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Is there a significant difference between melatonin and other hypnotics?

Do you think at a practical level, there is any significant difference between melatonin (Circadin) and other hypnotic drugs? Does it have real benefit over short-acting hypnotics?

Specialist’s response: The choice of medications to treat insomnia includes benzodiazepines such as temazepam, the so-called Z drugs – zaleplon (Sonata), zolpidem and zopiclone – melatonin, a pineal hormone, and sedative antidepressants such as mirtazapine and trazodone.
    Once it has been established that the sleep dysfunction is primary and not secondary to another physical or mental illness that requires treatment an hypnotic may be necessary, especially if simple sleep hygiene measures are ineffective.
    The aim should be to prescribe for the short term. Problems arise with this strategy where, for example, patients are at high risk of developing dependency. This is the case with the alcohol-dependent patient and benzodiazepines and is likely to be so with the Z drugs, which also act at the benzodiazepine receptor.
    Another factor is the need to avoid daytime sedation, which can be a problem even with short-acting hypnotics, and of course patients sometimes exceed the dose or take an extra tablet if awake through the night.
    Melatonin provides information about day length by its pattern of secretion, regulating core body temperature, alertness and many metabolic functions. Melatonin may be prescribed for patients aged 55 and over. It regulates the sleep-wake cycle without causing daytime sedation and is nonaddictive.1 Melatonin is not likely to be as strong a sleep inducer as the benzodiazepines and its main role may be to re-regulate sleep disrupted by shift working and long distance aircraft travel.2

References
1. Arendt J, et al. Br J Psychiatry 2008;193:267-9.
2. Cardinali DP, et al. Lancet 2008;373:439-41.

Dr Martin Livingston MD, FRCPsych is consultant psychiatrist and honorary senior clinical lecturer

How should digoxin be initiated for housebound patients with atrial fibrillation and heart failure?

What is the best way of initiating digoxin in the community for housebound patients with atrial fibrillation and heart failure, bearing in mind that very frequent monitoring of digoxin levels may not always be practical?

Specialist's response: Along with thromboprophylaxis, rate control is an appropriate and safe option for the older, sedentary, asymptomatic individual with atrial fibrillation and heart failure.1 Current guidelines recommend both beta-blockers and digoxin for heart rate control,2 although digoxin may be inadequate for control of ventricular rate during exercise or when sympathetic tone is increased.3 Breakthrough tachycardia may be associated with fatigue and/or dyspnea but these considerations are less important in housebound patients. Digoxin is a rational choice since cardiac function will be improved by slowing of ventricular rate and positive inotropism while avoiding a potentially deleterious excess decrease in blood pressure induced by beta-blockade.
    Conventionally, digoxin is initiated by means of a loading dose but this is unnecessary in people with chronic atrial fibrillation unless symptoms are problematic. The usual maintenance dose is 125-250µg per day, although 62.5µg may be adequate in older subjects with poor renal function. If a maintenance dose is employed without a loading dose, drug accumulation and activity develop slowly because steady state is not reached for 4-5 half-lifes (about one week).
    Adjustment of digoxin dosage should be based on clinical judgement. Target resting heart rate in atrial fibrillation is less than 80-100bpm,4 although there are little data in patients with heart failure. Toxicity is best judged by occurrence of rare side-effects (anorexia/nausea). Monitoring of digoxin levels is of limited use since there is a poor relation between therapeutic (or unwanted) efforts and drug concentrations. However, monitoring for toxicity may be warranted if there is renal failure and in older patients when the first sign of toxicity may be a serious arrhythmia. The normal therapeutic range is 1-2µg per litre in a venous sample 6-8 hours after an oral dose.
    To avoid toxicity, lower doses are recommended in renal impairment (reduced digoxin clearance), in congestive heart failure (reduced metabolic clearance) and in hypokalaemia or hypercalcaemia (potentiation of toxicity). Since heart failure patients will usually be taking diuretics and drugs which block the renin angiotensin system, serum potassium should be monitored to adjust digoxin dose. Low dose beta-blocker is also a recommended component of management of chronic stable heart failure. Combination therapy with digoxin and a beta-blocker provides better control of heart rate with a lower risk of toxicity than with high-dose digoxin.1 Furthermore, digoxin in combination with beta-blocker is associated with a mortality rate less than that observed with digoxin alone.5

References
1. Roy D, et al. N Engl J Med 2008;358:2667-77.
2. Dickstein K, et al. Eur Heart J 2008;29:2388-442.
3. Farshi R, et al. J Am Coll Cardiol 1999;33:304-10.
4. Rawles JM. Br Heart J 1990;63:157-61.
5. Fauchier L, et al. Am J Cardiol 2009;103:248-54.

