Opioids
| 1. NAME |
| 1.1 Substance |
| 1.2 Group |
| 1.3 Synonyms |
| 1.4 Identification numbers |
| 1.4.1 CAS number |
| 1.4.2 Other numbers |
| 1.5 Main brand names, main trade names |
| 1.6 Main manufacturers, main importers |
| 2. SUMMARY |
| 2.1 Main risks and target organs |
| 2.2 Summary of clinical effects |
| 2.3 Diagnosis |
| 2.4 First aid measures and management principles |
| 3. PHYSICOCHEMICAL PROPERTIES |
| 3.1 Origin of the substance |
| 3.2 Chemical structure |
| 3.3 Physical properties |
| 3.3.1 Colour |
| 3.3.2 State/form |
| 3.3.3 Description |
| 3.4 Other characteristics |
| 3.4.1 Shelf-life of the substance |
| 3.4.2 Storage conditions |
| 4. USES |
| 4.1 Indications |
| 4.1.1 Indications |
| 4.1.2 Description |
| 5. ROUTES OF EXPOSURE |
| 5.1 Oral |
| 5.2 Inhalation |
| 5.3 Dermal |
| 5.4 Eye |
| 5.5 Parenteral |
| 5.6 Other |
| 6. KINETICS |
| 6.1 Absorption by route of exposure |
| 6.2 Distribution by route of exposure |
| 6.3 Biological half-life by route of exposure |
| 6.4 Metabolism |
| 6.5 Elimination and excretion |
| 7. PHARMACOLOGY AND TOXICOLOGY |
| 7.1 Mode of action |
| 7.1.1 Toxicodynamics |
| 7.1.2 Pharmacodynamics |
| 7.2 Toxicity |
| 7.2.1 Human data |
| 7.2.1.1 Adults |
| 7.2.1.2 Children |
| 7.2.2 Relevant animal data |
| 7.2.3 Relevant in vitro data |
| 7.3 Carcinogenicity |
| 7.4 Teratogenicity |
| 7.5 Mutagenicity |
| 7.6 Interactions |
| 7.7 Main adverse effects |
| 8. TOXICOLOGICAL ANALYSIS AND BIOMEDICAL INVESTIGATIONS |
| 9. CLINICAL EFFECTS |
| 9.1 Acute poisoning |
| 9.1.1 Ingestion |
| 9.1.2 Inhalation |
| 9.1.3 Skin exposure |
| 9.1.4 Eye contact |
| 9.1.5 Parenteral exposure |
| 9.1.6 Other |
| 9.2 Chronic poisoning |
| 9.2.1 Ingestion |
| 9.2.2 Inhalation |
| 9.2.3 Skin exposure |
| 9.2.4 Eye contact |
| 9.2.5 Parenteral exposure |
| 9.2.6 Other |
| 9.3 Course, prognosis, cause of death |
| 9.4 Systematic description of clinical effects |
| 9.4.1 Cardiovascular |
| 9.4.2 Respiratory |
| 9.4.3 Neurological |
| 9.4.3.1 CNS |
| 9.4.3.2 Peripheral Nervous System |
| 9.4.3.3 Autonomic Nervous System |
| 9.4.3.4 Skeletal and smooth muscle |
| 9.4.4 Gastrointestinal |
| 9.4.5 Hepatic |
| 9.4.6 Urinary |
| 9.4.6.1 Renal |
| 9.4.6.2 Other |
| 9.4.7 Endocrine and Reproductive Systems |
| 9.4.8 Dermatological |
| 9.4.9 Eye, ear, nose, throat, local effects |
| 9.4.10 Haematological |
| 9.4.11 Immunological |
| 9.4.12 Metabolic |
| 9.4.12.1 Acid-Base Disturbance |
| 9.4.12.2 Fluid and electrolyte disturbances |
| 9.4.12.3 Others |
| 9.4.13 Allergic Reactions |
| 9.4.14 Other clinical effects |
| 9.4.15 Special risks |
| 9.5 Other |
| 9.6 Summary |
| 10. MANAGEMENT |
| 10.1 General principles |
| 10.2 Life supportive procedures and symptomatic/specific treatment |
| 10.3 Decontamination |
| 10.4 Elimination |
| 10.5 Antidote treatment |
| 10.5.1 Adults |
| 10.5.2 Children |
| 10.6 Management discussion |
| 11. ILLUSTRATITIVE CASES |
| 11.1 Case reports from literature |
| 12. ADDITIONAL INFORMATION |
| 12.1 Specific preventive measures |
| 12.2 Other |
| 13. REFERENCES |
| 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) |
OPIOIDS
International Programme on Chemical Safety
Poisons Information Monograph (Group Monograph) G023
Pharmaceutical
This Monograph contains the following sections:
1. Name, 2. Summary, 4. Uses, 7. Pharmacology and Toxicology,
9.Clinical Effects, 10.Management.
