Tablets, f/c, varenicline (as tartrate) 500 micrograms (white), net price 56-tab pack = £54.60; 1 mg (blue) 28-tab pack = £27.30, 56-tab pack = £54.60; starter pack of 11 × 500-microgram tabs with 14 × 1-mg tabs = £27.30. Label: 3
4.10.3 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 symptoms within 8 hours, with peak symptoms at 36–72 hours; symptoms subside substantially after 5 days. Methadone or buprenorphine withdrawal occurs later, with longer-lasting symptoms.
Opioid substitution therapy
Methadone 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 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.
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 before starting a withdrawal regimen.
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.
NICE guidance
Methadone and buprenorphine for the management of opioid dependence (January 2007)
Oral methadone and buprenorphine are recommended for maintenance therapy in the management of opioid dependence. Patients should be committed to a supportive care programme including a flexible dosing regimen administered under supervision for at least 3 months, until compliance is assured. Selection of methadone or buprenorphine should be made on a case-by-case basis, but methadone should be prescribed if both drugs are equally suitable.
Buprenorphine Buprenorphine is an opioid-receptor partial agonist (it has opioid agonist and antagonist properties). Buprenorphine is preferred by some patients because it is less sedating than methadone; 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 when used in conjunction with other sedating drugs, and has fewer drug interactions. Dose reductions may be easier than with methadone 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 before induction with naltrexone 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, 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. It is possible to titrate the dose of buprenorphine within one week — more rapidly than with methadone therapy — but care is still needed to avoid toxicity or precipitated withdrawal; dividing the dose on the first day may be useful.
In patients taking methadone who want to switch to buprenorphine, the dose of methadone should be reduced to a maximum of 30 mg daily before starting buprenorphine treatment. If the dose of methadone is over 10 mg daily, buprenorphine can be started at a dose of 4 mg daily and titrated according to requirements; if the methadone dose is below 10 mg daily, buprenorphine can be started at a dose of 2 mg daily.
Buprenorphine should not normally be used in patients with liver dysfunction. Baseline liver function tests and documentation of viral hepatitis status is recommended before commencing therapy, and regular liver function tests should be performed throughout treatment.
A combination preparation containing buprenorphine with naloxone (Suboxone®) can be prescribed for patients when there is a risk of dose diversion for parenteral administration; the naloxone component precipitates withdrawal if the preparation is injected, but it has little effect when the preparation is taken sublingually.
Methadone Methadone, a long-acting opioid agonist, is usually administered in a single daily dose as methadone 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 to buprenorphine because it has a more pronounced sedative effect.
Methadone 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 maintenance treatment may take several weeks.
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 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 or buprenorphine should be undertaken gradually during the second trimester; for example, the dose of methadone may be reduced by 2–3 mg 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 or buprenorphine 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 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.
Breast-feeding The dose of methadone should be kept as low as possible in breast-feeding mothers and the infant should be monitored for sedation (high doses of methadone carry an increased risk of sedation and respiratory depression in the neonate).
Buprenorphine is excreted in low concentrations in breast milk and has low oral bioavailability; however, neonates should be monitored for drowsiness, adequate weight gain, and developmental milestones.
Increased sleepiness, breathing difficulties, or limpness in breast-fed babies of mothers taking opioid substitutes should be reported urgently to a healthcare professional.
