Sleepless in South Africa: Insomnia is not just a night-time problem

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[Find the meaning and references behind the names: Long, Deep, Med]

CPD Article: Sleepless in South Africa: insomnia is not just a night-time problem 277 Vol 54 No 4 S Afr Fam Pract 2012 Introduction Sleep is a universal need that is essential for well-being. Processes which are regulated during sleep include tissue growth and healing, synaptic function and memory, temperature regulation, energy metabolism and immune regulation. Lack of sleep causes significant distress, with increased irritability, reduced capacity for judgement and motor skills, compromised cognitive function and an increased drive to sleep. In the long term, lack of sleep may promote weight gain, enhance insulin resistance, compromise immune function and increase the risk of depression 1 It is no wonder that people view an inability to sleep as an alarming symptom, and avidly search for interventions to alleviate their problem What is “normal” sleep? Healthy individuals usually sleep for seven to nine hours each night, although the timing, duration and internal structure of the sleeping period may vary. Normally we experience two distinct brain states during sleep. Firstly, rapid eye movement (REM) sleep, a state in which dreaming occurs, accompanied by rapid eye movements but overall reduced body muscle tone. All other sleep during the night is classified as non-rapid eye movement (NREM) sleep. There are four distinct phases within the NREM state. Stage 1 indicates the transition from wakefulness to the onset of sleep. Stage 2 is classified as light sleep, during which the body temperature drops and the muscles relax. Stages 3 and 4 of NREM sleep are known as “slow-wave” sleep or deep sleep, and are a prerequisite for feeling refreshed on awakening. Normally, sleep progresses through NREM stages 1–4 within about 60–90 minutes. This is followed by a period of REM sleep, after which the cycle repeats. In general, a standard night’s sleep comprises 50% NREM stage 1–2 (light), 25% NREM stage 3–4 (deep) sleep and 25% REM sleep. Changes in the quantity (duration) and intensity (proportion of REM/light/slow wave sleep) of sleep occur across the life cycle: REM sleep is increased in babies, while geriatrics exhibit reduced REM and increased NREM stages 1-2 sleep 2 What is insomnia? Insomnia is a general term defined as “complaints of disturbed sleep in the presence of adequate opportunity and circumstance for sleep.” “Disturbed sleep” is further explained as difficulty with the initiation, maintenance, duration, or quality of sleep that results in the impairment of daytime functioning. Thus, patients with insomnia have difficulty falling asleep and difficulty staying asleep (i.e. waking before a desired wake time). They also experience a reduction in restorative sleep, contributing to a feeling of tiredness during the day. Depending on the persistence of symptoms, insomnia is categorised as transient insomnia, which lasts less than one week; short-term insomnia lasting one to four weeks; and chronic insomnia where symptoms last longer than one month. Sleepless in South Africa: insomnia is not just a night-time problem Moch S, MSc(Med), MEd Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand Keywords: sleeplessness, insomnia, treatment, pharmacological, non-pharmacological Abstract Sleep is necessary for normal growth and development. Lack of sleep causes considerable personal impairment that may impose a substantial societal burden on productivity and quality of life. Insomnia, whether transient or chronic, responds to both pharmacological and non-pharmacological interventions. Cognitive behaviour therapy can effect sustained improvement in insomnia but requires motivation and commitment on the part of the patient and a trained therapist to guide the process. Benzodiazepine receptor agonists and benzodiazepines reduce sleep latency and increase total sleep time in insomniacs. However, their effects are not sustained after stopping the medication. Long-term safety of these medications has not been formally established. Combination of psychological and pharmacological therapies reduces the effect of psychological interventions. Thus, in determined patients psychological therapy should precede drug therapy © Medpharm Reprinted with permission from S Afr Pharm J 2010;77(7)18-26

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[Find the meaning and references behind the names: Heart, Job]

