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Psychotropic Drugs and the Perioperative Period: A Proposal FRITS J. HUYSE, M.D., PH.D., DAAN J. TOUW, PHARM.D., PH.D.
ROB STRACK VAN SCHIJNDEL, M.D., JAAP J. DE LANGE, M.D., PH.D.
Evidence-based guidelines for the perioperative management of psychotropic drugs are lacking.
The level of evidence is low and is based on case reports, open trials, and non-systematic re-views. However, the interactions and effects mentioned indicate that patients who use psychotrop-ics and require surgery have an enhanced perioperative risk. A group of clinicians from severalclinical disciplines determined which risks should be considered in an integrated preoperativeassessment, as well as how psychotropics might interfere with these risks. The risks that shouldbe considered in the perioperative period are the extent of the surgery, the patient’s physicalstate, anesthesia, the direct and indirect (Phase I and II) effects of psychotropics, risk of with-drawal symptoms, and risk of psychiatric recurrence or relapse. Because of new drug develop-ments, the risk of interactions increases. The literature has not provided articles that systemati-cally address these risks. On the basis of a systematic analysis of the available literature guidedby the formulated perioperative risks, a proposal for the perioperative management of psycho-tropics was formulated. Patients who use lithium, monoamine oxidase inhibitors, tricyclics, andclozepine have serious drug–drug interactions, with increased physical risks, including with-drawal, and therefore qualify for American Society of Anesthesiologists (ASA) Classification 3.
From the perspective of the physical risk, they require discontinuation. However, from the per-spective of the risk of withdrawal and psychiatric relapse and recurrence, these patients deserveintensive, integrated anesthetic/psychiatric management. For patients on selective serotonin reup-take inhibitors (SSRIs) who are mentally and physical stable (ASA Classification 2), the risk ofwithdrawal seems to justify their continuation. Yet, patients on SSRIs with higher physical or psy-chiatric risks should be seen in consultation. Both the physical and psychiatric risks of patientswho use antipsychotics and other antidepressants should be regarded as enhanced. From a physi-cal perspective, they qualify for ASA Classification 2. From the perspective of withdrawal andpsychiatric recurrence or relapse, they should be seen by (their) psychiatrists. Preoperative as-sessment clinics offer the opportunity to assess and evaluate these risks in order to deliver pa-tient-tailored integrated care. Authors propose a model for quality management. Received December 23, 2003; revised April 16, 2004; January 5, 2005;accepted February 4, 2005. From the Dept. of General Internal Medicine, In1988,acallwasmadeforamorepreventiveandstruc- tured approach to the preoperative assessment and pre- University Medical Center, Groningen, the Netherlands; the Depts. of and postoperative medical evaluation of surgical patients.1 Intensive Care and Anesthesiology, University Medical Center, VrijeUniversiteit, Amsterdam; and Apotheek Haagse Ziekenhuizen, The The clinical objective for preoperative assessment was a Hague, The Netherlands. Send correspondence and reprint requests to Dr.
move toward evidence-based guidelines. This should lead Huyse, Dept. of Internal Medicine, Hanzeplein 1, PO Box 30.001, to reduction of morbidity and mortality and enhancement 9700RB Groningen, the Netherlands; e-mail: [email protected] Copyright ᭧ 2006 The Academy of Psychosomatic Medicine of quality of care. Also, it should result in a reduction of Psychosomatics 47:1, January-February 2006 costs by avoiding unnecessary procedures. It has guided of available information.5 Because the risks involved come the development of pre-assessment clinics, where surgical from intensivistic, anesthesiological, pharmacological, ge- patients are procedurally evaluated before elective surgery.
riatric, and psychiatric perspectives, in this article, medical This offers an opportunity to change from ad-hoc psychi- specialists who represent these perspectives will combine atric consultations in inpatients admitted for surgery, where available evidence and clinical reasoning to formulate a pro- the anesthesiologist or surgeon perceives a specific surgical posal for perioperative psychotropic drug-management in problem related to psychotropic drug use, to a more inte- elective surgery. For the above-mentioned reasons, the evi- grated approach in a pre-assessment clinic; this would dence might be thin; however, the primary objective is to include guidelines for psychotropic drug-management in provide a framework for integrating clinical reasoning and the perioperative period. Their focus should be on risk- a model for integrated risk-management that can be part of management to prevent perioperative mortality, physical morbidity, withdrawal problems, and acute or long-termrelapse of psychiatric morbidity, thereby preventing last- Such guidelines should include indications for inter- Through clinical reasoning, the authors formulated a series disciplinary consultations. The need for a systematic ap- of risks to be considered in patients who use psychotropics proach toward perioperative psychotropic drug-manage- and apply for elective surgery. These risks are described ment was first addressed in a study assessing the use of under Decisions to Be Made, in the Results section. The psychotropic drugs in a preoperative-assessment clinic literature is reviewed to evaluate the empirical evidence population. Three hundred surveys were distributed, with available against these formulated risks. This is described a response rate of 53%. Of those who responded, 43% used under Available Evidence, also in the Results section. A psychotropic drugs. Of these patients, 35% used antide- MEDLINE search combining “anesthesia” or “preopera- pressants; 34%, benzodiazepines; 19%, combinations of tive care” or “perioperative care” and “mental disorders” these and other psychotropics, such as antipsychotics, lith- or “psychotropic drugs,” “antipsychotic agents,” “antide- pressant agents,” or “serotonin reuptake inhibitors,” A survey (response rate: 75%) among 150 United States “monoamine oxidase inhibitors,” or “lithium” did reveal anesthesiology programs, assessing the current practice of that evidence on the level of metaanalysis, randomized their perioperative handling of chronic medications, re- clinical trials, or practice guidelines was not available, ex- vealed a large inter-practice variation.3 The average rates for cept for the guideline suggested by Drugs and Therapeu- discontinuation of the most prevalent types of medication tics Bulletin.4 The main evidence was on the level of non- were the following: aspirin: 82%, ibuprofen: 77%, mono- systematic reviews, open trials, and case reports assessing amine-oxidase inhibitors (MAOIs): 51%, diuretics: 38%, tri- selective aspects of the earlier-formulated physical and cyclics: 9%, and oral contraceptives, 4%. In a recent series psychiatric risks. As a result of clinical reasoning and avail- of articles in Drugs and Therapeutics Bulletin, which is a able evidence, we make a proposal for drug-management U.K. independent review for doctors and pharmacists from for psychotropics. The following drugs have been evalu- the consumers’ association, it is stated that there are few ated: lithium, MAOIs, tricyclic antidepressants (TCAs), se- published data to formulate a guideline for chronic drug- lective serotonin reuptake inhibitors (SSRIs), other anti- management in the perioperative period.4 Therefore, they depressants, classic antipsychotics, second-generation conclude that physicians generally rely on their own expe- antipsychotics, and clozapine. The risks of benzodiazepine rience, which explains the large inter-practice variation.3 use for excess sedation or withdrawal related to perioper- The best evidence for the development of clinical guidelines ative use are not discussed because this is part of day-to- is from randomized, controlled trials. Yet, the area of drug– day anesthetic practice,6 nor are specific perioperative risks drug interactions is not an area for such studies because the discussed in patients with substance abuse.
