IV CONSTITUTIONAL GOVERNMENT MINISTÉRIO DA SAÚDE

Standard Treatment Guidelines Modules:

Neurology, Pain control and Mental Health in Referral Hospitals.

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Ref. No.MS/DG/CRSF/10/82

To : All health wokers in Timoe-Leste : All multi and bilateral organization supporting the Ministry of Health

Subject : Introduction to the East Timor Standart Treatment Guidelines

Along with discussions to update the Essential Medecines List (EML) which was approved January 2010, we have now also been able to finalize the second edition of the Standart Treatment Guidelines (STGs). This time, STGs have been prepared both for Primary Care level and for referral hospitals. The first draft standard treatment guideline was prepared for Primary Care in 2002 and has been lying with us since then. Unfortunately, several subjects could not be finished in that edition, due to different opinions and frequent treatment changes. The first edition was compiled with the help of consultants, Dr. Rudiger Kilian (Clinical Pharmacist) and Dr. Ali Sallami (Pharmacologist) who compiled the first guideline Edition, from drafts prepared by the Ministry and/or by specialists in national programs such as IMCI, Malaria et cetera. The first draft edition of standard treatment guidelines have now been compared with the latest literature and evidence based medicine, and also adjusted to match existing diagnostic resources available in healthcare in Timor Leste. Updating and corrections of the first draft from 2002 has now been done with advice and assistance of Dr Sam Tornquist (Clinical Pharmacologist/infectious diseases). This revision has both used input from evidence based medicine and a thorough process of consensus-building through workshops with prescribers. This process has also created a mechanism for future revision of treatment guidelines in Timor Leste. Several anomalies have now been set straight and we are confident that the information now contained in this STG is up to date and also matching the reality in Timor Leste. A standart treatment guideline is not a fixed document for ever, since medical scientific knowledge changes over time. Still, once the STG have been formally approved and agreed, this is an important tool to ensure quality of care and good clinical practice. I therefore request that all clinicians, contributors and programs shall follow these guidelines. Future updates of Standard Treatment Guidelines will be organized and coordinated by the Ministry of Health to match important changes in international evidence based medicine. The next revision will be due in the next two years. SAMES has updated its catalog and adjusted the buying program in line with the new medecines. However, since the buying procedures are taking time, the new product might not arrive in country for some time yet. There is also considerable amount of money involved in the discontinued items. You are requested to use up these supplies before changing your prescribing habits to the new medecines. Your are also requested not to use suspensions and injections where those are not really required. Do not practice polypharmacy.

I take this opportunity to thank all the contributors and the editors for their excellent work, and wish that the information in this book could guide your in your daily works of practicing medecines.

CC : The Minister of Health of RDTL The Vice – Minister of Health of RDTL

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List of authors, clinical reviewers and referees: Baucau district referral hospital Family name Given name Specialty / position Dr Calvino Luis Ocana Orthopedics Dr Da Silva Nilton General Practitioner Dr De Rosa Abraham G General Practitioner Dr dos Santos Valentin Ob/Gyn Dr Estrada Delmis Doural Dermatology Dr Estrada Rene Oscare Dermatology Dr Gusmao dos Santos Celia A. Surgery Dr Hernandez Armando Anaesthetics Dr Laborde Barbara Ochra Paediatrics Dr Macaret Maria E Neonatology Dr Monsale Ancieto Internal Medicine Dr Mora Yaima General Practitioner Dr Murillo Rostico R. Ob/Gyn Dr Mwaura Phillip Surgery Dr Olivares Rene Luis E General surgery Dr Sanches M Angilberto Internal Medicine Dr Santana Jose Antonino Pediatric surgery Dr Sevilleno Edna Pediatric Dr Tornquist Sam Infectious diseases Suai, Cova Lima district referral hospital Dr Cortez L Liodemis General Practitioner Dr De Carvalho Irene Hospital Director, General Practitioner Dr Fajarda Tamayo Annie YS General Practitioner Dr Magno Julia R.C. Clinical Director, General Practitioner Dr Pupo Paiper Imaelda Paediatrician Dr Rjaboshenko Oleksiy Obstetrics & Gynecol. Dr Tornquist Sam Infectious diseases Maliana district referral hospital Dr Ajete Valdes Norgelis Mercedes Farmacology Dr Balenten Fournier Ernan Obstetrics & Gynaecology Dr Cabriales Pedroso Yaneisy General Practitioner Dr Calderon Reynoso Irene Alicia Pediatrician Dr Cid Medina Lissette General Practitioner Dr Cuellar Prieto Dagoberto General Practitioner Dr Fernandez Muniz Adilia Otilia General Practitioner Dr Hernandez Suares Odalys Harina Radiologist Dr Pineda Chacon Roberto Internal medicine Dr Vittorino Bere Talo Hospital Director, General Practitioner Dr Zaldivar Reyes Jorge General Practitioner Dr Tornquist Sam Infectious diseases Mobissi district referral hospital Dr Da Costa Dr.Horacio Sarmento General Practitioner Dr Pereira Gabriela da C.M General Practitioner Dr.Guitherez Francis Saison Obstetrics & Gynaecology Dr.Uris Hernandez Ramirez MGI Dr.Feliz Alesandro Lafiilla del Tores MGI Dr.Custadia B. Florindo General Practitioner Dr.Gonzales Amaro Matilde Maza Pediatrician Dr. Raimundo Danilo Gyaecology Dr. Quiala Alberto Surgery Dr. Hechararria Vidalina Internal medicine Dr. Ximenes Juliana Faria Internal medicine

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Table of Contents Abbreviations and acronyms...... 8 Acknowledgements ...... 8 Introduction ...... 9 Selection of medicines in the Guidelines and Essential Medicines List…………………………………….9 Generic names…………………………………………………………………………………………………….10 Neurology in referral hospitals...... 11 Orofacial conditions and pain…………………………………………………………………………………….11 Facial nerve (Bell's) palsy ...... 11 Trigeminal neuralgia ...... 11 …………………………………………………………………………………………………………..12 ...... 13 Epilepsy…………………………………………………………………………………………………………….15 Involuntary movement disorders………………………………………………………………………………..19 Parkinson's disease ...... 19 Essential tremor ...... 19 Chorea ...... 20 -treatment-induced dystonia...... 20 CNS ……………………………………………………………………………………………………..20 Meningitis ...... 20 Bacterial meningitis - Management prior to hospitalisation ...... 20 Immediate and early hospital management of meningitis ...... 21 Empirical treatment of meningitis before organism is known ...... 21 Directed treatment, against identified pathogens...... 22 Listeria monocytogenes meningitis ...... 22 Neisseria meningitidis ...... 22 Pneumococci - Streptococcus pneumoniae meningitis ...... 23 Pneumococci meningitis with Strains relatively resistant to penicillin (MIC 0.125 to 1 mg/L) ...... 23 Herpes simplex encephalitis, suspected or proven ...... 24 Central with Herpes zoster (shingles) ...... 24 Acute pain of herpes zoster ...... 25 Postherpetic neuralgia…………………………………………………………………………………………….25 Cerebrovascular disorders……………………………………………………………………………………….26 Stroke………………………………………………………………………………………………………………..26 Subarachnoid haemorrhage……………………………………………………………………………………..26 Prevention and management of risk-factors…………………………………………………………………..27 Primary stroke-prevention ...... 27 Stroke-prophylaxis in patient with atrial fibrillation...... 28 Secondary stroke-prevention ...... 28 Acute stroke and hypertension ...... 28 Module: Pain-Control in Referral Hospitals...... 29 Pain control…………………………………………………………………………………………………………29 Short overview - key analgetic ……………………………………………………………………………29 ...... 29 Paracetamol overdose ...... 30 Acetylsalicylic acid – ...... 31 NSAIDs Non-steroidal antiinflammatory drugs ...... 32 NSAIDs and patients who are taking ; ...... 33

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Opiates / opioids ...... 33 Codeine ...... 34 Morphine ...... 34 Pethidine ...... 34 Methadone ...... 35 Co- ...... 35 Naloxone - Opiate ...... 35 Concurrent use of and opioid analgesics ...... 36 Pain control for adults…………………………………………………………………………………………….36 1. Mild pain in adults ...... 36 2. Moderate Pain in adults ...... 37 3. Severe pain in adults ...... 37 Pain control for children…………………………………………………………………………………………..38 1. Mild pain in children ...... 38 2. Moderate pain in children ...... 39 3. Severe pain in children ...... 39 Pain syndromes and specific conditions……………………………………………………………………….40 Musculoskeletal pain ...... 40 General recommendations for treatment of limb pain………………………………………………………..41 Pain of specific anatomical origin……………………………………………………………………………….42 Spinal pain ...... 42 Acute low back pain ...... 43 Chronic low back pain ...... 43 Mechanical neck pain ...... 43 Neck pain with nerve root involvement ...... 44 Rheumatoid arthritis ...... 44 Acute pain ...... 44 Nontraumatic acute joint pain ...... 45 Traumatic acute joint pain ...... 46 Osteoarthritis ...... 46 Rheumatoid arthritis (RA)...... 47 Juvenile rheumatoid arthritis / Juvenile chronic arthritis ...... 48 Postoperative pain control………………………………………………………………………………………..49 The post-operative phase ...... 49 Control of trauma pain ...... 51 Maintenance of pain control ...... 52 Burn pain ...... 53 Management of pain for burned patients in hospital care...... 54 Burns dressings and debridement ...... 55 Obstetric pain ...... 55 Gynaecological pain ...... 55 Headache ...... 55 Special cases of pain caused by viral infections………………………………………………………………55 Herpes zoster pain ...... 55 Acute pain of herpes zoster ...... 56 Postherpetic neuralgia ...... 57 5

