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Opioids
POISONOUS SUBSTANCES
Opioids
Nitrogen and Nitrogen Oxides
D Nicholas Bateman
Jan Meulenbelt
Nitrogen is a colourless, odourless gas. It causes hypoxic asphyxia by displacing oxygen. Spillage of liquid nitrogen on the eyes or skin causes extreme cooling, leading to cold burns. Of the oxides (Figure 1), NO and NO2 occur naturally. In ambient air, NO is oxidized to NO2. NO2 exists principally as N2O4; at higher temperatures, more NO2 is present. Exposure to NO2 concentrations of 45–100 mg/m3 (1 mg/m3 is about 0.5 ppm) for short periods causes only mild respiratory effects. Exposure for longer than 1 hour to 100 mg/m3 can induce pulmonary oedema. Even brief exposure to more than 500 mg/m3 may cause life-threatening pulmonary damage.
Opioid poisoning is an increasing problem in developed countries (Figure 1). It is important to distinguish drugs obtained illicitly from those obtained by prescription, because the quality and ingredients of the preparations vary. Combinations of opioids with other respiratory depressants (particularly benzodiazepines) are hazardous. Opioids act on specific opioid receptors, which can be classified into subtypes. In cases of poisoning, details of these subclassifications are generally irrelevant. The toxicity of opioids relates primarily to their effects on opioid receptors. With some agents, other properties of the drug molecule may be important. The features of opioid intoxication include pin-point pupils, respiratory depression, depression of consciousness, vomiting, delayed gastrointestinal motility (particularly delayed gastric emptying) and reduced blood pressure and pulse rate. The principal differences in the effects of the different drugs relate to their speed of onset, which may be influenced by the route of administration. Opioid addicts tend to take the drugs by inhalation or intravenously to experience a rapid onset of effects. The onset of action of methadone is slower than other opioids because of its slow absorption (peak effect about 6 hours after administration). Codeine and dihydrocodeine are metabolized to more potent end products (morphine and dihydromorphine, respectively). The duration of action of opioids relates to their rate of elimination (Figure 2). Most are metabolized in the liver. Partial agonists – several opioid compounds stimulate opioid receptors, but not to a maximum effect. In their presence, other drugs acting on the same receptor systems are less easily bound; full agonists and antagonists are both less effective. The principal partial agonists in current use are buprenorphine (now used primarily in a sublingual formulation in the management of opioid addicts) and dihydrocodeine. Pure opioid antagonists – naloxone and naltrexone are pure opioid antagonists. They cause no effects when given alone in opioid-naïve individuals, but may produce withdrawal symptoms in addicts. Naltrexone is longer acting and is generally used orally in the management of opioid-dependency syndromes. Naloxone is used intravenously but has a shorter duration of action; in most individuals, the half-life is 45–90 minutes – much shorter than the half-life of opioids. Use of naloxone in the management of opioid poisoning is therefore based on administration of an appropriate dose to reverse the effect of the opioid ingested; the dose is titrated to achieve this. Some patients may require several milligrams. In patients who have not responded to 2.4 mg, the diagnosis of opioid poisoning should be reconsidered. Repeat doses of naloxone or an infusion may be required in patients who have taken long-acting opioids. An infusion of about 60% of the dose required to wake the patient per hour is sufficient
Mechanism of toxicity: NO2 is the most toxic nitrogen oxide. It is a strong oxidant and thus reacts with various biomolecules, directly or via the formation of free radicals. NO may induce pulmonary damage. Clinical features: NO2 has a low solubility in water; little dissolves in the upper airway mucus, exposing the lower respiratory tract to relatively high concentrations. Patients are generally symptom-free during the first hours post-exposure; nausea or minor irritation of the upper airways occurs occasionally. After several hours (depending on concentration and duration of exposure), adult respiratory distress syndrome may manifest. The clinical findings are dyspnoea, tachypnoea, hypoxaemia, decreased lung compliance, and diffuse pulmonary infiltrates on chest radiography. Management: patients must be admitted for observation. If arterial blood gases and chest radiography remain normal in the first 12 hours, they can be discharged and supervised as out-patients. In severe cases, supportive therapy and maintenance of gas exchange by mechanical ventilation are needed. Corticosteroids do not reduce pulmonary damage and may induce harmful pulmonary effects. Prophylactic systemic antibiotics are not recommended.
