels of cyclic AMP activate the sodium-potassium channels and produce a high level of action potentials in these adrenergic neurons. This adrenergic arousal is one basis for the symptoms of opiate withdrawal and takes about 7 days to readjust to normal levels of adenyl cyclase activity and the associated resolution of opiate withdrawal symptoms. This molecular model of adrenergic neuronal activation during withdrawal has had important treatment implications, such as the use of clonidine for opioid withdrawal.
Tolerance and withdrawal commonly occur with chronic daily use as quickly as 6–8 weeks depending on the dose and frequency of dosing. Tolerance appears to be primarily a pharmacodynamic rather than pharmacokinetic effect, with relatively limited induction of the cytochrome P450 or other liver enzymes. The metabolism of opiates occurs in the liver primarily through the cytochrome P450 systems of 2D6 and 3A4. They then are conjugated to glucuronic acid and excreted in small amounts in feces. The plasma half-lives generally range from 2.5 to 3 h for morphine and more than 22 h for methadone. The shortest half-lives of several minutes are for fentanyl-related opiates and the longest are for buprenorphine and its active metabolites, which can block opiate withdrawal for up to 3 days after a single dose. Tolerance to the mental effects of opioids leads to the need for ever-increasing amounts of drugs to sustain the desired euphoriant effects—as well as to avoid the discomfort of withdrawal. This combination has the expected consequence of strongly reinforcing dependence once it has started. The role of endogenous opioid peptides in opioid dependence is uncertain.
The clinical aspects of abuse are tied to route of administration and the rapidity of an opiate bolus in reaching the brain. Intravenous and smoked administration is routine not only because it is the most efficient route but also because it rapidly produces a bolus of high drug concentration in the brain. This bolus produces a “rush,” followed by euphoria, a feeling of tranquility, and sleepiness (“the nod”). Heroin produces effects that last 3–5 h, and several doses a day are required to forestall manifestations of withdrawal in dependent persons. Symptoms of opioid withdrawal begin 8–10 h after the last dose. Many of these symptoms reflect increased activity of the autonomic nervous system. Lacrimation, rhinorrhea, yawning, and sweating appear first. Restless sleep followed by weakness, chills, gooseflesh (“cold turkey”), nausea and vomiting, muscle aches, and involuntary movements (“kicking the habit”), hyperpnea, hyperthermia, and hypertension occur in later stages of the withdrawal syndrome. The acute course of withdrawal may last 7–10 days. A secondary phase of protracted abstinence lasts for 26–30 weeks and is characterized by hypotension, bradycardia, hypothermia, mydriasis, and decreased responsiveness of the respiratory center to carbon dioxide.
Opioid effects on organs
Besides the brain effects of opioids on sedation and euphoria and the combined brain and peripheral nervous system effects on analgesia, a wide range of other organs can be affected. The cough reflex is inhibited through the brain, leading to the use of some opiates as an antitussive, and nausea and vomiting are due to brainstem effects on the medulla. The release of several hormones is inhibited including corticotropin-releasing factor (CRF) and luteinizing hormone, which reduce cortisol and sex hormone levels, respectively. The clinical manifestations of these reductions can involve poor responses to stress and reductions in sex drive. An increase in prolactin also contributes to the reduced sex drive in males. Two other hormones affected are decreased thyrotropin and increased growth hormone. Respiratory depression results from opiate-induced insensitivity of brainstem neurons to increases in carbon dioxide. This depression contributes to overdose, but in patients with pulmonary disease even opiate doses well below those typical of overdose can produce clinically significant complications. In overdoses, aspiration pneumonia is a common complication due to loss of the choking reflex. Opiates reduce gut motility, which is helpful for diarrhea, but can lead to nausea, constipation, and anorexia with weight loss. Deaths have occurred in early methadone maintenance programs due to severe constipation and toxic megacolon. Opiates may prolong QT intervals and lead to sudden death in some patients. Two opiates particularly noted for this complication are methadone and a long-acting form of methadone called LAAM that was withdrawn from the market. Orthostatic hypotension may occur due to histamine release and peripheral blood vessel dilation, which is an opiate effect usefully applied to managing acute myocardial infarction.