Mental Health services, referral hospitals...... 58 The acutely confused, aggressive patient - delirium…………………………………………………………58 Sedation of the acutely disturbed patient ...... 59 Substance abuse; Alcohol and narcotic drug addiction………………………………………………………61 Alcoholism...... 61 Alcohol overdose ...... 61 Acute alcohol withdrawal ...... 61 Delirium tremens ...... 62 Barbiturate abuse and overdose ...... 63 Treatment of barbiturate overdose...... 64 Barbiturate withdrawal ...... 65 Benzodiazepine abuse ...... 65 Benzodiazepine overdose ...... 65 Benzodiazepine withdrawal ...... 66 Opiate / opioid abuse and addiction ...... 67 Acute opiate / opioid overdose ...... 67 Opioid / opiate detoxication and withdrawal ...... 68 Control of autonomous nervous system symptoms during opioid withdrawal; ...... 68 Treatment of anxiety and agitation during opoid withdrawal ...... 69 Long-term treatment of patient with history of opioid dependence ...... 70 CNS addiction and abuse ...... 71 Amphetamine and cocaine ...... 71 Amphetamine derivative overdose toxicity ...... 71 addiction and abuse ...... 72 Cannabis or Hashisch ...... 72 Schizophrenia………………………………………………………………………………………………………73 Signs and symptoms of schizophrenia ...... 73 Principles of treatment for schizophrenia ...... 74 Treatment of a first episode of schizophrenia ...... 74 Treatment of schizophrenia when low degree of effect is required: ...... 74 Treatment of schizophrenia if a more sedative effect is needed: ...... 74 Management of acute psychosis (including mania): ...... 75 After the acute phase: ...... 75 Treatment of acute dystonic reactions, laryngeal dystonia: ...... 76 Treatment of relapse of schizophrenia ...... 76 Management of treatment-resistant schizophrenia ...... 77 Long-acting or depot for schizophrenia ...... 77 Management of adverse reactions during use of medicine ...... 78 Management of acute dystonia ...... 78 Management of akathisia ...... 78 Management of drug-induced Parkinsonism ...... 79 Tardive dyskinesia ...... 79 Neuroleptic (antipsychotic) malignant syndrome...... 79 Mood disorders…………………………………………………………………………………………………….80 Anxiety and associated disorders ...... 80 6

Anxiety adjustment disorder ...... 80 Obsessive-compulsive disorder ...... 80 Phobic disorders ...... 81 Acute stress disorder ...... 82 Post-traumatic stress disorder ...... 82 Sleep disorders…………………………………………………………………………………………………….82 Insomnia ...... 82 in the elderly ...... 83 General principles for the use of hypnotics in the elderly are: ...... 83

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Abbreviations and acronyms bd Bis die, twice per day g Gram hr Hour Hb Haemoglobin IU International unit IM Intramuscular IV Intravenous mg Milligram mL Millilitre mmHg Millimetres of mercury PV Per vaginam, by vaginal dosage qid Quarter in die. 4 times per day qds Quarter die sumendus, to be taken 4 times per day qqh Quarta quaque bora. Every 4 hour SC Subcutaneous SL Sublingual stat Statim, immediately, as initial dose tid Ter in die, 3 times per day tds Ter die sumendus, to be taken 3 times per day

Acknowledgements

The development and revision of standard treatment guidelines has been funded through the HSSP SP program, with funding from the World Bank, European Commission and AusAID. Additional support has been provided from the WHO and from also from the Cuban medical Cadres, both in the form of participation in active clinical revision and in translation. Special acknowledgement shall also be presented to all Timorese physicians and managers of district referral hospitals, for their active and very valuable contribution and active contribution to the revision workshops which have been carried out in the hospitals. Special thanks and acknowledgements shall also be expressed to individual specialists based in the national hospital who also have contributed.

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Introduction

Standard treatment guidelines are currently used World-wide as a tool both to improve the uniform delivery of good quality care, and to optimize the effective and efficient use of resources. Evidence based medicine is the foundation for decision about what is most appropriate treatment approach to the most prevalent diseases for each level of healthcare. Standard treatment guidelines, or clinical practice guidelines are now in use in Europe, USA, Australia, through South East Asia and elsewhere in the World. A first edition of Standard treatment guidelines for primary care was launched in Timor Leste by the year 2004.

That first 2004 edition of Standard Treatment Guidelines for primary care has now been revised. The revision has been carried out through a process of dialogue at district referral hospitals throughout Timor Leste.

The review has focused on appropriate clinical practice and rational drug-use at district referral hospitals. At the same time, the review also considered clinical practice and treatments in primary care, based on experience from outreach from district hospitals in support to primary healthcare. The review thus incorporated a high degree of experience from daily healthcare in Timor Leste.

We want thank all physicians and other healthcare personnel who have provided their valuable contribution and shared all their experience with us in this work.

Selection of medicines in the Guidelines and Essential Medicines List.

The medicines included in the Standard treatment guidelines and Essential Medicines List for East Timor have been selected based on the World Health Organization (WHO) essential medicines lists for adults and children. In addition, the medicine selection also match the drug selection of national programs, such as IMCI. The selection only includes medicines that fit the key criteria:

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• Proven and documented efficacy and documeted safety / risk profile. Meaning that drugs with unknown risk, unknown safety and unknown ability to give medical benefit have not been included. • Relevance to the pattern of prevalent diseases. Meaning that the selected drugs shall be well documented as effective as as safe as possible, for treatment of common and commonly serious disease occuring in Timor Leste. • Preference for well known medicines. • Single compound medicines are preferred Generic names

As Policy, the generic names for medicines shall be used.

Every medicine has a name for the chemical active substance, an international non-proprietary name (INN). The INN or Generic name is the official name of the active substance in the medicine, regardless of who manufactures the medicine product. A so called Brand name is also chosen by each manufacturer to facilitate association of one particular product, with a particular company for the purpose of marketing. Many medicines are manufactured by several different companies and marketed under several different brand names. As example, there are more than 40 brand names of products containing the active substance amoxicillin in South East Asia. Since Timor Leste is procuring medicines by international competitive tenders, different brand name products of Amoxicillin may be used in Timor Leste during during different years. Consequently, it is important that all health workers systematically use the generic (INN) name of the medicine instead of using the brand-names. Reasons for this are also: • To prevent confusion about which medicine is being prescribed • Generic names are more informative than brand names and facilitate purchasing of products from multiple suppliers, whether as brand name or generic products. • Generic prescribing also facilitates product substitution whenever appropriate. It may take a little time to get used to the generic names for medicines however; once learned the generic name does not change – unlike the many brand names.

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Neurology in referral hospitals.

Orofacial conditions and pain.

In the assessment of the patient with orofacial pain, be aware of the possibility of a serious underlying organic lesion, especially if there are neurological signs with reduced sensation or impaired corneal reflex. Orofacial pain may also be due to dental disease, involving the teeth, the oral mucosa or jaw .

Facial nerve (Bell's) palsy

If a lower motor neurone facial palsy is incomplete, and remains incomplete one week after onset of the palsy, the chances for ultimate full or near full recovery is so good that active treatment is not necessary. If blinking is impaired, cover the eye on the affected side. If the paralysis is complete or nearly complete, or the of taste is lost on the anterior two-thirds of the tongue on the affected side, the prognosis for recovery is less certain. Overall some 80 % of all persons with facial palsy can expect a full recovery eventually.

Treatment with per oral in moderate - high dose should begin as soon as possible. Give; Prednisolone 15 mg orally, 4 times a day. The full corticosteroid dose is continued for a week, unless recovery has already begun. After that, the dose is halved to: Prednisolone 10 mg orally, 3 times a day for 3 days, then: Prednisolone 5 mg orally, 3 times a day for 3 days, before ceasing therapy.

Trigeminal neuralgia

This condition is characterised by sudden, brief and very severe recurrent pain, involving the distribution of one or more branches of the Vth cranial (trigeminal) nerve; pain is more common on one side of the face, usually affecting second or third division of the nerve.

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Brief nature of the pain, may be described as ‘stabbing’ or as ‘electric shock’. Pain is precipitated by some form of stimulation such as talking, chewing or touching the face.

Give; 100 mg orally, twice daily, initially, increasing the dose gradually, to avoid drowsiness. Doses of 400 mg orally, twice daily may be required by some patients. After pain relief has been maintained for several weeks, the dose should be gradually reduced to establish the minimum dose. Failure of medical treatment is an indication for surgical intervention.

Headache

Headache is very common. It is not a diagnosis, but a symptom. The correct diagnosis of the cause of the headache pain needs a thorough evaluation, if it is severe or frequent. It is important to remember that can have serious causes.

Headache, short overview; • Infections – Malaria, Meningitis, usually gradual onset with fever and general debility. Malaria, Dengue and other infections cause moderate, generalized, pulsating constant headache. Meningitis causes headache that radiates down the neck, with the patient usually acutely ill, febrile and confused, stiff neck, and unable to raise a straight leg. • Tension headache is due to stress or anxiety, with tension in the frontal or occipital muscles. Occasionally due to visual defects. Common. • Chronic daily headache – Headache occurs on more days than not for a period of three months or more. Can be caused by long-term use of drug use. • Sinusitis – pain and tenderness around the sinuses • Migraine – Often there is family history. Frontal and unilateral headache that may be associated with vomiting, photophobia and visual sensations. Often there is an aura stage where the patient experiences visual disturbances before onset of headache. • Cluster headache is an unilateral pain with from 30 minutes to 3 hours duration, which often occurs at night with 1-8 attacks per day for several weeks or months. Usually with running nose, and eyes. More common in males.

