Methadone - Methadone Detox

Methadone, sold under the brand names Dolophine among others, is an opioid used to treat pain and as maintenance therapy or to help with detoxification in people with opioid dependence. Detoxification using methadone can either be done relatively rapidly in less than a month or gradually over as long as six months. While a single dose has a rapid effect, maximum effect can take five days of use. The effects last about six hours after a single dose and a day and a half after long-term use in people with normal liver function. Methadone is usually taken by mouth and rarely by injection into a muscle or vein.

Side effects are similar to those of other opioids. Commonly these include dizziness, sleepiness, vomiting, and sweating. Serious risks include opioid abuse or a decreased effort to breathe. Abnormal heart rhythms may also occur including prolonged QT. The number of deaths in the United States involving methadone poisoning was 4,418 in 2011, which was 26% of total deaths from opioid poisoning. Risks are greater with higher doses. Methadone is made by chemical synthesis and acts on opioid receptors.

Methadone was developed in Germany around 1937 to 1939 by Gustav Ehrhart and Max Bockmühl. It was approved for use in the United States in 1947. Methadone is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system. Globally in 2013, about 41,400 kilograms were manufactured. It is regulated similarly to other narcotic drugs. In the United States it is not very expensive.

Medical uses

Methadone maintenance

Methadone is indicated for the maintenance treatment of opioid dependency (i.e. opioid use disorder per the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM)). A 2009 Cochrane review found that methadone was effective in retaining people in treatment and in the suppression of heroin use as measured by self-report and urine/hair analysis but did not affect criminal activity or risk of death.

The treatment of opiate-dependent persons with methadone will follow one of two routes. MMT (methadone maintenance therapy) is prescribed to individuals who wish to abstain from illicit drug use but have failed to maintain abstinence from opiates for significant periods. The duration of methadone maintenance ranges from a few months to lifetime maintenance. Methadone reduction programs are suitable for addicted persons who wish to stop using drugs altogether. The length of the reduction program will depend on the starting dose and speed of reduction, this varies from clinic to clinic and from person to person. In addition, enrollment in methadone maintenance has the potential to reduce the transmission of infectious diseases associated with opiate injection, such as hepatitis and HIV. The principal effects of methadone maintenance are to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with opiates, however methadone abuse can c ause the very opposite of what its original intention is. When used correctly, methadone maintenance has been found to be medically safe and non-sedating, and provide a slow recovery from opiate addiction It is also indicated for pregnant women addicted to opiates.

In Russia, methadone treatment is illegal. Gennadiy Onishchenko, Chief Sanitary Inspector, claimed in 2008 that health officials are not convinced of the treatment's efficacy. Instead, doctors encourage immediate cessation of drug use, rather than the gradual process that methadone substitution therapy entails. Patients are often given sedatives and non-opiate analgesics to cope with withdrawal symptoms.

Pain

In recent years, methadone has gained popularity among physicians for the treatment of other medical problems, such as an analgesic in chronic pain. Methadone is a very effective pain medication. Due to its activity at the NMDA receptor, it may be more effective against neuropathic pain; for the same reason, tolerance to the analgesic effects may be lesser compared to other opioids. The increased usage comes as doctors search for an opioid drug that can be dosed less frequently than shorter-acting drugs like morphine or hydrocodone. Another factor in the increased usage is the low cost of methadone.

On 29 November 2006, the U.S. Food and Drug Administration issued a Public Health Advisory about methadone titled "Methadone Use for Pain Control May Result in Death and Life-Threatening Changes in Breathing and Heart Beat". The advisory went on to say that "the FDA has received reports of death and life-threatening side effects in patients taking methadone. These deaths and life-threatening side effects have occurred in patients newly starting methadone for pain control and in patients who have switched to methadone after being treated for pain with other strong narcotic pain relievers. Methadone can cause slow or shallow breathing and dangerous changes in heart beat that may not be felt by the patient." The advisory urged that physicians use caution when prescribing methadone to patients who are not used to the drug and that patients take the drug exactly as directed.