1. NAME
1.1 Substance
Opioids
1.2 Group
Potent opioids:
Natural Opium
Morphine
Diamorphine (Heroin)
Alphaprodine
Amileridine
Alfentanyl
Fentanyl
Sufentanyl
Nalbuphine
Buprenorphine
Butorphanol
Dextromoramide
Dezocine
Ketobemidone
Meptazinol
Pentamorphone
Pentazocine
Pethidine
Less potent opioids:
Tincture Of Opium
Paregoric
Codeine
Hydromorphone
Oxymorphone
Hydrocodone
Oxycodone
Tramadol
Dextropropoxyphene
Others:
Diphenoxylate
Loperamide
Methadone
1.3 Synonyms
Pethidine: meperidine;
1.4 Identification numbers
1.4.1 CAS number
1.4.2 Other numbers
ATC classification index:
Analgesics (N02) / Opioid (N02A)
1.5 Main brand names, main trade names
1.6 Main manufacturers, main importers
2. SUMMARY
2.1 Main risks and target organs
Opioid drugs produce their major effects on the Central
Nervous System (CNS) and the bowel through mu receptors. In
higher doses, they can interact with the other receptors.
Main risks include:
- respiratory depression, coma, hypotension and
non-cardiogenic pulmonary oedema.
- psychological or/and physical dependence.
2.2 Summary of clinical effects
Addicts use opioids for the excitement, euphoria,
sensation of well-being and alteration of mood that they
produce. The rapid onset of these effects with an intravenous
bolus is called a "flash" or "rush".
Opioids may cause nausea, vomiting, drowsiness, decreased gut
motility, urinary retention, constipation, bradycardia,
hallucinations, convulsions and coma. Hypotension can occur.
Rhabdomyolysis with myoglobinuria and renal failure also
occurs.
Respiratory depression is common and may lead to cyanosis and
respiratory arrest. In severe cases, there may be
non-cardiogenic pulmonary oedema and cardiovascular
collapse.
Opioids usually produce pinpoint pupils, but they can be
dilated if the patient is hypoxic.
Dextropropoxyphene poisoning may also result in cardiac
arrhythmias (including ventricular extrasystoles, bigeminy,
ventricular tachycardia, ventricular fibrillation, heart
block and sudden death). Serious effects usually occur within
a few minutes of intravenous injection, and within an hour of
oral ingestion, but can be delayed with methadone or
slow-release preparations.
2.3 Diagnosis
The triad of coma, pinpoint pupils and depressed
respirations strongly suggests opioid poisoning. The finding
of needle tracks is suggestive of addiction, and further
supports the diagnosis.
2.4 First aid measures and management principles
After ingestion of large doses and if the patient is
conscious, consider administration of oral activated
charcoal.
In patients with severe respiratory depression, assisted
ventilation and cardiovascular monitoring are required.
Naloxone can be used as an antidote in severe poisoning and
may be useful for the diagnosis in suspected opioid
poisoning.
3. PHYSICOCHEMICAL PROPERTIES
3.1 Origin of the substance
3.2 Chemical structure
3.3 Physical properties
3.3.1 Colour
3.3.2 State/form
3.3.3 Description
3.4 Other characteristics
3.4.1 Shelf-life of the substance
3.4.2 Storage conditions
4. USES
4.1 Indications
4.1.1 Indications
4.1.2 Description
Their main use is in the treatment of
moderate-to-severe pain, but they are also used as
anti-diarrhoeal and anti-tussive agents.
Their ability to induce euphoria has led them to be
frequently abused, giving rise to psychological and
physical dependence.
(Reynolds, 1989).