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• Temporal arteritis – a vascular disorder which typically produces severe throbbing pain over the temporal area, marked tenderness over the affected arteries, ischaemic pain in the jaws. Vision can be impaired and aggressive emergency- treatment is needed to prevent permanent blindness. Characterised by a marked rise in ESR. • Subarachnoid haemorrhage – Sudden onset of severe occipital headache often associated with collapse, brief unconsciousness and confusion, stiff neck and elevated pressure. Brain Tumour – The headache is usually occipital worsening in the morning and associated with vomiting. Slowly progressive weakness on one side, convulsions, visual changes, impaired speech, vomiting and mental changes may be associated with headache. • Hypertension – throbbing, there is a history of cardiovascular or renal disease, BP is elevated on examination and there may be retinal changes.

Migraine

Treatment of an acute attack of migraine: Give Aspirin 600 to 900 mg orally, every 4 hours Or; Paracetamol 1 to 1.5 g orally, every 4 hours, to a maximum daily dose of 4 g

Prophylaxis of migraine: If a patient experiences more than 2 acute attacks of migraine per month then regular prophylactic is useful: Give: Aspirin, per oral: 150mg once a day. If this is ineffective, then use: or Atenolol, oral: 50 -100mg daily If Atenolol does not prevent attacks, use: , oral, 10 - 50 mg, at night, initially, gradually increasing the dose depending on the response and side effects, up to a maximum of 150 mg orally, at night.

To stop vomiting, give; , per orally Adult: single dose of 10-20 mg at first sign of attack preferably 10-15 minutes before the antimigraine drug. Adolescent; single dose of 5-10 mg, (5 mg if body weight less than 60 kg) Or; Promethazine, per orally 25mg. Give intramuscularly if the patient is vomiting. 13

Metoclopramide has the added advantage of promoting gastric emptying and peristalsis

If these measures fail to relieve a previous attack, then use: 1 mg + caffeine 100 mg (oral), at the time of prodrome or onset of headache if there is no prodrome, and repeat 1 mg orally, in 1 hour if necessary Adult: 1-2 tablets at onset; maximum dose 4 tablets in 24 hours; not to be repeated at intervals of less than 4 days; maximum dose 8 tablets in one week.

NB: The frequency use of ergotamine should be limited to no more than twice per month. It should never be prescribed as a prophylactic. Rebound headache may occur after ergotamine. No more than 4 to 6 mg of ergotamine should be taken per 24 hour period. No more than 8 to 10 mg should be used in any one week. Ergotamine may cause peripheral vasospasm: Warn the patient to stop treatment immediately if numbness or tingling of extremities develops and to contact doctor.

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Epilepsy

Epilepsy is a disorder of the central nervous system that is characterised by spontaneous recurrent seizures. Epilepsy is a common condition with major impact on the lives of people with epilepsy and their families over many years. Diagnosis is not difficult and treatment is simple and effective in most cases. Many people with epilepsy in East Timor do not receive the needed treatment for two main reasons: They believe that epilepsy is a supernatural problem and not a medical condition that can be treated with medication. Treatment has not been widely available.

We refer further to the National Epilepsy program and its Flow-charts for diagnosis and treatment of Epilepsy.

Choice of drugs: The diagnostic flowchart selects Carbamazepine for all patients except those identified as having juvenile myoclonic epilepsy or generalized tonic-clonic seizures on awakening. See Flow charts of the National Epilepsy program;

Treatment Flow charts according to National Epilepsy Program:

Carbamazepine for adults, Carbamazepine for children, for adults.

Dosage: Very low doses are used initially, to avoid side effects. To control generalized tonic-clonic seizures, many Timorese patients require only 200mg Carbamazepine per day. Some patients will require higher doses and in approximately 20-30%, some seizures will continue despite treatment. Dose increases shall be slow and gradual.

This means that it may take several months to reach the optimal dose. This should be explained to the patient to prevent the the patient to think that the treatment is ineffective.

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Carbamazepine, per oral Adult: initially, 100-200 mg 1-2 times daily, increased slowly to usual dose of 0.8-1.2 g daily in divided doses; in some cases 1.6-2 g may be needed; Elderly: reduce the start-dose Child: 2mg/kg/dose every 8 hours; Increase doses in steps taking over 2 weeks, to 5-10mg/kg/dose every 8 hours.

Sodium Valproate as is effective in controlling tonic-clonic seizures, particularly in primary generalised epilepsy, generalised absences and myoclonic seizures. It may also be tried in patients with atypical absence, atonic and tonic seizures.

Sodium valproate (Valproic acid), per oral Adult: initially, 600 mg daily given in 2 divided doses, preferably after food, increasing by 200 mg/day at 3-day intervals to a maximum of 2.5 g daily in divided doses, usual maintenance dose is 1-2 g daily (20-30mg/kg daily); Child: 5 mg/kg/dose every 8-12 hours; if required dose can be increased to 20mg/kg/dose every 8-12 hours.

Duration of treatment: When a patient on treatment has had no seizures for a long time, there are two possible explanations: 1. The epilepsy has resolved 2. The epilepsy is still present but medication is stopping seizures.

The only way to know which possibility is correct, is to slowly stop the medication and see what happens. This should not be done until there have been no seizures for at least 2 years and consultation with a doctor is recommended. If the seizures return, the medication should be started again.

Reasons behind treatment failure: Treatment may fail for the following reasons • Wrong diagnosis. The most likely condition incorrectly diagnosed as epilepsy is syncope (“pinsang”). This is unlikely if the diagnostic flowchart is applied closely. • Not taking tablets – accidentally (forgetting), deliberately or because tablets are not available. • Fever may provoke seizures in people with epilepsy (do not confuse with febrile seizures “vestidu mutin”) 16

• Diarrhea and vomiting may lead to nonabsorption of drugs • Sleep deprivation • Excess alcohol – either by an effect on the brain or because medication is forgotten.

Drug interactions: Carbamazepine is metabolized by the liver and accelerates the breakdown of many other drugs that are also metabolized by the liver. This interaction increases the breakdown of hormonal contraceptives, resulting in pregnancy or breakthrough bleeding. This can be overcome by doubling the dose of given per oral contraceptive pills, from 1 to 2 tablets per day, and by shortening the time between injections of Depo Provera from 12 to 10 weeks.

Carbamazepine interacts with some anti-Tuberculosis drugs, such as Rifampicin. This lowers the Rifampicin levels in the blood. However, if a patient with epilepsy requires TB treatment, the epilepsy medication should not be stopped. The dose of anti-TB medication can be adjusted, or the andi-epilepsy treatment can be changed to use Valproate.

Erythromycin slows the breakdown of carbamazepine. If a patient is on a high dose of carbamazepine, this can lead to overdosae. Another should be used instead of Erythromycin.

Pregnancy: Approximately 2-3% of babies whose mothers are healthy are born with some type of malformations. Treatment with anti-epilepsy medication doubles this to 4-6%. However, untreated epilepsy in the mother causes more harm to the baby. If a woman is pregnant or wishes to become pregnant, epilepsy medication should therefore NOT be stopped.

Reasons include • If medication is stopped, the mother will have seizures which is dangerous both for the baby and for the mother. • Folic acid should always be given in extra doses to the pregnant women under anti-epilepsy treatment. This reduces risk for harm. It is safe for women taking epilepsy medication to breastfeed. Only a small amount of the drug reaches the milk and is not harmful.

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Febrile seizures: Febrile seizures (“vestidu mutin”) occur in about 5% of normal children aged between 6 months and 5 years, when they have a fever. A fever from any cause can do this.

They are generalized tonic-clonic seizures. They usually do not happen again and therefore, do not need long term treatment. However, seizures and fever can also occur with cerebral malaria and with meningitis and encephalitis.

For this reason, if a child experiences a seizure with fever, cerebral malaria and meningitis should also be suspected.

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Involuntary movement disorders The term, movement disorders, is used to describe a variety of disorders including tremor, chorea, dystonia and tics. It is important to reach a clear, definite diagnosis before starting drug therapy. However, if specific diagnostic tests are unavailable the need for treatment must be decided on the basis of clinical assessment.

Parkinson's disease The diagnosis of Parkinson’s disease is a clinical one, based on the presence of tremor, rigidity and bradykinesia. Many factors influences the therapeutic decision making such as the degree of confidence in the diagnosis, the degree of functional and social disability, age and the general psychological and neurological condition of the patient. Individual response can be variable.

Mild level of disease Amantadine hydrochloride has a modest effect on Parkinson’s disease and is sometimes used initially in very mild disease or in the elderly. For patients with mild disease, Use; Amantadine 100 mg orally, twice a day. Reduced dosage is required in patients with renal impairment.

Moderate level of disease Give: Levodopa/carbidopa 50/12.5 mg (half a tablet) per orally, immediately after meals, initially, gradually increasing to 100/25 mg orally, 3 times a day In some patients higher doses are necessary to control symptoms. An increase in the total daily dose and increased frequency of dosing is eventually necessary in most patients.