Patients with long-term pain will sometimes have to perform so-called opioid rotation. What this means is switching from one opioid to another, usually at intervals of between a few weeks, or more commonly, several months. Opioid rotation may allow a lower equivalent dose, and hence fewer side effects may be encountered to achieve the desired effect. Then, over time, tolerance increases with the new opioid, requiring higher doses. This, in turn, increases the possibility of adverse reactions and toxicity. So then it is time to rotate again to another opioid. Such opioid rotation is standard practice for managing patients with tolerance development. Usually when doing opioid rotation, one cannot go down to a completely naive dose, because there is cross-tolerance carried over to the new opioid. However, methadone has a lower cross-tolerance when switching to it from other opioids, than other opioids. This means that methadone can start at a comparatively lower dose than othe r opiates, and the time for the next switch will be longer.

Opioid detoxification

Methadone is also approved in the US for detoxification treatment of opioid addiction; however, its use in this regard must follow strict federal regulations. Outpatient treatment programs must be certified by the Federal Substance Abuse and Mental Health Services Administration (SAMHSA) and registered by the Drug Enforcement Administration (DEA) in order to prescribe methadone for opioid detoxification.

Adverse effects

Adverse effects of methadone include:

• Sedation
• Diarrhea or constipation
• Flushing
• Perspiration and sweating
• Heat intolerance
• Dizziness or fainting
• Weakness
• Chronic fatigue, sleepiness and exhaustion
• Sleep problems such as drowsiness, trouble falling asleep (Insomnia), and trouble staying asleep
• Constricted pupils
• Dry mouth
• Nausea and vomiting
• Low blood pressure
• Hallucinations or confusion
• Headache
• Heart problems such as chest pain or fast/pounding heartbeat
• Abnormal heart rhythms
• Respiratory problems such as trouble breathing, slow or shallow breathing (hypoventilation), light-headedness, or fainting
• Loss of appetite, and in extreme cases Anorexia
• Weight gain
• Memory loss
• Stomach pains
• Itching
• Difficulty urinating
• Swelling of the hands, arms, feet, and legs
• Feeling restless or agitated
• Mood changes Euphoria, disorientation
• Nervousness or anxiety
• Blurred vision
• Decreased libido, missed menstrual periods, difficulty in reaching orgasm, and impotence
• Skin rash
• Seizures
• Central sleep apnea

Withdrawal symptoms

Physical symptoms

• Lightheadedness
• Tearing of the eyes
• Mydriasis (dilated pupils)
• Photophobia (sensitivity to light)
• Hyperventilation syndrome (breathing that is too fast/deep)
• Runny nose
• Yawning
• Sneezing
• Nausea, vomiting, and diarrhea
• Fever
• Sweating
• Chills
• Tremors
• Akathisia (restlessness)
• Tachycardia (fast heartbeat)
• Aches and pains, often in the joints and/or legs
• Elevated pain sensitivity
• Blood pressure that is too high (hypertension, may cause stroke)

Cognitive symptoms

• Suicidal ideation
• Susceptibility to cravings
• Depression
• Spontaneous orgasm
• Prolonged insomnia
• Delirium
• Auditory hallucinations
• Visual hallucinations
• Increased perception of odors (olfaction), real or imagined
• Marked decrease or increase in sex drive
• Agitation
• Anxiety
• Panic disorder
• Nervousness
• Paranoia
• Delusions
• Apathy
• Anorexia (symptom)

Withdrawal symptoms are significantly more prolonged but also less intense than withdrawal from opiates with shorter half-lives.

When detoxing at a recommended rate (typically 1â€"2 mg per week), withdrawal is either minimal or nonexistent, as the patient's body has time to adjust to each reduction in dose.

Methadone is sometimes administered in an oral form of sugary syrup. This preparation has been proposed to cause significant tooth decay. Methadone causes dry mouth, reducing the protective role of saliva in preventing decay. It is known that most opiates increase craving for carbohydrates. General decrease in personal hygiene due to these factors combined with sedation have been noted to cause extensive damage to the teeth.

