Drug reference
Excessive sleepiness associated with narcolepsy with or without cataplexy ▶BY MOUTH ▶Adult: Initially 200 mg daily in 2 divided doses, dose to be taken in the morning and at noon, alternatively initially 200 mg once daily, dose to be taken in the morning, adjusted according to response to 200–400 mg daily in 2 divided doses, alternatively adjusted according to response to 200–400 mg once daily ▶Elderly: Initially 100 mg daily
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Arrhythmia. history of clinically significant signs of CNS stimulant-induced mitral valve prolapse (including ischaemic ECG changes, chest pain and arrhythmias). history of cor pulmonale. history of left ventricular hypertrophy. moderate to severe uncontrolled hypertension
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History of alcohol abuse. history of depression. history of drug abuse. history of mania. history of psychosis. possibility of dependence
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ECG required before initiation.
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MHRA/CHM ADVICE: MODAFINIL: POTENTIAL RISK OF CONGENITAL MALFORMATIONS DURING PREGNANCY (FEBRUARY 2020) Post-marketing reports show that the use of modafinil in pregnancy is suspected to cause congenital malformations such as congenital heart defects, hypospadias, and orofacial clefts. Healthcare professionals are advised that modafinil is contra- indicated in pregnancy; alternative treatment options should be used, including behaviour modifying measures, sleep hygiene, and scheduled daytime naps. Females of childbearing potential should be advised on the use of contraception (see Conception and Contraception) and informed of the risk of congenital malformations.
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→Appendix 1: modafinil
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▶Common or very common Anxiety. appetite abnormal. arrhythmias. asthenia. chest pain. confusion. constipation. depression. diarrhoea. dizziness. drowsiness. dry mouth. gastrointestinal discomfort. headaches. mood altered. nausea. palpitations. sensation abnormal. sleep disorders. thinking abnormal. vasodilation. vision disorders ▶Uncommon Allergic rhinitis. arthralgia. asthma. behaviour abnormal. central nervous system stimulation. cough aggravated. diabetes mellitus. dry eye. dysphagia. dyspnoea. eosinophilia. epistaxis. gastrointestinal disorders. hypercholesterolaemia. hyperglycaemia. hyperhidrosis. hypertension. hypotension. increased risk of infection. leucopenia. libido decreased. memory loss. menstrual disorder. movement disorders. muscle complaints. muscle tone increased. muscle weakness. oral disorders. pain. peripheral oedema. psychiatric disorders. skin reactions. speech disorder. suicidal ideation. taste altered. thirst. tremor. urinary frequency increased. urine abnormal. vertigo. vomiting. weight changes ▶Rare or very rare Hallucination. psychosis ▶Frequency not known Angioedema. delusions. fever. hypersensitivity. lymphadenopathy. severe cutaneous adverse reactions (SCARs) SIDE-EFFECTS, FURTHER INFORMATION Discontinue treatment if rash develops. Discontinue treatment if psychiatric symptoms develop.
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The MHRA advises females of childbearing potential should use effective contraception during treatment and 2 months after last treatment.
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Avoid.
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Avoid—present in milk in animal studies.
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Manufacturer advises caution in severe impairment (risk of increased plasma concentrations). Dose adjustments Manufacturer advises dose reduction of 50% in severe impairment.
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Use with caution—limited information available.
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Monitor blood pressure and heart rate in hypertensive patients.