Nitrogen oxides • • • • • • • •
Nitrous oxide – N2O Nitric oxide, nitrogen monoxide – NO Nitrogen dioxide – NO2 Nitrogen trioxide – NO3 Nitrogen tetroxide – N2O4 (dimer of NO2) Dinitrogen trioxide –N2O3 Dinitrogen pentoxide – N2O5 NOx – a collective name for NO, NO2 and N2O4
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64
© 2003 The Medicine Publishing Company Ltd
POISONOUS SUBSTANCES
Drug-related poisoning deaths in England and Wales Drug
Number of deaths 1993
1994
1995
1996
1997
1998
1999
2000
• Heroin and morphine
187
276
357
464
445
646
754
926
• Paracetamol
463
468
526
480
562
523
473
455
• Antidepressants
461
476
489
540
539
510
493
449
• Methadone
232
269
310
368
421
364
398
238
• Temazepam
173
163
138
98
104
444
82
73
• Cocaine
12
24
19
18
38
66
88
80
• Barbiturates
44
46
46
30
20
35
26
17
• Ecstasy
8
27
10
16
11
16
26
36
• Cannabis
14
18
17
11
13
5
8
11
In 2000, there were 2968 drug-related deaths in England and Wales Source: Office for National Statistics
1
to maintain most patients in a physiologically stable state. Because naloxone reverses the effect of opioids on the gut, there may be a paradoxical increase in absorption of orally ingested compounds, increasing the opioid effects. With slow-onset agents (e.g. methadone), patients require careful monitoring for several hours after the start of the infusion to ensure that appropriate levels of reversal are achieved.
Specific opioids Diamorphine (diacetylmorphine) and morphine – diamorphine is rapidly broken down to morphine in plasma; at post-mortem, it is almost impossible to detect the presence of diamorphine. In clinical use, therefore, these drugs are interchangeable. Diamorphine is more water soluble, but is not more potent. Both drugs
Common opioids and their important properties Opioid • Morphine
Approximate half-life 3 hours
Comments Active metabolite morphine-6-glucoronide
• Diamorphine
3 hours (morphine)
Rapidly metabolized to morphine Active metabolite morphine-6-glucoronide
• Codeine
3.5 hours
5–15% converted to active metabolite morphine (under genetic control)
• Dihydrocodeine
3.5–4.5 hours
Partial agonist Active metabolites (e.g. dihydromorphine) (under genetic control)
• Methadone
12–18 hours
Slow onset, long action
• Tramadol
6 hours
Central 5-HT and noradrenergic effects Causes seizures
• Dextropropoxyphene
15 hours
Sodium channel blocker causes arrhythmias Active metabolite norproxyphene (half-life 27 hours) also causes arrhythmias
• Buprenorphine
6 hours
Partial agonist Slow absorption by buccal route – peak 3–4 hours after administration
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© 2003 The Medicine Publishing Company Ltd
POISONOUS SUBSTANCES
have short half-lives, and some oral preparations are slow release. The onset and offset of drug action are therefore less predictable, and overdoses may lead to delayed-onset, long-lasting clinical effects. Morphine is metabolized in the liver to an active metabolite (morphine-6-glucoronide). In some animal models, this is more potent as an opioid agonist than morphine. It is excreted primarily by the kidney, and accumulates in patients with renal insufficiency and in the elderly. In some patients, this may be sufficient to produce features of opioid poisoning at apparently normal therapeutic doses. The effects of morphine-6-glucoronide are reversed by naloxone. Codeine and dihydrocodeine are pro-drugs. They are weakly effective on their own, but their principal effects in clinical use are likely to result from conversion by CYP2D6 in the liver to active morphine and dihydromorphine respectively. CYP2D6 is polymorphic (under genetic control) and is only weakly active in 8% of the population. In overdose in these individuals, the parent compounds may be active and, in the case of dihydrocodeine, their actions are less easily reversed by naloxone. Methadone is a long-acting opioid used in opioid dependency. Its onset is slow, and it therefore gives less of a ‘hit’ than morphine or diamorphine. It can cause death, however, particularly in naïve patients, and care must be taken to compare the dose in overdose with that normally prescribed for the patient. Other co-ingested drugs that may cause respiratory depression (e.g. benzodiazepines) increase the risk. Management of methadone poisoning is similar to that of any other standard