Overdose

Most people who have overdosed on methadone may show some of the following symptoms:

• Miosis (constricted pupils)
• Hypoventilation (breathing that is too slow/shallow)
• Drowsiness Sleepiness, disorientation, sedation, unresponsiveness
• Skin that is cool, clammy, and pale
• Limp muscles, trouble staying awake, nausea.
• Unconsciousness and coma
• Excessive vomiting

The respiratory depression of an overdose can be treated with naloxone. Naloxone is preferred to the newer, longer acting antagonist naltrexone. Despite methadone's much longer duration of action compared to either heroin and other shorter-acting agonists, and the need for repeat doses of the antagonist naloxone, it is still used for overdose therapy. As naltrexone has a longer half-life, it is more difficult to titrate. If too large a dose of the opioid antagonist is given to a dependent patient, it will result in withdrawal symptoms (possibly severe). When using naloxone, the naloxone will be quickly eliminated and the withdrawal will be short lived. Doses of naltrexone take longer to be eliminated from the patient's system. A common problem in treating methadone overdoses is that, given the short action of naloxone (versus the extremely longer-acting methadone), a dosage of naloxone given to a methadone-overdosed patient will initially work to bring the patient out of over dose, but once the naloxone wears off, if no further naloxone is administered, the patient can go right back into overdose (based upon time and dosage of the methadone ingested).

Tolerance and dependence

As with other opioid medications, tolerance and dependence usually develop with repeated doses. There is some clinical evidence that tolerance to analgesia is less with methadone compared to other opioids; this may be due to its activity at the NMDA receptor. Tolerance to the different physiological effects of methadone varies; tolerance to analgesic properties may or may not develop quickly, but tolerance to euphoria usually develops rapidly, whereas tolerance to constipation, sedation, and respiratory depression develops slowly (if ever).

Driving

Methadone treatment may impair driving ability. Drug abuse patients had significantly more involvement in serious crashes than non-abuse patients in a study by the University of Queensland. In the study of a group of 220 drug abuse patients, most of them poly-drug abusers, 17 were involved in crashes killing people, compared with a control group of other patients randomly selected having no involvement in fatal crashes. However, there have been multiple studies verifying the ability of methadone maintenance patients to drive. In the UK, persons who are prescribed oral Methadone can continue to drive after they have satisfactorily completed an independent medical examination which will include a urine screen for drugs. The licence will be issued for 12 months at a time and even then, only following a favourable assessment from their own doctor. Individuals who are prescribed methadone for either IV or IM administration cannot drive in the UK, mainly due to the increased sedation ef fects that this route of use can cause.

Mortality

In the United States, deaths linked to methadone more than quadrupled in the five-year period between 1999 and 2004. According to the U.S. National Center for Health Statistics, as well as a 2006 series in the Charleston (West Virginia) Gazette, medical examiners listed methadone as contributing to 3,849 deaths in 2004. That number was up from 790 in 1999. Approximately 82 percent of those deaths were listed as accidental, and most deaths involved combinations of methadone with other drugs (especially benzodiazepines).

Although deaths from methadone are on the rise, methadone-associated deaths are not being caused primarily by methadone intended for methadone treatment programs, according to a panel of experts convened by the Substance Abuse and Mental Health Services Administration, which released a report titled "Methadone-Associated Mortality, Report of a National Assessment". The consensus report concludes that "although the data remain incomplete, National Assessment meeting participants concurred that methadone tablets and/or diskettes distributed through channels other than opioid treatment programs most likely are the central factors in methadone-associated mortality."

In 2006, the U.S. Food and Drug Administration issued a caution about methadone, titled “Methadone Use for Pain Control May Result in Death.” The FDA also revised the drug's package insert. The change deleted previous information about the usual adult dosage. The Charleston Gazette reported, "The old language about the 'usual adult dose' was potentially deadly, according to pain specialists."

Detection in biological fluids

Methadone and its major metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), are often measured in urine as part of a drug abuse testing program, in plasma or serum to confirm a diagnosis of poisoning in hospitalized victims, or in whole blood to assist in a forensic investigation of a traffic or other criminal violation or a case of sudden death. Methadone usage history is considered in interpreting the results as a chronic user can develop tolerance to doses that would incapacitate an opioid-naive individual. Chronic users often have high methadone and EDDP baseline values.

