Original Author: Bruce Alexander, Pharm.D, BCPP
Latest Reviser: Bruce Alexander, Pharm.D, BCPP
Creation Date: 1996
Peer Review Status: Internally Peer Reviewed
Addiction to the drugs of this group is characterized by the appearance of three interrelated phenomena. These are, tolerance - which refers to the diminution in the effect of the drug on repeated administration; physical dependence - which is defined as an altered psychological state brought about by repeated administration of a drug, which necessitates continued use of the drug to prevent the appearance of characteristic signs and symptoms, i.e., withdrawal; and habituation - which refers to compulsive use of the drug.
In the second quarter of 1980, heroin/morphine, methadone and d-propoxyphene were involved in 25%, 8.3%, and 8% respectively, of 911 drug overdose deaths (Drug Abuse Warning Network 1979). Overall, narcotic analgesic were involved in 520 (57%) of the 911 fatalities.
The total cost of opiate addiction in the United States was estimated in 1977 to exceed $5 billion per year, which excludes the cost of the destructive effect of criminality associated with drug abuse (Martin 1977). It is estimated there were 500,000 opiate addicts in the U.S. in the early 1970s, and that half of them were regularly using opiates at any one time. The average cost of drugs that an active addict uses per year is estimated to be $5,000 resulting in a total cost of $1.25 billion annually. Loss of productivity for those unemployed addicts also is estimated to be $1.25 billion. Because of the young age of addicts and the decrease in life expectancy the loss of productivity results in a cost of some $2.0 billion. The cost to the public of providing treatments to addicts is in the order of $0.5 billion per year.
WITHDRAWAL
Morphine and Heroin
Generally a severe abstinence syndrome occurs if an individual has received 250 mg of morphine or 80-120 mg of heroin per day for 18 to 20 days. A milder morphine abstinence syndrome may occur with lower morphine doses (30 mg) and shorter duration of use.
The abstinence syndrome is characterized by restlessness, lacrimation, rhinorrhea, yawning, perspiration, goose flesh ("cold turkey"), restless sleep and mydriasis during the first 24 hours (onset usually 8 to 12 hours after a reduction in dose or cessation of use). As the syndrome progresses, these symptoms become more severe and may be accompanied by twitching and spasms of muscles; kicking movements, severe aches in the back, abdomen, and legs; abdominal and muscle cramps; hot and cold flashes; insomnia; nausea, vomiting, and diarrhea; coryza and severe sneezing; and increases in body temperature, blood pressure, respiratory rate, and heart rate. These symptoms reach peak intensity in 36 to 72 hours following withdrawal of the drug or following the injection of a narcotic antagonist. Without treatment, the syndrome runs its course in 5 to 7 days, even though craving for the drug may continue for months (Fraser et al 1961).
Codeine
Codeine, as an analgesic, is 1/10 to 1/12 as potent as morphine.
Himmelsbach (1934) found doses of 240 to 600 mg of codeine were needed to substitute for 50 to 150 mg of morphine, given parenterally four times daily. When codeine was abruptly discontinued in these same patients, mild morphine-like abstinence symptoms occurred over the first 30 hours, followed by suddenly severe symptoms which continued until the fourth and fifth days, when recovery began. Fraser et al (1960) reported in direct addiction tests that the average daily dose of codeine attained by eight post-addicts within 18 days was about 1500 mg per day (range 1200 to 1800 mg). Nalorphine given after 30 to 45 days of drug administration precipitated mild to moderate abstinence, as did abrupt withdrawal at 60 days.
Oxycodone (dihydrohydroxycodeinone)
Oxycodone is a modified codeine compound that has an analgesic potency and duration of action similar to morphine (Pradhan and Dutta 1977).
Oxycodone is available in the U.S. only in combination with other analgesics. Percodan-Demi contains 4.5 mg of oxycodone and ASA 325 mg. Tylox capsules contain 4.88 oxycodone and 500 mg acetaminophen. Five mg oxycodone in combination with acetaminophen 325 mg is available as oxycodone HC1 and Acetaminophen Tablets (Phillips Roxane) and Percocet-5 tablets.
Addiction liability and the withdrawal syndrome of oxycodone are similar to those of morphine (Pradhan and Dutta 1977).
Dihydromorphinone (Dilaudid)
This compound is a semi-synthetic derivative of morphine, it is eight times as potent as morphine but its duration of action is somewhat shorter.
Withdrawal symptoms from dihydromorphinone, although qualitatively similar to morphine, are not usually as severe (Pradhan and Dutta 1977).
