The vast majority of opioid-poisoned patients follow predictable clinical courses that can be anticipated based on our understanding of opioid receptor pharmacology. However, certain opioids taken in overdose may produce atypical manifestations. Therefore, careful clinical assessment and institution of empiric therapy usually are necessary to ensure proper management (Table 38–4).
TABLE 38–4.Classification, Potency, and Characteristics of Opioids and Opioid Antagonists ||Download (.pdf) TABLE 38–4. Classification, Potency, and Characteristics of Opioids and Opioid Antagonists
|Opioid (Representative Trade Name) ||Typea ||Derivation ||Analgesic Dose (mg) (via route, equivalent to 10 mg of morphine SCb) ||Commentsa,c |
|Alvimopan (Entereg) ||Ant ||Synthetic ||Nonanalgesic (12 PO) ||Peripherally acting antagonist; reverses opioid constipation |
|Buprenorphine (Suboxone) ||PA ||Semisynthetic ||0.4 IM ||Opioid substitution therapy requires 6–16 mg/day (contains naloxone) |
|Butorphanol (Stadol) ||AA ||Semisynthetic ||2 IM || |
|Codeine ||Ag ||Natural ||120 PO ||Often combined with acetaminophen; requires demethylation to morphine by CYP2D6 |
|Dextromethorphan (Robitussin DM) ||NEC ||Semisynthetic ||Nonanalgesic (10–30 PO) ||Antitussive; psychotomimetic via NMDA receptor |
|Diphenoxylate (Lomotil) ||Ag ||Synthetic ||Nonanalgesic (2.5 PO) ||Antidiarrheal, combined with atropine; difenoxin is potent metabolite |
|Fentanyl (Sublimaze) ||Ag ||Synthetic ||0.125 IM ||Very short acting (<1 hour) |
|Heroin (Diamorph) ||Ag ||Semisynthetic ||5 SC ||Diacetylmorphine, used therapeutically in some countries, schedule I medication in the United States |
|Hydrocodone (Vicodin, Hycodan) ||Ag ||Semisynthetic ||10 PO || |
|Hydromorphone (Dilaudid) ||Ag ||Semisynthetic ||1.3 SC || |
|LAAM (Orlaam) ||Ag ||Synthetic ||(Flexible oral dosingd) ||Long acting, potent metabolites; no longer distributed in United States because of QT interval prolongation |
|Levorphanol (Levodromoran) ||Ag ||Semisynthetic ||2 SC/IM || |
|Loperamide (Imodium) ||Ag ||Synthetic ||Nonanalgesic (2 PO) ||Antidiarrheal |
|Meperidine, pethidine (Demerol) ||Ag ||Synthetic ||75 SC/IM ||Seizures caused by metabolite accumulation |
|Methadone (Dolophine) ||Ag ||Synthetic ||10 IM ||Very long acting (24 hours) |
|Methylnaltrexone (Relistor) ||Ant ||Synthetic ||Nonanalgesic (8–12 SC) ||Peripherally acting antagonist; reverses opioid induced constipation |
|Morphine ||Ag ||Natural ||10 SC/IM || |
|Nalbuphine (Nubain) ||AA ||Semisynthetic ||10 IM || |
|Nalorphine ||AA ||Semisynthetic ||15 IM ||Historically used as an opioid antagonista |
|Naloxone (Narcan) ||Ant ||Semisynthetic ||Nonanalgesic (0.04 IV/IM) ||Short-acting antagonist (0.5 hours) |
|Naltrexone (Trexan, Revia) ||Ant ||Semisynthetic ||Nonanalgesic (50 PO) ||Very long-acting antagonist (24 hours) |
|Oxycodone (Percocet, OxyContin) ||Ag ||Semisynthetic ||10 PO ||Often combined with acetaminophen; OxyContin is sustained release |
|Oxymorphone (Numorphan, Opana) ||Ag ||Semisynthetic ||1 SC || |
|Paregoric (Parapectolin) ||Ag ||Natural ||25 mL PO ||Tincture of opium (0.4 mg/mL) |
|Pentazocine (Talwin) ||AA ||Semisynthetic ||50 SC ||Psychotomimetic via receptor |
|Propoxyphene (Darvon) ||Ag ||Synthetic ||65 PO ||Seizures, dysrhythmias |
|Tapentadol (Nucynta) ||Ag ||Synthetic ||50–100 PO ||Seizures |
|Tramadol (Ultram) ||Ag ||Synthetic ||50–100 PO ||Seizures possible with therapeutic dosing |
Morphine is poorly bioavailable by the oral route because of extensive first-pass elimination. Morphine is hepatically metabolized primarily to morphine-3-glucuronide (M3G) and, to a lesser extent, to morphine-6-glucuronide (M6G), both of which are cleared renally. Unlike M3G, which is essentially devoid of activity, M6G has μ-agonist effects in the CNS.23 However, M6G administered peripherally is significantly less potent as an analgesic than is morphine.160 The polar glucuronide has a limited ability to cross the blood–brain barrier, and P-glycoprotein is capable of expelling M6G from the cerebrospinal fluid. The relative potency of morphine and M6G in the brain is incompletely defined, but the metabolite is generally considered to be several-fold more potent.3
Codeine itself is an inactive opioid agonist, and it requires metabolic activation by O-demethylation to morphine by CYP2D6 (Fig. 38–3). This typically represents a minor metabolic pathway for codeine metabolism. N-Demethylation into norcodeine by CYP3A4 and glucuronidation are more prevalent but produce inactive metabolites. The need for conversion to morphine explains why approximately 5% to 7% of white patients, who are devoid of CYP2D6 function, cannot derive an analgesic response from codeine.83,101 An increasingly recognized phenomenon is that ultrarapid CYP2D6 metabolizers produce unexpectedly large amounts of morphine from codeine, with resulting life-threatening opioid toxicity.55,138
Opiate and opioid metabolism. Codeine can be O-methylated to morphine, N-demethylated to norcodeine, or glucuronidated to codeine-6-glucuronide (codeine-6-G). Morphine can be N-demethylated to normorphine or glucuronidated to either morphine-3-glucuronide (morphine-3-G) or morphine-6-glucuronide (morphine-6-G). Heroin is converted to morphine by a two-step process involving plasma cholinesterase and two human liver carboxylesterases known as human carboxylesterase-1 and human carboxylesterase-2.