Pharmacology

Methadone acts by binding to the µ-opioid receptor, but also has some affinity for the NMDA ionotropic glutamate receptor. Methadone is metabolized by CYP3A4, CYP2B6, CYP2D6 and is a substrate for the P-Glycoprotein efflux protein in intestine and brain. The bioavailability and elimination half-life of methadone is subject to substantial inter-individual variability. Its main route of administration is oral. Adverse effects include sedation, hypoventilation, constipation and miosis, in addition to tolerance, dependence and withdrawal difficulties. The withdrawal period can be much more prolonged than with other opiates, spanning anywhere from two weeks to several months. Many factors contribute to its metabolism and excretion rate including the individual's body weight, history of use/abuse, metabolic dysfunctions, renal system dysfunction, among others.

In the early 1950s, methadone (most times the racemic HCl salts mixture) was also investigated for use as an antitussive.

From this research came a generally non-controlledâ€"or controlled for having the same precursors and effects of strong pure agonist agents of the open chain type, this one a phenaloxam derivative, levopropoxyphene with optical isomerism and one of which appeared to have no narcotic properties but was an antitussive which did have dissociative effects if misused; the isomer form which is removed from the racemic salts to yield dextromethorphan, or remove the other isomer to purify a dextropropoxyphene, or left in to finish with a racemic salts mixture dimethorphan. The open chain opioids tend to have at least one isomer that is at some level a strong pure mu opioid receptor agent.

Isomethadone, noracymethadol, LAAM, and normethadone were first developed in Germany, United Kingdom, Belgium, Austria, Canada, and/or the United States in the thirty or so years after the 1937 discovery of pethidine, the first synthetic opioid used in medicine, prolonging and increasing length and depth of satiating any opiate cravings and generating very strong analgesia (the long metabolic half-life and the strong receptor affinity at the mu opioid receptor sites, therefore imparting much of the satiating and anti-addictive effects of methadone (by means of suppressing drugs cravings and the discovery in the early 1950s of methadone's antitussive properties first tested in dogs in Europe in 1952-1955 with different inert placebos, active placebos like codeine.

Mechanism of action

Levomethadone is a full µ-opioid agonist. Dextromethadone does not affect opioid receptors but binds to the glutamatergic NMDA (N-methyl-D-aspartate) receptor, and thus acts as a receptor antagonist against glutamate. Methadone has been shown to reduce neuropathic pain in rat models, primarily through NMDA antagonism. Glutamate is the primary excitatory neurotransmitter in the CNS. NMDA receptors have a very important role in modulating long-term excitation and memory formation. NMDA antagonists such as dextromethorphan (DXM), ketamine (a dissociative anaesthetic, also M.O.A+.), tiletamine (a veterinary anaesthetic) and ibogaine (from the African tree Tabernanthe iboga, also M.O.A+.) are being studied for their role in decreasing the development of tolerance to opioids and as possible for eliminating addiction/tolerance/withdrawal, possibly by disrupting memory circuitry. Acting as an NMDA antagonist may be one mechanism by which methadone decreases craving for opioids and tolera nce, and has been proposed as a possible mechanism for its distinguished efficacy regarding the treatment of neuropathic pain. The dextrorotary form (d-methadone) acts as an NMDA antagonist and is devoid of opioid activity: it has been shown to produce analgesia in experimental models of chronic pain. Methadone also acted as a potent, noncompetitive α₃β₄ neuronal nicotinic acetylcholine receptor antagonist in rat receptors, expressed in human embryonic kidney cell lines.

Metabolism

Methadone has a slow metabolism and very high fat solubility, making it longer lasting than morphine-based drugs. Methadone has a typical elimination half-life of 15 to 60 hours with a mean of around 22. However, metabolism rates vary greatly between individuals, up to a factor of 100, ranging from as few as 4 hours to as many as 130 hours, or even 190 hours. This variability is apparently due to genetic variability in the production of the associated cytochrome enzymes CYP3A4, CYP2B6 and CYP2D6. Many substances can also induce, inhibit or compete with these enzymes further affecting (sometimes dangerously) methadone half-life. A longer half-life frequently allows for administration only once a day in Opioid detoxification and maintenance programs. Patients who metabolize methadone rapidly, on the other hand, may require twice daily dosing to obtain sufficient symptom alleviation while avoiding excessive peaks and troughs in their blood concentrations and associated effects. This can also allow lower total doses in some such patients. The analgesic activity is shorter than the pharmacological half-life; dosing for pain control usually requires multiple doses per day.