Heroin users in particular tend to use opiates intravenously and be polydrug users, also using alcohol, sedatives, cannabinoids, and stimulants. None of these other drugs serve as substitutes for opioids, but they have desired additive effects. One needs to be sure that the person undergoing a withdrawal reaction is not also withdrawing from alcohol or sedatives, which might be more dangerous and more difficult to manage.
Besides the ever-present risk of fatal overdose, hepatitis B and AIDS are among the many potential complications of sharing contaminated hypodermic syringes. Bacterial infections lead to septic complications such as meningitis, osteomyelitis, and abscesses in various organs. Attempts to illicitly manufacture meperidine in the 1980s resulted in the production of a highly specific neurotoxin, MPTP, which produced parkinsonism in users.
Toxicity and overdose
Lethal overdose is a relatively common complication of opiate dependence and must be rapidly recognized and treated because naloxone provides a highly specific reversal agent that is relatively free of complications. The diagnosis generally does not rely on blood or urine toxicology results but on clinical signs and symptoms. The presentation involves shallow and slow respirations, pupillary miosis (mydriasis does not occur until significant brain anoxia supervenes), bradycardia, hypothermia, and stupor or coma. If naloxone is not administered, progression to respiratory and cardiovascular collapse leading to death occurs. At autopsy, cerebral edema and sometimes frothy pulmonary edema are generally found, but those pulmonary effects are most likely from allergic reactions to adulterants mixed with the heroin. Opiates generally do not produce seizures except for unusual cases of mixed drug abuse with the opiate meperidine or with high doses of tramadol.
TREATMENT Opioid Overdose
Beyond the acute treatment of opiate overdose with naloxone, clinicians have two general treatment paths: opioid maintenance treatment or detoxification. Most opioid-dependent individuals engage in multiple episodes of all three categories of treatment during the course of their drug-using careers. Agonist and partial agonist medications are commonly utilized for both maintenance and detoxification purposes. Alpha-2-adrenergic agonists are primarily used for detoxification. Antagonists are used to accelerate detoxification and then continued postdetoxification to prevent relapse. Only the residential medication-free programs have had success that comes close to matching that of the medication-based programs. Success of the various treatment approaches is assessed as retention in treatment, reduced opioid and other drug use, as well as secondary outcomes such as HIV risk behaviors, crime, psychiatric symptoms, and medical comorbidity.
Stopping opiates is like stopping most drugs of abuse—it is much easier to stop than to prevent relapses. Long-term relapse prevention for opioid-dependent persons requires combined pharmacologic and psychosocial approaches. Chronic users tend to prefer pharmacologic approaches; those with shorter histories of drug abuse are more amenable to detoxification and psychosocial interventions.
Opiate Overdose Treatment Managing overdose requires naloxone and support of vital functions, including intubation if needed. The opiate antagonist naloxone is given at 0.4–2 mg IV or IM, with an expected response within 1–2 min. If the overdose is due to buprenorphine, then naloxone might be required at total doses of 10 mg or greater, but primary buprenorphine overdose is nearly impossible because this agent is a partial opiate agonist. Partial agonism means that as the dose of buprenorphine is increased, it has greater opiate antagonist than agonist activity. Thus, a 0.2-mg buprenorphine dose leads to analgesia and sedation, while a hundred times greater 20-mg dose produces profound opiate antagonism, precipitating opiate withdrawal in a person who was opiate dependent on morphine or methadone. When 10 mg of naloxone fails to produce arousal in the patient, another cause of toxicity must be found. Before reaching such large naloxone doses, however, it is important to recognize that the goal is to reverse the respiratory depression and not to administer so much naloxone that it precipitates opiate withdrawal. Because naloxone only lasts a few hours and most opiates last considerably longer, close monitoring and an IV naloxone drip is frequently employed to provide a continuous level of antagonism for 24–72 h depending on the opiate used in the overdose (e.g., morphine vs. methadone). Other sedative drugs that produce significant overdoses must also be considered if naloxone has only a limited effect. The most common are benzodiazepines, which have produced overdoses and deaths in combination with buprenorphine. A specific antagonist for benzodiazepines—flumazenil at 0.2 mg/min—can be given to a maximum of 3 g/h, but it may precipitate seizures and increase intracranial pressure. Like naloxone, administration for a prolonged period is usually required since most benzodiazepines remain active for considerably longer than flumazenil.