Heroin is 3,6-diacetylmorphine, and its exogenous synthesis is performed relatively easily from morphine and acetic anhydride. Heroin has a lower affinity for the receptor than does morphine, but it is rapidly metabolized by plasma cholinesterase and liver human carboxylesterase (hCE)-2 to 6-monoacetylmorphine, a more potent μ agonist than morphine (Fig. 38–3).155 Users claim that heroin has an enhanced euphorigenic effect, often described as a “rush.” This effect likely is related to the enhanced blood–brain barrier penetration occasioned by the additional organic functional groups of heroin and its subsequent metabolic activation within the CNS. Interestingly, cocaine and heroin compete for metabolism by plasma cholinesterase and the two human liver carboxylesterases hCE-1 and hCE-2. This interaction may have pharmacokinetic and clinical consequences in patients who “speedball.”9,90
Heroin can be obtained in two distinct chemical forms: base or salt. The hydrochloride salt form typically is a white or beige powder and was the common form of heroin available before the 1980s.88 Its high water solubility allows simple IV administration. Heroin base, on the other hand, now is the more prevalent form of heroin in most regions of the world. It often is brown or black. “Black tar heroin” is one appellation referring to an impure South American import available in the United States. Because heroin base is virtually insoluble in water, IV administration requires either heating the heroin until it liquefies or mixing it with acid. Alternatively, because the alkaloidal form is heat stable, smoking or “chasing the dragon” is sometimes used as an alternative route. Street-level heroin base frequently contains caffeine or barbiturates,88 which improves the sublimation of heroin and enhances the yield.81
Widespread IV use has led to many significant direct and indirect medical complications, particularly endocarditis and AIDS, in addition to fatal and nonfatal overdose. Nearly two-thirds of all long-term (>10 years) heroin users in Australia had overdosed on heroin.40 Among recent-onset heroin users, 23% had overdosed on heroin, and 48% had been present when someone else overdosed.63 Risk factors for fatality after heroin use include the concomitant use of other drugs of abuse, particularly ethanol; recent abstinence, as occurs during incarceration153; and perhaps unanticipated fluctuations in the purity of available heroin.37,143 Because most overdoses occur in seasoned heroin users and about half occur in the company of other users,40 the prescribing of naloxone to heroin users for companion administration has become increasingly available but remains poorly studied.20 Although earlier administration of antidote could be beneficial, certain issues make this approach controversial. For example, despite the acknowledged injection skills of the other users in the “shooting gallery,” their judgment likely is impaired. In one survey, summoning an ambulance was the initial response to overdose of a companion in only 14% of cases.39 A survey of heroin users suggested they lacked an understanding of the pharmacology of naloxone, which might lead to inappropriate behaviors regarding both heroin and naloxone administration.152
Recognition of the efficacy of intranasal heroin administration, or snorting, has fostered a resurgence of heroin use, particularly in suburban communities. The reasons for this trend are unclear, although it is widely suggested that the increasing purity of the available heroin has rendered it more suitable for intranasal use. However, because intranasal administration of a mixture of 3% heroin in lactose produces clinical and pharmacokinetic effects similar to an equivalent dose administered IM, the relationship between heroin purity and price and intranasal use is uncertain.28,146 Needle avoidance certainly is important, reducing the risk of transmission of various infectious diseases, including HIV. Heroin smoking has also increased in popularity in the United States, albeit not to the extent in other countries (see Chasing the Dragon later). In addition, users of prescription drugs such as oxycodone or hydrocodone may change to heroin as the supplies of prescription opioids tighten and prices rise.87 Celebrities and blogs have popularized intranasal heroin use as a “safe” alternative to IV use. This usage is occurring despite a concomitantly reported rise in heroin deaths in regions of the country where its use is prevalent. Although intranasal use may be less dangerous than IV use from an infectious disease perspective, it is clear that both fatal overdose and drug dependency remain common.178
Adulterants, Contaminants, and “Heroin” Substitutes.
