Pioneer Valley Private Hospital, Mackay, Queensland 4740, Australia
* E-mail: kg{at}matilda.net.au
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Abstract |
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Keywords: analgesics, opioid ; complications, serotonin toxicity syndrome ; pharmacology, MAO inhibitors ; serotonin re-uptake inhibitor
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Introduction |
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Ever since the initial report by Oates in 195555 there have been periodic reviews in the literature concerning the safety, or otherwise, of opioid analgesics in patients who were taking MAOIs.9 13 36 47 54 61 68 78 The enduring difficulty in understanding the nature of the problem is related to several factors. First, the apparent serotonin re-uptake inhibitor (SRI) capacity of opioid analgesics is only partially documented even now, and it is possible they have other serotonergic effects. Also, until recently, there has been a lack of systematic data to accurately define the features of serotonin toxicity; and the spectrum concept of serotonin toxicity, that emphasizes it is a dose-related phenomenon not an idiosyncratic reaction, has only recently been formulated.20
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Definition and description |
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Serotonin toxicity has now been more clearly characterized as a triad of neuro-excitatory features.
The features that usually distinguish it from other states with which it might be confused are: myoclonus, clonus and hyperreflexia.12 20 27 28 80 83 Professor Whyte's group at the Hunter Area Toxicology Service (HATS) have prospectively documented over 2000 cases of serotonergic drug overdose. Whyte has applied decision tree rules to their large data set and found ... only clonus (inducible, spontaneous or ocular), agitation, diaphoresis, tremor and hyperreflexia were needed for accurate prediction of serotonin toxicity as diagnosed by a clinical toxicologist. The decision rules are detailed in their seminal paper,12 which should be studied. They demonstrate clearly that if, in the presence of a serotonergic agent, spontaneous clonus is present serotonin toxicity may be reliably diagnosed; failing that, if inducible clonus is present with agitation or diaphoresis serotonin toxicity may be reliably diagnosed.
Clinically, the onset of frank toxicity is usually rapid, because it results from drug combinations and starts when the second drug reaches effective blood levels. The general clinical picture is often alarming, and rapidly progressive after the first or second dose of the second serotonergic drug in the patient's regimen. The serotonin toxic patient is often initially alert, even hypervigilant, with tremor and hyperreflexia. Ankle clonus and myoclonus may be demonstrable. Neuromuscular signs are initially greater in the lower limbs, then become more generalized as toxicity increases. Patients may exhibit such pronounced tremors as to cause concern that they may precipitate themselves from their bed to the floor. Then the autonomic features become more evident with fever, sweating, mydriasis, tachycardia and tachypnoea. These features fluctuate mildly, but are not usually severe, nor a management problem. Other symptoms may include shaking, shivering often including chattering of the teeth and sometimes trismus and even opisthotonous. Pyramidal rigidity is a late development in severe cases, and when it affects truncal muscles can impair ventilation. Rigidity, decreasing , and a fever of more than 38.5°C heralds life-threatening toxicity.
A possible differential diagnosis is often stated to be neuroleptic malignant syndrome (NMS) where bradykinesia results in a state of immobilization, akinesia and stupor, lead pipe or cogwheel rigidity, fever and autonomic instability. However, in clinical practice, the following features invariably clearly differentiate the two.20 79 82 84
NMS shares similarities with malignant hyperthermia (MH)40 41 77 and for the same reasons is unlikely to be confused with serotonin toxicity, except, perhaps, whilst a patient is under anaesthesia when hyperkinesia, hyperreflexia and clonus may be suppressed. Another possible differential diagnosis is anticholinergic delirium. Both anticholinergic delirium and serotonin toxicity can manifest with impairment of consciousness, tachycardia and pyrexia, but diaphoresis, clonus and hyperreflexia usually distinguish them and in anticholinergic toxicity the skin and mucous membranes are dry, and increased tone and hyper-reflexia are not present. Diaphoresis, clonus and hyperreflexia also make it difficult to confuse serotonin toxicity with drug withdrawal, for example alcohol or benzodiazepines. Exclusion criteria for the diagnosis of serotonin toxicity have been suggested,73 including recent administration of a neuroleptic and substance withdrawal. There is no logical justification for those, or any other features, assuming a hierarchical precedence over signs of serotonin toxicity, as has been discussed elsewhere.25 27 28 In contrast to MH and NMS, serotonin toxicity is directly and frequently related to ingestion of serotonergic agents (i.e. it is poisoning). Conversely, NMS and MH are rare idiosyncratic reactions. NMS is not more common after over-doses.37
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Implicated drugs |
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Familiarity with the drugs in Table 1 will ensure serious reactions are avoided. The old MAOIs are well-known, the most frequently encountered are phenelzine and tranylcypromine. The newer RIMA called moclobemide is an MAOI, as is linezolid, the new antibiotic. The standard SSRI antidepressants are also well-known, some other drugs with significant SRI potency are less familiar. These include the dual action antidepressants (SNRIs) venlafaxine, duloxetine, milnacipran and the weight reduction drug sibutramine. Some of the opioid analgesics are weak SRIs (see Table 2). The anti-histamine chlorpheniramine is available for the i.v. route of administration, and being an SRI might possibly provoke a reaction.