number of combinations of drugs is too high, and studies could easily become unethical. This is an area where thepatient is the “guinea pig,” and the clinician gains knowl- edge by being a good observer of clinical evidence of theseinteractions. On the other hand, possible hazards may be As seen in Table 1, there are two main risks to be dealt assessed by clinical reasoning, combining different pieces with in patients selected for elective surgery, who use psy- Psychosomatics 47:1, January-February 2006 Handling of Psychotropics in Elective Surgery chotropic drugs. The primary risk of psychotropic use to of surgery is operationalized as follows: 1) moderate (e.g., be considered is excess morbidity and mortality through appendectomy, mastectomy, TUR); 2) large (e.g., laparot- physical interferences. The physical risks of surgery in- omy, bowel-resection, cholecystectomy with choledocho- clude the extent of the surgery, the specific disease/handi- tomy, peripheral-vascular surgery, or major amputation); cap that requires surgery, physical comorbidity, and type and 3) very large (e.g., aorta surgery, abdomino-perineal of anesthesia. Psychotropic drug use should be seen as a resection, pancreatic- or liver resections, esophago-gas- physical comorbidity with risks of interaction and physical trectomy).7 In the Practice Advisory for Pre-anesthesia withdrawal. Thereby, it leads to excess physical morbidity Evaluation by the American Society of Anesthesiologists, and mortality. The second risk concerns the impact of dis- a comparable classification of surgical invasiveness is pro- continuation of psychotropic drugs on the psychological posed (low, moderate, or high) without further specifica- functioning of patients with existing psychiatric morbidity.
tion.8 Another measure for the impact of surgery is the This includes the risks of psychological withdrawal and direct operative mortality. However, in elective surgery, the direct operative mortality is very low and therefore is nota discriminative factor.
is the type and extent of surgery, its stress-inducing effects, The risk of the patient’s physical status and its related impact on the metabolism of, for instance, for the outcome of surgery comprises two components: cortisol, cathecholamines, and cytokines.7 A classification 1) the status related to the disease/handicap indicated for for the level of stress-induction by the different surgical surgery; and 2) the status related to the patient’s comorbid- procedures has been proposed. Procedures associated with ity. The impact of the disease/handicap is reflected in the moderate-to-severe stress, such as open abdominal surgery, direct operative mortality. The risk of the comorbidity is increase heart rate and plasma levels of cortisol, as well as classified in the generally accepted classification of the epinephrine and norepinephrine. Other procedures, which American Society of Anesthesiologists; the ASA classifi- do not induce such changes, are considered as minimally cation.9 Its main purpose is to differentiate among patients stress-inducing.7 The level of stress-induction for the size without comorbidity, those with light-to-moderate system Risks to be Considered in Patients Receiving Psychotropics in the Perioperative Period
Extent and Type of Surgery
Local Infiltration for Excisions Versus Larger Surgery
Effects on pharmacokineticsStress-inductionOral or abdominal surgeryNeed for post-operative ventilation Physical status, including substance use disorders
ASA classification9
I. Healthy patientII. Mild systemic diseaseIII. Severe systemic disease with functional limitationsIV. Severe systemic disease, constant threat to lifeV. Moribund, unlikely to survive 24 hours Anesthesia
See Table 2
BeneficialPossibleOf noteHazardousResults in the need to discontinue Oral, suppository, intramuscular, intravenous Yes/No/IrrelevantMost evidence available with benzodiazepines and haloperidol Psychiatric
Results in the need for psychiatric consultation Risk of psychiatric relapse or recurrence Results in the need for psychiatric consultation Psychosomatics 47:1, January-February 2006 problems with no functional impairment, and those with to cause severe disturbances. Interactions of note are those more serious system problems, with functional restrictions.