opioid, but remembering that the duration of action is longer. It is important to observe patients for at least 36 hours after substantial ingestion, to detect delayed onset of effects. Dextropropoxyphene – in the UK, dextropropoxyphene is usually marketed in combination with paracetamol as co-proxamol. In clinical trials, this combination is no more effective than paracetamol alone as an analgesic, but tends to cause a euphoriant effect and seems to lead to mild dependency in many patients. Dextropropoxyphene has an active metabolite (norproxyphene) that has no opioid properties, but which has marked effects on sodium channels on the myocardial membrane, similar to those of the parent drug. This results in prolongation of the QRS and, in overdose, a risk of severe ventricular arrhythmia, ventricular fibrillation and death. Co-proxamol is particularly hazardous in patients who are already hypoxic, because of the respiratory depressant effect of the opioid, and the paracetamol component adds to the complexity of the poisoning. In the UK, co-proxamol is a common cause of drug-induced death in overdose. In the author’s opinion, there is no clinical role for this combination drug. Tramadol is an opioid agonist that also has effects at 5-HT receptor systems. It may therefore cause convulsions in overdose, and these should be treated in the standard manner with a benzodiazepine. The risk of respiratory depression is increased because of the opioid effects. Fentanyl is increasingly used in terminal care and management of chronic pain. It is a short-acting opioid and is usually administered in a patch that is changed every 2 or 3 days. The drug is deposited in the skin as part of its absorption process, and its effects may therefore persist for some time after the patches have been removed. There is a risk of patch transfer to, for example,
MEDICINE
the patient’s sleeping partner, who may be naïve to the effects of the opioid. Buprenorphine is a partial agonist used in the management of opioid addicts. It has the advantage that it is administered sublingually and therefore cannot be ‘pouched’ in the mouth and spat into a container after administration. This makes it useful in settings such as prisons.
Opioid addiction Morphine and diamorphine are widely used by addicts and commonly bought on the street. The amount of drug purchased reflects the raw weight of the compound, but because dealers adulterate (‘cut’) the product they sell, the quantities taken are usually less than the user believes. For this reason, addicts should never be believed when they state the absolute quantity consumed daily. The drug can be ingested through the lungs via smoking (‘chasing the dragon’); the effect is rapid, but there is less opioid effect because some of the smoke is lost. As addicts become poorer, they often switch from smoking to injection. It is not true that smoking heroin is less addictive than injecting it. Patients who have been off heroin or who have switched suppliers may take doses larger than those they are used to. This may lead to rapid onset of respiratory depression, vomiting and cardiovascular collapse; in many cases, death results. In an attempt to reduce this risk, some agencies have established ‘injecting rooms’ where naloxone is available, but this is politically controversial. Drug traffickers (‘mules’) tend to swallow drugs wrapped in condoms or similar protective materials. Very severe opioid poisoning may occur if these leak, often leading to death. Drug users caught in possession may swallow the ‘wrap’, but the risk of serious effects is low if the amount swallowed is similar to the user’s normal daily dose.
FURTHER READING Chamberlain J M, Klein B L. A Comprehensive Review of Naloxone for the Emergency Physician. Am J Emerg Med 1994; 12: 650–9. Frolich M, Giannotti A, Modell J H. Opioid Overdose in a Patient using a Fentanyl Patch during Treatment with a Warming Blanket. Anesth Analg 2001; 93: 647–8. Goldfrank L, Weisman R S, Errick J K et al. A Dosing Nomogram for Continuous Infusion of Intravenous Naloxone. Ann Emerg Med 1986; 15: 566–70. Hendra T J, Gerrish S P, Forrest A R. Fatal Methadone Overdose. BMJ 1996; 313: 481–2. Spiller H A, Gorman S E, Villalobos D et al. Prospective Multicentre Evaluation of Tramadol Exposure. J Toxicol Clin Toxicol 1997; 35: 361–4.