BUPRENORPHINE
Indications adjunct in the treatment of opioid dependence; premedication, peri-operative analgesia, analgesia in other situations (section 4.7.2)
Cautions see Buprenorphine in section 4.7.2 and notes above; caution if pre-existing liver enzyme abnormalities, hepatitis B or C infection, or concomitant use of hepatotoxic drugs
Contra-indications see notes in section 4.7.2
Hepatic impairment see notes in section 4.7.2
Renal impairment see notes in section 4.7.2
Pregnancy see notes above
Breast-feeding see notes above
Side-effects see Buprenorphine, section 4.7.2
Dose
By sublingual administration, ADULT and CHILD over 16 years, initially, 0.8–4 mg on day 1, adjusted if necessary by 2–4 mg daily to usual dose of 12–24 mg daily (max. 32 mg daily); withdraw gradually
NICE Technology Appraisal
NICE recommended. See Methadone and buprenorphine for the management of opioid dependence (January 2007)
Buprenorphine (Non-proprietary) 
Tablets (sublingual), buprenorphine (as hydrochloride) 400 micrograms, net price 7-tab pack = £1.60; 2 mg, 7-tab pack = £2.12; 8 mg, 7-tab pack = £4.13. Label: 2, 26
Subutex® (Reckitt Benckiser) 
Tablets (sublingual), buprenorphine (as hydrochloride) 400 micrograms, net price 7-tab pack = £1.60; 2 mg, 7-tab pack = £6.35; 8 mg, 7-tab pack = £19.05. Label: 2, 26
BUPRENORPHINE WITH NALOXONE
Indications adjunct in the treatment of opioid dependence
Cautions see Buprenorphine
Contra-indications see notes in section 4.7.2
Hepatic impairment use lower initial doses and titrate dose carefully in mild to moderate impairment; avoid in severe impairment; see also notes above
Renal impairment use with caution if eGFR less than 30 mL/minute/1.73 m2
Pregnancy reproductive toxicity in animal studies — switch to buprenorphine; see also notes above
Breast-feeding amount of buprenorphine in breast milk probably too small to be harmful; naloxone not orally bioavailable; see also notes above
Side-effects see under Buprenorphine in section 4.7.2 and Naloxone in section 15.1.7; also weight loss, arthralgia; less commonly yawning, heat stroke, hypothermia, vaginitis, anaemia, thrombocytopenia, leucopenia, lymphadenopathy, leucocytosis, haematuria, urinary calculus, conjunctivitis, exfoliative dermatitis, acne, skin nodule, alopecia
Dose
See under preparation
Suboxone® (Reckitt Benckiser) 
Suboxone 2 mg/500 micrograms tablets (sublingual), buprenorphine (as hydrochloride) 2 mg, naloxone (as hydrochloride) 500 micrograms, net price 28-tab pack = £25.40. Label: 2, 26
Suboxone 8 mg/2 mg tablets (sublingual), buprenorphine (as hydrochloride) 8 mg, naloxone (as hydrochloride) 2 mg, net price 28-tab pack = £76.19. Label: 2, 26
Dose expressed as buprenorphine, ADULT and CHILD over 15 years, initially 2–4 mg once daily (an additional dose of 2–4 mg may be administered on day 1 depending on the individual patient’s requirement), increased in steps of 2–8 mg according to response; max. 24 mg daily; total weekly dose may be divided and given on alternate days or 3 times weekly (but max. 24 mg daily)
The Scottish Medicines Consortium has advised (February 2007) that Suboxone® should be restricted for use in patients in whom methadone is not suitable
METHADONE HYDROCHLORIDE
Indications adjunct in treatment of opioid dependence, see notes above; analgesia (section 4.7.2); cough in terminal disease (section 3.9.1)
Cautions see Methadone, section 4.7.2
Contra-indications see Methadone, section 4.7.2
Hepatic impairment see notes in section 4.7.2
Renal impairment see notes in section 4.7.2
Pregnancy see notes above
Breast-feeding see notes above
Side-effects see Methadone, section 4.7.2; overdosage: see Emergency Treatment of Poisoning
Important Methadone, even in low doses is a special hazard for children; non-dependent adults are also at risk of toxicity; dependent adults are at risk if tolerance is incorrectly assessed during induction
Incompatibility Syrup preserved with hydroxybenzoate (parabens) esters may be incompatible with methadone hydrochloride.