The history of heroin adulteration and contamination has been extensively described. Retail (street-level) heroin almost always contains adulterants or contaminants. What differentiates the two is the intent of their admixture. Adulterants typically are benign because inflicting harm on the consumer with their addition would be economically and socially unwise, although adulterants occasionally are responsible for epidemic deaths. Interestingly, most heroin overdose fatalities do not have serum morphine concentrations that substantially differ from those of living users, raising the unlikely possibility that the individual death is related to an adulterant or contaminant.38
Historically, alkaloids, such as quinine and strychnine, were used to adulterate heroin to mimic the bitter taste of heroin and to mislead clients. Quinine may have first been added in a poorly reasoned attempt to quell an epidemic of malaria among IV heroin users in New York City in the 1930s.71 That quinine adulteration was common is demonstrated by the common practice of urine screening for quinine as a surrogate marker for heroin use. However, quinine was implicated as a causative factor in an epidemic of heroin-related deaths in the District of Columbia between 1979 and 1982. Toxicity attributed to quinine in heroin users includes cardiac dysrhythmias (Chap. 16), amblyopia, and thrombocytopenia. Quinine adulteration currently is much less common than it was in the past. Trend analysis of illicit wholesale and street-level heroin adulteration over a 12-year period in Denmark revealed that although caffeine, acetaminophen (APAP), methaqualone, and phenobarbital all were prevalent adulterants, quinine was not found.88 Recent data on adulteration in the United States are unavailable. Many other adulterants or contaminants, including thallium, lead, cocaine, and amphetamines, are reported.
Poisoning by scopolamine-tainted heroin reached epidemic levels in the northeastern United States in 1995.68 Exposed patients presented with acute psychosis and anticholinergic signs. Several patients were treated with physostigmine, with excellent therapeutic results.
Clenbuterol, a β2-adrenergic agonist with a rapid onset and long duration of action, was found to be a contaminant in street heroin in the Eastern United States in early 2005. Users rapidly developed nausea, chest pain, palpitations, dyspnea, and tremor. Physical findings included significant tachycardia and hypotension, as well as hyperglycemia, hypokalemia, and increased lactate concentrations on laboratory evaluation, and a few fatalities occurred.79,197 The initial patients were thought to be cyanide poisoned. Several patients were treated with β-adrenergic antagonists or calcium channel blockers and potassium supplementation with good results.
IV injection and insufflation are the preferred means of heroin self-administration in the United States. In other countries, including the Netherlands, the United Kingdom, and Spain, a prevalent method is “chasing the dragon” whereby users inhale the white pyrolysate that is generated by heating heroin base on aluminum foil using a handheld flame. This means of administration produces heroin pharmacokinetics similar to those observed after IV administration.73 Chasing the dragon is not a new phenomenon, but it has gained acceptance recently among both IV heroin users and drug-naïve individuals. The reasons for this shift are diverse but probably are related to the avoidance of injection drug use with its concomitant infectious risks.
In the early 1980s, a group of individuals who smoked and inhaled heroin in the Netherlands developed spongiform leukoencephalopathy. Other causes of this rare clinicopathologic entity include prion-related infections such as bovine spongiform leukoencephalopathy, hexachlorophene, pentachlorophenol, and metal poisoning, although none appeared responsible for this phenomenon. Since the initial report, similar cases have been reported in other parts of Europe and in the United States.100,109 Initial findings may occur within 2 weeks of use and include bradykinesia, ataxia, abulia, and speech abnormalities. Of those whose symptoms do not progress, half may recover. However, in others, progression to spastic paraparesis, pseudobulbar palsy, or hypotonia may occur over several weeks. Approximately half of individuals in this group do not develop further deficits or improve, but death occurs in approximately 25% of reported cases. The prominent symmetric cerebellar and cerebral white matter destruction noted on brain computed tomography and magnetic resonance imaging corresponds to that noted at necropsy.95,129
The syndrome has the characteristics of a point-source toxic exposure, but no culpable contaminants have been identified, although aluminum concentrations may be elevated.51 A component or pyrolysis product unique to certain batches of “heroin” is possible.16 Treatment is largely supportive. Based on the finding of regional mitochondrial dysfunction on functional brain imaging and an elevated brain lactate concentration, supplementation with 300 mg four times a day of coenzyme Q has purported benefit but has not undergone controlled study.100
Fentanyl and Its Analogs.