where disturbances have been reported and where caution Among the patients with physical comorbidity, there are is necessary when the combinations are used; and 4) haz- two specific groups who are of interest from the perspective ardous interactions, when the drug combination should be of psychotropic drug use: First, there are those patients who avoided. These concern well-documented interactions have, because of their physical morbidity, diminished func- that have caused life-threatening incidents. The authors tional capacity of organs that are crucial for the metabolism reviewed the available literature along these criteria but of drugs and their excretion; the kidney and the liver.10–12 did not specify the criteria of their literature search. Other The same is true for frail elderly patients, because of re- available ratings for the severity of drug–drug interac- duced compensational capacity of several organ systems.13 tions, which broaden the scope beyond surgery, use com- These are patients at risk for delirium. Such risks should parable classifications.16 Overviews of relevant interac- have been taken into account at prescription. The second tions in comorbid patients seen in consultation–liaison group comprises addicted patients. These patients might practice have recently become available.17,18 Given that underreport their physical state or might not report their drug–drug interactions result from individual profiles of addiction and, as a consequence, suffer withdrawal, in- drugs, and as drug development is an ongoing process, cluding delirium, and may have complex behavioral prob- and new relevant complications of drugs or interactions lems that interferes with medical care. In this group, effects are reported on a daily basis, the risk of individual drug– of anesthetics might be influenced by enzyme-induc- drug interactions should be assessed through available tion.12,14 Furthermore, these patients are at risk for organ- The third factor influencing perioperative Discontinuation: Preoperative Fasting and Route of Ad- morbidity and mortality is related to anesthesia, itself, and the increase in this risk due to the combination of anesthetic routes of administration of drugs because of the anesthe- drugs with other drugs, such as psychotropics. Modern an- siological procedures. It influences the decisions concern- esthesia is flexible. This flexibility offers an opportunity to ing the (dis)continuation of drugs and the change to par- reduce or avoid drug–drug interactions. Before the decision enteral administration. Before surgery, the process of on type of anesthesia, direct and indirect effects through gastric-emptying is important for the timing of discontin- drug–drug interactions should be considered. Therefore, uation of oral drugs. According to current knowledge, pa- we recommend a critical evaluation of use and duration, as tients can use drugs with oral sips until 2 hours before the well as monitoring of psychotropic drug prescriptions at operation.4,19,20 This is also in line with more recent rec- pre-assessment; we need to determine the possible inter- ommendations of preoperative oral carbohydrate nutrition actions with drugs for coexisting physical morbidity, as to prevent postoperative insulin-resistance in elective sur- well as drug–drug interactions with the proposed anesthet- gery.21,22 Oral- and abdominal surgery might be an indi- ics—effects such as hemodynamic instability, including cation for an additional period of fasting. Oral surgery, such cardiac conduction changes, and the effects on CNS func- as in ear-nose-and-throat surgery, might be followed by the tioning in case of postoperative metabolic instability. A introduction of gastric tubes, which facilitates the appli- severity grading for drug–drug interactions pertinent to the cation of nonparenteral drugs. Also, knowledge of intra- anesthesiologist was presented in a recent overview.13 It venous and intramuscular replacement drugs is needed.23 proposes the following classification: 1) beneficial inter-actions, where the combination is used to produce a usefuland advantageous result for the patient; 2) possible inter- Withdrawal and Psychiatric Recurrence or Relapse actions, where an interaction can be expected on a theo- risk of discontinuation of psychotropics for the induction retical basis or because of pharmacological profiles of the of withdrawal syndromes, psychiatric recurrence, or re- drugs. Such interactions are known to cause minor-to- lapse should be assessed. The first risk of discontinuation moderate changes in physiological functioning, and clini- is the immediate effect of discontinuation in terms of physi- cians should be aware that an interaction of any severity is cal and psychological withdrawal. The second risk of dis- possible should these drugs be used again; 3) interactions continuation is the risk of recurrence or relapse and its time of note, where the drug combination can have the potential Psychosomatics 47:1, January-February 2006 Handling of Psychotropics in Elective Surgery succinylcholine, are worthy of note.15 The last affect both the latency and the reversal of neuromuscular blockade.40 A summary of the drug management characteristics for sur- Withdrawal and Psychiatric Recurrence or Relapse gery patients is presented in Table 2.
available clinical evidence suggests that there is no with-drawal effect after abrupt discontinuation of lithium.41,42 Abrupt discontinuation of lithium in a patient with bipolardisorder increases the risk of recurrence of the illness, es-pecially mania, within the next few months. (No direct ef- Pharmacodynamic and Pharmacokinetic Aspects fects have been found.) This increased risk exceeds the risk ium gives relief of bipolar disorder by an unknown mech- of recurrence in the natural course of the illness.43–45 anism. Lithium is only available as tablets. After oral ad-ministration, lithium is well absorbed and distributed over IV-IM Change and Alternative Drugs total body water. Lithium is eliminated exclusively by renal practice, there are no intramuscular (IM) or intravenous excretion, with a half-life of 20–27 hours after a single (IV) preparations of lithium available. Antipsychotics used dose. This might increase to 36 hours in case of chronic in the acute phase of manic episodes are an option, specif- use. Lithium is glomerular-filtrated, and 80% is reabsorbed ically, haloperidol, as there is extensive experience with in the proximal tubulus. The reabsorption is related to so- this drug in physically ill patients.46 (See “First-Generation Antipsychotics” for listing of effects on cardiac conduc-tion, such as QTc47,48 [www.qtdrugs.org]).
Lithium has a narrow therapeutic window.