CPD Article: Sleepless in South Africa: insomnia is not just a night-time problem 278 Vol 54 No 4 S Afr Fam Pract 2012 Transient insomnia usually occurs in response to a specific stimulus such as a minor medical problem (e.g. toothache) or an immediate stressor such as friction with a colleague at work. More than 75% of adults report such symptoms, but usually the insomnia is quickly resolved once the stimulus has been ameliorated. Chronic insomnia is more common in women, the elderly and patients with other chronic medical or psychiatric illnesses. It has a prevalence of 10–15% and is associated with mood disturbance, occupational difficulties, interpersonal problems with concomitant social and economic consequences and a reduced quality of life 3,4 Pathophysiology Current theories of the pathophysiology of insomnia have in common the premise that insomnia is a disorder of hyperarousal that is experienced throughout the day. In the cognitive model, sleep disruption occurs as a result of worrying about life stressors. A vicious cycle ensues when disrupted sleep adds to existent anxiety. People literally cannot sleep because they are worried about the consequences of not sleeping (on top of all their other worries). In contrast, the physiological model proposes an imbalance between alerting neuromediators and sleeppromoting agents in the brain which results in higher brain glucose metabolism during sleep and increased cardiac and metabolic rates throughout the day. The daytime state of hyperarousal may be masked by fatigue due to lost sleep, making the 24-hour nature of insomnia less apparent 5 These two theories combine in the psychophysiological model of insomnia, which hypothesises that after developing acute (short-term) insomnia following a specific triggering event, patients associate the bed environment with wakefulness. This is a maladaptive conditioned response which perpetuates the cycle of hyperarousal, despite resolution of the precipitating factor. This presentation is classified as primary insomnia, since the sleep disorder occurs in the absence of a current secondary cause 6 Secondary causes of insomnia Insomnia resulting from a definitive source occurs more commonly than primary insomnia 7 Treatment of the secondary causes can resolve the sleep problem, but sometimes there is value in treating the insomnia concurrently with the primary problem (e.g. in depressed patients), since resolution of the sleep difficulty may speed up recovery 8 However, this is not always the case, and caution is advised when treating conditions such as gastro-oesophageal reflux (GORD) and benign prostatic hyperplasia (BPH). In patients with sleep-related GORD, insomnia improves following treatment with proton-pump inhibitors, while hypnotics such as zolpidem exacerbate the acid reflux problem and may perpetuate the insomnia 9 Another example where care should be taken in treating insomnia concurrent with its cause is in patients with BPH, who wake up multiple times during the night to go to the bathroom as the condition causes incomplete emptying of the bladder. This disturbed sleep contributes to daytime tiredness, since the frequent night-time awakenings derange the sleep pattern. If the patient uses over-the-counter sleep aids (such as the antihistamine diphenhydramine), this could exacerbate urinary retention and thus night time awakenings 10 Accurate diagnosis and treatment of a primary problem causing secondary insomnia (listed in Table 1) is essential in the management of such cases. However, health care practitioners should remain sensitive to the patient’s sleep needs Table I: Secondary causes of insomnia 6 Type of secondary insomnia Examples Adjustment insomnia Insomnia associated with active psychosocial stressors, e.g. divorce, job stress Inadequate sleep hygiene Insomnia associated with lifestyle habits that impair sleep Insomnia due to a psychiatric disorder Active anxiety or depression Insomnia due to a medical condition Restless leg syndrome, chronic pain, fibromyalgia, nocturnal cough, sleep apnoea, menopause (hot flushes), gastro-oesophageal reflux disease, benign prostatic hyperplasia, hyperthyroidism, pregnancy, heart failure Insomnia due to a drug or substance See Table II for further details Several sleep problems that result in impaired quality and quantity of sleep are not considered forms of secondary insomnia, but are rather classified as sleep disorders themselves. These include disorders of the circadian rhythm such as jet lag and shift work sleep disorder, and parasomnias such as sleepwalking and night eating syndrome 3 An additional frequent secondary cause of insomnia is drug use. The general practitioner can provide a useful service in conducting a review of the medication to determine if drug use is contributing to a patient’s insomnia. The following medicines and substances listed in Table II are known to reduce sleep and stimulate brain hyperarousal 11 Of interest is that while alcohol may reduce sleep latency (the time taken to fall asleep), it also reduces NREM stages 3 and 4 (deep sleep) and increases the number of night time awakenings, thus reducing both the quality and quantity of “refreshing” sleep. This contributes to daytime fatigue and worsens insomnia. It is ironical that many patients use alcohol to help themselves fall asleep, not appreciating the fact that the substance itself is perpetuating their sleep problems. In addition, if patients mix alcohol with other drugs for insomnia such as benzodiazepines or benzodiazepine receptor agonists, they further shorten sleep latency but also aggravate sleep cycle disturbances and intensify sleeprelated breathing disorders such as sleep apnoea. This

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[Find the meaning and references behind the names: Low, Good]