Pentazocine (Talwin)
Pentazocine is one of many compounds synthesized as part of an attempt to develop an effective analgesic with little or no abuse potential. It has both agonistic actions and weak opioid antagonistic activity. In terms of analgesic effect, a 30 to 50 mg dose given parenterally is approximately equal to 10 mg of morphine. In terms of peak effect pentazocine is approximately 1/4 as potent orally as parenterally.
Postaddicts given high doses spaced closely enough to produce continuous action (e.g., 60 to 90 mg every 4 hours) consistently develop physical dependence that can be demonstrated by abrupt withdrawal or precipitated by naloxone (Jasinski et al 1970). The withdrawal syndrome after chronic doses of more than 500 mg per day is similar in some respects to the characteristics of opioid withdrawal, though milder. The withdrawal symptoms include abdominal cramps, chills, elevated temperature, vomiting, sweating, lacrimation, anxiety, and drug-seeking behavior.
In contrast to morphine and other opioids, pentazocine does not prevent or ameliorate the morphine withdrawal syndrome. Instead, when high doses of pentazocine are given to subjects physically dependent on morphine, its antagonistic actions, although weak, precipitate withdrawal symptoms.
Oral pentazocine tablets were reformulated (Talwin NX) recently to contain the opiate antagonist, naloxone. In theory, if the tablet was dissolved and injected, the naloxone, which is not absorbed orally, would prevent any opiate effects. In addition, if the person was opiate-dependent, withdrawal would occur. Recent reports indicate the Talwin NX was still being abused (Lahmeyer and Craig 1987).
Meperidine (Demerol)
Meperidine is 1/8 to 1/10 as potent an analgesic as morphine and its duration of action extends from 2 to 4 hours (Pradhan and Dutta 1977).
The abstinence syndrome usually develops within 3 hours after the last dose, reaches its peak within 8 to 12 hours, and then declines. Symptoms that are worse than morphine withdrawal include muscle twitching, restlessness and nervousness, whereas, nausea, vomiting and diarrhea tend to be less severe (Isbell and White 1953).
Propoxyphene (Darvon)
It is estimated that 90 to 120 mg of propoxyphene orally is required to produce analgesia equal to that of 60 mg of codeine or 600 mg of aspirin.
Abrupt discontinuation of chronically administered propoxyphene (up to 800 mg per day given for almost 2 months) results in mild abstinence symptoms. Higher doses of propoxyphene are limited by confusion, delusions and hallucinations. Propoxyphene at 800 mg per day reduces the intensity of morphine withdrawal somewhat less effectively than do 1500 mg doses of codeine (Fraser and Isbell 1960).
Nalbuphine (Nubain)
Nalbuphine like pentazocine and butorphanol, has both agonist and antagonistic properties. It is equi-potent in analgesic effect to morphine and is available only in the injectable form.
Physical dependence on nalbuphine has been demonstrated in patients with a history of narcotic abuse. Doses of nalbuphine 147-240 mg/d were administered up to 51 days (Jasinski and Mansky 1972). Abrupt withdrawal of the drug after chronic administration was followed by an abstinence syndrome that was more intense than pentazocine abstinence.
Butorphanol (Stadol) (Vandam 1980)
Butorphanol, like pentazocine, has both agonist and antagonistic properties. It is about 3 to 7 times as potent as morphine and 40 times as potent as meperidine.
When butorphanol 48 mg daily (equivalent to 240 mg morphine) was given to former opioid addicts for 35 days, the subjects had the usual analgesic effects associated with opiates. Abrupt withdrawal of butorphanol resulted in similar effects at 24 hours as morphine and progressed in severity to a peak at 48 hours
Likewise, naloxone administration produced typical opioid withdrawal symptoms.
Methadone (Dolophine) (Martin and Jasinski 1973).
Methadone is qualitatively and quantitatively similar to morphine, except that its duration of action is longer upon repeated administration than morphine.
The abrupt withdrawal of methadone produces a syndrome that is qualitatively similar to morphine but it develops more slowly and is more prolonged, although usually less intense. Symptoms do not start until 24 to 48 hours after the last dose and peak in intensity about the third day. The symptoms may not decrease until the third week. This early abstinence syndrome is followed by a secondary or protracted abstinence syndrome of physiological and psychological disturbances that may last for months.