Toxicity is expressed by gastrointestinal symptoms, ECG The greater the extent of the surgery and changes, and CNS symptoms.24 Lithium is well tolerated the higher the ASA classification, the higher the risk for by the cardiovascular system. Its use is not absolutely con- complications due to dysequilibrium of electrolytes traindicated in patients with coexisting cardiovascular dis- through gastrointestinal, cardiovascular, and renal dysre- ease;25 however, cases of changes of the smoothing of the gulations, and, therefore, the risk of further dysregulation, T-wave,26,27 ventricular arrhythmia,28,29 and myocardi- resulting in neurological complications.
tis29,30 have been reported. Sinus dysfunction can lead toextreme atropine-resistant sinus bradycardia, which might Irreversible and Reversible Monoamine Oxidase happen with normal as well as toxic blood levels,31–36 and might only become manifest during anesthesia.37 Toxicityis related to plasma levels of more than 1.5 mmol/liter, but Pharmacodynamic and Pharmacokinetic Aspects might occur at lower levels. When the plasma sodium con- reversible MAOIs tranylcypromine and phenelzine and the centration is low or when the patient is dehydrated, lithium selective and reversible MAOI moclobemide act by inhi- clearance falls, and blood lithium levels rise. Lithium- bition of the metabolic breakdown of norepinephrine and related polydipsia, specifically when not compensated, and serotonin by the MAO enzyme. Thereby, they increase the a complicated postoperative course are serious additional level of norepinephrine and serotonin at the receptor site.
Tranylcypromine and phenelzine irreversibly inhibit MAO,and, after cessation, it takes 1–4 weeks for the enzyme to The interaction with NSAIDs (nonsteroidal regain its activity. Moclobemide is a reversible inhibitor, anti-inflammatory drugs) is reported as hazardous.15,38 The with an elimination half-life of 1–3 hours. All MAOIs are toxicity of lithium can be increased by drugs that reduce lithium excretion or increase reabsorption in the kidney;these are drugs such as NSAIDs, ACE-inhibitors, thiazide There are no direct effects relevant for sur- diuretics, and metronidazole.24,39 The effect of the loop di- uretics on lithium excretion is far less than the effect of thethiazides. Furthermore, lithium clearance can be increased Hazardous interactions in both reversible by CO2-anhydrase inhibitors. The interactions with neu- and irreversible MAOIs and anesthesia have been re- romuscular-blocking agents, specifically pancuronium and ported.15 They include opioid analgesics (specifically peth- Psychosomatics 47:1, January-February 2006 Clozapine
Antipsychotics
First-Generation
Tricyclics
Elective
Patients
Management
Psychotropic
Proposal
A
Psychosomatics 47:1, January-February 2006 Handling of Psychotropics in Elective Surgery idine), nefopam (a non-opioid analgesic), and sympathi- been case reports of acute exacerbations.64,65 From the sur- comimetics. These interactions are twofold—effects on the gical perspective, a period of discontinuation of 2 weeks blood pressure and on the CNS. Serious, including lethal, of the irreversible blockade of MAO is needed for its res- pressor effects have been reported because of interactions toration. It is suggested that patients on irreversible MAOIs with indirectly-acting sympathicomimetic agents (amphet- could change some weeks before the surgery to reversible amine, ephedrine, metaraminol). These release intracellular MAOIs, to reduce the period of discontinuation.66 Because stores of norepinephrine, and produce epinephrine-related the effects of moclobemide discontinuation are reversed hypertensive crises.49,50 Directly-acting sympathicomi- within 16 hours, and no (or only rare) withdrawal has been metic agents (norepinephrine, epinephrine, isoprenaline) described, the period of discontinuation starts on the day are regarded as safer. However, in animal studies, a three- fold potentiation of the pressor effect of epinephrine bymoclobemide has been reported.51 Epidural or intrathecal IV-IM Change and Alternative Drugs anesthesia results in a blockade of the sympathetic system.
ing, there is no IV replacement available.
Consequently, on theoretical grounds, a combination ofMAOI and such type of anesthesia is contraindicated. The few case reports in the literature are contradictory, how- pressure and its need for adjustment, the higher the chance ever.52,53 The reaction on the CNS has two mechanisms:54 of interactions between MAOIs and (indirect-acting) sym- a Type I reaction is an excitatory form that is attributable pathicomimetics. The higher the chance of cardiovascular to a central serotonergic overactivity; the serotonergic syn- instability, the higher the chance of interactions.15,67 drome.55,56 Pethidine, pentazocine, and dextromethorphanblock presynaptic reuptake of serotonin. Therefore these drugs potentiate the development of a serotonin syndrome.
In such patients, “MAOI-safe” surgery, which excludes Pharmacodynamic and Pharmacokinetic Aspects pethidine (meperidine) and dextromethorphan and includes clic antidepressants act by presynaptic inhibition of the up- the use of morphine and fentanyl, is recommended.57–59 take of norepinephrine and serotonin. They also block post- The Type II reaction is a depressive form, and is supposed synaptic cholinergic, histaminergic, and alpha1-adrenergic to be related to the inhibition of hepatic microsomal en- receptors. Tricyclic antidepressants are well absorbed in zymes, leading to the accumulation of free narcotics and, the gastrointestinal tract, but there is a large first-pass effect as a result, CNS depression. Irreversible MAOIs need to in the liver. Elimination is metabolic by Cytochrome P450 be stopped for 2 weeks for the regeneration of MAO and isoenzymes (Phase I metabolism), followed by conjugation normal monoamine metabolism. Even in such patients, car- of hydroxide metabolites (Phase II mechanism). In addition diovascular collapse during anesthesia has been reported.60 to the variation between the individual drugs of this class, With morphine, a Type II (depressive) reaction has been there is also a large inter-individual variation; elimination reported.54 Therefore, all reviews recommend discontinu- half-life varies from 12 to 24 hours for extensive metabol- ation of the drug. As far as concerns about the discontin- uation of the reversible MAOIs, the literature is contradic-tory.51,61,62 All tricyclics lower the seizure threshold.