Gordon McInnes BSc, MD, FRCP, FFPM, FBPharmacolS is professor of clinical pharmacology and honorary consultant physician in the Division of Cardiovascular and Medical Sciences, Western Infirmary, University of Glasgow, president of the BHS, member of the steering committee of ASCOT and executive committee of VALUE, and UK national co-ordinator of HOT

How should lamotrigine medication timing be adjusted for travels abroad?

How would you advise a patient taking once daily lamotrigine for her epilepsy to adjust the timing of her medication when she travels to the west coast of America for a 10 day holiday?

Specialist's response: The simplest answer is to take the medication every 24 hours – so for example an evening dose in the UK becomes a midday dose in California. Suggest that she set a reminder on her mobile phone and leave the phone on UK time while away.
    Alternatively, it probably matters little if the dose is a few hours late on the trip out and a few hours early on the trip back.
    A third option is to top up with an approximately one-third dose on the way out to accommodate the long day, then skip that one-third dose on the way back.
    Much hangs on whether the patient is seizure free and driving; whether lamotrigine dose is maximal (500mg daily) or not, and whether there are any side-effects. In epilepsy management it often helpful to consider whether the priority is to minimise seizures or side-effects.
    Sleep deprivation and alcohol – both of which are an agenda with foreign travel – may worsen epilepsy, particularly primary epilepsies such as juvenile myoclonic epilepsy. So be more than usually cautious about alcohol on the flight and while away; when jet lagged, err on the side of too much not too little sleep.

Dr Giles Elrington MD, FRCP, consultant neurologist at Barts and the London NHS Trust and Colchester General Hospital.

How to explain the long-term osteoporosis risk to teenagers for Depo-Provera?

What is the current state of play with depot medroxyprogesterone acetate (DMPA; Depo-Provera) and the risk of long-term osteoporosis? How do we explain this to all the feckless 15 year olds for who it is the only thing that seems to work?

Specialist's response: Depot medroxyprogesterone acetate (DMPA; Depo-Provera) use remains a valid contraceptive option for women. Its potential impact on bone mineral density (BMD) must be balanced against the consequences of unintended pregnancy. The use of DMPA is associated with a slight decrease in BMD, which is largely, if not completely, reversible when it is stopped. I would advise the feckless girls to stop smoking. This is an excellent article you might want to refer to: The use of depot-medroxyprogesterone acetate in contraception and its potential impact on skeletal health. Guilbert ER, et al. Contraception 2009;79(3):167-77.

Professor Margaret Rees DPhil FRCOG is a reader in reproductive medicine at the University of Oxford, honorary consultant and visiting professor at the Faculty of Medicine, University of Glasgow and adjunct associate professor at the Department of Obstetrics, Gynecology and Reproductive Sciences, University of Medicine and Dentistry of New Jersey

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Why are first-generation antihistamines used in an emergency setting?

The main difference between first-, and second- and third-generation antihistamines is in sedation. Why in an emergency setting, is oral Piriton (chlorphenamine) still used instead of a second- or third-generation drug? Is the older drug more effective or does it work faster?