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There can be variation in the licensing of different medicines containing the same drug. Forms available from special-order manufacturers include: oral suspension, oral solution Tablet ▶Modafinil (Non-proprietary) Modafinil 100 mg Modafinil 100mg tablets | 30 tablet P £105.21 DT = £3.41 Modafinil 200 mg Modafinil 200mg tablets | 30 tablet P £105.21 DT = £6.44 ▶Provigil (Teva UK Ltd) Modafinil 100 mg Provigil 100mg tablets | 30 tablet P £52.60 DT = £3.41 Substance dependence Substance dependence Guidance on treatment of drug misuse The UK health departments have produced guidance on the treatment of drug misuse in the UK. Drug Misuse and Dependence: UK Guidelines on Clinical Management (2017) is available at www.gov.uk/government/publications/drug-misuse- and-dependence-uk-guidelines-on-clinical-management. Alcohol dependence See Alcohol dependence p. 517. Nicotine dependence See Smoking cessation p. 520. Opioid dependence The management of opioid dependence requires medical, social, and psychological treatment; access to a multidisciplinary team is recommended. Treatment for opioid dependence should be initiated under the supervision of an appropriately qualified prescriber. Untreated heroin dependence shows early withdrawal Nervous system symptoms within 8 hours, with peak symptoms at 36–72 hours; symptoms subside substantially after 5 days. Methadone hydrochloride p. 524 or buprenorphine p. 468 withdrawal occurs later, with longer-lasting symptoms. Opioid substitution therapy Methadone hydrochloride and buprenorphine are used as substitution therapy in opioid dependence. Substitute medication should be commenced with a short period of stabilisation, followed by either a withdrawal regimen or by maintenance treatment. Maintenance treatment enables patients to achieve stability, reduces drug use and crime, and improves health; it should be regularly reviewed to ensure the patient continues to derive benefit. The prescriber should monitor for signs of toxicity, and the patient should be told to be aware of warning signs of toxicity on initiation and during titration. A withdrawal regimen after stabilisation with methadone hydrochloride or buprenorphine should be attempted only after careful consideration. Enforced withdrawal is ineffective for sustained abstinence, and it increases the risk of patients relapsing and subsequently overdosing because of loss of tolerance. Complete withdrawal from opioids usually takes up to 4 weeks in an inpatient or residential setting, and up to 12 weeks in a community setting. If abstinence is not achieved, illicit drug use is resumed, or the patient cannot tolerate withdrawal, the withdrawal regimen should be stopped and maintenance therapy should be resumed at the optimal dose. Following successful withdrawal treatment, further support and monitoring to maintain abstinence should be provided for a period of at least 6 months. Missed doses Patients who miss 3 days or more of their regular prescribed dose of opioid maintenance therapy are at risk of overdose because of loss of tolerance. Consider reducing the dose in these patients. If the patient misses 5 or more days of treatment, an assessment of illicit drug use is also recommended before restarting substitution therapy; this is particularly important for patients taking buprenorphine because of the risk of precipitated withdrawal. Buprenorphine Buprenorphine is preferred by some patients because it is less sedating than methadone hydrochloride; for this reason it may be more suitable for employed patients or those undertaking other skilled tasks such as driving. Buprenorphine is safer than methadone hydrochloride when used in conjunction with other sedating drugs, and has fewer drug interactions. Dose reductions may be easier than with methadone hydrochloride because the withdrawal symptoms are milder, and patients generally require fewer adjunctive medications; there is also a lower risk of overdose. Buprenorphine can be given on alternate days in higher doses and it requires a shorter drug-free period than methadone hydrochloride before induction with naltrexone hydrochloride p. 519 for prevention of relapse. Patients dependent on high doses of opioids may be at increased risk of precipitated withdrawal. Precipitated withdrawal can occur in any patient if buprenorphine is administered when other opioid agonist drugs are in circulation. Precipitated opioid withdrawal, if it occurs, starts within 1–3 hours of the first buprenorphine dose and peaks at around 6 hours. Non-opioid adjunctive therapy, such as lofexidine hydrochloride p. 526, may be required if symptoms are severe. To reduce the risk of precipitated withdrawal, the first dose of buprenorphine should be given when the patient is exhibiting signs of withdrawal, or 6–12 hours after the last use of heroin (or