The effects on the cardiac conduction system, such as QTc, Withdrawal and Psychiatric Recurrence or Relapse and their relation to arrhythmias, have been amply de- Treatment with irreversible MAOIs is a clear indicator of scribed. The main effects are on rate, rhythm, and contrac- psychiatric treatment of a disorder with a complicated tility through four mechanisms: 1) anticholinergic action; course. Abrupt discontinuation of classical MAOIs can re- 2) interference with reuptake of adrenergic amines; 3) direct sult in severe withdrawal syndromes presenting as medical myocardial depression; and 4) alterations in membrane per- emergencies such as serious depression, suicidality, hallu- meability.48,69 The anticholinergic properties might induce cinations, and paranoid delusions. The withdrawal syn- an a-dynamic ileus, glaucoma, and postoperative delirium.
dromes and, consequently, the prevention of an MAOIwithdrawal-precipitated syndrome is a high priority.63,64 It Hazardous interactions of tricyclics have is not absolutely clear whether these are pure withdrawal been reported on blood pressure in combination with sym- symptoms or they reflect recurrence or relapse; there have pathicomimetics,15 and induction of seizures has been re- Psychosomatics 47:1, January-February 2006 ported with enflurane.15,70 Reported interactions of note are line, fluoxetine, and paroxetine. They act by presynaptic longer-lasting effects of antimuscarinics.15 In patients us- inhibition of serotonin reuptake. All drugs are orally well- ing tricyclic and tetracyclic antidepressant agents, the cir- absorbed and eliminated by hepatic metabolism. The elim- culatory effects of adrenaline and noradrenaline are poten- ination half-life of fluvoxamine is 17–23 hours and cital- tiated, respectively, 2 and 9 times.71 The mechanism of opram, 36 hours. Paroxetine has an elimination half-life of action of the resulting hypertensive crisis is related to the 24 hours, sertraline of 26 hours, and fluoxetine of 2–3 days.
amine reuptake-blocking properties of the tricyclics.72 Car- Sertraline and fluoxetine, however, are converted to active diac effects of atropine in patients treated with tri- and metabolites with an elimination half-life of 3–5 days and tetracyclic antidepressant medication were assessed in a 7–9 days, respectively. The elimination half-life of fluox- prospective, controlled design. There was no evidence that etine and its active metabolite, norfluoxetine, are prolonged these drugs rendered the heart more susceptible to the car- diac effects of atropine.72 Recently, Malan et al.73 reportedsevere, refractory hypotension during anesthesia in a pa- The direct effects of serotonergic reuptake tient on chronic clomipramine therapy. Hypotensive crises inhibitors (SSRIs) are related to serotonergic potentiation can be avoided by using indirect-acting sympathetic pres- and are therefore gastrointestinal symptoms, headache, an- sor amines.67 The effects of norepinephrine might be re- orexia, agitation, sleeplessness, and bleeding.55,56,59,77 Ex- cept for the gastrointestinal effects (5% to 10%), the inci-dence of these phenomena is low. The increased risk of Withdrawal and Psychiatric Recurrence or Relapse gastrointestional bleeding is about three times that of pa- large variation of withdrawal symptoms has been reported.
tients not using these drugs. The absolute risk is small and The main group of symptoms is related to cholinergic with- comparable to the risk in aspirin and NSAID use. This risk drawal: gastrointestinal symptoms; symptoms of general is increased when a combination of an SSRI and aspirin or malaise; and sleep disturbances, including vivid dreams an NSAID is used. In a recent cohort study in the Neth- and (hypo)mania. Also, there might be movement disorder- erlands, the increased risk appeared to be related to the related symptoms, such as parkinsonism and akathisia and degree of serotonin-reuptake inhibition, being most ele- cardiac arrhythmia.64 These symptoms appear during the vated in fluoxetine, sertraline, clomipramine, and paroxe- first 2 days after discontinuation and last for about 2 weeks tine use.78 Also, SSRIs are among the psychotropics those smoothed by gradual discontinuation.64 In patients on with the highest risk of the development of the syndrome maintenance therapy for depressive disorder who discon- of inappropriate secretion of ADH (SIADH), sustained re- tinue their medication, the relapse rate is estimated to be 2 lease of ADH resulting in hyponatremia, serum hypo- to 4 times higher in the year after discontinuation, com- osmolality, and less than maximally-diluted urine. Al- though its mechanism is unknown, and SIADH is relatedto pulmonary and neurological diseases, as well as drugs, IV-IM Change and Alternative Drugs SIADH should primarily be seen as a direct effect of international variability in the availability of intravenous tricyclics. An exception might be clomipramine and ami-triptyline.23 The interactions occur through the effects of the SSRIs on the Cytochrome P450 system (Phase I).
