67 - Zuclopenthixol acetate

Zuclopenthixol acetate

66 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Zuclopenthixol acetate Zuclopenthixol acetate (ZA) is widely used in the UK and elsewhere in Europe, and is best known by its trade name Acuphase®. Zuclopenthixol itself is a thioxanthene dopamine antagonist first introduced in the early 1960s. ZA is not a rapidly tranquillising agent. Its elimination half-­life is around 20 hours. IM injection of zuclopenthixol base results in rapid absorption and a duration of action of 12–24 hours. By slowing absorption after IM injection, the biological half-­life (and so duration of action) becomes dependent on the rate of release from the IM reservoir. This can be achieved by esterification of the zuclopenthixol molecule, the rate of release being broadly proportional to the length of the ester carbon chain. Thus, zuclopenthixol decanoate is slow to act but very long-­acting as a result of retarded release after IM injection. ZA (with eight carbon atoms fewer) would be expected to provide relatively prompt release but with an intermediate duration of action. The intention of the manufacturers was that the use of ZA would obviate the need for repeated IM injections in disturbed patients. An initial pharmacokinetic study of ZA included 19 patients ‘in whom calming effect by parenteral neuroleptic was considered necessary’.56 Zuclopenthixol was detectable in the plasma after 1–2 hours but did not reach peak concentrations until around 36 hours after dosing. At 72 hours, plasma levels were around one-­third of those at 36 hours. The clinical effect of ZA was not rapid – 10 of 17 patients exhibited minimal or no change in psychotic symptoms at 4 hours. Sedation was evident at 4 hours but it had effectively abated by 72 hours. A follow-­up study by the same research group57 examined more closely the clinical effects of ZA in 83 patients. The authors concluded that ZA produced ‘pronounced and rapid reduction in psychotic symptoms’. In fact, psychotic symptoms were first assessed only after 24 hours and so a claim of rapid effect is not reasonably supported. Sedative effects were measured after 2 hours when a statistically significant effect was observed – at baseline mean sedation score was 0.0 (0 = no sign of sedation) and at 2 hours 0.6 (1 = slightly sedated). Maximum sedation was observed at 8 hours (mean score 2.2; 2 = moderately sedated). At 72 hours mean score was 1.1. Dystonia and rigidity were the most commonly reported adverse effects. Two independently conducted open studies produced similar results – a slow onset of effect peaking at 24 hours and still being evident at 72 hours.58,59 The first UK study was reported in 1990.60 In the trial, a significant reduction in psychosis score was first evident at 8 hours and scores continued to fall until the last measurement at 72 hours. Of 25 patients assessed only 4 showed signs of tranquillisation at 1 hour (19 at 2 hours and 22 at 24 hours). A comparative trial of ZA61 examined its effects and those of IM/oral haloperidol and IM/oral zuclopenthixol base (in multiple doses over 6 days). The two non-­ester, IM/ oral preparations produced a greater degree of sedation at 2 hours than did ZA but the effect of ZA and zuclopenthixol was more sustained than with haloperidol over 144 hours (although patients received more zuclopenthixol doses). No clear differences between treatments were detected, with the exception of the slow onset of effect of ZA. The number of doses given varied substantially: ZA 1–4; haloperidol 1–26; and zuclopenthixol 1–22. This is the key (and perhaps unique) advantage of ZA – it reduces the need for repeat doses in acute psychosis. Indeed, this was the principal finding of the first double-­blind study of ZA.62 Participants were given either ZA or haloperidol IM

