Dependence
GENERAL TERMINOLOGY:
Drug Addiction:
Drug addiction is a state of periodic or chronic intoxication detrimental to
the individual and to society, produced by repeated consumption of the
drug. The characteristics of addiction include:
1- An overpowering or compulsion desire or need to continue taking the
drug and to obtain it by any means.
2- Tolerance, a tendency to increase to dose. The higher doses are
required to achieve the same effects.
3- Psychic and physical dependence on the effect of the drug.
4- Withdrawal symptoms on abstinence from the drug.
Drug Habituation:
Drug habituation is a condition resulting from the repeated consumption of
drug and characterized by:
1- A desire, but not a compulsion, to continue taking the drug for the
sense of improved wellbeing.
2- Little or no tendency to increase the dose.
3- Some degree of psychic dependence on the effect of the drug, for the
sense of physical dependence and hence of withdrawal syndrome.
4- Detrimental effect on the individual.
Drug Dependence:
 Drug dependence has replaced the terminology of addiction and
habituation.
 Drug dependence is a state of physical or psychic dependence or both on
a drug, arising in a person following administration of that drug on a
periodic or continuous basis. There is a compulsion to continue taking
the drug in order to maintain its effects and to avoid withdrawal
symptoms. Tolerance may or may not be present.

Physical Dependence:
- It is a state that develops as a result of adaptation (tolerance) in
response to repeated drug use. The person requires continued
administration of the drug to maintain normal function and to
prevent withdrawal symptoms to occur if the drug is abruptly
stopped the degree of physical dependence may be judged by the
severity of the withdrawal symptoms.

Psychic Dependence:
- It refers to detrimental effects on the abusers and on the society due
to behavioral disturbances (sense of physical dependence).
Tolerance:
 Tolerance is the reduction in response to the drug after repeated
administration. Thus, a higher dose is required to produce the same
effect that was once obtained at a lower dose.
 For example, diazepam in a first-time user produces sedation at doses
of 5 to 10mg, but those who repeatedly use it to produce a kind mg
“high” may become tolerant to doses of several hundreds of mg, reach
in some abusers to 1000mg/day.
 Cross tolerance refers to the fact that repeated use of drugs in a given
category confers tolerance not only to the drug being but also to other
drugs in the same structural and mechanistic category. For example,
users of heroin also are tolerant to other narcotics.
 Mechanism of tolerance:
1- Pharmacokinetic or dispositional tolerance: it refers to changes in
the distribution or metabolism of the drug after its repeated
administration. The rate of drug metabolism is increased, reducing the
concentrations in the blood and at the site of drug action. For example,
barbiturates stimulate the production of higher levels of hepatic
microsomal enzymes, causing more rapid removal and breakdown of
barbiturates.
2Pharmacodynamic tolerance: it refers to adaptive changes that
have taken place within systems affected by the drug, so that response
to given concentration is reduced.
3Opiate receptor theory: the rate of metabolism of narcotics does
not increase with prolonged usage as barbiturates; an interesting
mechanism based on opiate receptor theory may explain the
phenomena of tolerance and withdrawal. The central nervous system
has stereospecific opiate receptors. As both exogenous and endogenous
(as encephalin) narcotics decrease sodium permeability in membranes
with opiate receptors, the use of narcotic agonists decreases the need
for encephalin secretion. As encephalin production and secretion
decreases more exogenous narcotic can be tolerated without excessive
adverse effects such as sedation and respiratory depression. Sudden
cessation of narcotic use does not allow enough time for resumption of
adequate encephalin production. This result in increased sodium
permeability with subsequent neuronal hyper-excitability, and
withdrawal symptomatology.
Withdrawal (abstinence) syndrome:
It refers to withdrawal signs and symptoms which occur when drug
administration in a physically dependent person is abruptly terminated.
Medical addict:
It is a term used to describe a patient who take medicine in correct dose
for appropriate medical indication, but may show tolerance, physical
dependence and withdrawal symptoms if the drug is stopped abruptly
rather than gradually.
Factors affecting drug dependence and abuse:
1- Factors related to the drug abused: availability, cost, purity, mode of
administration, and short drug half-life.