5. ROUTES OF EXPOSURE
5.1 Oral
5.2 Inhalation
5.3 Dermal
5.4 Eye
5.5 Parenteral
5.6 Other
6. KINETICS
6.1 Absorption by route of exposure
6.2 Distribution by route of exposure
6.3 Biological half-life by route of exposure
6.4 Metabolism
6.5 Elimination and excretion
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
The acute toxic effects are an accentuation of
the pharmacodynamic effects.
Addicts use the opioids for the excitement, euphoria,
sensation of well-being and alteration of mood that
they produce. The rapid onset of these effects with an
intravenous bolus is called a "flash" or "rush".
Chronic effects include:
- respiratory: acute pulmonary oedema may be due to a
direct toxic effect , as may be acute bronchospasm
(Oliver, 1986; Anderson, 1986; Conti et al., 1990;
Del Los Santos-Sastre, 1986)).
- rhabdomyolysis: the commonly accepted explanation
is that it is due to compression of muscle during
prolonged coma aggravated by hypoxia, acidosis and
hypovolaemia. A direct effect has been suggested
(Conti et al., 1990; D'Agostino & Ernest, 1979;
Pearce & Cox, 1980).
- renal. Renal damage may progress to terminal renal
insufficiency. Genetic factors (African Carribean),
and impurities in the opioids (especially if bought
on the street) have been suggested (Vassals &
Pezzano, 1987; Cunningham et al., 1980; Uzan et
al., 1988).
- cutaneous. The effects may be systemic or local.
They may be due to adulterants, bacterial
contamination or direct effects of opioids (Louria
et al., 1967; Ellenhorn & Barceloux, 1988)..
- immunological. Opioid addiction leads to reduced
resistance to cutaneous and respiratory
infections.
- splenomegaly due to antigenic stimulation has been
described.
7.1.2 Pharmacodynamics
Mu receptors were the first opioid-binding
sites described. Mu receptors are further classified
into mu1 and mu2 subclasses. Mu1 receptors have a high
affinity for morphine and are postulated to have
supraspinal analgesic properties. Stimulation of mu1
receptors causes almost none of the unwanted effects
of the opioids. Mu2 receptors have a lower affinity
for opioids than mu 1. Most of the adverse effects of
opioids can be attributed to stimulation of the mu2
receptors. These include respiratory depression,
delayed gastrointestinal motility, urinary retention,
bradycardia, miosis, euphoria and physical
dependence.
(Goodman et al., 1990).
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
7.2.1.2 Children
7.2.2 Relevant animal data
7.2.3 Relevant in vitro data
7.3 Carcinogenicity
7.4 Teratogenicity
7.5 Mutagenicity
7.6 Interactions
The depressant effects of some opioids may be
exaggerated and prolonged by phenothiazine, MAO inhibitors
and tricyclic antidepressants.
7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSIS AND BIOMEDICAL INVESTIGATIONS
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
Opioids may cause nausea, vomiting, drowsiness,
decreased gut motility, urinary retention,
constipation, bradycardia, hallucinations, confusion
and coma. Hypotension occurs occasionally.
Rhabdomyolysis may also occur.
Miosis is a characteristic (but not invariable) sign
of opioid poisoning.
Some opioids have a histamine-releasing effect which
can cause urticaria, pruritus, flushing and
hypotension. Such reactions may occur with therapeutic
doses.
Respiratory depression is common and may lead to
cyanosis and respiratory arrest. In severe cases,
there may be non-cardiogenic pulmonary oedema and
cardiovascular collapse.
Cardiac arrhythmias have been reported with
dextropropoxyphene.
Serious effects usually occur within an hour of oral
ingestion, but can be delayed with methadone or
slow-release preparations.
Acute poisoning may occur in "body-packers" after
leakage of contents.
(Conti et al., 1990)
9.1.2 Inhalation
Acute poisoning has been described after
sniffing heroin ("chasing the dragon") (Conti et al.,
1990).
9.1.3 Skin exposure
No data
9.1.4 Eye contact
No data
9.1.5 Parenteral exposure
The intravenous route is the preferred route in
the addict.
Acute poisoning has also been reported after
subcutaneous administration (Conti et a., 1990).