Most important are inhibition of the metabolism through higher chance of instability of circulatory volume and re- competition and the related increased serotonergic activ- lated blood pressure. In patients using these tricyclics, the ity, which might result in a serotonergic syndrome. The circulatory effects of adrenaline and noradrenaline are po- most hazardous combinations are combinations of SSRIs tentiated because of their amine reuptake-blocking prop- or a combination of SSRIs with MAOIs or serotonergic TCAs such as clomipramine. Although no hazardous in-teractions in anesthesia are mentioned, the combination Selective Serotonergic Reuptake Inhibitors (SSRIs) with pethidine, pentazocine, and tramadol can result in aserotonergic syndrome comparable with the combination Pharmacodynamic and Pharmacokinetic Aspects of MAOIs.15,56,58,59 In the anesthesia literature, avoidance SSRIs at present comprise fluvoxamine, citalopram, sertra- of these opioid analgesics is recommended.59 The literature Psychosomatics 47:1, January-February 2006 Handling of Psychotropics in Elective Surgery describes another mechanism for the development of a se- tions). It mainly inhibits norepinephrine reuptake. No ex- rotonin syndrome. The supposed mechanism is that com- plicit complications are mentioned in the literature in com- petition with other highly protein-bound drugs—in this bination with surgery. Mianserine is an alpha2 antagonist case, lidocaine, midazolam, and fentanyl—results in an in- with alpha1-, serotonin-, and histamine-antagonistic prop- creased free-drug fraction.81 Because of the inhibition of erties. Mianserine is regarded as cardiac-safe.87 A special one or more cytochrome P450 enzymes, a combination of risk for mianserine is the higher incidence of neutropenia enzyme-inhibiting psychotropic and type IC antiar- in elderly patients.88 There is one case report in the Japa- rhythmic drugs with a narrow therapeutic window should nese literature of severe hypotension during anesthesia in only be given after consulting with a clinical pharmacol- a patient who used amantadine and mianserine.89 Mirta- ogist experienced with drug–drug interactions. Because of zapine is an alpha2-antagonist and also blocks serotonin inhibition of the cytochrome P450 3A4 by a metabolite of and histamine receptors. No explicit complications are midazolam, combinations of SSRIs with midazolam mentioned in the literature in relation to cardiac conduction should be monitored with caution, specifically when com- or surgery. Venlafaxine is a serotonin-norepinephrine reup- bined with fluoxetine. The same is true for the combination take inhibitor. At high doses, it also inhibits dopamine with warfarin, because of interactions with the CYP2C iso- reuptake, but its clinical relevance is unclear. Because of enzymes. An interaction relevant for the postoperative pe- its serotonergic characteristics, it might contribute, in com- riod is the inhibition of the metabolism of tramadol by binations with other serotonergic drugs, to a serotonergic paroxetine, resulting in excess sedation and an impairment syndrome.55,57 Venlafaxine has a low incidence of clini- of the analgesic action.82 Because of genetic polymor- cally significant increases in blood pressure.90 No signifi- phism, clinical implications vary in patients. Specific at- cant conduction abnormalities nor arrhythmias have been tention should be paid to possible interactions with drugs reported.90 However, no studies with venlafaxine have been performed in cardiovascular-compromised patients.90Venlafaxine is, in-vitro, a weak inhibitor of CYP2D6, but Withdrawal and Psychiatric Recurrence or Relapse it has less propensity for important metabolic interac- Withdrawal is a recognized clinical problem in SSRI tions.91 Except for fentanyl-induced rigidity during emer- use.83–86 It is recognized in the anesthesiological literature gence from general anesthesia, until now, no serious com- as a reason for the continuation of these drugs during sur- plications during surgery have been reported.92 gery.66 The withdrawal symptoms are dizziness, lethargy,palpitations, gastrointestinal complaints, a flu-like syn- drome, sensory phenomena, sleep disturbances, and psy-chic phenomena, such as anxiety, agitation, and tearfulness.
Pharmacodynamic and Pharmacokinetic Aspects There is a wide variety in the incidence of the withdrawal psychotics block dopamine2, histamine, ␣1-adrenergic, and phenomena. The symptoms seem to be the most intensive cholinergic receptors. The antipsychotic effect is probably in the SSRIs with a short half-life, specifically, paroxetine.
based on their antidopaminergic action. Pharmacokineticsare highly variable, with half-life ranging from 2 hours, for IV-IM Change and Alternative Drugs droperidol, to 2 weeks, for the intramuscularly-adminis- of SSRIs are presently not readily available.
trated esterified depot preparations.
The main side effects of the first generation drugs through the P450 mechanism, it is not so much the of antipsychotics are extrapyramidal symptoms. A seldom, extent of the surgery but the comorbidity that increases the but serious, complication of antipsychotic drugs is sudden risk of (avoidable) complications. Therefore, patients with death related to a prolongation of the QTc interval and a higher ASA classification potentially have an increased torsades des pointes. The problem is most evident in the phenothiazines, specifically thioridazine. These drugs arenowadays replaced by high-potency antipsychotics, inwhich sudden death is less a problem. Therefore, there is a need for careful preoperative evaluation and periopera- The risks of maprotiline can be compared with the tive cardiac monitoring for electrocardiographic changes tricyclics (see Tricyclic Antidepressant Agents: Interac- in patients using antipsychotic agents.47,48,93 Psychosomatics 47:1, January-February 2006 No hazardous interactions are mentioned for lated to other existing physical comorbidity, such as cardiac phenothiazines.15 Hypotension is reported as a hazardous pathology, influencing the conduction system, or infectious interaction in combinations of haloperidol or droperidol or cerebral pathology, which is a risk of the induction of a with ketanserin, a serotonergic 5HT2 antagonist with weak selective alpha1-receptor blocking properties. Seizures arereported with desflurane, a volatile anesthesia.15,94 Inter- actions of note are reported for the phenothiazines with The empirical evidence of possible interactions with antimuscarines. Clinically-relevant interactions with other anesthetics is almost lacking. However, it is evident that classes of first-generation antipsychotics are not mentioned the use of these drugs, which have an advantage in the in most reviews. Potentiation of the effects of narcotic an- treatment of patients with schizophrenia because of their algesics is reported. Chlorpromazine and thioridazine, lack of extrapyramidal effects, can result in medical com- which can selectively block ␣-adrenergic receptors, might plications, such as weight gain, diabetes, and an increase lead to interactions with drugs with sympathicomimetic ac- in lipids, as well as sudden death due to torsades de tion, such as epinephrine, resulting in vasodilatation and hypotension.67 With halogenated inhalation anesthetics,hypotension has been reported for several antipsychotic agents. Excess central and peripheral anticholinergic ef-fects have been reported in elderly patients in combinations The main clinical complications reported are agranu- of chlorpromazine or thioridazine with atropine or scopol- locytosis and hyperthermia. It affects cardiac conduction.99 During anesthesia, hypotension has been reported.100 Incase of discontinuation of clozapine, dystonias, dyskine- Withdrawal and Psychiatric Recurrence or Relapse sias, delirium, and rapid onset of psychosis have been re- There are withdrawal symptoms comparable to the cholin- ported, which require emergency psychiatric-specialist in- ergic rebound effect described for the tricyclic antidepres- sant agents. These symptoms appear 1 to 4 days after dis-continuation and abate over 7 to 14 days.64,95 There is an argument that early relapse is related to dopaminergic hy-persensitivity of the brain due to pharmacological with- The available empirical evidence is—except for the risk of drawal, whereas the delayed relapse might reflect the nat- withdrawal and relapse of psychiatric illness—on the level ural course of the illness.96 In a metaanalysis including 66 of nonsystematic reviews and case reports. Despite the fact articles and 4,365 patients with schizophrenia, it is reported that a systematic review of this multidimensional topic that patients who continue antipsychotics, in contrast to would be preferred, we decided that it would be too com- those who stop, the relapse rate is 16%, versus 53% for plicated and would be based on a low level of evidence.