Advanced disease Refer to specialist neurologist.

Essential tremor Essential tremor includes familial and late life tremor. Not all patients require or want treatment with medication and relaxation therapy may be of benefit. The following agents are sometimes helpful; however complete 19

alleviation of tremor should not be expected: 10 mg per orally, twice daily, increasing gradually to a maximum of 240 mg per orally, daily or until adverse effects occur.

Chorea In many instances chorea does not require specific pharmacological treatment especially if it is symptomatic of a systemic disease or drug-induced. If therapy is thought desirable, then small doses of a neuroleptic agent such as haloperidol or fluphenazine can be tried.

Give : Haloperidol 0.5 mg orally, twice daily

Drug-treatment-induced dystonia. Neuroleptic medication and dopamine receptor blocking agents (such as metoclopramide) can induce severe generalised dystonia including oculogyric crisis. Give: Benztropine 1 to 2 mg intramuscularly or intravenously. See further the STG chapter “Mental Health”.

CNS infections.

Meningitis Common causes of bacterial meningitis are due to infection with Neisseria meningitidis, Streptococcus pneumoniae, Listeria monocytogenes and Haemophilus influenzae type b. The last is more common in children, rare in adults. In neonates, Group B Streptococci, Listeria monocytogenes and Gram-negative rods are all important pathogens which need to be considered in case of CNS infection. Malaria and Tuberculosis need always also to be remembered.

Lumbar puncture Lumbar puncture is an essential to obtain diagnostic data to guide the treatment of patient with suspected CNS infection or cerebrovascular disease.

Bacterial meningitis - Management prior to hospitalisation See also IMCI and the WHO “Blue Book” Guidelines for Hospital care of children. 20

Prompt and early treatment of bacterial meningitis reduces both mortality and morbidity. If bacterial meningitis is suspected on clinical grounds and there is risk for delay in transfer to hospital, administer an immediate dose of intravenous or intramuscular benzylpenicillin. This is given before transfer to hospital. This empirical treatment is motivated by to the fact that Meningococcal septicaemia may very rapidly become fatal. Give: Benzylpenicillin 60 mg/kg (for all ages) up to 3 g intravenously Or intramuscularly. In patients hypersensitive to penicillin or in remote areas where further parenteral therapy may be substantially delayed (> 6 hours), Give: Ceftriaxone 50 mg/kg (for all ages) up to 2 g intravenously. If possible, blood samples for culture should be collected prior to administration of any antibiotic, and be sent along with the patient to hospital.

Immediate and early hospital management of meningitis If the patient arrives in hospital without having received high-dose penicillin, (unless all tests can be carried out within 20 minutes of arrival), it is essential to give empirical to cover all common pathogens before tests are done. This should be done even if this means to give antibiotics before a lumbar puncture is performed. Blood cultures and a throat swab should be collected as soon as the patient arrives in hospital to maximise the chance of culturing the organism responsible for causing the meningitis.

Empirical treatment of meningitis before organism is known Empirical therapy that covers the three most common pathogens; Give: Cefotaxime 2 g (children: 50 mg/kg up to 2 g) intravenously, 6- hourly Or: Ceftriaxone 2 g (children: 50 mg/kg up to 2 g) intravenously, 12- hourly for 7 to 10 days

Plus also: Give: Benzylpenicillin 1.8 g (children: 60 mg/kg up to 1.8 g) IV, repeated every 4-hour for 7 to 10 days Or give; Ampicillin 2 to 3 g (children: 50 mg/kg up to 2 to 3 g) IV, repeated every 4- to 6-hourl for 7 to 10 days.

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Directed treatment, against identified pathogens. Haemophilus influenzae type b Give; Cefotaxime 2 g (children: 50 mg/kg up to 2 g) intravenously, 6- hourly Or; Ceftriaxone 2 g (children: 50 mg/kg up to 2 g) intravenously, 12- hourly for 7 to 10 days. If proven to be susceptible, Give; Ampicillin 2 to 3 g (children: 50 mg/kg up to 2 to 3 g) intravenously, 4- to 6-hourly for 7 to 10 days.

Provide treatment with antibiotic prophylaxis for all household contacts Give: Ceftriaxone 1 g (children: 50 mg/kg up to 1 g) intramuscularly, daily for 2 days.

Listeria monocytogenes meningitis Penicillin and (amoxy)ampicillin appear equally efficacious. There is some evidence that the addition of cotrimoxazole is beneficial. In patients hypersensitive to penicillin, cotrimoxazole may be used alone. Therapy often needs to be prolonged, even for 3 to 6 weeks. The value of adding an aminoglycoside is not clear.

Give; Cotrimoxazole 160/800 mg (children: 5/25 mg/kg up to 160/800 mg) intravenously, repeted every 6-hour.

Plus either; Benzylpenicillin 1.8 g (children: 60 mg/kg up to 1.8 g) intravenously, 4-hourly Or; Amoxicillin 3 g (children: 50 mg/kg up to 3 g) intravenously, 6- hourly.

Neisseria meningitidis Give; Benzylpenicillin 1.8 g (children: 60 mg/kg up to 1.8 g) intravenously, repeat the dose every 4-hour for 5 to 7 days. For patients hypersensitive to penicillin, give Cefotaxime 2 g (children: 50 mg/kg up to 2 g) intravenously, 6-hourly

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Or; Ceftriaxone 2 g (children: 50 mg/kg up to 2 g) intravenously, 12- hourly for 5 to 7 days Provide antibiotic prophylaxis for: the index case, unless treated with ceftriaxone or cefotaxime all household contacts and other contacts, eg close friends, healthcare workers close contacts in a childcare facility

A suitable regimen for meningitis prophylaxis: Use; Ceftriaxone 2 g (children: 50 mg/kg up to 2 g) intramuscularly, as a single dose Or; Ciprofloxacin 500 mg orally, as a single dose.

Pneumococci - Streptococcus pneumoniae meningitis Treat infection with Cefotaxime or Ceftriaxone, in the same doses as for treatment of infection with Haemophilus influenzae b. Use the combination of Cefotaxime and Vancomycin as empirical treatment combination in cases when there is a risk for cephalosporin resistance. Penicillin-susceptible strains (MIC < 0.125 mg/L) Give: Benzylpenicillin 2.4 g (children: 60 mg/kg up to 2.4 g) intravenously, 4-hourly, for 10 days. Very ill patients may require treatment for up to 3 weeks.

Pneumococci meningitis with Strains relatively resistant to penicillin (MIC 0.125 to 1 mg/L) Strains of Streptococcus pneumoniae with intermediate resistance against penicillin are occuring at an increasing incidence throughout South East Asia. If the MIC of cefotaxime is founf to be 0.5 mg/L or less, then treatment can be given with Cefotaxime or Ceftriaxone for 10 days, at the same doses as given for treatment of meningitis caused by Haemophilus influenzae type b. Treatment failure may still occur, requiring treatment as for penicillin-resistant strains, below. Penicillin-resistant strains (MIC > 1 mg/L) or cefotaxime-resistant strains Resistant strains are occasionally encountered. Combination therapy then uses high-dose Vancomycin in combination with Rifampicin. Always refer to specialist.

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Herpes simplex encephalitis, suspected or proven Typical clinical features include the rapid onset of headache, fever and vomiting, progressing to the development of focal neurological abnormalities such as dysphasia and hemiparesis and focal and generalised seizures. Treatment should be started as soon as the condition is suspected. Use; Aciclovir 10 mg/kg (children 10mg/kg or 500mg/m2) I.V., 8- hourly for 2 weeks.

NB: Note that determining the dose for a child by body surface area will generally result in a greater dose than when dose is calculated by body weight.

Central nervous system infection with Herpes zoster (shingles)

Acute herpes zoster Herpes zoster affects about 20 percent of the population, mostly elderly. Pain due to herpes zoster may occur before, along with or following a rash. Pain persisting for > 4 weeks after crusting of the vesicles, is considered postherpetic neuralgia. Overall, about 10 percent of patients with herpes zoster subsequently develop postherpetic neuralgia. Older patients are more likely to experience severe pain and complications.

Tteatment objectives are to achieve: relief of acute pain; prevent development of postherpetic neuralgia; decrease the chance of neurological or ophthalmological complications.

If the rash has been present for less than 72 hours, treatment with Aciclovir has been proven to give a significant reduction of acute pain, duration of rash, reduce viral shedding and reduce risks for development of ophthalmological complications. Acute herpes zoster is a greater risk in immunocompromised patients.

Antiviral therapy should be considered in patients:

• with involvement of critical areas, eg eye, perineum, limbs or neck • who are immunosuppressed • who are more than 60 years of age 24

• with severe acute pain

Start treatment as early as possible with Aciclovir 800 mg (children: 100 mg/kg up to adult dose in 5 divided doses) per orally, repeated 5 times daily, for 7 days

NB: There is no proven value of antiviral therapy in the immunocompetent patient if it is commenced more than 72 hours after onset of rash.

Acute pain of herpes zoster

Herpetic lesions are usually painful, but occasionally pain precedes the rash. The pain of acute herpes zoster is usually mild, but can also be intense, especially on the face. In most cases severity of the pain diminishes gradually and resolves completely over a few weeks. The elderly are more likely to have severe and/or persistent pain. In patients younger than 60 years, and who are not immunologically compromised, only symptomatic treatment is indicated. Use; Aspirin 600 mg orally, every 4 hours as necessary, Or; Paracetamol 0.5 to 1 g orally, every 3 to 6 hours as necessary, to maximum 4 g / day.