Opioids may cause nausea, vomiting, drowsiness,
decreased gut motility, urinary retention,
constipation, bradycardia, hallucinations, confusion
and coma when taken in overdose. Hypotension occurs
occasionally. Rhabdomyolysis may also occur.
Miosis is a characteristic sign of opioid
poisoning.
Some opiates have a histamine-releasing effect which
can cause a urticaria, pruritus, flushing and
hypotension. Such reaction may occur with therapeutic
doses.
Respiratory depression is common and may lead to
respiratory arrest. In severe cases there may be a
non-cardiogenic pulmonary oedema and cardiovascular
collapse.
9.1.6 Other
No data
9.2 Chronic poisoning
9.2.1 Ingestion
Dependence has been described.
9.2.2 Inhalation
Dependence has been described. Spongiform
leuco-encephalitis may occur with heroin.
9.2.3 Skin exposure
No data
9.2.4 Eye contact
No data
9.2.5 Parenteral exposure
The primary risks of chronic intoxication in
drug abusers are physical and psychological
dependence, systemic complications due to opioids,
adulterants and multiple drug abuse, and infectious
complications, particularly AIDS and hepatitis B and
C.
9.2.6 Other
No data
9.3 Course, prognosis, cause of death
If treatment is rapidly instituted, the outcome is
generally good (Conti et al., 1990; Larpin et al., 1990).
Complications include:
- aspiration pneumonia which may be severe,
- haemodynamic disturbances (bradycardia, hypotension and
vasovagal collapse),
- hypothermia,
- rhabdomyolysis
- non cardiac pulmonary oedema,
- convulsions (due to impurities in «street drugs»)
- hypoxic brain damage.
Death can result from prolonged apnoea or a hypersensitivity
reaction.
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
9.4.2 Respiratory
9.4.3 Neurological
9.4.3.1 CNS
9.4.3.2 Peripheral Nervous System
9.4.3.3 Autonomic Nervous System
9.4.3.4 Skeletal and smooth muscle
9.4.4 Gastrointestinal
9.4.5 Hepatic
9.4.6 Urinary
9.4.6.1 Renal
9.4.6.2 Other
9.4.7 Endocrine and Reproductive Systems
9.4.8 Dermatological
9.4.9 Eye, ear, nose, throat, local effects
9.4.10 Haematological
9.4.11 Immunological
9.4.12 Metabolic
9.4.12.1 Acid-Base Disturbance
9.4.12.2 Fluid and electrolyte disturbances
9.4.12.3 Others
9.4.13 Allergic Reactions
9.4.14 Other clinical effects
9.4.15 Special risks
9.5 Other
9.6 Summary
10. MANAGEMENT
10.1 General principles
Rapidly assess the vital signs.
Maintain an airway.
Assure ventilation (there is a danger of underestimating the
severity of respiratory depression).
Administer oxygen by nasal cannulae, face mask, or
endotracheal tube.
Ensure intravenous access.
Infuse isotonic glucose solution.
Monitor the electrocardiogram.
Overenthusiastic administration of the specific antidote
naloxone can provoke acute withdrawal in those habituated to
opioids, and this can complicate treatment. Naloxone is a
competitive antagonist. It is relatively ineffective in
treating poisoning by partial agonists, particularly
buprenorphine.
Careful titration of the dose of antidote administered should
allow the treatment of respiratory depression (assuring a
respiratory rate above 14 breaths per minute) without
provoking acute withdrawal.
Decontamination if indicated (for example, with
body-packers).
10.2 Life supportive procedures and symptomatic/specific treatment
Standard treatment of opioid overdose is (Baud & Bismuth,
1987):
- artificial ventilation or mask ventilation
- use of naloxone
Failure to regain consciousness requires consideration of
prolonged cerebral anoxia or poisoning by other psychotropic
drugs.
Treatment of a complicated opioid overdose may require:
- infusion of plasma expanders for cardiovascular collapse
unresponsive to naloxone. Pressor amines may also be used.
If there is no response, then measurement of CVP, and
pulmonary artery catheterization allow more precise
haemodynamic treatment. Hyperdynamic circulation and
increased cardiac output and a fall in peripheral
resistance and a slight increase in heart rate may appear
if fluids are given to preserve renal function.