those who stopped over a mean period of 9.7 months. The We came to the conclusion that it would not result in a relapse rate is much higher in patients who stop suddenly.
level of empirical evidence superior to expert opinion.
In those who stop abruptly, within 10 weeks, 25% had Consequently, the proposal is based on available literature, symptoms, and, after 30 weeks, 50% had symptoms.95 expert opinions, and integrated thinking. Therefore, theproposal serves to support clinical reasoning. Specifically, IV-IM Change and Alternative Agents in cases with complex psychiatric illness, patient-oriented best known intravenous preparation, especially in medi- perioperative management needs to be prepared by the in- cally ill persons, as it is the drug of choice in delirium volved physical specialist, the anesthetist, the psychiatric patients.48,97 Still, haloperidol carries the risk of torsades consultant, and the outpatient psychiatrist. The literature de pointes, arrhythmias, and neuroleptic malignant syn- suggests that the risk of psychotropics in surgery is pri- marily related to the type of psychiatric disorder, the psy-chotropic drug, physical comorbidity, and related drugs.
The extent of surgery seems less relevant. Therefore, in influence the interactions between anesthesia and antipsy- every patient who uses psychotropics and is in need of chotics. Combinations of certain antipsychotics and anes- surgery, psychotropic drug management should be consid- thetics should be avoided. The main risks seem to be re- ered. The perioperative risk related to psychotropics in- Psychosomatics 47:1, January-February 2006 Handling of Psychotropics in Elective Surgery creases in combination with physical illness. In terms of once because no withdrawal symptoms occur. Patients’ ASA classification, patients who use psychotropics qualify fluid intake should be thoroughly assessed to adjust peri- at least for an ASA Classification 2: Physical complications operative intravenous hydration in case of polydipsia as from mild systemic disease contribute to postoperative clinical manifestation of a partial diabetes insipidus. Also, morbidity and mortality.9 We suggest following Dawson’s thyroid hormones, sodium, potassium, and creatinine classification for quantification of the seriousness of drug– should be assessed. Taking a half-life of 24 to 36 hours drug interactions as well as for the direct effects of the into account, we propose that lithium be discontinued 72 drugs; these are then linked to the ASA classification sys- hours before surgery. When postoperative, and the patient tem.15 Possible interactions are suggested to be rated as has normal ranges of potassium, sodium, and creatinine, is ASA 2, whereas interactions of note and hazardous inter- hemodynamically stable, and is able and allowed to drink, actions should be rated as ASA 3. The issue of preoperative lithium should be restarted, with control of blood levels, fasting relevant to patients who can continue drugs, seems within 1 week. This is most important because the psychi- to offer more flexibility nowadays. Intravenous adminis- atric risk of recurrence or relapse is hazardous. The same tration of psychotropics only seems indicated in patients drug regimen should be provided as in the preoperative with unstable psychiatric disease, such as psychosis or bi- period unless kidney function has declined (in case of a caesarean section, the dosage needs adjustment because ofshifts in fluid distribution).103 Patients should always be seen by a consulting psychiatrist. An integrated anesthetic/intensivistic/psychiatric management should be decided The only reason not to stop lithium treatment is minor The physical perioperative risk of patients who use surgery, with local anesthesia, meaning infiltration anes- psychotropics is such that, from a preventive perspective, thesia, for an atherome cyst, but not using larger nerve- or they require systematic evaluation integrated into preop- erative assessment. Patients who use lithium, MAOIs, tri-cyclics, and clozapine have hazardous drug interactions,with serious physical risks, including withdrawal, which cannot be avoided. Therefore, such patients qualify for There are two hazardous risks of drug–drug interac- ASA Classification 3. From the perspective on the man- tions. The serotonergic risk (Phase I) can be prevented by agement of the physical risk, they require drug discontin- avoiding drugs that prevent presynaptic uptake of seroto- uation. Because the risk of acute withdrawal is high and nin, such as pethidine, pentazocine, and dextromethorphan.
there is a risk of psychiatric relapse or recurrence, these The risk of hemodynamic instability is less controllable.
patients require intensive individualized integrated anes- Therefore, we recommend that irreversible MAOIs be dis- thetic/intensivistic/psychiatric management. In patients on continued. When discontinued, they can be restarted when SSRIs who are mentally and physical stable (ASA Clas- the patient is hemodynamically stable, is able and allowed sification 1), the risk of withdrawal seems to justify their to drink, and is not on new, potentially interacting drugs.