2- Factors related to the user: genetic factors, psychiatric symptoms
(depressed or stressed persons are more vulnerable to drug abuse), desire
for new pleasure, and speed for developing acquired tolerance.
3- Environmental factors: social setting, community and religion attitudes
(alcohol dependence is a major problem in Non-Moslem countries).
Dangerous of drug dependence:
1- Moral and psychic effects:
 Personal violence and murder: the need to obtain money to sustain
the habit may lead to squalor, theft and prostitution.
 The addict is careless, dishonest with loss of decency and selfrespect.
2- Physical effects:
a. Complications of infections:
 The repeated injection of drug damages the peripheral veins in the
arms, hands, and leg. Over use of the same veins leads to thrombosis
and phlebitis, as the injected substance is either irritative or
unsterile. The veins become dark in color under the skin, may be
hard and cord-like due to thrombosis and fibrosis and may even
ulcerate. When healed, there may be white or slivery linear scar.
 Skin abscesses.
 Fat necrosis and chronic myositis.
 Septicemia and sub-acute bacterial endocarditis.
b. Shared syringes: the use of shared syringes and needles between
groups of addicts can transmit hepatitis B and C, and HIV virus.
c. Micro-emboli in the lungs and liver: this occurs as solid drugs are
often dissolved in unsterile conditions in a spoon, sometimes by
crushing tablets. Fragments may be injected and lead to micro-emboli
in the lungs and liver, where they can form granulomas and even
abscesses.
d. Pulmonary tuberculosis and pneumonias: from reduced resistance
and poor nutrition.
e. Accidents: traffic, falls and fires, because of the impairment of
alertness and behavior, especially where hallucinogenic compounds
such as LSD are used.
f. Specific pathologic organ changes: differ according to each drug.
3- Withdrawal symptoms: when the drug administration in a physically
dependent person is abruptly terminated. Manifestations of withdrawal
differ from drug to drug.
4- Death from over-dosage and hypersensitivity:
 Deaths may occur very rapidly with the intravenous use of heroin. A firsttime user may collapse and die rapidly on their first injection, due to
hypersensitivity to the drug. The needle and syringe may still be in the vein
when the body is found. A habituated user may suddenly die, due to either
hypersensitivity had developed or the dose is over-strong.
 In all these situations, death seems due to acute left ventricular failure
and gross pulmonary edema.
The commonly used drugs of dependence are:
1- Opioids (Narcotics): morphine, heroin, codeine, methadone, tramadol,
etc.
2- Sedatives & Hypnotics: barbiturates & benzodiazepines.
3- Stimulants: amphetamine derivatives, cocaine, phencyclidine.
4- Hallucinogens: cannabis preparations, solvents, LSD, mescaline, etc.
5- Nicotine and tobacco preparations.
OPIOIDS (NARCOTICS)
Definition:
The term (opioids) or (narcotics) is an all-inclusive term for any endogenous
or exogenous substances that are capable of producing morphine-like
effects or binding to the opioid receptors.
Classification:
* Opioids may be classified according to source as:
I- Exogenous opioids (narcotic agonists):
a) Natural narcotics (opium derivatives): morphine, codeine
(methyl morphine).
- Opium is the brown dried juice exuded from the scarified wall of
the green unripe capsule of (Papaver somniferous) or poppy
plant. Opium contains more than 20 alkaloids such as:
- Hypnotic group as morphine and codeine.
- Convulsant group as papaverine, thebaine, and narcotine.
b) Semisynthetic marcotics: heroin (diacetylmorphine), hydromorphone,
oxymorphone, oxycodone.
c) Synthetic narcotics: meperidine (Demerol), diaphenoxylate, (lomotil),
methodone (dolophine), propoxyphene (darvon).
II- Endogenous opioids: they are the natural ligands at all opiate receptors
sites (central and peripheral nervous system, and gastrointestinal tract) and
include encephalin, endorphins and dynorphins.
* Opioids may be classified according to their effects in relation to
morphine as pure agonist, pure antagonist, or mixed agonistantagonist:
1- Pure narcotic agonists: morphine, heroin, codeine, etc…...