Dose
Initially 10–30 mg daily, (10–20 mg daily if tolerance low or not known, up to 40 mg daily if tolerance high and under supervision of experienced prescriber); increased as necessary during first week by 5–10 mg daily (max. weekly increase 30 mg) until no signs of withdrawal nor evidence of intoxication; then increased every few days as necessary up to usual dose range 60–120 mg daily; CHILD not recommended (see also important note above)
Note Methadone hydrochloride doses in the BNF may differ from those in the product literature
NICE Technology Appraisal
NICE recommended. See Methadone and buprenorphine for the management of opioid dependence (January 2007)
Methadone (Non-proprietary) 
Oral solution 1 mg/mL, methadone hydrochloride 1 mg/mL, net price 100 mL = £1.39, 500 mL = £6.95, 2.5 L = £32.10. Label: 2
Sugar free oral solution 1 mg/mL, methadone hydrochloride 1 mg/mL, net price 30 mL = 62p, 50 mL = £1.04, 100 mL = £2.08, 500 mL = £6.30, 2.5 L = £32.50. Label: 2
Brands include Metharose® (sugar-free), Physeptone (sugar-free)
Important Methadone oral solution 1 mg/mL is 2½ times the strength of Methadone Linctus (section 3.9.1). Many preparations of Methadone oral solution are licensed for opioid drug addiction only but some are also licensed for analgesia in severe pain
Injection, methadone hydrochloride 25 mg/mL, net price 2-mL amp = £1.77; 50 mg/mL, 1-mL amp = £1.77
Brands include Synastone®
Methadose® (Rosemont) 
Oral concentrate, methadone hydrochloride 10 mg/mL (blue), net price 150 mL = £12.01; 20 mg/mL (brown), 150 mL = £24.02. Label: 2
Note The final strength of the methadone mixture to be dispensed to the patient must be specified on the prescription
Important Care is required in prescribing and dispensing the correct strength since any confusion could lead to an overdose; this preparation should be dispensed only after dilution as appropriate with Methadose® Diluent (life of diluted solution 3 months) and is for drug dependent persons
Adjunctive therapy and symptomatic treatment
Adjunctive therapy may be required for the management of opioid withdrawal symptoms. Loperamide may be used for the control of diarrhoea; mebeverine for controlling stomach cramps; paracetamol and non-steroidal anti-inflammatory drugs for muscular pains and headaches; metoclopramide or prochlorperazine may be useful for nausea or vomiting. Topical rubefacients can be helpful for relieving muscle pain associated with methadone withdrawal. If a patient is suffering from insomnia, short-acting benzodiazepines (section 4.1) or zopiclone 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 is an alpha2-adrenergic agonist. It may alleviate some of the physical symptoms of opioid withdrawal by attenuating the increase in adrenergic neurotransmission that occurs during opioid withdrawal. Lofexidine 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 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. The patient should take part of the dose at bedtime to offset insomnia associated with opioid withdrawal.
Monitoring of blood pressure and pulse rate is recommended on initiation, for at least 72 hours or until a stable dose is achieved, and on discontinuation; treatment should be discontinued gradually over 2–4 days to reduce the risk of rebound hypertension.
LOFEXIDINE HYDROCHLORIDE
Indications management of symptoms of opioid withdrawal
Cautions severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease, bradycardia, hypotension (monitor pulse rate and blood pressure); history of QT prolongation, concomitant administration of drugs that prolong QT interval; metabolic disturbances; withdraw gradually over 2–4 days (or longer) to minimise risk of rebound hypertension and associated symptoms; depression; interactions: Appendix 1 (lofexidine)
Renal impairment caution in chronic impairment
Pregnancy use only if benefit outweighs risk — no information available
Breast-feeding use only if benefit outweighs risk — no information available
Side-effects dry mucous membranes; hypotension, bradycardia; dizziness, drowsiness; QT-interval prolongation also reported
Dose
ADULT and CHILD over 12 years, initially 800 micrograms daily in divided doses, increased as necessary in steps of 400–800 micrograms daily to max. 2.4 mg daily in divided doses; max. single dose 800 micrograms; recommended duration of treatment 7–10 days if no opioid use (but longer may be required)
Note Lofexidine unlicensed for children under 18 years of age
Opioid-receptor antagonists
Naloxone is an opioid-receptor antagonist used to reverse opioid overdose. Patients dependant on opioids can be given a supply of naloxone to be used in case of accidental overdose; see Emergency Treatment of Poisoning.