Schizophrenia and related psychoses CHAPTER 1 and assessed over 3 days. Changes in Brief Psychiatric Rating Scale and Clinical Global Impression scores were near identical on each daily assessment. However, only 1 of 23 patients taking ZA required a second injection, whereas 7 of 21 required a repeat dose of haloperidol. Speed of onset was not examined. Similar findings were reported by Thai researchers comparing the same treatments63 and in three other studies of moderate size (n = 44,64 n = 40,65 n = 5066). In each study, the timing of assessments was such that time to onset of effect could not be determined. Overall, the utility of ZA in rapid tranquillisation is limited by a somewhat delayed onset of both sedative and antipsychotic actions. Sedation may be apparent in a minority of patients after 2–4 hours, but antipsychotic action is evident only after 8 hours. If ZA is given to a restrained patient, their behaviour on release from restraint is likely to be unchanged and will remain as such for several hours. ZA has a role in reducing the number of restraints for IM injection but it has no role in rapid tranquillisation. Guidelines for the use of zuclopenthixol acetate (Acuphase) ■ ■ZA is not a rapidly tranquillising agent. It should be used only after an acutely psychotic patient has required (or is likely to require) repeated injections of short-­acting antipsychotic drugs such as haloperidol or olanzapine, or sedative drugs such as lorazepam. It is perhaps best reserved for those few patients who have a prior history of good response to Acuphase. ■ ■ZA should be given only when enough time has elapsed to assess the full response to previously injected drugs: allow 15 minutes after IV injections; 60 minutes after IM. ■ ■ZA should never be administered for rapid tranquillisation (the onset of effect is too slow) or to a patient who is physically resistant (risk of intravasation and oil embolus) or to neuroleptic-­naïve patients (risk of prolonged EPSEs).

68 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Rapid tranquillisation summary In an emergency situation: Assess whether there may be a medical cause.67 Optimise regular prescription. The aim of pharmacological treatment is to calm the patient but not to over-­sedate. Note that lower doses should be used for children, adolescents and older adults. Patients’ levels of consciousness and physical health should be monitored after administration of parenteral medication (see protocol). Step intervention 1 De-­escalation, time out, placement, etc., as appropriate 2 Offer oral treatment If patient is prescribed a regular antipsychotic: Lorazepam 1–2mg Promethazine 25–50mg Monotherapy with buccal midazolam may avoid the need for IM treatment Dose: 10mg Note that this preparation is unlicensed If patient is not already taking a regular oral or LAI antipsychotic: ■ ■Olanzapine 10mg or ■ ■Risperidone 1–2mg or ■ ■Quetiapine 50–100mg or ■ ■Haloperidol 5mg (with promethazine 25mg). ECG is required in UK/EU Repeat after 45–60 minutes, if necessary. Consider combining sedative and antipsychotic treatment. Go to step 3 if two doses fail or sooner if the patient is placing themselves or others at significant risk. 3 Consider IM treatment Lorazepam 2mgab Have flumazenil to hand in case of benzodiazepine-­induced respiratory depression Promethazine 50mg IM promethazine is a useful option in a benzodiazepine-­tolerant patient Olanzapine 10mgd IM olanzapine should not be combined with an IM benzodiazepine, particularly if alcohol has been consumed68 Aripiprazole 9.75mg Less hypotension than olanzapine, but less effective6,13,69 Haloperidol 5mg Haloperidol should be the last drug considered. The incidence of acute dystonia is high; combine with IM promethazine and ensure IM procyclidine is available. Pretreatment ECG required Repeat after 30–60 minutes if insufficient effect. Combinations of haloperidol and lorazepam or haloperidol and promethazine may be considered if single drug treatment fails. Drugs must not be mixed in the same syringe. IM olanzapine must never be combined with IM benzodiazepine. 4 Consider IV treatment Diazepam 10mg over at least 2 minutesbe Repeat after 5–10 minutes if insufficient effect (up to 3 times) Have flumazenil to hand 5 Seek expert advicef Consider transfer to medical unit for administration of IM ketamine Notes a. Carefully check administration and dilution instructions, which differ between manufacturers. Many centres use 4mg. An alternative is IM midazolam 5–15mg. 5mg is usually sufficient. The risk of respiratory depression is dose-­related with both drugs but generally greater with midazolam. b. Caution in the very young and elderly and those with pre-­existing brain damage or impulse control problems, as disinhibition reactions are more likely.70 (Continued)