A variety of topical therapies have been recommended. Use Calamine lotion topically, to the painful areas Or; lignocaine 5% gel topically, with an occlusive if possible, to the painful areas If pain is severe, add Codeine 30 to 60 mg per orally, every 4 hours as necessary. There is no proof that systemic alone prevent postherpetic neuralgia or other neurological complications of herpes zoster.

Postherpetic neuralgia

The pain of postherpetic neuralgia is usually severe and has a variety of characteristics. It may present as burning, aching and monotonous pain, or as paroxysmal ‘shock-like’ stabbing or lancinating pain. The patient almost always has severe pain following light brushing of the skin. The skin of the affected area may be depigmented and scarred but 25

the degree of scarring bears no relationship to the severity or quality of pain. This condition is difficult to treat. Careful individualisation of therapy often is important. A variety of topical therapies have been recommended for both acute herpes zoster and postherpetic neuralgia. Simple analgesics or ibuprofen may be sufficient for some patients without the need for other interventions and are worth trying for a few days. Tricyclic are the most effective drugs for treatment of postherpetic neuralgia, and can deliver relief in 40 to 65 percent of the cases. Most controlled studies have used Amitriptyline. Success is more likely if the therapy is commenced early. Tricyclics should be taken for 3 to 6 months after pain is reduced or abolished.

Use; Amitriptyline 10 to 50 mg orally, at night

For elderly patients, a low initial dose of should be prescribed and the dose increased weekly until pain relief or unacceptable side effects occur. To reach the maximal effect may take weeks.

In a minority of patients with lancinating pain, addition of Carbamazepine may be useful. Give; Carbamazepine 100 mg orally, twice daily initially, increasing the dose gradually until relief is obtained, to avoid drowsiness. Doses of 400 mg orally, twice a day may be required by some patients. Cerebrovascular disorders Stroke Acute stroke or transient ischaemic attack is a medical emergency. Refer urgently to hospital The current approach in the management of stroke depends on local resources.

Subarachnoid haemorrhage

Vasospasm and rebleeding are the main causes of morbidity and mortality. Vasospasm manifests as an altered conscious state or increased neurological deficit. 26

Refer urgently to hospital. Give: Nimodipine 1 mg (5 mL) per hour intravenously, for 2 hours, then 2 mg (10 mL) per hour intravenously for 24 to 48 hours after surgery (for Grades 1 and 2), or for 5 days after surgery (for Grades 3 to 5), or as clinically indicated. Followed by; Nimodipine 60 mg orally, every 4 hours for up to 21 days (generally 10 to 14 days), depending upon clinical recovery.

Prevention and management of risk-factors.

Well documented risk factors for stroke are shown below. Less well documented risk factors include obesity, stress, sedentary life, dyslipidaemia, the role of genetic factors, migraine, excessive alcohol consumption and oral contraceptive use.

Risk factor Approximate relative risk

Atrial fibrillation 5

Hypertension 4

Smoking 4

Age (by decade from age 20) 2

Cardiovascular disease 2

Primary stroke-prevention Control of hypertension and cessation of smoking are among the most important factors to manage in order to prevent stroke. For patients with atrial fibrillation prophylaxis should be given with anticoagulants or antiplatelet drugs. See further STG Chapter Cardiovascular.

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Stroke-prophylaxis in patient with atrial fibrillation

Approximate stroke risk / year Recommended treatment

Valvular atrial fibrillation 15-20% Warfarin target INR: 2-3

Nonvalvular atrial fibrillation 2% Aspirin 100-300 mg/day (NVAF) with no other risk factors

NVAF plus 1 risk factor 7% Warfarin (target INR: 2-3)

NVAF plus 2 or 3 risk factors 18% Warfarin (target INR: 2-3)

NVAF with risk factors but 7-18% Aspirin 100-300 mg/day contraindication to warfarin

Secondary stroke-prevention After transient ischaemic attack or minor stroke

The risk of stroke after a transient ischaemic attack or minor stroke is high. treatment reduces the risk of subsequent stroke significantly. Give; Aspirin 100 to 300 mg orally, once daily.

Acute stroke and hypertension

Blood pressure is often elevated as a result of the stroke. In most instances this settles spontaneously and aggressive drug treatment should be avoided since this may cause extension of stroke. For information regarding the management of severe hypertension.

See further the STG chapter about “Cardiovascular diseases”.

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Module: Pain-Control in Referral Hospitals. Pain control The origin of pain can be be divided into three main types; nociceptive, neurogenic, or psychogenic. Different types of pain, requires different treatment approaches. For nociceptive pain, treatment can be given with paracetamol, aspirin, other NSAIDs and with opiates / opioids. NSAIDs are more useful for superficial pain arising from the skin, buccal mucosa, joints and . Opiates/opioids are more useful for pain originating from deeper visceral structures. Antidepressants and are used together with opioids for the treatment of neuropathic pain. Muscle pain may require muscle relaxants and a drug such as baclofen. The type of pain need to be accurately characterizd before treatment is started. It need also be made clear what is possible to achieve with pain control, and what need to be done to deal with underlying condition. For example, glyceryl trinitrate only gives pain relief, and does not affect the prognosis in the patient with angina pectoris.

Nociceptive pain is due to stimulation of superficial or deep tissue pain receptors (noci-ceptors) from tissue injury or inflammation. Neurogenic pain is due to a disturbance at any point from the primary afferent conducting system to receptive centres in the CNS. This includes a subgroup of conditions with actual nerve cell or axonal damage due to inflammation, trauma or degenerative disease. This produces a particularly intractable form of neurogenic pain, labelled neuropathic pain. Examples include postherpetic neuralgia, diabetic neuropathy or nerve plexus avulsion. When the primary lesion is in CNS, this causes “central pain”. Psychogenic pain is seen in the absence of any discernible injurious process. Nonetheless, it is as valid an entity and as distressing as pain from other sources.

Short overview - key analgetic drugs.

Paracetamol. Paracetamol has analgesic and antipyretic properties, very little anti- inflammatory activity. 29

It can be used alone for less severe pain or in combination with an opioid. Research results suggests that to increase dose from 600 mg to 1000 mg may not result in much additional pain relief. Dose per 24 hours should never be over 4 g in adults and children over 12 years of age. This is because of serious risk of hepatotoxicity with overdose. Paracetamol is mainly metabolised by conjugation in the liver. The liver breaks down paracetamol to reactive metabolites, which however binds up by glucuronate and sulphate as long as Paracetamol is used in normal dose. The liver can however be overburdened at too high doses. The reactive metabolites formed by the liver then cause severe liver damage. The risk of hepatotoxicity is higher in persons with history of alcohol abuse and malnutrition. Paracetamol is effective for control of simple intermittent pain without substantial inflammatory component. It is also safer than NSAIDs, since it does not increase the risk for peptic ulcer. Adults: Standard dose of paracetamol is 0.5 to 1 g per orally, repeated if needed every 4 to 6 hour. The maximum dose is 4 g per 24-hour period. Children; Standard dose of paracetamol for children is 15 mg/kg/dose per orally, repeated if needed every 4 to 6 hour, up to a maximum dose of 90 mg/kg per 24 hour.

Paracetamol overdose

As little as 10–15 g of paracetamol may cause severe liver damage. Patients who have taken an overdosae of paracetamol should be transferred to hospital urgently. Per oral activated charcoal should be given if paracetamol has been taken in bigger dose than 150 mg/kg, or more than 10 g (whichever is smaller).

Acetylcysteine or methionine can protect the liver if given as soon as possible. Antidote should be given latest within 10–12 hours from the time overdose of paracetamol was taken. Acetylcysteine intravenously is most effective within 8 hours of overdose. But it is still effective for up to, and possibly beyond 24 hours.

Alternatively, methionine may be given by mouth provided the overdose was ingested within 10–12 hours and the patient is not vomiting. But acetylcysteine is the preferred treatment. 30

Concurrent use of activated charcoal and specific oral should be avoided. In remote areas per oral methionine may be used, if intravenous administration of acetylcysteine is not possible or practical outside hospitals.

Give; Acetylcysteine by intravenous infusion. For the Adult and Child: Initially, 150 mg/kg in 200 ml glucose 5% infurion is given over 15 minutes, followed by 50 mg/kg in 500 ml glucose 5% over 4 hours. Then give 100 mg/kg in 1000 ml 5% glucose over 16 hours.

Children are given the same dose acetylcysteine as adults. But the volume of the infusion may need to be reduced ,to avoid fluid overload. Where treatment by intravenous infusion is not practical, such as in remote areas, then instead use methionine for treatment of Paracetamol overdose,

Give; Methionine tablets: 2.5 g is given as start dose. After the start- dose, treatment is continued by 3 further doses of 2.5 g repeated every 4 hour. Precautions: severe liver disease;

Avoid concurrent use with activated charcoal.

Acetylsalicylic acid – Aspirin.

Aspirin doses between 300 to 600 mg gives analgesic effect comparable to paracetamol at standard doses. Aspirin causes a greater risk for adverse gastrointestinal adverse. The standard dose of aspirin is 600 mg per orally, every 4 hours as necessary.

As the daily dose increases to and above 2 g for antiinflammatory therapy, dosing frequency can be reduced because the half-life of salicylates increases at high doses.

In children less than 12 years the use of aspirin has been caused Reye’s syndrome, a serious adverse reaction disorder affecting both liver and central nervous system.