Naltrexone is an opioid-receptor antagonist that precipitates withdrawal symptoms in opioid-dependent subjects. Because the effects of opioid-receptor agonists are blocked by naltrexone, it is prescribed as an aid to prevent relapse in formerly opioid-dependent patients.
NICE guidance
Naltrexone for the management of opioid dependence (January 2007)
Naltrexone is recommended for the prevention of relapse in formerly opioid-dependent patients who are motivated to remain in a supportive care abstinence programme. Naltrexone should be administered under supervision and its effectiveness in preventing opioid misuse reviewed regularly.
NALTREXONE HYDROCHLORIDE
Indications adjunct to prevent relapse in formerly opioid-dependent patients (who have remained opioid-free for at least 7–10 days); adjunct to prevent relapse in formerly alcohol-dependent patients (section 4.10.1); treatment should be initiated and supervised by an appropriate specialist
Cautions liver function tests needed before and during treatment; test for opioid dependence with naloxone before treatment; avoid concomitant use of opioids but increased dose of opioid analgesic may be required for pain (monitor for opioid intoxication)
Note Patients should be warned that an attempt to overcome the blockade of opioid receptors by overdosing could result in acute opioid intoxication
Contra-indications patients currently dependent on opioids
Hepatic impairment avoid in acute hepatitis, hepatic failure, or severe impairment
Renal impairment avoid in severe impairment
Pregnancy use only if benefit outweighs risk
Breast-feeding avoid — potential toxicity
Side-effects nausea, vomiting, abdominal pain, diarrhoea, constipation, reduced appetite, increased thirst, chest pain, anxiety, sleep disorders, headache, increased energy, irritability, mood swings, dizziness, chills, urinary retention, delayed ejaculation, decreased potency, joint and muscle pain, increased lacrimation, rash, increased sweating; rarely hepatic dysfunction, depression, suicidal ideation, tinnitus, speech disorders; very rarely hallucinations, tremor, idiopathic thrombocytopenia, exanthema
Dose
Relapse prevention in opioid dependence, ADULT over 18 years (initiate in specialist clinics only), 25 mg initially then 50 mg daily; total weekly dose (350 mg) may be divided and given on 3 days of the week for improved compliance (e.g. 100 mg on Monday and Wednesday, and 150 mg on Friday)
Relapse prevention in alcohol dependence, ADULT and CHILD over 16 years [unlicensed under 18 years], 25 mg [unlicensed dose] on first day, increased to 50 mg daily if tolerated
NICE Technology Appraisal
NICE recommended. See Naltrexone for the management of opioid dependence (January 2007)
Naltrexone (Non-proprietary) 
Tablets, naltrexone hydrochloride 50 mg, net price 28-tab pack = £22.34
Brands include Adepend®, Opizone®
Nalorex® (Bristol-Myers Squibb) 
Tablets, yellow, f/c, scored, naltrexone hydrochloride 50 mg, net price 28-tab pack = £22.34
4.11 Drugs for dementia
Acetylcholinesterase inhibiting drugs are used in the treatment of Alzheimer’s disease, specifically for mild to moderate disease. Rivastigmine is also licensed for mild to moderate dementia associated with Parkinson’s disease. The evidence to support the use of these drugs relates to their cognitive enhancement.
Treatment with drugs for dementia should be initiated and supervised only by a specialist experienced in the management of dementia.