Specialist's response: The antihistamines used in an emergency setting will depend on whether the patient is self-treating or not. Early intramuscular adrenaline, is the first-line treatment for an anaphylactic reaction and antihistamines are a second-line treatment only.1
    In primary or secondary care, a parenteral antihistamine should be used to treat anaphylaxis because rapid onset of action is very important. Second generation, antihistamines are not widely available as parenteral preparations; therefore the current Advanced Life Support (ALS) guidelines recommend intravenous or intramuscular chlorphenamine as a secondary treatment for anaphylaxis. Oral chlorphenamine is not recommended for use in an emergency.1
    In the community, prescribing oral antihistamines for treating early symptoms of anaphylaxis is controversial – as it is argued that this can potentially delay the timely administration of adrenaline. However, most allergists will co-prescribe an EpiPen (adrenaline) and antihistamine for their patients but provide a clear action plan so that patients know the exact indications for self-administering adrenaline.
    The ideal antihistamine should be rapid in onset, nonsedating, long lasting and in liquid form (if prescribed for children). Oral chlorphenamine should not be prescribed for the emergency treatment of anaphylaxis in the community because it has a slower onset of action compared to second-generation antihistamines and side-effects including sedation. In contrast, second-generation antihistamines – eg certirizine and fexofenadine – have a rapid onset of action compared to first-generation antihistamines, are less likely to interact with other prescribed medications and also have fewer side-effects.2 Therefore second-generation antihistamines are the preferable treatment option.

References
1. Soar J, Pumphrey R, Cant A, et al.; Working Group of the Resuscitation Council (UK). Emergency treatment of anaphylactic reactions – guidelines for healthcare providers. Resuscitation 2008;77:157-69.
2. Simons FE. Advances in H1-antihistamines. N Engl J Med 2004;351:2203-17.

Dr Sophie Farooque MRCP is an allergist and clinical research fellow at the MRC Centre and Asthma UK Centre in Allergic Mechanisms for Asthma (King’s College London); she is also a member of the BSACI’s Standards of Care Committee and is an author of the BSACI guidelines for the management of allergic and nonallergic rhinitis

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Can dopamine agonists precipitate behavioural changes?

I have a patient in her mid 60s with Parkinson’s disease (PD). After some years on a dopamine agonist she is now taking levodopa. At a recent consultation she told me that her husband and friends have all noticed that she is much more confident to the point of being quite aggressive at times. She is also full of energy. Before her diagnosis she was quite timid and easy going. She wondered if it might be the pills that had caused this change?

Specialist's response: Cognitive change is common in people with PD, including those on no treatment, but is typically worsened by drugs that treat the movement disorder. This applies less to levodopa than to other PD drugs.
    Dopamine agonists are reported occasionally to worsen or trigger risk-taking behaviour, particularly gambling, sometimes other related behaviour such as excessive eBay use. So it is reasonable to consider that her medication may be contributing to her behavioural change, though it is not the only possible cause. I would see her with her husband, check bloods including thyroid, enquire about memory inefficiency, sleep disturbance (excess by day, less by night), hallucinosis (people and animals – which patients often don't volunteer) and delusional beliefs. I would also review safety as a driver.
    If there is significant or disabling cognitive change I would gradually reduce or stop medication, particularly the dopamine agonist and any other nonlevodopa drugs for PD, and consider later if necessary a prescription of Rivastigmine (Exelon). Cognitive change in PD tends to fluctuate and vary though the underlying trend is progressive worsening over years, and is usually the reason why people with PD can no longer cope in their own home; so early detection, careful support, and minimising drug risks with sacrifice of mobility to preserve cognition, is important.

Dr Giles Elrington MD, FRCP, consultant neurologist at Barts and the London NHS Trust and Colchester General Hospital.

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When should patients take a triptan for a migraine attack?

The BNF states that they should be taken during the headache phase of the attack. Do they work if taken during the aura phase? The patient information leaflet for some triptans states that they should be taken at “onset of attack”.

Specialist's response: Triptans should be taken when the headache has started and the patient is sure of a pending migraine. Clinical trials have shown that triptans taken during the aura before the headache has started do not reduce the headache whereas when taken when the headache has started the response is good. This is also our clinical experience. Taking a triptan too early is actually a frequent reason for ineffectiveness of triptans which can be resolved by treating only when the headache has started.
    The pharmacological reason is thought to be that the triptan-specific receptors on the trigeminovascular system only become externalised,and thus available for interaction, when the trigeminovascular system is activated (which is clinically reflected as having headache).
    Patients who have aura would regard that as the start of the attack so should be told to take triptans only at the start of the headache not at the start of the aura.

Professor Michel D. Ferrari MD, PhD, Leiden University Medical Centre, Leiden, The Netherlands

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