CPD Article: Sleepless in South Africa: insomnia is not just a night-time problem 279 Vol 54 No 4 S Afr Fam Pract 2012 dangerous practice should be discouraged, and general practitioners should take opportunities to counsel patients against the use of alcohol as a sleep aid 11 Sleep study terminology The following are some of the terms employed in the study of sleep disorders • Sleep latency: The time it takes to fall asleep after the lights have been turned out. Sleep latency may be prolonged in insomnia, and treatments for insomnia aim to reduce sleep latency • Sleep efficiency: The ratio between total sleep time and total time spent in bed (which is ideally more than 85%) • Total sleep time: The cumulative time spent asleep • Polysomnogram: A test conducted in a sleep laboratory which measures brain activity, eye movements, heart rate, blood pressure, blood oxygenation, air inflow (through the nose), snoring, and chest effort during breathing. Polysomnography is used to diagnose sleep apnoea and other sleep-related breathing disorders, sleep-related seizure disorders and narcolepsy • Multiple sleep latency test: A daytime sleep study where the patient relaxes in a quiet room and brain activity is measured to document if the patient falls asleep and what phases and stages of sleep occur. The test is carried out multiple times through the day, since ability to fall asleep changes throughout the day. This is usually one of the tests for narcolepsy Nonpharmacological therapy Nonpharmacological therapy should precede medication, as patient education regarding good lifestyle habits in relation to sleep can improve insomnia. Sleep hygiene education Most patients benefit from education concerning appropriate sleep habits and behaviours regardless of the cause of their insomnia, since poor sleep habits can perpetuate sleep disturbances and impede recovery. Good sleep hygiene practices should include the following: 12 • Maintaining a regular sleep-wake cycle (even on weekends) • Using the bedroom only for sleep and sex. • Comfortable, quiet, and dark bedroom environment. • Developing a relaxing bedtime routine. • Regular exercise but not within a few hours of bedtime. • Avoidance of alcohol, caffeine and nicotine, especially a few hours before bedtime • No late, heavy meals before bedtime. • No daytime napping. • No disturbances at bedtime (e.g. disruptive noises). • No clock close to the bed, to prevent clock watching. • Avoiding excessive wakeful time in bed (more than 20 minutes) In addition to advice on sleep hygiene, patients should be encouraged to keep a “sleep diary” to document their progress in implementing better sleeping practices and to highlight further areas for intervention. Since insomnia is largely a self-reported phenomenon, it may be instructive for patients to quantify their sleep in relation to their lifestyle habits, as this can help them to develop a perspective on the severity of their symptoms. A sleep diary could include information on bedtime, time to sleep onset, total sleep time, number of night time awakenings, level of refreshment, daytime sleepiness, daytime naps, use of medications, and related events 13 Cognitive-behavioural therapy Cognitive therapy aims to increase patients’ awareness of their specific unrealistic expectations about sleep and misconceptions surrounding the cause of insomnia. A combination of cognitive and behavioural techniques (Table III) may assist the patient to confront the individual issues and deal with them from a psychological standpoint, thus interrupting the chronicity of the insomnia cycle. The advantages of using cognitive/behavioural strategies include a low adverse-effect profile and good evidence of sustained improvement in sleep parameters over six months. However, such strategies produce only slow improvement of symptoms, require personnel trained in provision of the techniques, necessitate firm commitment from the patient to adhere to the long-term regimen, may incur out-of-pocket costs to the patient, and are hampered by the perception that pharmacological interventions are more efficacious 14,15 Table II: Drugs which cause secondary insomnia 1-3,6 Drug Examples Alcohol Beer, wine, liquor Antidepressants SSRIs (e.g. fluoxetine), SNRIs (e.g. venlafaxine), MAOIs (e.g. moclobemide) Beta blockers More common with lipophilic drugs, e.g. propranolol Bronchodilators Theophylline Corticosteroids Prednisolone Decongestants Phenylephrine Diuretics Increase thirst and increase the need to go to the bathroom, both exacerbating insomnia HMG-CoA reductase inhibitors More common with lipophilic drugs, e.g. simvastatin Stimulants Caffeine, nicotine, modafinil, methylphenidate, levodopa, d-norpseudoephedrine, amphetamine, cocaine SSRI: selective serotonin reuptake inhibitor, SNRI: serotonin and noradrenaline reuptake inhibitor, MAOI monoamine oxidase inhibitor, HMG-CoA: 3-hydroxy-3-methylglutaryl-coenzyme A