continuation. Patients who use other psychotropics should One strategy to discontinue irreversible MAOIs is to be regarded as qualifying for ASA Classification 2 and change, in the weeks before surgery, to a reversible MAOI.
require individualized evaluation of their perioperative The reversible MAOI moclobemide only needs to be dis- continued for 24 hours to restore the depleted neurotrans-mitters. It can be restarted as soon as the patient is hemo- dynamic stable and is able and allowed to drink. However, Lithium’s direct effects cause hazardous risks in sur- patients have a serious risk of withdrawal, psychiatric re- gery. This is specifically true when hemodynamic instabil- lapse, or recurrence. These patients should always be seen ities occur, and renal excretion becomes impeded through by (their) psychiatrists. An integrated anesthetic/intensivis- interference with sodium and potassium metabolism. The tic/psychiatric strategy should be decided upon.
physical risk of intoxication, with its detrimental and fatal The only reason not to stop MAOIs is minor surgery, risks for the CNS, is unacceptable. Therefore, lithium dis- with local anesthesia, meaning infiltration anesthesia for an continuation is recommended. Lithium can be stopped at atherome cyst, but no larger nerve- and central blockades.
Psychosomatics 47:1, January-February 2006 serine, mirtazapine, and venlafaxine is thin. No seriouscomplications are described in the literature. There is a risk There are two hazardous drug interaction risks to be of withdrawal symptoms, however. When the patient is avoided: the direct effects on the cardiac system and the mentally stable, there is no need for a psychiatric consul- interactions with anesthetic drugs regulating the cardiovas- tation. Specifically, in patients with more complex physical cular system. However the literature is controversial.
comorbidity (ASA Classification 2) and with unstable psy- Therefore, we suggest discontinuation of TCAs in all pa- chiatric illness, they should be both seen by their psychi- tients with ASA Classification of 2 and higher, even in atrist and anesthesiologist. They should balance the risks minor surgery with local anesthesia. Because abrupt dis- and decide on individualized management.
continuation can cause serious withdrawal symptoms, thedrugs should be gradually discontinued over 2 weeks be-fore surgery. We recommend a preoperative ECG after dis- continuation to have a baseline assessment before surgery.
The potentiation of sedation is an interaction of note When, postoperatively, the patient is hemodynamically sta- and a controllable phenomenon. The anesthesia literature ble, is able and allowed to drink, and is not on new, poten- is quite conclusive about the continuation of the drug in tially interfering drugs, the medication should be restarted.
the perioperative period. As ECG abnormalities occur in Specifically, in elderly patients, this start should be gradual these patients, a preoperative ECG should be done and because of possible orthostatic effects. When the patient is evaluated for a prolonged QTc interval in patients with mentally stable, there is no need for a psychiatric consul- comorbid physical illness (ASA 2).43 Patients should be tation. Specifically, patients with more complex physical seen by their psychiatrist in the perioperative period.
comorbidity and unstable psychiatric illness should be seenby their psychiatrist.
There is not enough evidence for a specific proposal.
It is proposed that patients should be seen by their psychi- The risks of drug interactions with SSRIs are impor- atrist and an integrated anesthetic/psychiatric regimen tant. They are related to serotonergic effects of pethidine, pentazocine, and dextromethorphan, which prevent pre-synaptic uptake of serotonin and might induce a seroto- nergic syndrome. The interactions can be avoided by se-rotonin-free anesthesia and analgesia. Interactions with Clozapine has hazardous risks of drug interactions re- existing physical illness and the related drug regimens sulting in effects on circulation. This risk requires drug should have been taken into account at initiation of therapy.
discontinuation. Discontinuation of clozapine can cause Discontinuation can cause withdrawal symptoms, specifi- hazardous withdrawal phenomena. Moreover, patients cally in the short-acting SSRIs. Therefore, we propose that treated with clozapine have a high risk of psychiatric re- SSRI not be discontinued in order to prevent anesthetic currence or relapse. Therefore, we recommend psychiatric interactions. The exception to this rule should be when the consultation well in advance of surgery to come to an in- SSRI is used in combination with aspirin or an NSAID and tegrated anesthetic/intensivistic/psychiatric management when the SSRI is used in patients over 80 years of age. In these patients, the balance of risks of withdrawal and bleed-ing should at least be discussed. As long as the patient is preoperatively assessed and recorded as mentally stable,there is no need for a psychiatric consultation.
The intention of the proposal is to stimulate the develop-ment of a preventive, integrated risk assessment in psy-chiatrically vulnerable patients using psychotropic drugs and who are in need of elective surgery. The presented Compared with the other drugs—except for the pres- model allows indicator-based integration in pre-assessment sure-effects of maprotiline—the available evidence of the clinics through use of the ASA classification system. In- risks of perioperative complications of maprotiline, mian- dications for perioperative psychotropic risk management, Psychosomatics 47:1, January-February 2006 Handling of Psychotropics in Elective Surgery including psychiatric referral, have been operationalized.
We acknowledge W.A. Nolen for his critical review of This could be combined with a more generic assessment the manuscript and for related suggestions. of integrated health risk and needs, such as is possible withthe INTERMED method.104,105 Such a model would allow APPENDIX 1.
Websites for Information on Drug–Drug
for the prediction of outcomes of surgery, practice audit, Interactions
and research. Regarding the size of the problem, the vul- http://www.drugdigest.org/dd/Interaction/ChooseDrugs/1,4109,00.
nerability of the patients and the often-lacking reimburse- ment as part of health plans, this is an area that deserves a http://medicine.iupui.edu/flockhart/http://www.dal.ca/ϳpharmwww/druginfo/drugprobleminteraction.
more proactive approach in order to enhance the quality of References
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