- mechanical ventilation with PEEP is the preferred
treatment of non cardiac pulmonary oedema which usually
responds rapidly. Ventilation may be stopped after 2 to 4
days. It may also be required for hypoxemia.
- diazepam is used to control convulsions
- other measures may be required to treat pulmonary
aspiration, rhabdomyolysis, or hyperthermia.
Dextropropoxyphene: ECG monitoring is advised for at least
8 hours following dextropropoxyphene exposure. Cardiac
arrhythmias should be treated with either phenytoin or
atenolol. Disopyramide, lignocaine, procainamide, quinidine
and atropine are all contra-indicated since they may
exacerbate the conduction defects.
Treatment of withdrawal syndrome in opioid abuser:
The management of the withdrawal syndrome should not be
exclusively pharmacological in nature but should include a
full evaluation of the patient to determine the most
appropriate approach to therapy. One of two general
approaches is commonly adopted. The first comprises
substitution of the drug with a longer-acting opioid, such as
methadone, followed by a gradual reduction in dosage of the
substitute drug. The second comprises use of various
pharmacological agents, such as clonidine and/or a
benzodiazapine, which will mitigate symptoms and signs of
withdrawal. Psychological support may be necessary. Indeed,
some schools of thought contend that psycho-social support
alone is the only effective treatment for opioid withdrawal
states.
When clonidine is employed, the dose is 0.006 mg/kg/day, in
divided doses, adjusted as necessary according to withdrawal
symptoms and clonidine side-effects (such as sedation and/or
postural hypotension). The dosage of clonidine should then be
gradually reduced, typically over a one- to two-week
period.
If symptoms and signs of opioid withdrawal do not respond to
the use of clonidine and/or benzodiazepines, then the use of
propantheline (for stomach cramps) or atropine (for
diarrhoea) may be considered.
Opioid-dependent individuals with co-existent medical or
surgical conditions requiring pain relief should receive
conventional treatment, including if necessary the
administration of opioids.
Substitution is preferred to drug withdrawal during
pregnancy.
(Ellenhorn & Barceloux, 1988, Goodman et al., 1990).
Acute withdrawal in the neonate can be treated with dilute
morphine solution (Paregoric elixir-400 micrograms morphine
per mL), 0.2 mL every 3 to 4 hours as needed to relieve
symptoms without causing sedation. If there is no response,
the dose can be increased in steps of 0.1 mL (0.04 mg
morphine) (Goldfrank & Bresnitz, 1990). Diazepam,
chlorpromazine and phenobarbitone may be required as
sedatives for several days or weeks.
10.3 Decontamination
In the case of ingestion of large doses of opioids,
oral activated charcoal can be recommended.
If there is a suspicion that the patient is a body packer,
then the following are required:
- rectal (and vaginal) examination and plain erect and
supine abdominal X-rays. Examination of the colon with
water soluble contrast medium, sigmoidoscopy, enema, and
stool examination for several days, may all be needed
(Karhunen et al., 1987; Marc et al., 1989).
Packets in the stomach cannot be removed by gastric lavage.
Induced emesis should be avoided. Close monitoring is
required because of the high risk of rupture of the packets
- foreign objects in the gastro-intestinal tract may require
whole bowel irrigation with polyethylene glycol solution
with stool examination. Surgery may be indicated for
mechanical obstruction or if there is evidence of packet
rupture.
10.4 Elimination
Haemodialysis, haemoperfusion and peritoneal dialysis
are not recommended (Ellenhorn & Barceloux, 1988).
10.5 Antidote treatment
10.5.1 Adults
Naloxone is a specific competitive antagonist.
It can be administered by intravenous (IV) bolus, IV
infusion or intramuscular (IM) routes. Adverse effects
and problems include:
- a short duration of action (10 to 45 minutes)
compared with that of opioids; symptoms of
poisoning can reappear after the initial injection,
with consequent risk of respiratory depression and
apnoea, necessitating repeat administration.
- an acute withdrawal syndrome may appear a few
minutes after the injection, peaking at 30
minutes
- there is a risk of rebound sympathetic activity,
with acute pulmonary oedema and cardiac
arrhythmia.
(Buad & Bismuth, 1987; Ellenhorn & Barceloux, 1988;
Goodman et al., 1990).