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[Find the meaning and references behind the names: Real, Fast]

CPD Article: Sleepless in South Africa: insomnia is not just a night-time problem 281 Vol 54 No 4 S Afr Fam Pract 2012 Table III: Cognitive behavioural therapy for insomnia 6,16 Type of cognitive behavioural therapy Description Stimulus-control therapy Encompasses aspects of the good sleep hygiene routine: training the patient to associate their bed with restful sleep rather than reading, watching TV or working in bed Sleep-restriction therapy Reduce time in bed to estimated total sleep time (minimum five hours), then increase time in bed by 15 minutes per week. This “retraining” decreases performance anxiety about falling asleep and incrementally extends total sleep time Relaxation therapy Physical component: progressive muscle relaxation, biofeedback Mental component: imagery training, meditation, hypnosis Cognitive therapy Education to alter faulty beliefs and attitudes about sleep Pharmacological therapy When sleep disturbance causes significant distress or impairment, pharmacotherapy is usually the modality of choice owing to the short time to clinical effect in comparison with psychotherapy. While pharmacotherapy for short-term insomnia can be successful in breaking the cycle of sleeplessness, long-term pharmacotherapy for chronic insomnia is currently limited by the dependence potential of the medications used, tolerance to their clinical effects (with concomitant loss of efficacy) and adverse effects of prolonged use 17 In order to reduce the possibility of adverse occurrences with the long-term use of hypnotic agents, the following principles of drug use should be implemented: • Identification of secondary causes and initiation of their appropriate treatment before attempting drug therapy for sleeplessness • Initiate insomnia pharmacotherapy at low dose, then titrate to clinical effect • Use short duration of therapy (two to four weeks) and/ or intermittent dosing (alternate nights or three times a week) • Be aware of escalating doses or patient resistance to stopping therapy • When discontinuing hypnotic agents, gradually taper doses downwards Although in theory these principles are sound, it has been reported that the majority of sleep medication is used over long periods of time, usually on a nightly basis for several years 18 The problem with this is that clinical trials demonstrating efficacy of hypnotic medications were conducted over short periods (not more than six months) thus long-term value of such medications has not been established 19 The only exception is the new drug eszopiclone (not yet available in South Africa) for which a clinical trial showing improved sleep on self-report measures was conducted over 12 months 20 Further research on “real world” use of medications to aid sleep is necessary to inform how we advise patients with chronic sleep difficulties Table IV is a compilation of drugs which induce sleepiness. Where acceptable evidence has been published for clinical use of the drug in the management of insomnia, the drugs are listed in bold typeface. Where the drugs are being used “off label”, or there is currently insufficient evidence, the drugs have been included for completeness, since many patients turn to these substances to augment insomnia treatment Combined therapy for insomnia If used according to recommendations, current literature suggests that benzodiazepine-receptor agonist (BZRA) hypnotics and benzodiazepines (BZDs) are effective in the short-term treatment of insomnia and can maintain their efficacy over extended time periods (years) with little harm 19 However, as soon as the medicines are stopped, insomnia recurs 22 In contrast, cognitive behaviour interventions can improve insomnia in the short term, and these improvements are sustained over a two-year follow-up period 23 It would seem ideal to be able to combine these two therapies. However, studies of such combined regimens have yielded disappointing results. In these combined protocols, benefit was maintained over 24 months in the group that received cognitive therapy alone but was not sustained in the group that had both medication and cognitive behavioural therapy 24,25 Silber speculates that “patients are less committed to learning and practicing cognitive behavioural therapy techniques if they can control insomnia with medications.” 6 In support of this theory, it has been shown that in patients with chronic insomnia who are attempting to stop BZD therapy, patients who received cognitive behavioural therapy during the drug tapering process managed to achieve and maintain drug freedom, compared with patients who did not receive cognitive therapy 26,27 In our “fast-fix” society, it is understandable that patients are attracted to therapies that assure rapid results, but responsible healthcare practitioners should ensure that the issue of long-term, sustainable benefit is addressed, before therapy is commenced Insomnia and good medical practice The occurrence of insomnia may be alarming for patients, and the general practitioner is ideally placed to give supportive advice concerning management of the problem 28 The general practitioner can assist patients to: • Recognise insomnia and reasons for daytime fatigue. • Investigate possible secondary causes for insomnia including social habits and drug usage • Make the decision to investigate further causes of the insomnia.