Schizophrenia and related psychoses CHAPTER 1 Rapid tranquillisation summary  (Continued) c. Promethazine has a slow onset of action but is often an effective sedative. Dilution is not required before IM injection. May be repeated up to a maximum of 100mg/day. Wait 1–2 hours after injection to assess response. Note that promethazine alone has been reported, albeit very rarely, to cause NMS,71 although it is an extremely weak dopamine antagonist. Note also the potential pharmacokinetic interaction between promethazine and haloperidol (reduced metabolism of haloperidol) which may confer risk if repeated doses of both are administered. d. Recommended by NICE only for moderate behavioural disturbance, but data from a large observational study also support efficacy in clinical emergencies. e. Use diazepam to avoid injection site reactions. Lorazepam can also be given IV. IV therapy may be used instead of IM when a very rapid effect is required. IV therapy also ensures near immediate delivery of the drug to its site of action and effectively avoids the danger of inadvertent accumulation of slowly absorbed IM doses. IV doses can be repeated after only 5–10 minutes if no effect is observed. Midazolam can also be used IV but respiratory depression is common.1 f. Options at this point are limited, although the wider use of IM ketamine has improved the range of options available. IM amylobarbitone and IM paraldehyde have been used in the past but are used now only extremely rarely and are generally not easy to obtain. IV olanzapine, IV droperidol and IV haloperidol are possible but adverse effects are fairly common. ECT is also an option. Rapid tranquillisation – physical monitoring After any parenteral drug administration, monitor as follows: ■ ■Temperature ■ ■Pulse ■ ■Blood pressure ■ ■Respiratory rate Every 15 minutes for 1 hour and then hourly until the patient is ambulatory. Patients who refuse to have their vital signs monitored or who remain too behaviourally disturbed to be approached should be observed for signs/symptoms of pyrexia, hypoxia, hypotension, over-­sedation and general physical well-­being. All patients should be continuously observed (‘in sight’) for at least 1 hour and until clearly ambulatory. If the patient is asleep or unconscious, the continuous use of pulse oximetry to measure oxygen saturation is desirable. A nurse should remain with the patient until ambulatory. ECG and haematological monitoring are also strongly recommended when parenteral antipsychotics are given, especially when higher doses are used.72,73 Hypokalaemia, stress and agitation place the patient at risk of cardiac arrhythmia74 (see section on ‘QT prolongation’). ECG monitoring is formally recommended for all patients who receive haloperidol.

70 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Remedial measures in rapid tranquillisation Problem Remedial measures Acute dystonia (including oculogyric crises) Give procyclidine 5–10mg IM or IV Reduced respiratory rate (<10/minute) or oxygen saturation (<90%) Give oxygen, raise legs, ensure patient is not lying face down Give flumazenil if benzodiazepine-­induced respiratory depression suspected (see protocol) If induced by any other sedative agent: transfer to a medical bed and ventilate mechanically Irregular or slow (<50/minute) pulse Refer to specialist medical care immediately Fall in blood pressure (>30mmHg orthostatic drop or <50mmHg diastolic) Have patient lie flat, tilt bed towards head Monitor closely Increased temperature Risk of NMS and perhaps arrhythmia; check creatine kinase urgently Guidelines for the use of flumazenil Indication for use If, after the administration of lorazepam, midazolam or diazepam, respiratory rate falls below 10/minute Contraindications Patients with epilepsy who have been receiving long-­term benzodiazepines Caution Dose should be carefully titrated in hepatic impairment Dose and route of administration Initial: 200mcg intravenously over 15 seconds if required level of consciousness not achieved after 60 seconds, then Subsequent dose: 100mcg over 15 seconds Time before dose can be repeated 60 seconds Maximum dose 1mg in 24 hours (one initial dose and eight subsequent doses) Adverse effects75 Patients may become agitated, anxious or fearful on awakening. Seizures may occur in regular benzodiazepine users. Cardiac arrhythmia (supraventricular tachycardia) Management Adverse effects usually subside Monitoring: ■ ■What to monitor? Respiratory rate ■ ■How often? Continuously until respiratory rate returns to baseline level Flumazenil has a short half-­life (much shorter than diazepam) and respiratory function may recover and then deteriorate again Note: If respiratory rate does not return to normal or patient is not alert after initial doses given, assume that sedation is from some other cause