1) Slow administration of an initial intravenous dose
of 0.4 to 2 mg in adults, titrated until the
respiratory rate is above 14 breaths per minutes, but
without provoking signs of acute withdrawal. If the
initial dose has no effect, it can be repeated after 2
or 3 minutes.
2) Maintenance treatment, which may be needed because
of the short duration of action of naloxone, is given
by infusing 1.6 to 2.4 mg naloxone in isotonic (5%)
glucose solution, or by syringe pump, at a rate
sufficient to maintain the respiratory rate above 14
breaths per minute (usually 0.4 to 0.8 mg per hour).
This is especially important if large doses of
slow-release preparations or longer-acting agents
(such as methadone)have been taken. If artificial
ventilation is required because of respiratory
insufficiency or pulmonary oedema, then naloxone
should be stopped.
10.5.2 Children
The initial dose in children is 10 to 30
microgram per kg, followed by a dose of 100 microg per
kilogram if there is no response. Infusion should be
at a rate of 30 microg per kg per hour. Infusion may
be recommended in the case of opioids with a long
half-life (e.g. methadone, dextropropoxyphene and
buprenorphine).
10.6 Management discussion
11. ILLUSTRATITIVE CASES
11.1 Case reports from literature
12. ADDITIONAL INFORMATION
12.1 Specific preventive measures
12.2 Other
13. REFERENCES
Anderson K (1986) Bronchospam and intravenous street heroin.
Lancet, 1: 1208
Baud FJ & Bismuth C (1987) Traitement d'urgence de l'overdose. Rev
Prat, 37: 1723-1727
Cunningham EE, Brentjens JR, Zielezny MA, Andres GA, Venuto RC
(1980) Heroin nephropathy. A clinicopathologic and epidemiologic
study. Am J Med, 68: 47-53
D'Agostino RS & Ernest NA (1979) Acute myoglobinuria and heroin
snorting. JAMA, 241: 277
Del Los Santos-Sastre S, Capote-Gil F, Gonzales-Castro A (1986)
Airway obstruction and heroin inhaling. Lancet, 2: 1158
Ellenhorn MJ & Barceloux DG (1988). Medical toxicology. Diagnosis
and treatment of human poisoning. New York, Elsevier, 698-709
Goldfrank LR & Bresnitz EA (1990). Opioids. In: Goldfrank LR,
Toxicologic Emergencies, 4th ed, East Norwalk, Appleton & Lange,
433-445
Goodman, Gilman A, Rall TW, Nies AS, Taylor P (1990). Goodman and
Gilman's The pharmacological basis of therapeutics, 8th ed,
New-York, Pergamon Press, 489-504
Karhunen PJ, Penttilä A, Panula A (1987) Detection of heroin
"body-packers" at Helsinski airport. Lancet, 1: 1265
Larpin R, Vincent A, Perret C (1990) Morbidite et mortalite
hospitalières de l'intoxication aiguë par les opiaces. Presse Med,
19: 1403-1406
Louria DB, Hensle T, Rose J (1967) The major medical complications
of heroin addiction. Ann Intern Med, 67: 1-22
Marc B, Gherardi R, Baud F, Cattin JM, Garnier R, Diamant-Berger O
(1989). Transport in corpore de stupefiants: diagnostic et
traitement medical. Encyclop Med Chir - Instant Med, 17-20
Oliver RM (1986) Bronchospasm and heroin inhalation. Lancet, 1:
915
Pearce CJ & Cox JGC (1980) Heroin and hyperkalaemia. Lancet, 2:
923
Uzan M, Volochine L, Rondeau E, Viron B, Mougenot B, Beaufils H,
Pourriat JL, Chauveau P (1988) Les atteintes renales associees à
l'abus d'heroïne. Nephrologie, 9: 217-221
Vassals T & Pezzano M (1987) Les complications medicales de
l'heroinomanie. Rev Prat, 37: 1729-1734
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)
Author: Medical Toxicology Unit,
Guy's and St Thomas' Trust
Avonley Road, London SE14 5ER, UK
Date: August, 1996
Reviewers: R Ferner, M Mathieu-Nolf, MO Rambourg Schepens
(coordinator)
London, March, 1998
Editor: Dr M.Ruse (IPCS, February, 1999)
Codeine (PIM 140)
Dextropropoxyphene (PIM 442)
Diamorphine (PIM 261)