Support of vital functions may include oxygen and positive-pressure breathing, IV fluids, pressor agents for hypotension, and cardiac monitoring to detect QT prolongation, which might require treatment. Activated charcoal and gastric lavage may be helpful for oral ingestions, but intubation will be needed if the patient is stuporous.
Opiate Withdrawal Treatment The principles of detoxification are the same for all drugs: to substitute a longer-acting, orally active, pharmacologically equivalent drug for the abused drug, stabilize the patient on that drug, and then gradually withdraw the substituted drug. Methadone is admirably suited for such use in opioid-dependent persons, and the partial mu agonist buprenorphine is another option. Clonidine, a centrally acting sympatholytic agent, has also been used for detoxification. By reducing central sympathetic outflow, clonidine mitigates many of the signs of sympathetic overactivity. Clonidine has no narcotic action and is not addictive. Lofexidine, a clonidine analogue with less hypotensive effect, is being developed for use.
Methadone for Detoxification Methadone dose tapering regimens for detoxification range from 2 to 3 weeks to as long as 180 days, but this approach is controversial given the relative effectiveness of methadone maintenance and the low success rates of detoxification. Unfortunately, the vast majority of patients tend to relapse to heroin or other opiates during or after the detoxification period, indicative of the chronic and relapsing nature of opioid dependence.
Buprenorphine for Detoxification Because it is a partial agonist, buprenorphine produces fewer withdrawal symptoms and may allow briefer detoxifications compared with full agonists like methadone, but it does not appear to have better outcomes than methadone tapering. Buprenorphine is superior to the alpha-2-adrenergic agonist clonidine in reducing symptoms of withdrawal, retaining patients in a withdrawal protocol, and in treatment completion.
Alpha-2-Adrenergic Agonists for Detoxification Several alpha-2-adrenergic agonists have relieved opioid withdrawal by suppressing central noradrenergic hyperactivity. Alpha-2-adrenergic agonists moderate the symptoms of noradrenergic hyperactivity via actions in the central nervous system. Clonidine relieves some signs and symptoms of opiate withdrawal such as lacrimation, rhinorrhea, muscle pain, joint pain, restlessness, and gastrointestinal symptoms, but it is not a drug of abuse or dependence. Unfortunately, clonidine is associated with significant hypotension, which has stimulated investigation of lofexidine, guanfacine, and guanabenz acetate. Lofexidine can be dosed up to ~2 mg/d and appears to be associated with fewer adverse effects, and it is therefore likely to replace clonidine as the leading opioid withdrawal treatment in this drug class. Clonidine or lofexidine are typically administered orally, in three or four doses per day, with dizziness, sedation, lethargy, and dry mouth as the primary adverse side effects. Completion rates of managed withdrawal assisted with clonidine and other alpha-2-adrenergic agents vs. methadone have been comparable.
Rapid and Ultrarapid Opiate Detoxification The opioid antagonist naltrexone typically combined with an alpha-2-adrenergic agonist has been purported to shorten the duration of withdrawal without significantly increasing patient discomfort. Another benefit to rapid opiate detoxification (ROD) is the reduced time between opioid use and the commencement of sustained naltrexone treatment for prevention of relapse (discussed later). ROD completion rates using naltrexone and clonidine range from 75 to 81% compared to 40 to 65% for methadone or clonidine alone. Buprenorphine in combination with naltrexone and clonidine reduced ROD from 3 days to 1 day of detoxification. Ultrarapid opiate detoxification is an extension of ROD using anesthetics, but is highly controversial due to the medical risks and mortality associated with it.