TREATMENT OF WITHDRAWAL
Methadone
Because opiate abusers give inconsistent and unreliable drug histories, opiate administration is warranted only after the initial appearance of the signs and symptoms of physical withdrawal. The appearance of the withdrawal syndrome insures that the user is indeed addicted and requires tapering with methadone. The severity of physical withdrawal symptoms is generally graded on a one to four scale as shown below on the following dosing schedule.
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Table 1. Severity rating for opiate withdrawal |
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Signs and Symptoms |
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Grade 1: Lacrimation, rhinorrheadiaphoresis, yawning, restlessness, and insomnia |
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Grade 2: Dilated pupils, pilorection, muscle twitching, myalgia, arthralgia, abdominal pain |
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Grade 3: Tachycardia, hypertension, tachypnea, fever, anorexia, nausea, extreme restlessness |
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Grade 4: Diarrhea, vomiting, dehydration, hyperglycemia, hypotension |
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The initial methadone dose is determined by the presenting signs and symptoms. Supplementary doses of 5 to 10 mg of methadone are provided if withdrawal signs either are not suppressed or reappear during the first 24 hours. Once the initial 24-hour dose is established, the dose is tapered at a rate of 20% per day or every other day. The methadone is given on a bid or tid dosage schedule with the nursing staff taking vitals prior to each dose. It is unusual for a patient to require more than 40 mg during the initial 24 hours of withdrawal (Khantzian and McKenna 1979).
If the patient is initially unable to tolerate oral medications, 10 mg of methadone IM should be given and followed as soon as possible with the initial oral dose of methadone as calculated from the presenting withdrawal grade.
Clonidine
Clonidine is an alpha-2 adrenergic agonist indicated for the treatment of hypertension (Pettinger 1975). The mechanism of antihypertensive activity is central stimulation of post-synaptic adrenergic receptors (Schmitt and Schmitt 1969, VanZwieten 1973). These receptors mediate inhibition of efferent sympathetic outflow resulting in a decreased sympathetic stimulation of the heart, kidneys, and peripheral vasculature. Removal of clonidine-induced blockade of sympathetic outflow allows for increased catecholamine secretion which is reflected by increased catecholamine secretion which is reflected by increases in urinary norepinephrine and epinephrine levels (Hunyor 1973).
Investigators utilizing radioactive isotopes have identified the locus coeruleus (LC) as an area with a high density of opiate receptors. The LC is a nucleus in the anterior pons consisting exclusively of norepinephrine containing cells and serves as a brain alarm modulator which may be essential to human emotions and behaviors.
Morphine depresses spontaneous and electrical or pharmacological stimulation of LC cells, but tolerance does develop to this depression (Korf et al 1974). The application of naloxone, an opiate antagonist, to the LC or systemic administration to an opiate-dependent animal results in an increased rate of firing of the LC neurons similar to the increase that has been associated with stress. Drugs which deplete central stores of norepinephrine, such as alpha-methyl-p-tyrosine, suppresses characteristic abstinence symptoms that occur in an opiate-dependent animal when opiate are withdrawn or an opiate antagonist is administered (Strombon and Svenson 1978). These findings support the theory that manifestation of opiate withdrawal depends on adequate stores of central norepinephrine.
Clonidine, like morphine, blocks the spontaneous or stimulated firing of the LC (Aghajanian 1978, Gold et al 1978). When clonidine is administered to a dependent animal that is exhibiting signs of withdrawal the signs of withdrawal are decreased and the increased activity in the LC is inhibited. When piperoxane, an alpha-2 blocking agent, is administered to non-opiate-dependent animals it accelerates the firing of the LC neurons and precipitates signs similar to those associated with abstinence. Piperoxane also reverse the clonidine inhibition of withdrawal symptoms in dependent animals, similar to the actions of naloxone on morphine-induced inhibition (Aghajanian 1978). On the basis of these findings, it has been concluded that the LC contains both opiate and noradrenergic receptors and that clonidine and morphine have similar, but independent, depressant effects on the LC (Aghajanian 1978).
In 1978 Gold et al reported clonidine could suppress symptoms of opiate withdrawal in 10 methadone dependent patients whose medication was abruptly discontinued. Gold et al (1978, 1979, 1979) reports success in controlled and uncontrolled trials. The studies report clonidine eliminates objective signs of withdrawal but in the doses used it does not completely suppress subjective withdrawal complaints, like anxiety, restlessness, insomnia, and muscle aches.