The early drugs that were involved in these interactions with MAOIs (pethidine and imipramine) are weak SRIs and, because there is a doseeffect relationship, they usually fail to produce a reaction. The practical consequences of this can be seen clearly from the work published by Evans-Prosser in 1968. As a result of the uncertainty in this area Churchill-Davidson9 developed a testing procedure for checking whether patients on MAOIs were going to exhibit a reaction to analgesics. Evans-Prosser modified this procedure in 1968 and described an experiment in which they gave 15 patients injections of pethidine, morphine or water, in graduated doses, under controlled conditions in hospital. The maximum dose of pethidine was 75 mg and morphine 7.5 mg. All of the 15 patients received, in blind random order, each of these three treatments. They administered a maximum single dose of 75 mg pethidine to 15 subjects, none of whom experienced any serotonergic symptoms. Serotonin toxicity was not then well defined or understood, so they could not have known the key symptoms to elicit, so did not examine patients for hyperreflexia or clonus, they measured the pulse and arterial pressure. A lack of awareness of what specific symptoms to look for continues, even now, to inhibit detection of these reactions. Evans-Prosser's group of patients represents the only case series of this sort, and even now constitutes valuable data. This confirms the predictions of the spectrum concept of serotonin toxicity, which is that weak SRIs like pethidine are sometimes capable of precipitating serotonin toxicity, but only in susceptible individuals, or with particularly large doses. The complete list of the references relating to serotonin toxicity and analgesics, located through a search of the listed papers and standard databases (approximately 40), are detailed at www.psychotropical.com. There are some cases detailed there that do not appear in any other review of the subject.5 20 33 Pethidine has undoubtedly caused a number of severe reactions, and some fatalities;48 57 58 60 63 70 the other SRI analgesics have also precipitated some fatalities.31 53 59 60 64 69 Especially when considered in relation to the Evans-Prosser paper above, this is a clear illustration of how a small case series, using usual therapeutic doses, may lead to a false sense of security, because the doseeffect relationship is not sufficiently appreciated. This is especially important when phamacokinetic and pharmacodynamic interactions coincide, which can elevate blood levels above those found in the average patient. We now know that differences in cytochrome P450 enzymes produce 2050-fold variations in serum levels between different patients.34
The limited available clinical and experimental data agree that morphine analogues are not SRIs, nor do any of them precipitate serotonin toxicity with MAOIs (morphine, codeine, oxycodone, buprenorphine). There are no reports of serotonin toxicity with those drugs. The phenylpiperidine series opioids, pethidine (meperidine), tramadol, methadone and fentanyl (and congeners), and dextromethorphan and propoxyphene, are probably all borderline, being weak serotonin re-uptake inhibitors.10 These drugs have been implicated in multiple reports, which are almost certainly serotonin toxicity, as judged by a subjective interpretation of the old case reports20 and informed by more accurate recent data concerning the characteristic features of serotonin toxicity.12 More precise data about SRI potency from human cloned receptor assays would be valuable, because we can reliably predict that only those drugs that are potent SRIs or releasers will precipitate serotonin toxicity. Unfortunately, the only published data are from the paper by Codd,10 which used older assay methods. The central internet accessible database maintained by Roth's group (called the PDSP Ki database at http://pdsp.cwru.edu/pdsp.php)65 contains no additional data (as of March 2005) on any of the drugs listed in Table 2.