Agonist medications for opioid dependence
Methadone maintenance substitutes a once-daily oral opioid dose for three-to-four times daily heroin. Methadone saturates the opioid receptors, and by inducing a high level of opiate tolerance, blocks the desired euphoria from additional opiates. Buprenorphine, a partial opioid agonist, also can be given once daily at sublingual doses of 4–32 mg daily, and in contrast to methadone it can be given in an office-based primary care setting.
Methadone’s slow onset of action when taken orally, long elimination half-life (24–36 h), and production of cross-tolerance at doses from 80 to 150 mg are the basis for its efficacy in treatment retention and reductions in IV drug use, criminal activity, and HIV risk behaviors and mortality. Methadone can prolong the QT interval at rates as high as 16% above the rates in non-methadone-maintained, drug-injecting patients, but it has been used safely in the treatment of opioid dependence for 40 years.
While France and Australia have had sublingual buprenorphine maintenance since 1996, the USFDA approved it as a Schedule III drug in 2002 for managing opiate dependence. Unlike the full agonist methadone, buprenorphine is a partial agonist of mu-opioid receptors with a slow onset and long duration of action, allowing for alternate-day dosing. Its partial agonism reduces the risk of unintentional overdose but limits its efficacy to patients who need the equivalent of only 60–70 mg of methadone, and many patients in methadone maintenance require higher doses up to 150 mg daily. Buprenorphine is combined with naloxone at a 4:1 ratio in order to reduce its abuse liability. A subcutaneous buprenorphine implant has also been tested, but results are not yet available.
In the United States, the ability of primary care physicians to prescribe buprenorphine for opioid dependence presents an important and far-reaching opportunity to improve access and quality of treatment as well as reduce social harm. Europe, Asia, and Australia have found reduced opioid-related deaths and drug-injection-related medical morbidity with buprenorphine available in primary care. Retention in office-based buprenorphine treatment has been greater than 70% at 6-month follow-ups.
Antagonist medications for opioid dependence
The rationale for using narcotic antagonist therapy is that blocking the action of self-administered opioids should eventually extinguish the habit, but this therapy is poorly accepted by patients. Naltrexone, a long-acting orally active pure opioid antagonist, can be given three times a week at doses of 100–150 mg and a depot form for monthly administration is available. Because it is an antagonist, the patient must first be detoxified from opioid dependence before starting naltrexone. When taken chronically for even years, it is safe, associated with few side effects (headache, nausea, abdominal pain), and can be given to patients infected with hepatitis B or C without producing hepatotoxicity. However, most providers refrain from prescribing it if liver function tests are 3–5 times above normal levels. Naltrexone maintenance combined with psychosocial therapy is effective in reducing heroin use, but medication adherence is low. Depot injection formulations lasting up to 4 weeks markedly improve adherence, retention, and drug use. Subcutaneous naltrexone implants in Russia, China, and Australia have doubled treatment retention and reduced relapse to half that of oral naltrexone.
Most opiate addicts enter medication-free treatments in inpatient, residential, or outpatient settings, but 1-to 5-year outcomes are very poor compared to pharmacotherapy except for residential settings lasting 6 to 18 months. The residential programs require full immersion in a regimented system that has progressively increasing levels of independence and responsibility within a controlled community of fellow drug abusers. These medication-free programs, as well as the pharmacotherapy programs, also include counseling and behavioral treatments designed to teach interpersonal and cognitive skills for coping with stress and for avoiding situations leading to easy access to drugs or to craving. Relapse is prevented by having the individual very gradually reintroduced to greater responsibilities and to the working environment outside of the protected therapeutic community.
Preventing opiate abuse represents a critically important challenge for physicians. Opiate prescriptions are the most common source of drugs accessed by adolescents who begin a pattern of illicit drug abuse; in the United States, 9000 adolescents become opiate abusers every day. The major sources of these drugs are family members, not drug dealers or the Internet. Pain management involves giving sufficient opiates to relieve the pain over as short a period of time as the pain warrants. The patient then needs to dispose of any remaining opiates, not save them in the medicine cabinet, because this behavior leads to diversion to adolescents. Finally, physicians should never prescribe opiates for themselves.