other short-acting opioid), or 24–48 hours after the last dose of methadone hydrochloride. It is possible Nervous system to titrate the dose of buprenorphine within one week—more rapidly than with methadone hydrochloride therapy—but care is still needed to avoid toxicity or precipitated withdrawal; dividing the dose on the first day may be useful. A combination preparation containing buprenorphine with naloxone p. 526 (Suboxone ®) can be prescribed for patients when there is a risk of dose diversion for parenteral administration; the naloxone hydrochloride p. 1440 component precipitates withdrawal if the preparation is injected, but it has little effect when the preparation is taken sublingually. Where there is a risk of diversion of opioid substitution medicines, or difficulties with adherence to daily supervised opioid substitution medication, buprenorphine prolonged- release injection may be an option. Methadone Methadone hydrochloride, a long-acting opioid agonist, is usually administered in a single daily dose as methadone hydrochloride oral solution 1 mg/mL. Patients with a long history of opioid misuse, those who typically abuse a variety of sedative drugs and alcohol, and those who experience increased anxiety during withdrawal of opioids may prefer methadone hydrochloride to buprenorphine because it has a more pronounced sedative effect. Methadone hydrochloride is initiated at least 8 hours after the last heroin dose, provided that there is objective evidence of withdrawal symptoms. A supplementary dose on the first day may be considered if there is evidence of persistent opioid withdrawal symptoms. Because of the long half-life, plasma concentrations progressively rise during initial treatment even if the patient remains on the same daily dose (it takes 3–10 days for plasma concentrations to reach steady-state in patients on a stable dose); a dose tolerated on the first day of treatment may become a toxic dose on the third day as cumulative toxicity develops. Thus, titration to the optimal dose in methadone hydrochloride maintenance treatment may take several weeks. Opioid substitution during pregnancy Acute withdrawal of opioids should be avoided in pregnancy because it can cause fetal death. Opioid substitution therapy is recommended during pregnancy because it carries a lower risk to the fetus than continued use of illicit drugs. If a woman who is stabilised on methadone hydrochloride or buprenorphine for treatment of opioid dependence becomes pregnant, therapy should be continued [buprenorphine is not licensed for use in pregnancy]. Many pregnant patients choose a withdrawal regimen, but withdrawal during the first trimester should be avoided because it is associated with an increased risk of spontaneous miscarriage. Withdrawal of methadone hydrochloride or buprenorphine should be undertaken gradually during the second trimester, with dose reductions made every 3–5 days. If illicit drug use occurs, the patient should be re-stabilised at the optimal maintenance dose and consideration should be given to stopping the withdrawal regimen. Further withdrawal of methadone hydrochloride p. 524 or buprenorphine p. 468 in the third trimester is not recommended because maternal withdrawal, even if mild, is associated with fetal distress, stillbirth, and the risk of neonatal mortality. Drug metabolism can be increased in the third trimester; it may be necessary to either increase the dose of methadone hydrochloride or change to twice-daily consumption (or a combination of both strategies) to prevent withdrawal symptoms from developing. The neonate should be monitored for respiratory depression and signs of withdrawal if the mother is prescribed high doses of opioid substitute. Signs of neonatal withdrawal from opioids usually develop 24–72 hours after delivery but symptoms may be delayed for up to 14 days, so monitoring may be required for several weeks. Symptoms include a high-pitched cry, rapid breathing, hungry but ineffective suckling, and excessive wakefulness; severe, but rare symptoms include hypertonicity and convulsions. Opioid substitution during breastfeeding Doses of methadone and buprenorphine should be kept as low as possible in breast-feeding mothers. Increased sleepiness, breathing difficulties, or limpness in breast-fed babies of mothers taking opioid substitutes should be reported urgently to a healthcare professional. Adjunctive therapy and symptomatic treatment Adjunctive therapy may be required for the management of opioid withdrawal symptoms. Loperamide hydrochloride p. 71 may be used for the control of diarrhoea; mebeverine hydrochloride p. 93 for controlling stomach cramps; paracetamol p. 465 and non-steroidal anti-inflammatory drugs for muscular pains and headaches; metoclopramide hydrochloride p. 452 or prochlorperazine p. 407 may be useful for nausea or vomiting. Topical