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[Find the meaning and references behind the names: John]

CPD Article: Sleepless in South Africa: insomnia is not just a night-time problem 282 Vol 54 No 4 S Afr Fam Pract 2012 Drug name Trade names Type Mechanism of action Clinical use Adverse ef fects Zolpidem Adco-zolpidem ® , Ivedal ® , Mylan zolpidem ® , Noxidem ® , Stilnox ® , Zolnoxs ® , Zolpihexal ® BZRAs These hypnotic agents bind to benzodiazepine receptors (even though they ar e structurally dif fer ent fr om benzodiazepines) and cause postsynaptic hyperpolarisation Ef fective for decr easing the time to sleep onset zolpidem and eszopiclone have longer half-lives and ther efor e ar e also useful for sleep maintenance; both can be used for longer than 30 days Pr oposed less r ebound insomnia and better safety pr ofile than benzodiazepines Although less than benzodiazepines, these drugs ar e still implicated in causing withdrawal symptoms, physical dependence and tolerance to chr onic therapy Use with caution in patients with sleep apnoea, r espiratory disease and hepatic dysfunction Zolpidem incr eases the risk of parasomnias, e.g. night eating syndr ome Zaleplon has such a short half-life that it may be administer ed on waking during the night, pr ovided four mor e hours of sleep ar e intended Zopiclone Adco-zopimed ® , Alchera ® , Austell-zopiclone ® , Imovane ® , Sandoz zopiclone ® , Z-dorm ® , Zopigen ® , Zopivane ® Eszopiclone Not available in South Africa Zaleplon Br otizolam Lendormin ® BZDs Enhance the ef fects of GABA, causing postsynaptic hyperpolarisation which r educes neur onal transmission Ef fective for decr easing the time to sleep onset and pr olonging sleep duration. However , ef ficacy declines when used continuously for mor e than 30 days. Intermittent use (alter nate nights or thr ee times a week) is ther efor e recommended BZDs have lar gely been superseded by BZRAs in the management of insomnia because of their superior tolerability Although long half-life drugs (e.g. diazepam) ar e useful for concomitant anxiety , they cause daytime sedation and impair motor skills and ar e ther efor e not r ecommended for chr onic insomnia Short half-life drugs, e.g. T emazepam cause r ebound insomnia and anxiety All benzodiazepines impair memory BZD use incr eases the risk of falls and hip fractur es in elderly patients CYP 3 A 4 inhibitors, e.g. azole antifungals, macr olide antibiotics, pr otease inhibitors and grapefruit juice may incr ease BZD toxicity CYP 3 A 4 inducers, e.g. carbamazepine and St John’ s wort can decr ease BZD ef fectiveness BZDs ar e potentially addictive Use with caution in patients with sleep apnoea, depr ession, psychosis, respiratory disease, hepatic or r enal impairment and the elderly Alcohol or other CNS depr essants potentiate BZD ef fects and concomitant use could lead to toxicity Diazepam A-Lennon Diazepam ® , Valium ® Flunitrazepam Hypnor ® , Rohypnol ® , Sandoz flunitrazepam ® Flurazepam Dalmadorm ® Loprazolam Dormonoct ® Lormetazepam Loramet ® , Noctamid ® Midazolam Adco-Midazolam ® , Dormicum ® , Midacum ® , Midanium ® , Midazoject ® Nitrazepam Ar em ® , Mogadon ® , Sandoznitrazepam ® Temazepam Normison ® Triazolam Halcion ® Diphenhydramine Betasleep ® Firstgeneration antihistamines Block histamine-1 receptors Available over -the counter for tr eatment of short-term insomnia. Not indicated for chr onic insomnia Tolerance develops to the sedative ef fects of antihistamines Caution in patients with glaucoma and f BPH (owing to anticholiner gic ef fects of antihistamines) Incr eased risk of orthostatic hypotension (exacerbating the risk of falls in the elderly) Not r ecommended for use in childr en Daytime sedation may occur Doxylamine Restwel ® , Somnil ® Phenobarbitone Lethyl ® , in various pain combinations, e.g. Pr opain Forte ® Barbiturates Allosterically modulates the ef fects of GABA, causing postsynaptic hyperpolarisation Not r ecommended for insomnia management Narr ow therapeutic index Lethal in over dose Quick development of tolerance High abuse potential Many drug interactions Induces hepatic micr osomal enzymes Table IV : Drugs which incr ease sleepiness (drugs with pr oven benefit in the management of insomnia ar e indicated in bold type) 2,3,6,11,17,21