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© 2003 The Medicine Publishing Company Ltd
Opioids
Nitrogen and Nitrogen Oxides
D Nicholas Bateman
Jan Meulenbelt
Nitrogen is a colourless, odourless gas. It causes hypoxic asphyxia by displacing oxygen. Spillage of liquid nitrogen on the eyes or skin causes extreme cooling, leading to cold burns. Of the oxides (Figure 1), NO and NO2 occur naturally. In ambient air, NO is oxidized to NO2. NO2 exists principally as N2O4; at higher temperatures, more NO2 is present. Exposure to NO2 concentrations of 45–100 mg/m3 (1 mg/m3 is about 0.5 ppm) for short periods causes only mild respiratory effects. Exposure for longer than 1 hour to 100 mg/m3 can induce pulmonary oedema. Even brief exposure to more than 500 mg/m3 may cause life-threatening pulmonary damage.
Opioid poisoning is an increasing problem in developed countries (Figure 1). It is important to distinguish drugs obtained illicitly from those obtained by prescription, because the quality and ingredients of the preparations vary. Combinations of opioids with other respiratory depressants (particularly benzodiazepines) are hazardous. Opioids act on specific opioid receptors, which can be classified into subtypes. In cases of poisoning, details of these subclassifications are generally irrelevant. The toxicity of opioids relates primarily to their effects on opioid receptors. With some agents, other properties of the drug molecule may be important. The features of opioid intoxication include pin-point pupils, respiratory depression, depression of consciousness, vomiting, delayed gastrointestinal motility (particularly delayed gastric emptying) and reduced blood pressure and pulse rate. The principal differences in the effects of the different drugs relate to their speed of onset, which may be influenced by the route of administration. Opioid addicts tend to take the drugs by inhalation or intravenously to experience a rapid onset of effects. The onset of action of methadone is slower than other opioids because of its slow absorption (peak effect about 6 hours after administration). Codeine and dihydrocodeine are metabolized to more potent end products (morphine and dihydromorphine, respectively). The duration of action of opioids relates to their rate of elimination (Figure 2). Most are metabolized in the liver. Partial agonists – several opioid compounds stimulate opioid receptors, but not to a maximum effect. In their presence, other drugs acting on the same receptor systems are less easily bound; full agonists and antagonists are both less effective. The principal partial agonists in current use are buprenorphine (now used primarily in a sublingual formulation in the management of opioid addicts) and dihydrocodeine. Pure opioid antagonists – naloxone and naltrexone are pure opioid antagonists. They cause no effects when given alone in opioid-naïve individuals, but may produce withdrawal symptoms in addicts. Naltrexone is longer acting and is generally used orally in the management of opioid-dependency syndromes. Naloxone is used intravenously but has a shorter duration of action; in most individuals, the half-life is 45–90 minutes – much shorter than the half-life of opioids. Use of naloxone in the management of opioid poisoning is therefore based on administration of an appropriate dose to reverse the effect of the opioid ingested; the dose is titrated to achieve this. Some patients may require several milligrams. In patients who have not responded to 2.4 mg, the diagnosis of opioid poisoning should be reconsidered. Repeat doses of naloxone or an infusion may be required in patients who have taken long-acting opioids. An infusion of about 60% of the dose required to wake the patient per hour is sufficient
Mechanism of toxicity: NO2 is the most toxic nitrogen oxide. It is a strong oxidant and thus reacts with various biomolecules, directly or via the formation of free radicals. NO may induce pulmonary damage. Clinical features: NO2 has a low solubility in water; little dissolves in the upper airway mucus, exposing the lower respiratory tract to relatively high concentrations. Patients are generally symptom-free during the first hours post-exposure; nausea or minor irritation of the upper airways occurs occasionally. After several hours (depending on concentration and duration of exposure), adult respiratory distress syndrome may manifest. The clinical findings are dyspnoea, tachypnoea, hypoxaemia, decreased lung compliance, and diffuse pulmonary infiltrates on chest radiography. Management: patients must be admitted for observation. If arterial blood gases and chest radiography remain normal in the first 12 hours, they can be discharged and supervised as out-patients. In severe cases, supportive therapy and maintenance of gas exchange by mechanical ventilation are needed. Corticosteroids do not reduce pulmonary damage and may induce harmful pulmonary effects. Prophylactic systemic antibiotics are not recommended.