Fentanyl is a short-acting opioid agonist that has approximately 50 to 100 times the potency of morphine. It is well absorbed by the transmucosal route, accounting for its use in the form of a “lozenge.” Fentanyl is widely abused as a heroin substitute (intentionally or because of adulteration) and is the controlled substance most often abused by anesthesiologists.12
Transdermal fentanyl in the form of a patch (Duragesic) was approved in 1991 and is widely used by patients with chronic pain syndromes. Fentanyl has adequate solubility in both lipid and water for transdermal delivery (Special Considerations: SC1).97 A single patch contains an amount of drug to provide a transdermal gradient sufficient to maintain a steady-state plasma concentration for approximately 3 days (eg, a 50 μg/h patch contains 5 mg). However, even after the patch is considered exhausted, approximately 50% of the total initial fentanyl dose remains. Interindividual variation in dermal drug penetration and errors in proper use, such as use of excessive patches or warming of the skin, may lead to an iatrogenic fentanyl overdose. Fentanyl patch misuse and abuse occur either by application of one or more patches to the skin or by withdrawal or extraction of the fentanyl from the reservoir for subsequent administration.177
Regional epidemics of heroin substitutes with “superpotent” activity occasionally produce a dramatic increase in “heroin-related” fatalities. Epidemic deaths among heroin users first appeared in Orange County, California, in 1979 and were traced to α-methylfentanyl sold under the brand name China White.98 Similar epidemics of China White poisoning occurred in Pittsburgh in 1988 and in Philadelphia in 1992, although the adulterant in these cases was 3-methylfentanyl, another potent analog. A later epidemic in New York City marked the reappearance of 3-methylfentanyl under the brand name Tango and Cash. Typically, patients present comatose and apneic, with no opioids detected on routine blood and urine analysis. In such cases, unsuspecting users had administered their usual “dose of heroin,” measured in 25-mg “bags” that contained variable amounts of the fentanyl analog. Because of the exceptional potency of this fentanyl analog (as much as 6000 times greater than that of morphine), users rapidly developed apnea.
The largest epidemic of more than 1000 fentanyl-related deaths occurred between 2005 and 2007 primarily in the Philadelphia, Chicago, and Detroit regions because of surreptitiously adulterated or substituted heroin. Fentanyl use was identified by postmortem urine and blood testing or through analysis of unused drug found on either the decedent or persons with whom the decedent shared drugs. In response to this large epidemic, drug users and others were counseled in overdose prevention and cardiopulmonary resuscitation and provided with “take-home” parenteral or intranasal naloxone.22
Sufentanil and alfentanil are anesthetic opioids with increased potency compared with fentanyl. In some regions of the country, fentanyl and both licit and illicit fentanyl analogs (eg, 3-methylfentanyl and para-fluorofentanyl) are common drugs of abuse. Experienced heroin users could not easily differentiate fentanyl from heroin, although in one study, heroin was noted to provide a more intense “rush.”102 Although unconfirmed, the xenobiotic used by Russian authorities to overcome terrorists and subdue a hostage situation in Moscow in October 2002 may have been carfentanil,191 a potent μ-receptor agonist that is commonly used as a positron emission tomography scan radioligand.
Although fentanyl is a more potent opioid agonist than heroin, the dose of naloxone required to reverse respiratory depression appears to be similar to that of other common opioids.176 This is because the binding affinity (Kd) of fentanyl at the μ opioid receptor is similar to that of both morphine and naloxone.107,183 In a typical overdose, the quantity of fentanyl is likely to be equipotent to typical heroin. However, if large quantities of fentanyl are involved in the poisoning, higher than normal doses of naloxone may be required for reversal. Use of other opioids, such as sufentanil and buprenorphine, which have higher affinity for opioid receptors (lower Kd1), may lead to the need for larger doses of naloxone to reverse the patient’s respiratory depression107 (Antidotes in Depth: A4).
Both oxycodone and hydrocodone are sold in fixed combination with APAP (eg, Percocet [oxycodone], Vicodin [hydrocodone]), raising concerns about the complications of APAP hepatotoxicity as the dose of opioid is escalated. Several opioids, including oxycodone and oxymorphone, can be obtained in a controlled-release form that contains a large quantity of opioid intended to be released over many hours. Up until recently, abusers were able to crush the tablet, which destroys the sustained-release matrix and liberates large amounts of insufflatable or injectable opioid. New tamper-resistant formulations, required of most extended release opioids, make physical or chemical release of the opioid difficult limiting this practice.149 Users can still ingest intact large dose pills. The psychoactive effects of these opioids are similar to each other and to other μ receptor agonists196,202 and often are used as a substitute for heroin. Opioid dependence, overdose, and death are common sequelae of oxycodone abuse.
In an attempt to transport illicit drugs from one country to another, “mules,” or body packers, ingest large numbers of multiple-wrapped packages of concentrated cocaine or heroin. When the authorities discover such individuals or when individuals in custody become ill, they may be brought to a hospital for evaluation and management. Although these patients generally are asymptomatic on arrival, they are at risk for delayed, prolonged, or lethal poisoning as a consequence of packet rupture.180 In the past, determining the country of origin of the current journey was nearly diagnostic of packet content. However, because most of the heroin imported into the United States now originates from South America, which is also the major source of imported cocaine, the discernment from cocaine on this basis is impossible. Given the current greater revenue potential of heroin, the majority of body packers carry heroin.61 Details of diagnosis and management are discussed in Special Considerations: SC5.