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[Find the meaning and references behind the names: Ong]

CPD Article: Sleepless in South Africa: insomnia is not just a night-time problem 283 Vol 54 No 4 S Afr Fam Pract 2012 Drug name Trade names Type Mechanism of action Clinical use Adverse ef fects Amitriptyline Tr epiline ® , T ryptanol ® , Sandoz Amitriptyline ® Antidepr essant drugs Tricyclic antidepr essant: inhibits r euptake of both ser otonin and noradr enaline Ther e is no evidence for use of these agents for insomnia that is not associated with depr ession. In depr essed patients with insomnia, these agents may be used if “alerting” antidepr essants r ender insomnia resistant to tr eatment. Mor e r esear ch is warranted to examine the pr omising ef fects of antidepr essants on r educing str ess hormones and hyperar ousal in chr onic insomnia Exer cise caution with amitriptyline, dothiepin and trazodone in elderly patients with pr ostatic enlar gement, since these drugs incr ease urinary retention Tricyclic antidepr essants cause car diac toxicity and can be lethal in over dose Trazodone incr eases the risk of priapism CYP 3 A 4 inhibitors, e.g. azole antifungals, macr olide antibiotics, pr otease inhibitors and grapefruit juice, may incr ease trazodone toxicity CYP 3 A 4 inducers, e.g. carbamazepine and St John’ s wort, can decr ease trazodone ef ficacy Trazodone has a shorter half-life than amitriptyline, and ther efor e has a smaller risk of mor ning hangover ef fect Owing to their lack of addictive potential, these drugs ar e used in patients with a history of substance abuse co-morbid with insomnia Trazodone Molipaxin ® Inhibits r e-uptake of ser otonin Mirtazapine Adco-Mirter on ® , Aspen Mirtazapine ® , Ber on ® , Mylan Mirtazapine ® , Remer on ® , Sandoz Mirtazapine ® Blocks α 2 receptors pr esynaptically , which results in disinhibition of noradr ener gic and ser otoner gic neur ons, thus incr easing neur otransmission Histamine blockade contributes to sedative ef fects Dothiepin Pr othiaden ® , Sandoz Dothiepin ® , Thaden ® Tricyclic antidepr essant: inhibits r euptake of both ser otonin and noradr enaline Chloral hydrate No longer available in South Africa Alcohol-r elated hypnotic agent Chloral hydrate is rapidly converted by alcohol dehydr ogenase to trichlor oethanol, which is a str ong hypnotic Poor evidence of either safety or ef ficacy (especially in childr en, wher e use of hypnotic agents is pr oblematic) Nausea and vomiting ar e common Ataxia Headache Nightmar es Respiratory depr ession in over dose Mepr obamate Equanil ® , analgesic combinations, e.g Stopayne ® Carbamate Suppr esses multiple CNS sites Not r ecommended for use in patients with insomnia Str ong abuse potential Adverse ef fects: Ataxia, dizziness, hypotension, syncope (which incr eases the risk of falls in the elderly) Chlorpr omazine Lar gactil ® Antipsychotic agents Sedative ef fects of these drugs ar e attributable to blockade of α 1 receptors in the CNS, as well as histamine-1 r eceptor blockade Of f-label use; insuf ficient evidence of safety and ef ficacy in management of chr onic insomnia Postural hypotension (which incr eases the risk of falls in the elderly) W eight gain Constipation Dizziness Akathisia Risperidone Aspen-Risperidone ® , DRL Risperidone ® , Mylan Risperidone ® , Perizal ® , Rispacor ® , Risper dal ® , Risperidone Hexal ® , Risperlet ® , Risponz ® , Zoxadon ® Olanzapine Zypr exa ® Quetiapine Ser oquel ®

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[Find the meaning and references behind the names: Ran]