Benefit is assessed by repeating the cognitive assessment at around 3 months. Such assessment cannot demonstrate how the disease may have progressed in the absence of treatment but it can give a good guide to response. Up to half the patients given these drugs will show a slower rate of cognitive decline. Drugs for dementia should be discontinued in those thought not to be responding. Many specialists repeat the cognitive assessment 4 to 6 weeks after discontinuation to assess deterioration; if significant deterioration occurs during this short period, consideration should be given to restarting therapy.
Donepezil is a reversible inhibitor of acetylcholinesterase. Galantamine is a reversible inhibitor of acetylcholinesterase and it also has nicotinic receptor agonist properties. Rivastigmine is a reversible non-competitive inhibitor of acetylcholinesterases; it is also licensed for treating mild to moderate dementia in Parkinson’s disease.
Acetylcholinesterase inhibitors can cause unwanted dose-related cholinergic effects and should be started at a low dose and the dose increased according to response and tolerability.
Memantine is a glutamate receptor antagonist; it is licensed for treating moderate to severe Alzheimer’s disease.
NICE guidance
Donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer’s disease (March 2011)
Donepezil, galantamine, and rivastigmine can be used for the treatment of mild to moderate Alzheimer’s disease. Memantine can be used for moderate Alzheimer’s disease in patients who are unable to take acetylcholinesterase inhibitors, and for patients with severe disease; combination treatment with memantine and an acetylcholinesterase inhibitor is not recommended. Treatment should only be prescribed under the following conditions:
Alzheimer’s disease must be diagnosed and treatment initiated by a specialist; treatment can be continued by general practitioners under a shared-care protocol;
the carers’ views of the condition should be sought before and during treatment;
treatment should continue only if it is considered to have a worthwhile effect on cognitive, global, functional, or behavioural symptoms.
Healthcare professionals should not rely solely on assessment scales to determine the severity of Alzheimer’s disease when the patient has learning or other disabilities, or other communication difficulties.
DONEPEZIL HYDROCHLORIDE
Indications mild to moderate dementia in Alzheimer’s disease
Cautions sick sinus syndrome or other supraventricular conduction abnormalities; susceptibility to peptic ulcers; asthma, chronic obstructive pulmonary disease; concomitant antipsychotic treatment — increased risk of neuroleptic malignant syndrome; interactions: Appendix 1 (parasympathomimetics)
Hepatic impairment caution in mild to moderate impairment, no information available for severe impairment
Side-effects nausea, vomiting, anorexia, diarrhoea; fatigue, insomnia, headache, dizziness, syncope, abnormal dreams, hallucinations, agitation, aggression; muscle cramps; urinary incontinence; rash, pruritus; less commonly gastric and duodenal ulcers, gastro-intestinal haemorrhage, bradycardia, seizures; rarely sino-atrial block, AV block, hepatitis, extrapyramidal symptoms; potential for bladder outflow obstruction; very rarely neuroleptic malignant syndrome
Dose
Initially 5 mg once daily at bedtime, increased if necessary after one month to max. 10 mg daily
NICE Technology Appraisal
NICE recommended. See Donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer’s disease (March 2011)
Donepezil (Non-proprietary) 
Tablets, donepezil hydrochloride 5 mg, net price 28-tab pack =£1.33; 10 mg, 28-tab pack = £1.76.
Orodispersible tablets, donepezil hydrochloride 5 mg, net price 28-tab pack = £7.17; 10 mg, 28-tab pack = £9.57. Counselling, administration
Counselling Donepezil orodispersible tablet should be placed on the tongue, allowed to disperse, and swallowed
Aricept® (Eisai) 
Tablets, f/c, donepezil hydrochloride 5 mg (white), net price 28-tab pack = £59.85; 10 mg (yellow), 28-tab pack = £83.89.