The main metabolic pathway involves N-demethylation by CYP3A4 in the liver and intestine to give 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). This inactive product, as well as the inactive 2-ethyl-5-methyl-3,3- diphenyl-1-pyrroline (EMDP), produced by a second N-demethylation, are detectable in the urine of those taking methadone.

• Methadone and its two main metabolites

Route of administration

The most common route of administration at a methadone clinic is in a racemic oral solution, though in Germany, only the R enantiomer (the L optical isomer) has traditionally been used, as it is responsible for most of the desired opioid effects. The single-isomer form is becoming less common due to the higher production costs.

Methadone is available in traditional pill, sublingual tablet, and two different formulations designed for the patient to drink. Drinkable forms include ready-to-dispense liquid (sold in the United States as Methadose), and "Diskets" which are tablets designed to disperse themselves rapidly in water for oral administration, used in a similar fashion to Alka-Seltzer. The liquid form is the most common as it allows for smaller dose changes. Methadone is almost as effective when administered orally as by injection. In fact, injection of methadone does not result in a "rush" as with some other strong opioids such as morphine or hydromorphone, because its extraordinarily high volume of distribution causes it to diffuse into other tissues in the body, particularly fatty tissue; the peak concentration in the blood is achieved at roughly the same time, whether the drug is injected or ingested. Oral medication is usually preferable because it offers safety, simplicity and represents a step away from injection-based drug abuse in those recovering from addiction. U.S. federal regulations require the oral form in addiction treatment programs. Injecting Methadone pills can cause collapsed veins, bruising, swelling, and possibly other harmful effects. Methadone pills often contain talc that, when injected, produces a swarm of tiny solid particles in the blood, causing numerous minor blood clots. These particles cannot be filtered out before injection, and will accumulate in the body over time, especially in the lungs and eyes, producing various complications such as pulmonary hypertension, an irreversible and progressive disease. The formulation sold under the brand name Methadose (flavoured liquid suspension for oral dosing, commonly used for maintenance purposes) should not be injected either. While it has been done in extremely diluted concentrations, instances of cardiac arrest have been reported, as well as damaged veins from sugars (even sugar-free syrups may cause this damage due to the presence of similarly-damaging artificial sweeteners). Oral medication also offers safety, simplicity and represents a step away from injection-based drug abuse in those recovering from addiction. U.S. federal regulations require the oral form in addiction treatment programs.

Patient information leaflets included in packs of UK methadone tablets state that the tablets are for oral use only and that use by any other route can cause serious harm. In addition to this warning, additives have now been included into the tablets formulation to make the use of them by the IV route more difficult.

History

Methadone was developed in 1937 in Germany by scientists working for I.G. Farbenindustrie AG at the Farbwerke Hoechst who were looking for a synthetic opioid that could be created with readily available precursors, to solve Germany's opium shortage problem. On September 11, 1941 Bockmühl and Ehrhart filed an application for a patent for a synthetic substance they called Hoechst 10820 or Polamidon (a name still in regular use in Germany) and whose structure had only slight relation to morphine or the opiate alkaloids. Bockmühl and Ehrhart, 1949 It brought to market in 1943 and was widely used by the German army during WWII.

In the 1930s, meperidine went into production in Germany; however, production of methadone, then being developed under the designation Hoechst 10820, was not carried forward because of side effects discovered in the early research. After the war, all German patents, trade names and research records were requisitioned and expropriated by the Allies. The records on the research work of the I.G. Farbenkonzern at the Farbwerke Hoechst were confiscated by the U.S. Department of Commerce Intelligence, investigated by a Technical Industrial Committee of the U.S. Department of State and then brought to the US. The report published by the committee noted that while methadone was potentially addictive, it produced less sedation and respiratory depression than morphine and was thus interesting as a commercial drug.

It was only in 1947 that the drug was given the generic name “methadone” by the Council on Pharmacy and Chemistry of the American Medical Association. Since the patent rights of the I.G. Farbenkonzern and Farbwerke Hoechst were no longer protected each pharmaceutical company interested in the formula could buy the rights for the commercial production of methadone for just one dollar (MOLL 1990).