Aspirin is therefore NOT recommended for use in children, with the exception of severe juvenile rheumatic disease. 31

If aspirin treatment cannot be avoided in children (juvenile rheumatoid arthritis), the standard dose is 60 to 90 mg/kg/day per orally, administered in 2 to 4 divided doses.

NSAIDs Non-steroidal antiinflammatory drugs Non-steroidal anti-inflammatory drugs (NSAIDs) may be used as simple analgesics.

These drugs are particularly useful when inflammation contributes to pain, such as musculoskeletal disorders.

If inflammation is intense and persistent, as in rheumatoid arthritis, NSAIDs can be given continuously if tolerated.

In other cases, osteoarthritis, they can be given intermittently.

Doses of NSAID and eliminatilon rate expressed as half-life.

Common daily Usual number of Half-life (hours) NSAID dose, (mg/day) doses/day (mean ± SD)

Aspirin* 1950-3900 3-4 0.25 ± 0.03

Diclofenac 75-150 2-3 1.1 ± 0.2

Ketoprofen 100-200 1-2 1.8 ± 0.4

Ibuprofen 1200-2400 2-3 2.1 ± 0.3

Indomethacin 50-150 3-4 4.6 ± 0.7

Naproxen 375-1000 2 14 ± 2

Piroxicam 10-20 1 57 ± 22

* The major metabolite of aspirin, salicylate, has a long half-life of 2 to 12 hours, which is longer at high doses

There is much variation in individual patient-response to different NSAIDs.

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Ibuprofen is the NSAID which is least likely to cause serious gastrointestinal adverse effects such as bleeding or perforation. Concomittant treatment with NSAID plus Ranitidin or Cimetidin, or proton pump inhibitor such as omeprazol, reduces the risk for gastrointestinal adverse effects and reduced risk for NSAID-induced gastric bleeding.

NSAIDs and patients who are taking anticoagulants;

Aspirin should be avoided in patients receiving any , but all NSAIDs increase the risk for gastrointestinal bleeding. Paracetamol should be used whenever possible.

Opiates / opioids

Opiate analgesics are used for severe pain. Equivalent doses for different opiates are presented below.

Acute equipotency ratio for opioid analgesics*

Drug Oral dose (mg) Parenteral dose (**) (mg)

Morphine 30 10

Codeine 240 120

Methadone 20 10

Oxycodone 30 15

Pethidine 300 75

*: These data are approximate but can used for when converting treatment os a patient from one route of drug administration to another. Adjustments are always needed for individual patients.

**: Intravenous, intramuscular and subcutaneous routes of administration

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Codeine Addition of an opiate, such as codeine, to aspirin or paracetamol can improve pain control, if other treatments have been inadequate. Codeine is 3-methylmorphine, e.g. an opium alkaloid. Codeine itself is much less active than morphine, but codeine is also tranformed by liver metabolism to morphine. A small proportion of patients can however not transform codeine to morphine, due to a metabolic defect and they will not get any pain relief. Codeine has much better per oral absorption than morphine. Standard adult dose of Codeine is 30 to 60 mg per orally, repeated every 4 hour.

Morphine

Morphine is the benchmark for opioids. It has a short elimination half-life of 2.5 to 3 hours. A liver metabolite, morphine-6-glucuronide and morphine-3- glucuronide are both excreted by the kidneys, and there is a risk for accumulation in patients with poor kidney function. Morphine is well absorbed, but liver metabolism reduces the amount reaching the systemic circulation to approximately 30 percent of the per oral dose. Morphine may be given by oral, subcutaneous, intramuscular, intravenous, epidural or intrathecal routes.

NB: Dose requirements vary markedly between individual patients.

Pethidine Pethidine is a synthetic opioid with similar actions to morphine. It has a shorter half-life than morphine and can not be given per oral. In contrast to morphine it is metabolised by oxidation and hydrolysis. It is excreted by the kidneys. There is risk for accumulation if given by repeated continued administration, especially in patients with poorkidney function. This makes pethidine unsuitable for chronic pain relief. It should not be used for more than 72 hours, such as for giving shorter-term analgesia, fr example post-operatively. Pethidine short half-life and greater metabolic capacity of the neonate to metabolize pethidine makes it preferable to morphine for use during labour. In gallbladder and pancreatic disease it has the advantage of not contracting the sphincter of Oddi.

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Methadone

Methadone has similar effects as morphine. It is not listed as first-line drug in management of chronic pain, but it is well absorbed per orally, and does not undergo any extensive first-pass metabolism. It has a long half-life, up to 72 hours and it can therefore be given once per day to prevent withdrawal in opioid-dependent patients. It can also be given once or twice per day for treatment of chronic pain as alternative to slow release morphine.

Co-analgesics A number of drugs whose major uses are other than as analgesics, have also a part to play in pain relief. They are often called coanalgesics, including: antidepressants, anticonvulsants, and also corticosteroids. Commonly used tricyclic antidepressants includes amitriptyline, and desipramine which have effective against neuropathic pain. Carbamazepine and sodium valproate can also be used to treat neuropathic pain.

Naloxone - Opiate antidote Naloxone is a pure oipoid antagonist. Its half-life is approximately 1 hour, which is shorter than the half-life of most opioids. Repeated administration is therefore usually needed to maintain its ability to reverse respiratory after opioid overdose.

Give Naloxone as injection of naloxone hydrochloride (400 micrograms/ml, 1-ml ampoule) for treatment of opioid overdosage, postoperative respiratory depression.

For reversing the effects from overdose of opioids, give Naloxone by intravenous injection,

Adults; 0.8–2 mg repeated at intervals of 2–3 minutes to a maximum of 10 mg, if respiratory function does not improve, question the diagnosis;

Children; 10 micrograms/kg; then give subsequent dose of 100 micrograms/kg if no response

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Concurrent use of antiemetics and opioid analgesics

Opioid analgesics often cause nausea and vomiting. Generally, drugs should only be used when the patients develop nausea or vomit after opioid analgesics. Since antiemetic drugs also can cause adverse effects, prophylactic use of anti-emetic drugs should only be given if vomiting would be deleterious; For example in patients after upper abdominal or intraocular surgery, in patients who are unable to protect their airways, or in patients known to vomit excessively after opioids. Common antiemetics are metoclopramide, droperidol, haloperidol. These drugs can cause severe extrapyramidal reactions, dystonia and oculogyric crises. The risk for this is higher in the young, in children and in the elderly patient with subclinical Parkinson's disease. This reaction can be controlled by injection of the antiparkinson drug benztropine, Give; Benztropine at the dose of 1 to 2 mg by intramuscular injection.

Pain control for adults.

1. Mild pain in adults

The drug of first choice for pain relief as well as antipyretic is Paracetamol.

Adult: Paracetamol 0.5 – 1 g every 4 to 6 hours to a maximum of 4 g daily.

Cautions: increased risk for hepatic toxicity in patients with history of alcohol dependence. Important: liver damage (and less frequently renal damage) following overdosage.

Or; Aspirin, acetylsalicylic acid per oral

Adults: 300 – 900 mg every 4 – 6 hours when necessary.

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Maximum 4 g per day. Contraindications: Do not give Aspirin to children and adolescents under 16 years or to the breast-feeding woman, due to risk for Reye’s syndrome.

2. Moderate Pain in adults

In addition to paracetamol (or aspirin),:

Give; Codeine phosphate, per oral Adult dose: 30 - 60 mg every 4 hours when necessary, to a maximum of 240 mg/day.

3. Severe pain in adults

When pain is acute and severe,

Give; Morphine administered by injection, intramuscular or subcutaneous Adult dose of Morphine: 5-10 mg every 4 hours if necessary.

For intramuscular or subcutaneous dose, use half of the estimated per oral dose. If morphine is giving by slow intravenous injection, give only quarter to half of needed intramuscular or subcutaneous dose.

Constipation is very common and patients should be encouraged to have high fibre diet and high fluid intake. Regular use may be needed in addition.

Respiratory depression can be produced by too large doses, which is treated with Naloxone.

In patients with severe vomiting, antiemetic treatment can be given for three days or more:

Give: Metoclopramide, per oral Adult dose: 10 mg (5 mg in young adults 15-19 years under 60 kg) three times per day;

Or: Promethazine, per oral 37

Adult dose: 12,5 mg to 25 mg, repeated at intervals not less than 4 hours (maximum, 100 mg in 24 hours) If vomiting is severe, promethazine may be given parenterally or rectally.

As alternative to morphine, severe pain can also be treated with Tramadol. Give per oral Tramadol, Adult dose; Per oral, tablets 50 – 100 mg as maximum per dose, repet once per 4 hours.

More than 400 mg per day by mouth is seldom needed.

Give parenteral Tramadol by IM injection or IV injection (over 2-3 minutes), or IV infusion Adult dose: 50 – 100 mg every 4 – 6 hours.

Post-operative pain: 100 mg initially then 50 mg every 10 – 20 minutes if necessary during first hour to total maximum 250 mg (incl initial dose) in first hour, then 50 – 100 mg every 4 – 6 hours; max 600 mg/day;

Key points Tramadol has fewer of the typical opioid side-effects (notably, less respiratory depression, less constipation and less addiction potential). Tramadol is not recommended for Children. In chronic pain, long-term pain relief is required. Analgesics should then be given per orally wherever possible, and at regular intervals to prevent recurrence of pain. Long-term use of morphine should be restricted to patients with Cancer or other terminal condition.