The opioid agonists in common clinical use tend to have specific binding affinity toward the μ opioid receptor subtype. The agonist–antagonists differ in that they interact with multiple receptor types and may have different effects at each receptor. Thus, although most opioids typically produce either agonist or antagonist effects, the agonist–antagonists generally have agonist effects at the κ-receptor subtype and antagonistic effects at the μ receptor subtype. Therefore, opioids such as pentazocine (Talwin) may elicit a withdrawal syndrome in a μ-opioid–tolerant individual because of antagonist effects at the μ receptor. This effect forms the basis of the claim offered by many methadone-dependent patients that they are “allergic to Talwin.” However, this same drug may act as an analgesic in nonopioid-using patients through its agonist effects at the κ1-receptor subtype. Although the clinical effects of agonist–antagonists after overdose resemble those of the other opioids, including lethal respiratory depression,131 they are less likely than the full agonists to produce severe morbidity or mortality (see Respiratory Depression above).
Historically, patients abusing pentazocine (Talwin) administered it with tripelennamine, a blue capsule, accounting for the appellation “T’s and Blues.” Although this mixture has largely fallen out of favor, pentazocine abuse occurs occasionally. The psychotomimetic effects noted with high doses of pentazocine likely are mediated by κ2 or perhaps σ receptors. Because pentazocine can be readily dissolved, IV injection was a preferred route for its abuse until the commercial formulation was altered to include 0.5 mg naloxone (Talwin NX), which is not orally bioavailable but fully active parenterally.
Xenobiotics Used in Opioid Substitution Therapy: Methadone and Buprenorphine
Two contrasting approaches to the management of patients with chronic opioid use exist, detoxification and maintenance therapy. Detoxification probably is most appropriate for patients motivated or compelled to discontinue opioid use. It can be performed either by tapered withdrawal of an opioid agonist or with the assistance of opioid antagonists. Maintenance therapy may include use of a long-acting opioid antagonist, such as naltrexone, to pharmacologically block the effects of additional opioid use. Alternatively, and more commonly, maintenance therapy involves opioid substitution therapy.19
Methadone is a synthetic μ opioid receptor agonist used both for treatment of chronic pain and as a maintenance substitute for opioid dependence. Methadone has been available for the latter use for more than 40 years through methadone maintenance treatment programs (MMTPs).43 In MMTPs, the opioid in use is replaced by methadone, which is legal, oral, and long acting. This opioid allows patients to abstain from activities associated with procurement and administration of the abused opioid and eliminates much of the morbidity and mortality associated with illicit drug use. Although often successful in achieving opioid abstinence, some methadone users continue to use heroin, other opioids, and other xenobiotics.92
Methadone is administered as a chiral mixture of (R,S)-methadone. In humans, methadone metabolism is mediated by several cytochrome P450 (CYP) isozymes, mainly CYP3A4 and CYP2B6, and to a lesser extent CYP2D6. CYP2B6 demonstrates stereoselectivity toward (S)-methadone,58 and in vivo data show that CYP2B6 slow metabolizer status is associated with high (S)- but not serum (R)-methadone concentrations.33 In clinical trials, QT prolongation was exacerbated in individuals who were CYP2B6 slow metabolizers, and this population had higher (S)-methadone concentrations.46 (R)-methadone is used in Germany and is both more effective and safer than the chiral mixture or the (S) enantiomer, but it is not available in the United States at the present time.
Methadone predictably produces QT interval prolongation because of blockade of the hERG (human ether-a-gogo related gene) channel. In the human heart, the hERG voltage-gated potassium channel mediates the rapidly activating delayed rectifier current (Chap. 16). Blocking potassium efflux from the cardiac myocyte prolongs cellular repolarization, prolonging the QT interval. Syncope and sudden death caused by ventricular dysrhythmias (eg, torsade de pointes) are the result. Initially described in case reports of patients on high doses of methadone, clinical trials now reveal that methadone can prolong the QT interval in a concentration-dependent fashion.112 Genetic factors in the metabolism of methadone46 and probably baseline QT status at the initiation of methadone therapy may underlie and potentially predict adverse effects. (S)-methadone binding to hERG is greater than twofold than that of (R)-methadone and accounts for the cardiotoxicity.84
A major difficulty is identification of individuals who are at risk for life-threatening dysrhythmias from methadone-induced QT intervalprolongation. Expert-derived guidelines recommend questioning patients about intrinsic heart disease or dysrhythmias, counseling patients initiating methadone therapy, and obtaining a pretreatment ECG and a follow-up ECG at 30 days and yearly.99 Patients who receive methadone doses of greater than 100 mg/day might warrant more frequent ECGs, particularly after dose escalation or change in comorbid disease staus.99 Although these guidelines are disputed by some and limited data exist on the utility of the ECG as a screening test for persons at risk for torsade de pointes from methadone, given its low cost, easy availability, and minimal invasiveness, the guideline recommendations seem practical and appropriate.91 Although therapeutic methadone is generally safe, rapid dose escalation during induction of therapy may unintentionally produce toxicity and, rarely, fatal respiratory depression.19 This adverse effect is generally the result of the combination of variable pharmacokinetics (unpredictable but generally long half-life) and the time lag for the development of tolerance.