GALANTAMINE
Indications mild to moderate dementia in Alzheimer’s disease
Cautions cardiac disease (including sick sinus syndrome or other supraventricular conduction abnormalities, unstable angina, congestive heart failure); electrolyte disturbances; susceptibility to peptic ulcers; asthma, chronic obstructive pulmonary disease, pulmonary infection; avoid in urinary retention, gastro-intestinal obstruction, and while recovering from bladder or gastro-intestinal surgery; history of seizures; interactions: Appendix 1 (parasympathomimetics)
Hepatic impairment
for immediate-release preparations in moderate impairment, initially 4 mg once daily (preferably in the morning) for at least 7 days, then 4 mg twice daily for at least 4 weeks; max. 8 mg twice daily; avoid in severe impairment
for modified-release preparations in moderate impairment, initially 8 mg on alternate days (preferably in the morning) for 7 days, then 8 mg once daily for 4 weeks; max. 16 mg daily; avoid in severe impairment
Renal impairment avoid if eGFR less than 9 mL/minute/1.73m2
Pregnancy use with caution
Breast-feeding avoid — no information available
Side-effects vomiting, nausea, abdominal pain, diarrhoea, dyspepsia, anorexia, weight loss, bradycardia, hypertension, syncope, hallucination, depression, dizziness, tremor, headache, drowsiness, malaise, muscle spasm, sweating; less commonly taste disturbance, palpitation, arrhythmias, first-degree AV block, hypotension, flushing, paraesthesia, dehydration, seizures, muscular weakness, blurred vision, tinnitus; rarely hepatitis, exacerbation of Parkinson’s disease
Dose
Initially 4 mg twice daily for 4 weeks increased to 8 mg twice daily for 4 weeks; maintenance 8–12 mg twice daily
NICE Technology Appraisal
NICE recommended. See Donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer’s disease (March 2011)
Galantamine (Non-proprietary) 
Tablets, galantamine (as hydrobromide) 8 mg, net price, 56-tab pack = £59.29; 12 mg, 56-tab pack = £74.10. Label: 3, 21
Oral solution, galantamine (as hydrobromide) 4 mg/mL, net price 100 mL =£437.00. Label: 3, 21
Note Sugar-free versions are available and can be ordered by specifying sugar-free on the prescription
Reminyl® (Shire) 
Tablets, f/c, galantamine (as hydrobromide) 8 mg (pink), net price 56-tab pack = £68.32; 12 mg (orange-brown), 56-tab pack = £84.00 Label: 3, 21
Oral solution, sugar-free, galantamine (as hydrobromide) 4 mg/mL, net price 100 mL with pipette = £120.00. Label: 3, 21
Modified release
Galantamine m/r preparations 
Capsules, m/r, galantamine 8 mg; 16 mg; 24 mg. Label: 3, 21, 25
Brands include Acumor XL®, Galsya XL®, Gatalin XL®, Lotprosin XL®, Reminyl XL®
Dose initially 8 mg once daily for 4 weeks increased to 16 mg once daily for 4 weeks; maintenance 16–24 mg daily
MEMANTINE HYDROCHLORIDE
Indications moderate to severe dementia in Alzheimer’s disease
Cautions history of convulsions; interactions: Appendix 1 (memantine)
Hepatic impairment avoid in severe impairment — no information available
Renal impairment reduce dose to 10 mg daily if eGFR 30–49 mL/minute/1.73 m2, if well tolerated after at least 7 days dose can be increased in steps to 20 mg daily; reduce dose to 10 mg daily if eGFR 5–29 mL/minute/1.73 m2; avoid if eGFR less than 5 mL/minute/1.73 m2
Side-effects constipation; hypertension; dyspnoea; headache, dizziness, drowsiness; less commonly vomiting, thrombosis, heart failure, confusion, fatigue, hallucinations, and abnormal gait; very rarely seizures; pancreatitis, psychosis, depression, and suicidal ideation also reported
Dose
Initially 5 mg once daily, increased in steps of 5 mg at weekly intervals to max. 20 mg daily
NICE Technology Appraisal
NICE recommended. See Donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer’s disease (March 2011)
Memantine (Non-proprietary) 