Methadone was introduced into the United States in 1947 by Eli Lilly and Company as an analgesic under the trade name Dolophine, which is now registered to Roxane Laboratories. Since then, it has been best known for its use in treating opioid dependence. A great deal of anecdotal evidence was available "on the street" that methadone might prove effective in treating heroin withdrawal and is not uncommonly used in hospitals and other de-addiction centers to enhance rates of completed opioid withdrawal. It was not until studies performed at the Rockefeller University in New York City by Professor Vincent Dole, along with Marie Nyswander and Mary Jeanne Kreek, that methadone was systematically studied as a potential substitution therapy. Their studies introduced a sweeping change in the notion that drug addiction was not necessarily a simple character flaw, but rather a disorder to be treated in the same way as other diseases. To date, methadone maintenance therapy has been the most systematically studied and most successful, and most politically polarizing, of any pharmacotherapy for the treatment of drug addiction patients.

Methadone was first manufactured in the USA by Eli Lilly, who obtained FDA approval on August 14, 1947, for their Dolophine 5 mg and 10 mg Tablets. Mallinckrodt Pharmaceuticals did not receive approval until December 15, 1947 to manufacture their bulk compounding powder. Mallinckrodt received approval for their branded generic, Methadose, on April 15, 1993 for their 5 mg and 10 mg Methadose Tablets. Mallinckrodt who also makes 5 mg, 10 mg and 40 mg generic tablets in addition to their branded generic Methadose received approval for their plain generic tablets on April 27, 2004.

The trade name Dolophine was created by Eli Lilly after World War II and used in the United States; the claim that Nazi leader Adolf Hitler ordered the manufacture of methadone and/or that the brand name Dolophine was bestowed in honor of Hitler is an urban legend. The pejorative term "adolphine" (never an actual name of the drug) appeared in the United States in the early 1970s as a reference to the aforementioned urban myth that the trade name Dolophine was a reference to Adolf Hitler.

Society and culture

Brand names

Brand names include Dolophine, Symoron, Amidone, Methadose, Physeptone, and Heptadon among others.

Cost

Methadone maintenance treatment

Methadone maintenance clinics in the US charge anywhere from $5 to $400 per week, which may be covered by private insurance or Medicaid.

In Germany, methadone maintenance treatment (MMT) is fully covered by all public and private insurance plans. The annual cost per person is less than 3000 euros, while heroin-assisted treatment costs up to 10,000 euros per year.

MMT cost analyses often compare the cost of clinic visits versus the overall societal costs of illicit opioid use.

As of 2015 China had the largest methadone maintenance treatment program with over 250,000 people in over 650 clinics in 27 provinces.

Medication

In the US, generic methadone tablets are not very expensive. The retail price ranges between $0.25 and $2.50 per defined daily dose. Brand-name methadone tablets may cost much more.

Controversy

Methadone substitution as a treatment of opiate addiction has been widely criticized in the social sciences for its role in social control of addicts. It is suggested that methadone does not function as much to curb addiction as to redirect it and maintain dependency on authorised channels. Several authors apply a Foucauldian analysis to the widespread prescription of the drug and use in institutions such as prisons, hospitals and rehabilitation centres. Such critique centers on the notion that substance addiction is reframed with a disease model. Thus methadone, which mimics the effects of opioids and renders the addict compliant, is labeled as a “treatment” and so obscures the disciplinary objectives of “managing undesirables”.

Regulation

Methadone is a Schedule II controlled substance in the United States, with an ACSCN of 9250 and a 2014 annual aggregate manufacturing quota of 31 875 kilos for sale. Methadone intermediate is also controlled, under ACSCN 9226 also under Schedule II, with a quota of 38 875 kilos. The salts of methadone in use are the hydrobromide (free base conversion ratio 0.793), hydrochloride (0.894), and HCl monohydrate (0.850). Methadone is also regulated internationally as a Schedule I controlled substance under the United Nations Single Convention on Narcotic Drugs of 1961.

References

External links

• ONDCP Fact Sheet
• DHHS, Centers for Disease Control and Prevention (CDC)
• Tapering off of methadone maintenance
• BEST PRACTICES: Methadone Maintenance Treatment* Fraser, Suzanne; valentine, kylie (2008). Substance and Substitution: Methadone subjects in liberal societies (1st ed.). Basingstoke: Palgrave Macmillan. p. 216. ISBN 9780230019980.