After a successful therapeutic response to the administration of naloxone, recurrence should be expected because the duration of effect of naloxone is only approximately 30 to 60 minutes. In many cases, continuous infusion of naloxone or possibly administration of a long-acting opioid antagonist is indicated to maintain adequate ventilation (Table 38–3).
Unintentional methadone overdose may be related to the manner in which MMTPs dispense the drug. Most patients attending MMTPs are given doses of methadone greater than needed to simply prevent withdrawal and in order to prevent surreptitious heroin or other opioid use.171 Additionally, many MMTPs provide their established patients with sufficient methadone to last through a weekend or holiday without the need to revisit the program. This combination of dose and quantity may allow diversion of portions of the dose without the attendant risk of opioid withdrawal. Furthermore, home storage of this surplus drug in inappropriate containers, such as juice containers or baby bottles,69 is a cause of unintentional methadone ingestion by children. Such events can be anticipated because methadone is frequently formulated as a palatable liquid and may not be distributed in child-resistant containers. The primary reason for distribution as a liquid, as opposed to the pill form given to patients with chronic pain syndromes, is to ensure dosing compliance at the MMTP. Unfortunately, death is frequent in children who overdose.108
Because prescription of methadone for maintenance therapy is restricted to federally licensed programs, it is inaccessible and inconvenient for many patients. Buprenorphine was approved in 2000 as a schedule III medication for office-based prescription, administered three times weekly, providing an attractive alternative for patients with substantially broader potential for obtaining outpatient therapy. However, because of the initial limitations on patient volume (subsequently expanded), the requirement for physician certification, and possibly the hesitation on the part of community physicians to welcome patients with substance use problems into their practices, many of the perceived benefits of buprenorphine therapy over methadone have not been realized.
Buprenorphine, a partial μ-opioid agonist, in doses of 8 to 16 mg sublingually, is effective at suppressing both opioid withdrawal symptoms and the covert use of illicit drugs. Buprenorphine, although still abused and misused, has a substantially better safety profile than methadone. That is, buprenorphine overdose is associated with markedly less respiratory depression than full agonists such as methadone, and there is no reported effect on the QT interval.
Buprenorphine competes with the extant opioid for the μ receptor; thus, administration of initial doses of buprenorphine in patients taking methadone for opioid substitution therapy can be complicated by opioid withdrawal, particularly in patients on higher doses of methadone. For this reason, the initial dose of buprenorphine is administered in the presence of a physician and when the patient is in mild withdrawal. Buprenorphine cessation results in a mild withdrawal syndrome and for this reason may prove efficacious in opioid detoxification programs.4 After the initial doses of buprenorphine, sublingual film containing both buprenorphine and naloxone (Suboxone) are prescribed to prevent their IV use.
At therapeutic doses, buprenorphine produces nearly complete occupancy of the μ opioid receptors, and its receptor affinity is sufficiently strong that it prevents other opioids from binding.66 Interestingly, naloxone may prevent the clinical effects of buprenorphine, but the reversal of respiratory effects by naloxone appears to be related in a nonlinear fashion. Relatively low bolus doses of IV naloxone have no effect on the respiratory depression induced by buprenorphine, but high doses (5–10 mg) caused only partial reversal of the respiratory effects of buprenorphine. More recently, data in healthy volunteers suggest a bell-shaped dose response to naloxone.148,181 Although doses that would reverse other opioids were ineffective (0.2–0.4 mg), increasing the dose of naloxone to 2 to 4 mg caused full reversal of buprenorphine respiratory depression. However, the onset of reversal is usually slower than occurs when antagonizing other opioids.181 Further increasing the naloxone dose to 5 to 7 mg caused a decline in reversal activity and actually increased the degree of respiratory depression. The reasons for this are unclear. Therefore, reversal of respiratory depression should be treated with a starting dose that is slightly higher than that used to reverse other opioids and increased slowly and titrated to reversal of respiratory depression. For example, a starting dose of naloxone of 0.02 mg/kg, or between 1 and 2 mg, is reasonable, and upward titration should not provide doses in excess of about 5 mg without careful consideration and monitoring. Furthermore, because respiratory depression from buprenorphine may outlast the reversal effects of naloxone boluses or short infusions, a continuous infusion of naloxone may be required to maintain respiratory function.