2- Pure narcotic antagonists: naloxone (narcan), naltrexone (trexan).
3- Mixed narcotic agonist-antagonists: Nalorphine (Nalline), Levalolorphan (Lorfan), and Nalbuphine (Nubain). These narcotics can be
used as antidotes in acute narcotic poisoning but should not be given
to addicts because of the danger of producing withdrawal symptoms,
or to normal persons because of the danger of producing morphinelike symptoms.
Pharmacokinetics:
 Most opioids are more effective when given parentally than orally:
opioids with good oral potency are codeine, oxycodone, and methadone.
 The metabolism of morphine, codeine, propoxyphene, oxycodone,
meperidine, and methadone is mostly hepatic. The hepatic metabolites
may be pharmacologically active and are excreted in the urine and feces.
 The biologic half-life of heroin is approximately 2.5 minutes; others
reports that it is 8-15 minutes. It is rapidly converted to biologically active
6-monoacetylmorphine (6-MM) in the liver, brain, kidney, and heart. 6MM is then slowly converted to morphine. Morphine is then conjugated
with glucuronic acid or excreted unchanged. Only morphine and 6-MM
are found in the urine of heroin addicts, which may also contain quinine
and other common adulterants of “street” heroin.
Therapeutic uses of opioids:
 Currently the widest clinical application of opioids is for acute or chronic
pain relief. Patients also may benefit from several of the non-analgesic
effects engendered by certain opioids. For example, codeine is widely used
as an antitussive agent and diphenoxylate as an anti-diarrheal drug.
 All opioids have similar effects, addiction potential, and cross-tolerance.
They vary in their analgesic potency, duration of action and extent of elicit
use. Heroin is a schedule I drug and can only be obtained illicitly; many
other narcotics are usually obtained from licit prescriptions.
 Prescriptions should be only in emergencies due to the risk of addiction.
The from includes: date, name, address of the doctor and the patient, and
should be filled in ink and signed by the doctor. The dose is written both in
figures and alphabets.
Mechanism of actions of opioids:
 Narcotics stimulate 3 centers:
 Vagal center resulting in slow pulse.
 Vomiting center leading to vomiting.
 Pupiloconstrictor center leading to meiosis.
● They depress the following centers:
 Sensory cortex leading to analgesia and euphoria which
are the important clinical effects of narcotic drugs.
 Cough center leading to suppression of cough i.e
antitussive.
 Heat regulating center leading to hypothermia.
 Respiratory center leading to central respiratory
depression.
Acute opioid poisoning:
● When used correctly for medical purposes, opioids are remarkably safe
and effective agents. However, acute toxicity may result from:
 Excessive therapeutic dosing.
 Suicidal attempts.
 Accidental overdosing in addicts.
● In general, patients poisoned by opioids agonists e.g. (morphine and
heroin) are at greater risk of death than are those exposed to antagonists
e.g. naloxone, or agonist-antagonists e.g. nalorphine.
● Determining that a patient is suffering from opioid toxicity is generally
more important that identifying the specific agent involved.
1.CNS:
 Mood changes, usually euphoria, but dysphoria may occur in painfree individuals or when synthetic narcotics are used.
 Altered mental status, from lethargy to coma, slurred speech and
ataxia.
2- Eyes: pinpoint fixed symmetrical pupils.
3- Respiratory system: hypoventilation, a characteristic smell in the breath
in case of opium, and respiratory depression (mechanism of death).
4- Cardiovascular system: orthostatic hypotension due to peripheral
vasodilatation, and bradycardia.
5- GIT: reduced bowel motility (constipation), nausea and vomiting.
6- Others: hypothermia with cold sweaty skin and cyanosis.
Diagnosis:
 History of exposure.
 Physical examination: the present of classic opioid toxidrome: CNS
depression, respiratory depression and meiosis.
 The response to naloxone.
 Chemical analysis.
Differential diagnosis:
 Pontine hemorrhage (state of coma with meiosis). In pontine
hemorrhage there are hyperpyrexia and quadriplegia.
 Other causes of toxic coma (alcohols, sedatives…).
Treatment:
1- Emergency stabilization of the ABCs…….