Pain control for children.

1. Mild pain in children First drug of choice is: Paracetamol, given in standard pediatric dose per oral or rectal. Child: 10 -15 mg/kg up to 4 times a day, as required for analgesia.

NB; Aspirin shall NOT be used in children under 16 years of age, because of the risk for severe adverse reaction; Reye’s syndrome. (Use of aspirin in children with rheumatic disease, is an exception)

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2. Moderate pain in children Treat with Paracetamol, (in pediatric standard dose) in combination with codeine phosphate,

Give; Codeine phosphate, per oral Child 1 – 12 years: 3 mg/kg/day in divided doses. To prevent constipation increase fluid intake, a high fibre diet helps to prevent constipation.

3. Severe pain in children Treat with Paracetamol, (in pediatric standard dose), combined with morphine:

Give Morphine, per oral, IV, IM Per Oral: 0.2 – 0.4 mg/kg/dose every 4 – 6 hours; increase if necessary for severe pain. IM: 0.1 – 0.2 mg/kg/dose every 4 – 6 hours. IV: 0.05 – 0.1 mg/kg/dose every 4 – 6 hours OR: 0.005 – 0.01 mg/kg/hour by IV infusion.

Review the pain management after every 2 to 3 doses and adjust if necessary until pain is well controlled. Morphine should only be prescribed by a doctor.

For patients with severe nausea and vomiting:

Give; Metoclopramide, per oral Child 1-3 years (10 -14 kg): 1 mg 2 to 3 times daily Child 3-5 years (15 -19 kg): 2 mg 2 to 3 times daily Child 5-9 years (20 – 29 kg): 2 mg 3 times daily Child 9-14 years (30 kg and over): 5 mg 3 times daily

NB: The maximum 24hr dose of metoclopramide is 0.5 mg/kg in children and in young adults. NB; Metoclopramide should not be used in children under 12 months of age because of the high risk for dystonic reactions.

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Caution Bolus IV opioid injections in infants less than 12 months old is more likely to cause respiratory depression than in older patients. Use only small doses, titrate against effect. In very young infants, procedures which result in only transient pain, such as venipuncture or bladder aspiration, are better performed without analgesia. Paracetamol can be given as an elixir, a suspension or as drops per orally, or as suppositories. Aspirin should NOT be used in children, except for very specific indications, because of the serious risk for Reye’s syndrome.

Pain syndromes and specific conditions.

Musculoskeletal pain Musculoskeletal pain is common. Examples include ‘tennis elbow’, painful neck or lower back and osteoarthritis. Often local treatments such as injection of corticosteroids, are more effective than per oral analgesics. Specific treatment of conditions like Paget’s disease, gout or rheumatoid arthritis will also relieve pain.

Treatment; Paracetamol in standard dose is often effective for the treatment of simple intermittent pain without a substantial inflammatory component. Other NSAIDs can be used for simple musculoskeletal pain. Any added effect due to higher potency, is accompanied by an increased risk of adverse effects. Codeine may be used for limited amount of time in chronic musculoskeletal conditions such as lower back if it is necessary to supplement paracetamol, aspirin or other NSAID. NSAIDs are particularly useful when inflammation contributes to pain of musculoskeletal disorders.

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Dose schedules for key NSAIDs

Common daily dose Usual number of Half-life (hours) NSAID (mg/day) doses/day (mean ± SD)

Aspirin 1950-3900 3-4 0.25 ± 0.03

Diclofenac 75-150 2-3 1.1 ± 0.2 ketoprofen 100-200 1-2 1.8 ± 0.4

Ibuprofen 1200-2400 2-3 2.1 ± 0.3

Indomethacin 50-150 3-4 4.6 ± 0.7

Naproxen 375-1000 2 14 ± 2

Piroxicam 10-20 1 57 ± 22

There is much variation in response to NSAIDs between individuals. As basic principle, NSAIDs should only be used at the lowest effective dose, for the shortest possible duration.

General recommendations for treatment of limb pain

For many cases of limb pain of mechanical origin, non- pharmacological methods can reduce pain and prevent recurrence. As example, peripatellar pain in patello-femoral osteoarthritis responds well to quadriceps strengthening via straight-leg raising.

RICE therapy

Rest Modified rest so that pain is not provoked, but activity is maintained

Ice Ice packs for 10 minutes every 1 to 2 hours

Compression Compression bandaging

Elevation For as long and often as possible, to reduce swelling

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In addition to appropriate physical therapy, paracetamol is the first drug of choice. NSAIDs are also useful for many short-term painful conditions affecting the limbs. Give; paracetamol (to a maximum daily dose of 4 g), with or without codeine, Or; any NSAID per orally, in the recommended regimens.

Pain of specific anatomical origin.

Spinal pain It is important to distinguish between acute and chronic forms of spinal pain, since each requires different therapeutic approaches.

A distinction should be made between common primarily mechanical disorders, and the less common primarily inflammatory processes which generally present with morning stiffness of significant duration. If there is accompanying pain radiating down a leg, it should be ascertained whether this is referred pain (the most common), or radicular pain (segmental weakness, loss of reflex). X-Ray should be considered if pain is unexplained or other pathology is suspected, eg the presence of osteoporosis or secondary carcinoma.

For common back pain of mechanical origin, physiotherapy and a specific exercise program can be helpful. Bed rest beyond 24 to 48 hours should be avoided, because it increases the risk of chronic back pain. If drug treatent tis needed, paracetamol is the first shoice.

For more intense pain, if inflammation is significant, NSAID may be helpful. Use; paracetamol (to a maximum daily dose of 4 g) Or; any NSAID per orally, in the recommended regimens. In the acute situation if paracetamol and/or NSAIDs are inadequate and pain is severe, addition of Codeine can help to relieve pain Give; codeine 30 to 60 mg orally, every 4 hours

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Acute low back pain The aim of treatment is to reduce pain, maintain function. Analgesia must be adequate.

Opioid analgesics should only be used in extreme cases, and only for maximum 48 hours. If there is no objective evidence of nerve root compression, rest should be limited. If there are signs suggestive of a disc lesion, sitting should be limited until symptoms improve.

If there is evidence of nerve root compression (segmental weakness L5 and/or S1), a longer period of rest may be needed. If resolution does not occur within 10 to 14 days, refer the patient for a specialist opinion.

Prolonged periods of immobility are potentially harmful with significant deterioration in most vital functions. Early mobilisation is essential once acute symptoms subside.

Chronic low back pain When low back pain persists for 3 months or more, the pain may be less distinct. Prolonged rest is contraindicated. Emphasis in treatment must be on specific back exercises and a general fitness program, to help restore muscle tone and well-being. If are necessary

Give; paracetamol (to a maximum daily dose of 4 g) or any NSAID per orally, in recommended standard doses. If this is unsuccessful, add; amitriptyline 25 to 75 mg orally, at night.

Mechanical neck pain In patients presenting with neck pain, a detailed history and examination followed by explanation about the benign nature of the condition can be a therapeutic measure in itself. Diagnosis of compression of cervical nerves is important, since the more unusual radicular pain indicates a possible need for surgery.

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Physiotherapy (traction, flexibility, strengthening exercises) is effective to increase mobility and reduce pain from the cervical spine.

Flares of neck pain with or without a referred components are treated with increased analgesia and/or physiotherapy to mobilise cervical soft tissue and joints. The use of a soft collar for up to 1 week is useful, if the pain is not decreasing.

Neck pain with nerve root involvement True radicular pain should be suspected if the pain is severe, ‘electrical’ in nature and/or burning in quality, well localised and associated with segmental muscle weakness and depressed reflexes.

This condition requires use of strong analgesia and a temporary soft collar.

Gentle neck traction and/or mobilisation of soft tissues and joints and gentle flexibility exercises which do not aggravate peripheral symptoms, may also help. Referra to specialist for further investigation to assess need for surgery.

Rheumatoid arthritis Neck pain in patient with RA: The neck should be temporarily rested in a soft collar and the underlying inflammation can be treated with an NSAID.

Most rheumatoid arthritis neck pain subsides, and it is not an indication by itself for treatment with prednisolone. Vigorous mobilisation, manipulation and heavy traction is contraindicated. However, gentle traction and mobilisation may useful.

The possibility of atlanto-axial subluxation should be kept in mind especially if intubation as part of anaesthesia is contemplated.

Acute joint pain An acutely painful joint may be due to trauma or to a nontraumatic cause.

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Nontraumatic acute joint pain A correct diagnosis is crucial to manage the patient with a single acutely inflamed joint. Septic arthritis should always be considered as a possible cause of joint pain. Also remember that patients on long-term corticosteroid treatment may not have typical signs. Clinical assessment together with X-rayand analysis of synovial fluid gives a working diagnosis.

Note the volume of synovial fluid, its colour, clarity, blood-staining and viscosity. Microscopic examination, including polarized light microscopy and culture is recommended.

If a noninfective cause is most likely, eg haemarthrosis in a patient with haemophilia or in recurrent gout, aspiration is not needed unless a superimposed infection also is suspected.

Septic arthritis may require repeated needle aspirations, and antiinflammatory drugs should be withheld since it first is important to assess response to antibiotic therapy.

Aspiration of fluid often results in immediate reduction of pain and is needed to make a microbiological diagnosis. The joint should then be splinted temporarily to reduce pain and inflammation. Acute joint pain often responds better to these measures than to systemic analgesics. Ice packs for 10 minutes every 1 to 2 hours is a further effective local method of pain relief. Heat is contraindicated.