As a partial agonist, buprenorphine has a ceiling effect on respiratory depression in healthy volunteers, with minimal plateau in analgesic effect.35 However, in some patients, despite the ceiling effect, clinically consequential respiratory depression may occur.179 Data from multiple case series indicate that most buprenorphine-related deaths are associated with concomitant use of other drugs, most often benzodiazepines, or to the IV injection of crushed tablets.179
The higher affinity (lower Kd) and partial agonism of buprenorphine should allow it to function as an antagonist to the respiratory depressant effects of heroin and improve spontaneous respiration. Although administration of sublingual buprenorphine for opioid overdose is reportedly successful in some case reports,194 this practice is largely unstudied and not recommended at this time. Interestingly, some reported deaths involved patients given buprenorphine tablets intravenously by fellow drug users for the treatment of heroin-induced respiratory depression.13
Meperidine, called pethidine outside of the United States, was previously widely used for treatment of chronic and acute pain syndromes. Meperidine produces clinical manifestations typical of the other opioids and may lead to greater euphoria.201 Pupillary constriction is less pronounced and, if it occurs, is less persistent than that associated with morphine.59 However, normeperidine, a toxic, renally eliminated hepatic metabolite, accumulates in patients receiving chronic high-dose meperidine therapy, such as those with sickle cell disease or cancer. A similar accumulation occurs in patients with kidney disease, in whom the elimination half-life increases from a normal of 14 to 21 hours to 35 hours.174 Normeperidine causes excitatory neurotoxicity, which manifests as delirium, tremor, myoclonus, or seizures. Based on animal studies, the seizures should not be expected to respond to naloxone.60 In fact, experimental evidence suggests that naloxone may potentiate normeperidine-induced seizures, presumably by inhibiting an anticonvulsant effect of meperidine.30 Hemodialysis using a high-efficiency membrane may be of limited clinical benefit but rarely, if ever, is indicated because the toxicity generally is self-limited.
Although primarily an opioid, meperidine is capable of exerting effects at other types of receptors. The most consequential nonopioid-receptor effects occur through the serotonin receptor. Blockade of the presynaptic reuptake of released serotonin may produce serotonin toxicity, which is characterized by muscle rigidity, hyperthermia, and altered mental status, particularly in patients using monoamine oxidase inhibitors (MAOIs) (Chap. 73). However, dextromethorphan (see Dextromethorphan later) also may produce toxicity. Conversely, the simultaneous use of MAOIs and morphine, fentanyl, or methadone is not expected to produce serotonin toxicity based on the currently appreciated pharmacology of these drugs. Despite its purported (and likely overstated) beneficial effects on biliary tract physiology, meperidine offers little to support its clinical use and has significant disadvantages. Meperidine use has been dramatically reduced or is closely monitored in many institutions and has been eliminated in other centers because of its adverse risk–benefit profile.
In 1982, several cases of acute, severe parkinsonian symptoms were identified in IV drug users.104 The patients were labeled “frozen addicts” because of the severe bradykinesia, and extensive investigations into the etiology of the problem ensued. This ultimately led to the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an inadvertent product of presumed errors in the attempted synthesis of the illicit meperidine analog MPPP (1-methyl-4-phenyl-4-propionoxy-piperidine). MPTP is metabolized to the ultimate toxicant MPP+ by monoamine oxidase-B in glial cells. Toxicity is inhibited by pretreatment with deprenyl, a monoamine oxidase-B inhibitor. MPP+ is a paraquatlike xenobiotic capable of selectively destroying the dopamine-containing cells of the substantia nigra by inhibiting mitochondrial oxidative phosphorylation.151 The index cases initially responded to standard antiparkinsonian therapy, but none improved substantially, and the effects of the medications waned.6 Although calamitous for exposed patients, MPTP has proved to be invaluable in the development of experimental models for the study of Parkinson disease. Several of the original “frozen” patients subsequently underwent stereotactic implantation of fetal adrenal tissue grafts into their basal ganglia, with significant clinical improvement.105
Dextromethorphan is devoid of analgesic properties altogether even though it is the optical isomer of levorphanol, a potent opioid analgesic. Based on this structural relationship, dextromethorphan is commonly considered an opioid, although its receptor pharmacology is much more complex and diversified. At high doses, dextromethorphan does bind to opioid receptors to produce miosis, respiratory depression, and CNS depression. Reversal of these opioid effects by naloxone is reported. Binding to the PCP site on the NMDA receptor and subsequent inhibition of calcium influx through this receptor-linked ion channel causes sedation. This same activity may account for its antiepileptic properties and for its neuroprotective effects in ischemic brain injury. Because NMDA receptor blockade also enhances the analgesic effects of μ-opioid agonists, combination therapy with morphine and dextromethorphan (MorphiDex) has been introduced.
Blockade of presynaptic serotonin reuptake by dextromethorphan may elicit serotonin toxicity in patients receiving MAOIs.166 Movement disorders, described as choreoathetoid or dystonialike, occasionally occur and presumably result from alteration of dopaminergic neurotransmission. Dextrorphan, the active O-demethylation metabolite of dextromethorphan, is produced by CYP2D6, an enzyme with a well-described genetic polymorphism.5 Whereas patients with the “extensive metabolizer” polymorphism appear to experience more drug-related psychoactive effects, poor metabolizers experience more adverse effects related to the parent compound.203
Dextromethorphan is available without prescription in cold preparations, primarily because of its presumed lack of significant addictive potential. However, abuse of dextromethorphan is increasing, particularly among high school students.9 This increase in use likely is related to the easy availability of dextromethorphan and its perceived limited toxicity. Common street names include “DXM,” “dex,” and “roboshots.” Users often have expectations of euphoria and hallucinations, but a dysphoria comparable to that of PCP commonly ensues. Reports of substantial cold medicine consumption raise several concerns, including APAP poisoning, opioid dependency, and bromide toxicity.82 This last concern relates to the common formulation of dextromethorphan as the hydrobromide salt. At times, the first clue may be an elevated serum chloride concentration when measured on certain autoanalyzers (Chaps. 6 and 19).