Tablets, memantine 10 mg, net price 28-tab pack = £4.89, 56-tab pack = £15.67; 20 mg, 28-tab pack = £12.71
Brands include Maruxa®, Nemdatine®
Ebixa® (Lundbeck) 
Tablets, f/c, scored, memantine hydrochloride 10 mg (yellow), net price 28-tab pack = £34.50, 56-tab pack = £69.01, 112-tab pack = £138.01; 20 mg (red), 28-tab pack = £69.01; treatment initiation pack, 7 × 5 mg (white), 7 × 10 mg, 7 × 15 mg (orange), and 7 × 20 mg = £43.13
Oral solution, memantine hydrochloride 5 mg/actuation (10 mg/mL), net price 50-mL pump pack = £61.61, 100-mL pump pack = £123.23
Counselling Solution should be dosed onto a spoon or into a glass of water
RIVASTIGMINE
Indications see under Dose
Cautions gastric or duodenal ulcers (or susceptibility to ulcers); monitor body-weight; sick sinus syndrome, conduction abnormalities; history of asthma or chronic obstructive pulmonary disease; history of seizures; bladder outflow obstruction; risk of fatal overdose with patch administration errors (see Counselling below); interactions: Appendix 1 (parasympathomimetics)
Hepatic impairment titrate according to individual tolerability in mild to moderate impairment; use with caution in severe impairment — no information available
Renal impairment titrate according to individual tolerability
Side-effects nausea, vomiting, diarrhoea, dyspepsia, anorexia, weight loss, increased salivation, abdominal pain, bradycardia, dizziness, headache, drowsiness, malaise, agitation, anxiety, tremor, confusion, insomnia, extrapyramidal symptoms (and worsening of Parkinson’s disease), urinary incontinence, sweating; less commonly atrial fibrillation, AV block, depression, syncope; rarely gastric and duodenal ulceration, angina, seizures, rash; very rarely gastro-intestinal haemorrhage, pancreatitis, tachycardia, hypertension, hallucinations; also reported dehydration, hepatitis, restlessness, aggression, sick sinus syndrome, skin hypersensitivity reactions
Note Transdermal administration less likely to cause gastro-intestinal disturbance
Note Treatment should be interrupted if gastro-intestinal side-effects occur and withheld until their resolution — retitrate dose if necessary
Dose
Mild to moderate dementia in Alzheimer’s disease or in Parkinson’s disease, by mouth, initially 1.5 mg twice daily, increased in steps of 1.5 mg twice daily at intervals of at least 2 weeks according to response and tolerance; usual range 3–6 mg twice daily; max. 6 mg twice daily; if treatment interrupted for more than several days, treatment should be retitrated from 1.5 mg twice daily
Mild to moderate dementia in Alzheimer’s disease, by transdermal application, initially apply 4.6 mg/24 hours patch to clean, dry, non-hairy, non-irritated skin on back, upper arm, or chest, removing after 24 hours and siting a replacement patch on a different area (avoid using the same area for 14 days); after at least 4 weeks, and if well tolerated, increase to usual maintenance dose of 9.5 mg/24 hours patch daily; after a further 6 months if well tolerated and cognitive deterioration or functional decline are demonstrated, the dose can be increased to 13.3 mg/24 hours patch daily (caution in patients with body-weight less than 50 kg); if treatment interrupted for more than three days, treatment should be retitrated from 4.6 mg/24 hours patch
Note When switching from oral to transdermal therapy, patients taking 3–6 mg by mouth daily should initially switch to 4.6 mg/24 hours patch, then titrate as above. Patients taking 9 mg by mouth daily should switch to 9.5 mg/24 hours patch if oral dose stable and well tolerated; if oral dose not stable or well tolerated. patients should switch to 4.6 mg/24 hours patch, then titrate as above. Patients taking 12 mg by mouth daily should switch to 9.5 mg/24 hours patch. The first patch should be applied on the day following the last oral dose
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