Nitrogen oxides • • • • • • • •
Nitrous oxide – N2O Nitric oxide, nitrogen monoxide – NO Nitrogen dioxide – NO2 Nitrogen trioxide – NO3 Nitrogen tetroxide – N2O4 (dimer of NO2) Dinitrogen trioxide –N2O3 Dinitrogen pentoxide – N2O5 NOx – a collective name for NO, NO2 and N2O4
1
MEDICINE
64
© 2003 The Medicine Publishing Company Ltd
POISONOUS SUBSTANCES
Drug-related poisoning deaths in England and Wales Drug
Number of deaths 1993
1994
1995
1996
1997
1998
1999
2000
• Heroin and morphine
187
276
357
464
445
646
754
926
• Paracetamol
463
468
526
480
562
523
473
455
• Antidepressants
461
476
489
540
539
510
493
449
• Methadone
232
269
310
368
421
364
398
238
• Temazepam
173
163
138
98
104
444
82
73
• Cocaine
12
24
19
18
38
66
88
80
• Barbiturates
44
46
46
30
20
35
26
17
• Ecstasy
8
27
10
16
11
16
26
36
• Cannabis
14
18
17
11
13
5
8
11
In 2000, there were 2968 drug-related deaths in England and Wales Source: Office for National Statistics
1
to maintain most patients in a physiologically stable state. Because naloxone reverses the effect of opioids on the gut, there may be a paradoxical increase in absorption of orally ingested compounds, increasing the opioid effects. With slow-onset agents (e.g. methadone), patients require careful monitoring for several hours after the start of the infusion to ensure that appropriate levels of reversal are achieved.
Specific opioids Diamorphine (diacetylmorphine) and morphine – diamorphine is rapidly broken down to morphine in plasma; at post-mortem, it is almost impossible to detect the presence of diamorphine. In clinical use, therefore, these drugs are interchangeable. Diamorphine is more water soluble, but is not more potent. Both drugs
Common opioids and their important properties Opioid • Morphine
Approximate half-life 3 hours
Comments Active metabolite morphine-6-glucoronide
• Diamorphine
3 hours (morphine)
Rapidly metabolized to morphine Active metabolite morphine-6-glucoronide
• Codeine
3.5 hours
5–15% converted to active metabolite morphine (under genetic control)
• Dihydrocodeine
3.5–4.5 hours
Partial agonist Active metabolites (e.g. dihydromorphine) (under genetic control)
• Methadone
12–18 hours
Slow onset, long action
• Tramadol
6 hours
Central 5-HT and noradrenergic effects Causes seizures
• Dextropropoxyphene
15 hours
Sodium channel blocker causes arrhythmias Active metabolite norproxyphene (half-life 27 hours) also causes arrhythmias
• Buprenorphine
6 hours
Partial agonist Slow absorption by buccal route – peak 3–4 hours after administration
2
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© 2003 The Medicine Publishing Company Ltd
POISONOUS SUBSTANCES
have short half-lives, and some oral preparations are slow release. The onset and offset of drug action are therefore less predictable, and overdoses may lead to delayed-onset, long-lasting clinical effects. Morphine is metabolized in the liver to an active metabolite (morphine-6-glucoronide). In some animal models, this is more potent as an opioid agonist than morphine. It is excreted primarily by the kidney, and accumulates in patients with renal insufficiency and in the elderly. In some patients, this may be sufficient to produce features of opioid poisoning at apparently normal therapeutic doses. The effects of morphine-6-glucoronide are reversed by naloxone. Codeine and dihydrocodeine are pro-drugs. They are weakly effective on their own, but their principal effects in clinical use are likely to result from conversion by CYP2D6 in the liver to active morphine and dihydromorphine respectively. CYP2D6 is polymorphic (under genetic control) and is only weakly active in 8% of the population. In overdose in these individuals, the parent compounds may be active and, in the case of dihydrocodeine, their actions are less easily reversed by naloxone. Methadone is a long-acting opioid used in opioid dependency. Its onset is slow, and it therefore gives less of a ‘hit’ than morphine or diamorphine. It can cause death, however, particularly in naïve patients, and care must be taken to compare the dose in overdose with that normally prescribed for the patient. Other co-ingested drugs that may cause respiratory depression (e.g. benzodiazepines) increase the risk. Management of methadone poisoning is similar to that of any other standard opioid, but remembering that the duration