Tramadol (Ultram) and tapentadol (Nucynta) are novel synthetic analgesics with both opioid and nonopioid mechanisms responsible for their clinical effects. Tramadol is a reuptake inhibitor of norepinephrine and 5-HT, and it has an active metabolite, formed via CYP2D6, that is a weak μ opioid receptor agonist.139 Tapentadol, which does not require activation, has relatively strong μ-opioid receptor agonism and inhibits the reuptake of norepinephrine but not serotonin.70 Both are available in immediate-release and extended-release formulations.
A large number of spontaneous reports to the FDA suggest that therapeutic use of tramadol may cause seizures, particularly on the first day of therapy. However, epidemiologic studies have not confirmed this association.56 Tramadol-related seizures are not responsive to naloxone but are suppressed with benzodiazepines. In fact, the package insert cautions against using naloxone in patients with tramadol overdoses because in animals treated with naloxone, the risk of seizure is increased. Correspondingly, one patient in a prospective series had a seizure that was temporally related to naloxone administration.167 Acute overdose of tramadol is generally considered non–life threatening, and most fatalities were associated with polysubstance overdose. Ultrarapid metabolizers at CYP2D6 may experience complications at conventional doses.48 Patients using MAOIs may be at risk for development of serotonin toxicity after taking tramadol.
Tramadol abuse is reported, but its extent is undefined. In a review of physician drug abuse in several states, tramadol was the second most frequent opioid reported.162 Opioid users recognized tramadol as an opioid only when given in an amount that was six times the therapeutic dose, but at this dose, the users did not develop opioidlike clinical effects such as miosis. Patients may develop typical opioid manifestations after a large overdose. Significant respiratory depression is uncommon and should respond to naloxone.167 Generally, urine drug screening for drugs of abuse is negative for opioids in tramadol-exposed patients. Tapentadol is relatively new to the market, and although its abuse potential remains concerning and case reports exist,94 there are insufficient epidemiologic data to identify diversion or abuse.41
Propoxyphene is a weak analgesic with limited efficacy data and serious safety concerns. Similar to its structural analog methadone, propoxyphene binds μ-opioid receptors and produces the expected opioid clinical findings. However, unanticipated properties of propoxyphene manifest after overdose. Propoxyphene and its hepatic metabolite, norpropoxyphene, produce myocardial sodium channel blockade identical to the type IA antidysrhythmics. This process results in QRS complex widening and negative inotropy (Chap. 64).
Although diphenoxylate is structurally similar to meperidine, its extreme insolubility limits absorption from the GI tract. This factor may enhance its use as an antidiarrheal agent, which presumably occurs via a local opioid effect at the GI μ receptor. However, the standard adult formulation may result in significant systemic absorption and toxicity in children, and all such ingestions should be deemed consequential. Diphenoxylate is formulated with a small dose (0.025 mg) of atropine (as Lomotil), both to enhance its antidiarrheal effect and to discourage illicit use.
Because both components of Lomotil may be absorbed and their pharmacokinetic profiles differ somewhat, a biphasic clinical syndrome is occasionally noted.115 Patients may manifest atropine poisoning (anticholinergic syndrome), either independently or concomitantly with the opioid effects of diphenoxylate. Delayed, prolonged, or recurrent toxicity is common and is classically related to the delayed gastric emptying effects inherent to both opioids and anticholinergics. However, these effects are more likely explained by the accumulation of the hepatic metabolite difenoxin, which is a significantly more potent opioid than diphenoxylate and possesses a longer serum half-life. Still, the relevance of gastroparesis is highlighted by the retrieval of Lomotil pills by gastric lavage as late as 27 hours after ingestion.
A review of 36 pediatric reports of Lomotil overdoses found that although naloxone was effective in reversing the opioid toxicity, recurrence of CNS and respiratory depression was common.115 This series included a patient with an asymptomatic presentation 8 hours after ingestion who was observed for several hours and then discharged. This patient returned to the ED 18 hours after ingestion with marked signs of atropinism. In this same series, children with delayed onset of respiratory depression and other opioid effects were reported, and others describe cardiopulmonary arrest 12 hours after ingestion. Naloxone infusion may be appropriate for patients with recurrent signs of opioid toxicity. Because of the delayed and possibly severe consequences, all children and all adult patients with potentially significant ingestions should be admitted for monitored observation in the hospital.
Loperamide (Imodium) is another insoluble meperidine analog that is used to treat diarrhea. This medication is available without a prescription, and the paucity of adverse patient outcomes reported in the medical literature suggests that the safety profile of this agent is good.