rubefacients can be helpful for relieving muscle pain associated with methadone hydrochloride withdrawal. If a patient is suffering from insomnia, short-acting benzodiazepines or zopiclone p. 512 may be prescribed, but because of the potential for abuse, prescriptions should be limited to a short course of a few days only. If anxiety or agitation is severe, specialist advice should be sought. Lofexidine Lofexidine hydrochloride p. 526 may alleviate some of the physical symptoms of opioid withdrawal by attenuating the increase in adrenergic neurotransmission that occurs during opioid withdrawal. Lofexidine hydrochloride can be prescribed as an adjuvant to opioid substitution therapy, initiated either at the same time as the opioid substitute or during withdrawal of the opioid substitute. Alternatively, lofexidine hydrochloride may be prescribed instead of an opioid substitute in patients who have mild or uncertain dependence (including young people), and those with a short history of illicit drug use. Opioid-receptor antagonists Patients dependant on opioids can be given a supply of naloxone hydrochloride p. 1440 to be used in case of accidental overdose. Naltrexone hydrochloride p. 519 precipitates withdrawal symptoms in opioid-dependent subjects. Because the effects of opioid-receptor agonists are blocked by naltrexone hydrochloride, it is prescribed as an aid to prevent relapse in formerly opioid-dependent patients. Opioid dependence in children In younger patients (under 18 years), the harmful effects of drug misuse are more often related to acute intoxication than to dependence, so substitution therapy is usually inappropriate. Maintenance treatment with opioid substitution therapy is therefore controversial in young people; however, it may be useful for the older adolescent who has a history of opioid use to undergo a period of stabilisation with buprenorphine or methadone hydrochloride before starting a withdrawal regimen. 8.1 Alcohol dependence Alcohol dependence Description of condition Alcohol dependence is a cluster of behavioural, cognitive and physiological factors that typically include a strong desire to drink alcohol, tolerance to its effects, and difficulties controlling its use. Someone who is alcohol- dependent may persist in drinking, despite harmful consequences, such as physical or mental health problems. In severely dependent patients who have been drinking excessively for a prolonged period of time, an abrupt reduction in alcohol intake may result in the development of an alcohol withdrawal syndrome, which, in the absence of medical management, can lead to seizures, delirium tremens, and death. Assisted alcohol withdrawal g Patients with mild alcohol dependence usually do not need assisted alcohol withdrawal. Patients with moderate dependence can generally be treated in a community setting unless they are at high risk of developing alcohol withdrawal seizures or delirium tremens; individuals with severe dependence should undergo withdrawal in an inpatient setting. Patients with decompensated liver disease should be treated under specialist supervision. A long-acting benzodiazepine, such as chlordiazepoxide hydrochloride p. 360 or diazepam p. 360, is recommended to attenuate alcohol withdrawal symptoms; local clinical protocols should be followed. In primary care, fixed-dose reducing regimens are used. This involves using a standard, initial dose (determined by the severity of alcohol dependence or level of alcohol consumption), followed by dose reduction to zero, usually over 7–10 days. In inpatient or residential settings, a fixed- dose regimen or a symptom-triggered regimen can be used. A symptom-triggered approach involves tailoring the drug regimen according to the severity of withdrawal and any complications in an individual patient; adequate monitoring facilities should be available. The patient should be monitored on a regular basis and treatment only continued as long as there are withdrawal symptoms. Carbamazepine p. 327 [unlicensed indication] can be used as an alternative treatment in acute alcohol withdrawal. Clomethiazole p. 511 may be considered as an alternative to a benzodiazepine or carbamazepine p. 327. It should only be used in an inpatient setting and should not be prescribed if the patient is liable to continue drinking alcohol. hNote: Alcohol combined with clomethiazole p. 511, particularly in patients with cirrhosis, can lead to fatal respiratory depression even with short-term use. g When managing withdrawal from co-existing benzodiazepine and alcohol dependence, the dose of benzodiazepine used for withdrawal should be increased. The initial daily dose is calculated, based on the requirements for alcohol withdrawal plus the equivalent regularly used daily dose of benzodiazepine. A single benzodiazepine (chlordiazepoxide hydrochloride p. 360 or diazepam p. 360) should