CPD Article: Sleepless in South Africa: insomnia is not just a night-time problem 284 Vol 54 No 4 S Afr Fam Pract 2012 Drug name Trade names Type Mechanism of action Clinical use Adverse ef fects Pr egabalin Lyrica ® Used for pain of diabetic neur opathy and postherpetic neuralgia Reduces neur onal transmission thr ough binding to the α 2 δ subunit on voltage-gated calcium channels Insuf ficient evidence of safety and ef ficacy in management of chr onic insomnia (used in patients with chr onic pain, who r eport impr oved sleep) W eight gain Peripheral oedema Neur ocognitive disturbances such as confusion, disturbed attention, abnormal thinking, and euphoric mood Gabapentin Epleptin ® , Neur exal ® , Neur ontin ® , Ran-Gabapentin ® Antiepileptic drug Ramelteon Not available in South Africa Melatoninreceptor agonist Binds to M 1 and M 2 receptors, helping to maintain cir cadian rhythm to support the normal sleep-wake cycle. Has a higher af finity for melatonin r eceptors than natural melatonin Ef fective for decr easing the time to sleep onset. Data ar e lacking on head-to-head trials with other hypnotic agents No documented dependence, tolerance, withdrawal syndr ome, motor or cognitive deficits or r ebound insomnia Not to be taken with or immediately after high-fat meals, as this delays absorption and r etar ds clinical ef fects Avoid in patients with sever e hepatic impairment Take immediately befor e bedtime or while in bed, since this drug has a rapid onset of action Agomelatine Valdoxane ® Anxiolytic antidepr essant agent Exerts an antidepr essant ef fect by blocking ser otonin r eceptors. In addition, it stimulates M 1 and M 2 receptors, helping to maintain cir cadian rhythm to support the normal sleep-wake cycle Impr oves sleep ef ficiency and slowwave sleep. Pr oposed as an adjunct to tr eatment of co-morbid depr ession and insomnia. Clinical evidence r emains anecdotal Headache Dry mouth Diarrhoea Fatigue L-tryptophan L-tryptophan is biotransformed to 5-hydr oxytryptophan, and is sold as either formulation Biosynthesised amino acid Tryptophan is the amino acid pr ecursor to ser otonin, which is a pr ecursor of melatonin L-tryptophan is pr oposed to impr ove both mood and sleep, owing to its potential conversion to ser otonin and melatonin. Clinical studies r emain inconclusive Orally ingested tryptophan is br oken down peripherally to ser otonin Raised levels of peripheral ser otonin contribute to adverse ef fects, such as diarrhoea and stomach cramping Small amounts cr oss the blood-brain barrier (which may explain its lack of ef ficacy) Melatonin Synthetically manufactur ed neur ohormone Stimulates M 1 and M 2 receptors (melatonin receptors). Augments endogenous melatonin Pr omotes sleep if taken in the after noon (not at bedtime). Can assist cir cadian rhythm r e-establishment in patients with jet-lag or shift-work sleep disor ders Ther e ar e issues with standar disation of ingr edients and dose variability in herbal pr oducts Herbal synthetic melatonin has a short half-life and is ther efor e only useful in r educing sleep latency , rather than in sleep maintenance Melatonin may r educe the ef ficacy of calcium-channel blockers and incr ease the ef fects of warfarin Caf feine, nicotine, alcohol and β blockers all r educe melatonin levels in the body . Valerian Biral ® , Restin ® Root of the plant Valeriana officinalis Unknown Evidence supporting valerian as a sleep aid r emains contradictory Ther e ar e issues with standar disation of ingr edients and dose variability in herbal pr oducts BZRA: benzodiazepine-r eceptor agonist (non-benzodiazepine), BZD: benzodiazepine, GABA: gamma-aminobutyric acid, CYP: cytochr ome P 450, CNS: central nervous system, BPH: benign pr ostatic hyperplasia

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[Find the meaning and references behind the names: Park, Dennis, Victor, Walsh, Brown, Pace, Smith, Harris, Schmidt, Jacob]

CPD Article: Sleepless in South Africa: insomnia is not just a night-time problem 285 Vol 54 No 4 S Afr Fam Pract 2012 • Assess lifestyle habits (including lack of exercise) which may exacerbate insomnia • Adhere to the treatment regimen prescribed. • Avoid drug interactions with insomnia medications and others • Stop medication for insomnia when indicated An important practical point to note is that both sleeplessness and medications used to treat this condition (e.g. BZDs and BZRAs) can slow reaction time and judgement, and may therefore contribute to motor vehicle accidents and accidents when operation machinery. Patients should be cautioned not to engage in such activities until they feel sure that their level of alertness is sufficient 29 The personal cost to the patient and societal cost of insomnia can be immense. This is an area where supportive, knowledgeable counselling can achieve great impact 30 References 1. Perlis ML, Smith MT, Pigeon WR. 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