2- GIT decontamination: gastric lavage with activated charcoal and
cathartics.
3- Antidotal therapy: Naloxone (Narcan) or Nalmefene
- Administration of naloxone may be both diagnostic and therapeutic.
- The goal is to reverse respiratory depression without inducing
withdrawal (in addict patients with acute toxicity).
- Consequently, 0.05 mg is a practical starting dose in most patients,
increasing to 0.4 mg, then to 2 mg, to be repeated every 15 minutes
until reversal of coma and respiratory depression or reaching a dose of
10 mg. If there is no response to 10 mg, then an opioid is unlikely to be
responsible for the respiratory depression.
- Evaluation of the return of respiratory depression should be monitored
continuously and re-sedation should be treated with either repeated
doses of the antagonist or, if necessary, with another bolus followed by
a continuous infusion.
Chronic opioid poisoning (opioid dependence):
● Heroine is preferred by addicts because it is more euphoric less
nauseating, and les constipating. Opioids may be taken orally, by inhalation,
intradermal, IM or IV.
● There are several broad groups of Opioids abusers: street addict
(commonly adolescent or young adult, most complications of Opioids abuse
generally occur in this group), health professional and medical addicts
(those with narcotic dependency secondary to chronic illness).
1- Moral and psychic effects: the addict is careless, dishonest: he may commit
a crime or an assault to obtain the drug. He is sedated so long as he is under
the effect of the drug.
2- Physical effects:
● Lungs: aspiration and infectious pneumonia, septic pulmonary emboli,
non-cardiogenic pulmonary edema. Possible mechanisms include
anaphylaxis, hypoxia, and capillary injury secondary to street adulterants
(quinine, and tale which may cause granulomatous reactions in the lung
leading to chronic core pulmonale.
● CNS: transverse myelitis, post-anoxic encephalopathy, paraplegia,
hoarseness, cerebral edema, respiratory arrest.
● Skin: flushing, pruritus, cellulitis, abscesses, ulcers, scars, and needle tracks.
● Systemic infections: the use of shared syringes and needles between
groups of addicts can transmit tetanus, hepatitis, malaria tuberculosis,
AIDS.
● Musculoskeletal: Septic arthritis, osteomyelitis, rhabdomyolysis.
● Endocrine: amenorrhea, sterility.
● Eye: toxic amblyopia.
● Cardiovascular: bacterial endocarditis, vasculitis, lymphedema.
● Gastrointestinal tract: constipation, and fecal impaction simulating
acute intestinal obstruction.
● Genitourinary: urgency, retention, delayed ejaculation, decreased libido.
3- Withdrawal symptoms: onset of withdrawal symptoms is usually within
12 hours of last opioid usage. Classic opioid withdrawal includes:
1- Minor: mydriasis, yawning, rhinorrhea, diffuse myalgias and cramps,
lacrimation, diaphoresis, and anorexia.
2- Moderate: restlessness, craving, insomnia, elevated blood pressure,
tachycardia and tachypnea.
3- Major: vomiting, diarrhea, hyperactive bowel sounds hypotension.
Treatment:
- The addict should be hospitalized for months in a special institute.
- Abrupt withdrawal is very dangerous.
- Gradual withdrawal and substitution program should be used.
1- Clonidine (catapress): at a dose of 5 ug/kg per oral. It blocks the release
of norepinephrine.
2- Methadone (Doloprine) maintenance programs: it blocks the euphoric
effect of other opiates, and prevents withdrawal symptoms. A daily
dose of 40mg of methadone orally will prevent withdrawal symptoms
in a chronic addict; 80mg will prevent heroin-induced euphoria. The
methadone dose is then gradually reduced by 20% daily. If signs of
withdrawal appear, dose reduction should proceed more slowly.
3- Naltrexone (trexan): is used for the treatment of heroine addiction. It is
a competitive antagonist and had a longer half life than naloxone. It
can block the “high” euphoria of heroine at a dose of 50mg/24hours
for 10 days, then 100mg/72 hours for another 10 days.
4- Barbiturates and tranquilizers may be used as sedative.
5- Supportive care and treatment of physical complications.