The opiate withdrawal schedule described by Gold et al (1979) utilizing clonidine, which is available as 0.1 and 0.2 mg tablets, required an average dose of 17 ug/kg/day. However, 25 ug/kg/day has been used to prevent methadone withdrawal symptoms in another study (Gold et al 1978). On the first day of clonidine administration, the patient is given a 6 ug/kg dose, which is repeated at bedtime (Gold et al 1979). For the next ten days, the patient is given 17 ug/kg of clonidine in divided doses of 7 ug/kg at 0800, 3 ug/kg at 1600, and 7 ug/kg at 2300. Clonidine doses should be held if the diastolic BP is below 60 mm Hg or marked sedation occurs. Sedation is noted to improve over 2 to 3 days. On days 11-14 the clonidine dose should be decreased by 50% and on day 15 discontinued.
The experience with the opiate user in Iowa suggests that clonidine doses used in the Gold studies is not tolerated because of hypotension and sedation. This is probably due to less tolerance to opiates. Recommended starting doses for our population is 3 ug/kg and typical daily doses do not exceed 10 ug/kg, divided into three doses.
Clonidine/naltrexone combination
Recent studies indicate combined use of the oral opiate antagonist, naltrexone, and clonidine can reduce the withdrawal protocol for methadone dependence to 4-5 days or in recent studies involving heroin to <3 days (Brewer et al 1988, Charney et al 1986, Kleber et al 1987). This study protocol is not currently recommended for routine clinical practice.
TREATMENT OF OPIATE OVERDOSE (Rumack 1980)
An acute overdose of any of the opiates or their derivates can result in coma, pulmonary edema, and cessation of respiration. The depth of coma and respiratory depression are inversely related to the patient's level of tolerance. Although, classically, pinpoint pupils are observed, the pupils may be dilated in overdoses when accompanied by severe acidosis, hypoxia, hypotension, bradycardia, respiratory depression, postictal states, or, most commonly, in cases of mixed overdose. Other signs and symptoms that may occur include urinary retention, muscle spasm, itching, leukocytosis, hyperpyrexia, hyperamylasemia, and a serological false positive test for syphilis. Since most of the opiate- like drugs slow gastric emptying, the revival of a patient may reinstitute peristalsis and result in further absorption of unabsorbed drug. Thus, the patient can lapse back into coma and thus cyclical coma can be observed in oral overdoses. Methadone overdoses can result in 24- to 48-hour periods of respiratory depression because of the long half-life of this drug. Chronic IV abusers often present with the telltale signs and symptoms of abscesses, acute transverse myelitis, anaphylaxis, arrhythmias, cellulitis, endocarditis, fecal impaction, glomerulonephritis, hyperglycemia or hypoglycemia, myoglobinuria, osteomyelitis, postanoxic encephalopathy, rhambdomyolysis, tetanus, and thrombophlebitis.
Following a single acute overdose, a narcotic antagonist is the treatment of choice. Naloxone (Narcan), a pure antagonist with no respiratory depressant effects, is capable of reversing all opiate overdoses. Being a pure antagonist, it is the drug of choice in mixed or unknown overdoses because it can be of diagnostic and therapeutic value simultaneously without harming the patient. The dose is 0.005 mg/kg IV with the adult dose ranging from 0.4 to 0.8 mg per IV dose. If an IV injection site is not available, it may be given IM, SQ, or sublingually with only a slightly slower absorption rate. Dose may require repeating every 20 to 60 minutes. The drug seems relatively safe in that IV doses of 24 mg and oral doses of 3 g have been taken without any ill effects. There is now data that suggest higher doses of naloxone may be required to treat codeine, propoxyphene, and pentazocine overdoses. If the initially recommended dose fails, a second dose of 2 to 4 mg, i.e., 5 to 10 ampoules, is given by IV push. Children should be given a minimum dose of 0.1 mg by IV push. Failure to respond to these high doses indicates the presence of a mixed overdose or a nonopiate-poisoned patient.
Nalorphine (Nalline), an agonist-antagonist drug formerly used in over- doses, can cause respiratory depression and therefore is now obsolete with the availability of naloxone.
Despite the rapid improvement produced by naloxone following an acute overdose, it is recommended that the patient be observed and supported for 24 to 48 hours.
Note: Opiate withdrawal can be precipitated in persons addicted to narcotics through treatment with narcotic antagonists if large doses are used.
Gastrointestinal Tract
Respiratory System
Ten mg of methadone has been lethal in a child. The quality of street opiates varies widely enough that accidental overdose often occurs because of a lack of quality control. In overdoses, heroin's presence in the blood and urine is detectable for about 36 hours.
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