Details of all cases involving analgesics (approximately 40) are contained in this author's updated review.29 In summary, all the opioid analgesics with serotonergic effects have been involved in serotonin toxicity reports, but none of the drugs without SRI capacity have been. There remains a possibility that drugs with anomalous properties, like tramadol and pethidine, may yet be revealed to be working as serotonin releasers. Recently developed assays to estimate these properties may elucidate the situation in the near future.66
There are a few individual case reports worthy of particular comment. In my opinion the Noble case report fatality53 was probably a result of serotonin toxicity. This patient was on MAOIs before cardiac surgery and was administered fentanyl. In the postoperative recovery phase the patient exhibited shivering and hyperpyrexia. The authors considered the possibility of serotonin toxicity and reached the conclusion that fentanyl cannot be assumed to be safe. A more recent report by Roy and colleagues, although not considered by its authors to be serotonin toxicity, may represent a hitherto unrecognized report of serotonin toxicity with fentanyl.68 Therefore, as predicted from the SRI potency data, there is a question mark over fentanyl, despite opinions in previous reviews that it is safe.1 8 72 However, its potency as an SRI is low, so as expected (and like pethidine) it has been reported to have been used with impunity.13 16 36 47 53 68 72 78 It is appropriate to note that it is probable that fentanyl has been used in a many cases in combination with MAOIs that have not been reported in the literature because there has been no problem. There is insufficient basis for an accurate estimate of the risk, which would seem to be so low that one could not suggest use of fentanyl (or its congeners) is strongly contra-indicated if there is no appropriate alternative. Although there are no SRI data concerning remifentanil, all fentanyl congeners have short half-lives and would be expected to be more safe because they are quickly reversible. Remifentanil's safe use in conjunction with MAOIs has been reported.75 It is to be expected that pharmacogenetics may enable advanced prediction of those cases likely to develop high blood levels and thus be at higher risk, and in the future such patients may be genetically screened before operation if they are on MAOIs.35
There are a number of lesser known drugs, such as the MAOIs linezolid and moclobemide, and the SRIs tramadol and sibutramine, which possess these properties and can therefore precipitate life threatening serotonin toxicity.23 26 We can therefore predict that combinations of linezolid with various lesser known SRIs, like sibutramine or even fentanyl, might possibly precipitate serious serotonin toxicity, or even cause fatalities.22 24 Deaths that might have been prevented are still occurring.4 56 76 The Ottey case is a salutary example of the clinical consequences that can result from a single dose of an SRI; this occurred in a European university hospital recently when imipramine 225 mg was administered to a patient already stabilized on 50 mg daily of tranylcypromine. The error was recognized and the patient was transferred to ITU. Rapid deterioration occurred with rigidity and hyperthermia of 40°C, the patient died within 24 h. No serotonin antagonists were used; neither does the report contain references indicating post hoc recognition of their possible benefit. A knowledge of the properties of these drugs may help to ensure that problems can avoided in most clinical situations, and treated appropriately if they occur.
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Treatment |
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The HATS treatment protocol builds on the data and recommendations reviewed previously by Gillman.20 21 Cyproheptadine (see Table 3), only available as tablets, is effective for the milder cases; current experience suggests doses of 12 mg orally (or crushed via nasogastric tube) initially, followed by 48 mg every 6 h. However, if charcoal has already been given, or the urgency of the situation requires rapid intervention, then chlorpromazine may be used via the i.v. route. At present there is no widely available 5-HT2A antagonist for i.v. use in humans except chlorpromazine. In severe toxicity (life-threatening cases) it has been used in more than 20 instances (in the HATS experience) with good effect and no fatalities: see also reference21 for a review of all other reported non-HATs cases. Fluid loading is advised before giving chlorpromazine (because of hypotension via adrenergic 2 receptor antagonism). HATS experience suggests dosing in the range of 12.525 mg i.v. initially, followed by 25 mg orally or i.v. every 6 h. Higher doses have also been used with apparent safety and effectiveness, all reported cases in the literature from 1955 have been systematically reviewed in detail.18 19 21 Chlorpromazine might possibly aggravate cardiotoxic or epileptogenic properties of other drugs (e.g. venlafaxine and TCAs). Further details of treatment with 5-HT2A antagonists are contained in recent toxicology texts.83 Benzodiazepines have recently been demonstrated to reduce pyrexia in serotonin toxic rats and may be a reasonable adjunctive treatment with 5-HT2A antagonists.4952 These recent developments strongly support the early work, reviewed by Gillman,20 concerning the effectiveness of 5-HT2A antagonists in preventing hyperpyrexia and death in an animal model of serotonin toxicity, and also for the treatment of serious serotonin toxicity in humans.21 28 83
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Conclusion |
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However, the clinical situation and the risks are now more clearly defined and understood and the information herein will enable many clinicians to be more confident when making decisions about patient management. Choices involving the known serotonergic opioids can now be made in particular clinical situations by balancing the advantages and disadvantages that there may be for individual patients with respect to particular drugs. The level of risk with known serotonergic opioids is probably low, but its unpredictable and serious nature makes it difficult to form judgments. All other factors being equal, it would seem prudent to use the drugs known not to be SRIs where possible. These judgments may be tempered by the knowledge that any reaction is dose-dependent and that we are now confident that reactions can be successfully treated, if severe, with 5-HT2A antagonists.
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Acknowledgments |
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References |
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