be used rather than multiple benzodiazepines. Inpatient withdrawal regimens should last for 2–3 weeks or longer, depending on the severity of benzodiazepine dependence. When withdrawal is managed in the community, or where there is a high level of benzodiazepine dependence, or both, the regimen should last for a minimum of 3 weeks (according to the patient’s symptoms). If alcohol withdrawal seizures occur, a fast-acting benzodiazepine (such as lorazepam p. 355 [unlicensed indication]) should be prescribed to reduce the likelihood of further seizures. If alcohol withdrawal seizures develop in a person during treatment for acute alcohol withdrawal, review their withdrawal drug regimen. h Delirium tremens g Delirium tremens is a medical emergency that requires specialist inpatient care. In patients with delirium tremens (characterised by agitation, confusion, paranoia, and visual Nervous system and auditory hallucinations), oral lorazepam p. 355 should be used as first-line treatment. If symptoms persist or oral medication is declined, parenteral lorazepam p. 355 [unlicensed], or haloperidol p. 404 [unlicensed] can be given as adjunctive therapy. If delirium tremens develops during treatment for acute alcohol withdrawal, the withdrawal drug regimen should also be reviewed. h Alcohol dependence g In harmful drinkers or patients with mild alcohol dependence, a psychological intervention (such as cognitive behavioural therapy) should be offered. In those who have not responded to psychological interventions alone or who have specifically requested a pharmacological treatment, acamprosate calcium p. 518 or oral naltrexone hydrochloride p. 519 can be used in combination with a psychological intervention. Acamprosate calcium p. 518 or oral naltrexone hydrochloride p. 519 in combination with a psychological intervention are recommended for relapse prevention in patients with moderate and severe alcohol dependence, to start after successful assisted withdrawal. Disulfiram p. 518 is an alternative for patients in whom acamprosate calcium p. 518 and oral naltrexone hydrochloride p. 519 are not suitable, or if the patient prefers disulfiram p. 518 and understands the risks of taking the drug. Nalmefene p. 518 is recommended for the reduction of alcohol consumption in patients with alcohol dependence who have a high drinking risk level, without physical withdrawal symptoms, and who do not require immediate detoxification (see National funding/access decisions for nalmefene p. 518). Patients with severe alcohol-related hepatitis with a discriminant function of 32 or more can be given corticosteroids but only after any active infection or gastro- intestinal bleeding is treated, any renal impairment is controlled, and following discussion of the potential benefits and risks of treatment. Corticosteroid treatment has been shown to improve survival in the short term (1 month) but not over a longer term (3 months to 1 year). It has also been shown to increase the risk of serious infections within the first 3 months of starting treatment. Patients with chronic alcohol-related pancreatitis should be offered nutritional support; those who have symptoms of steatorrhoea or who have poor nutritional status due to Exocrine pancreatic insufficiency p. 103 should be prescribed pancreatic enzyme supplements; supplements are not indicated when pain is the only symptom. h Wernicke’s encephalopathy g Patients with alcohol dependence are at risk of developing Wernicke’s encephalopathy; patients at high risk are those who are malnourished, at risk of malnourishment, or have decompensated liver disease. Parenteral thiamine p. 1141, followed by oral thiamine p. 1141, should be given to patients with suspected Wernicke’s encephalopathy, those who are malnourished or at risk of malnourishment, those who have decompensated liver disease or who are attending hospital for acute treatment. Prophylactic oral thiamine p. 1141 should also be given to harmful or dependent drinkers if they are in acute withdrawal, or before and during assisted alcohol withdrawal. h. Parenteral thiamine is available as part of a vitamin B substances with ascorbic acid p. 1142 preparation. Useful Resources Alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence. National Institute for Health and Care Excellence. Clinical guideline 115. February 2011. www.nice.org.uk/guidance/cg115 Alcohol-use disorders: diagnosis and management of Nervous system physical complications. National Institute for Health and Care Excellence. Clinical guideline 100. June 2010 (updated April 2017). www.nice.org.uk/guidance/cg100 ALDEHYDE DEHYDROGENASE INHIBITORS
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Initially 200 mg daily in 2 divided doses, dose to
First-line fragment. Read the complete Indications and Dose section above.
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