of action is longer. It is important to observe patients for at least 36 hours after substantial ingestion, to detect delayed onset of effects. Dextropropoxyphene – in the UK, dextropropoxyphene is usually marketed in combination with paracetamol as co-proxamol. In clinical trials, this combination is no more effective than paracetamol alone as an analgesic, but tends to cause a euphoriant effect and seems to lead to mild dependency in many patients. Dextropropoxyphene has an active metabolite (norproxyphene) that has no opioid properties, but which has marked effects on sodium channels on the myocardial membrane, similar to those of the parent drug. This results in prolongation of the QRS and, in overdose, a risk of severe ventricular arrhythmia, ventricular fibrillation and death. Co-proxamol is particularly hazardous in patients who are already hypoxic, because of the respiratory depressant effect of the opioid, and the paracetamol component adds to the complexity of the poisoning. In the UK, co-proxamol is a common cause of drug-induced death in overdose. In the author’s opinion, there is no clinical role for this combination drug. Tramadol is an opioid agonist that also has effects at 5-HT receptor systems. It may therefore cause convulsions in overdose, and these should be treated in the standard manner with a benzodiazepine. The risk of respiratory depression is increased because of the opioid effects. Fentanyl is increasingly used in terminal care and management of chronic pain. It is a short-acting opioid and is usually administered in a patch that is changed every 2 or 3 days. The drug is deposited in the skin as part of its absorption process, and its effects may therefore persist for some time after the patches have been removed. There is a risk of patch transfer to, for example,
MEDICINE
the patient’s sleeping partner, who may be naïve to the effects of the opioid. Buprenorphine is a partial agonist used in the management of opioid addicts. It has the advantage that it is administered sublingually and therefore cannot be ‘pouched’ in the mouth and spat into a container after administration. This makes it useful in settings such as prisons.
Opioid addiction Morphine and diamorphine are widely used by addicts and commonly bought on the street. The amount of drug purchased reflects the raw weight of the compound, but because dealers adulterate (‘cut’) the product they sell, the quantities taken are usually less than the user believes. For this reason, addicts should never be believed when they state the absolute quantity consumed daily. The drug can be ingested through the lungs via smoking (‘chasing the dragon’); the effect is rapid, but there is less opioid effect because some of the smoke is lost. As addicts become poorer, they often switch from smoking to injection. It is not true that smoking heroin is less addictive than injecting it. Patients who have been off heroin or who have switched suppliers may take doses larger than those they are used to. This may lead to rapid onset of respiratory depression, vomiting and cardiovascular collapse; in many cases, death results. In an attempt to reduce this risk, some agencies have established ‘injecting rooms’ where naloxone is available, but this is politically controversial. Drug traffickers (‘mules’) tend to swallow drugs wrapped in condoms or similar protective materials. Very severe opioid poisoning may occur if these leak, often leading to death. Drug users caught in possession may swallow the ‘wrap’, but the risk of serious effects is low if the amount swallowed is similar to the user’s normal daily dose.
FURTHER READING Chamberlain J M, Klein B L. A Comprehensive Review of Naloxone for the Emergency Physician. Am J Emerg Med 1994; 12: 650–9. Frolich M, Giannotti A, Modell J H. Opioid Overdose in a Patient using a Fentanyl Patch during Treatment with a Warming Blanket. Anesth Analg 2001; 93: 647–8. Goldfrank L, Weisman R S, Errick J K et al. A Dosing Nomogram for Continuous Infusion of Intravenous Naloxone. Ann Emerg Med 1986; 15: 566–70. Hendra T J, Gerrish S P, Forrest A R. Fatal Methadone Overdose. BMJ 1996; 313: 481–2. Spiller H A, Gorman S E, Villalobos D et al. Prospective Multicentre Evaluation of Tramadol Exposure. J Toxicol Clin Toxicol 1997; 35: 361–4.
66
© 2003 The Medicine Publishing Company Ltd