If analgesic therapy is required, first choice is to use; any per oral NSAID in standard dose. If necessary, an opioid analgesic may be added, Give; codeine 30 to 60 mg orally, every 4 hours as necessary

If pain is very severe or uncontrolled, morphine may be required.

Give; morphine 10 mg subcutaneously or intramuscularly, every 3 to 4 hours. Intraarticular corticosteroid/local anaesthetic should only be given when sepsis and major mechanical damage have been excluded. Refer to specialist.

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Traumatic acute joint pain Examination should take care to exclude the possibility of fractures and grade 3 (ie complete) ligament tears, as the joint may need to be immobilised in a cast or brace. Aspiration of a tense joint effusion will relieve pain significantly. In the initial 48 hours, follow the RICE method of management. If analgesic drug treatment is required, as first-line choice of drug treatment,

Give; any NSAID per orally, in the standard dose. If necessary, Codeine as opioid analgesic may be added,

Then give Codeine 30 to 60 mg orally, every 4 hours as necessary

If pain is very severe or uncontrolled, morphine may be required;

The give; Morphine 10 mg subcutaneously or intramuscularly, every 3 to 4 hour. After 2 to 7 days, physiotherapy is needed to restore full joint movement and to regain function and strength. Analgesia should be reduced simultaneously.

If pain does not settle refer to an orthopaedic specialist.

Osteoarthritis This condition is primarily due to a biochemical disturbance, resulting in cartilage loss. Prevalence increases with age. The aetiology is multi-factorial and includes hereditary factors, physical factors, previous injury and obesity.

Careful clinical evaluation to ascertain the cause of the pain is valuable. Effective measures include specific flexibility and strengthening exercises.

For pain control, paracetamol should be tried first.

Give; paracetamol (to a maximum daily dose of 4 g) orally, in the recommended regimen.

If paracetamol in full dose is inadequate to control pain, add or replace with low-dose NSAID. Increase dose only if response is

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unsatisfactory. Intermittent use of NSAID only during ‘flares’ of osteoarthritis pain may reduce the risk of toxicity.

Rheumatoid arthritis (RA). Rheumatoid arthritis is a serious disease affecting extraarticular structures as well as joints with significant risk for long-term loss of function and increased mortality. A hallmark of active rheumatoid arthritis, is synovial inflammation which if uncontrolled results in structural damage to joints. This is revealed by the appearance of articular bone erosions within the first few years of rheumatoid arthritis. Assessment of prognosis and initiation of effective treatment, should be performed within the first few months of disease onset.

Patients with suspected RA should be referred to specialist, as early as possible.

Once an active rheumatoid arthritis is diagnosed, disease-modifying antirheumatic drugs (DMARDs), should be started without waiting for the appearance of bone erosions.

The dose used should be adjusted to suppress synovitis.

Delayed or inadequate use of disease-modifying antirheumatic drugs lead to joint deformity and disability.

Disease-modifying antirheumatic drugs take some weeks to months to act and requires close monitoring because of risk for serious adverse effects.

Mild RA disease This is often treated well with hydroxychloroquine or sulphasalazine. Their adverse side effect are less problematic than other disease- modifying antirheumatic drugs.This is specialist care.

Moderate to severe RA disease Methotrexate is the drug of choice in moderate to severe rheumatoid arthritis. It has an onset of action within weeks and is safe if carefully monitored. Methotrexate at low dose is.This is specialist care.

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Nonsteroidal antiinflammatory drugs and analgesics Most rheumatologists still use NSAIDs to treat pain and inflammation of rheumatoid arthritis. These drugs do not alter the progress of the disease but simply relieve symptoms. In active disease any NSAID may be used. Paracetamol can also be useful in rheumatoid arthritis sometimes allowing a lower dose of NSAID to be used.

Symptoms during the night or early morning can be managed with help of long-acting per oral NSAIDs such as a long half-life or slo release preparations` or with NSAID suppositories.

Prednisolone For patients with moderate to severe disease not adequately controlled by NSAIDs and disease-modifying antirheumatic drugs, prednisolone treatment should be considered.

If the prednisolone dose is kept low, benefits may extend to prevent erosions while keeping an acceptably lo risk of adverse events.

Early use of systemic corticosteroids in patients who are poorly controlled on disease-modifying antirheumatic drugs, NSAIDs and intraarticular injections of corticosteroids, is recommended by many rheumatologists.

Give; Prednisolone 5 to 7.5 mg orally, daily, preferably in the morning. Prednisolone should only be started in consultation with a rheumatologist.

Resistant or difficult to treat rheumatoid arthritis Always refer to specialist.

Juvenile rheumatoid arthritis / Juvenile chronic arthritis Juvenile rheumatoid/chronic arthritis can present at any age, but the condition is most common in young females.

The diagnosis is one of exclusion as transient forms of post-viral arthritis can be indistinguishable in the early phase.

Always refer to specialist on suspicion. 48

Drug treatment: The principles of drug treatment begin with the safest and simplest effective therapy. Before using more toxic drugs, continue further 6 to 12 months if remission is induced.

Initially, use high-dose aspirin or any NSAID orally in standard dosage regimens. If response is inadequate over a test-period of 3 months, then proceed and select a disease-modifying antirheumatic drug, chosen to match severity of arthritis.

Corticosteroids are used in children with very severe disease. Referral; Patient with suspected juvenile rheumatoid arthritis must be referred to specialist.

Postoperative pain control

The most important factors in predicting requirements for postoperative analgesia are patient characteristics and the nature of the surgery. Clinical trial results have also shown that appropriate analgesic drugs given before surgery, can inhibit both peripheral and central pain pathways. This can reduce the post-operative requirement for analgesic drugs.

The post-operative phase

After minor procedures; After minor surgical procedures where a variable pain is anticipated, Give; paracetamol (to a maximum daily dose of 4 g), with or without codeine orally, in the recommended regimens.

After more extensive procedures; Pain resulting from more extensive tissue injury associated with surgery will generally require opioids. However, continuing inhibition of peripheral nociception by use of per oral NSAIDs can give an opioid-sparing effect especially after orthopaedic procedures. If per

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oral administration is not possible, following intraabdominal surgery, other routes may be chosen.

Give; any NSAID rectally, in the recommended standard dose regimen Or; ketorolac 10 to 30 mg intramuscularly, every 6 hours up to a maximum of 90 mg/day, for a treatment period not longer than 5 days.

For patients over 65 years, the dose of ketorolac must be reduced;

Use; Ketorolac 10 to 15 mg intramuscularly, every 6 hours up to a maximum of 60 mg/day for a period no greater than 5 days.

Subcutaneous opiate administration Opioids may be given subcutaneously as intermittent or continuous infusion through a small 25 G butterfly needle.

Give; morphine 15 mg subcutaneously or intramuscularly initially. If after 30 minutes pain still persists;

Give an additional dose of 7.5 mg and reassess after another 30 minutes. If there is still significant pain and no other cause for this pain is apparent, (Consider for example a distended bladder), give an addiitonal dose of 7.5 mg. If this dose together provides acceptable analgesia for at least a period of 2 hours, the total loading dose has been determined to be 30 mg.

Thereafter use 50 percent of this loading dose, ie 15 mg in this example, repeated every 2 to 4 hours, depending upon the time interval at which pain returns.

NB: Subcutaneous administration should be avoided in patients with poor perfusion.

Intramuscular opiate administration The morphine dose regimen described above is also used for I.M. administration. 50

Preferred injection sites in adults, children and infants is in the middle third of the vastus lateralis muscle as there are no major nerves or blood vessels in that area.

Alternative sites are the upper outer quadrant of the dorsogluteal muscle. Do not use this muscle for injection in children less than 3 years of age, since the muscle is not sufficiently developed.

Intravenous opiate administration The most effective way of maintaining steady-state concentrations of plasma opioid is by a controlled intravenous infusion. Because it takes approximately 5 half-lives to achieve this, infusion is best preceded by an intravenous bolus, with approximately 20 to 30 percent of the estimated intramuscular dose need. This is repeated at 10- to 15- minute intervals until good analgesia is established and the infusion commenced.

Give; morphine 5 mg intravenously, by slow bolus injection. Followed by; morphine 3 to 5 mg/hour intravenously, by continuous infusion, gradually reducing over 48 hours.

Note: If pethidine has been used for analgesia, its should not be repeated beyond 72 hours because of the risk of accumulation of its toxic metabolite - norpethidine.

Control of trauma pain Relieving pain in trauma is often neglected. Together with drugs, atention needs also to be paid to nonpharmacological techniques, including splinting / immobilisation, a warm reassuring environment and calm, confident action of healthcare personnel.

Major trauma with normal conscious state It is inhumane to deny analgesia to victims of major trauma. Intravenous morphine should be administered as soon as the airway is secured, breathing is adequate, circulation is stabilised and a baseline neurological state is recorded using the Glasgow Coma Scale and examination of the patient’s pupils.

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Initial analgesia The patient with major trauma should always have at least one intravenous line which should be used for analgesia as well as resuscitation. The administration of intravenous morphine in small repeated doses in controlled conditions under close observation maximises the placebo effect and creates a bond between the doctor and the patient while further history is being taken.

While standing next to the patient, Give; morphine 2.5 mg I.V., repeated every 2 to 3 minutes, until patient is comfortable. Smaller doses of morphine should be used in children or very old patients. The dose of morphine which is required to control the pain may vary considerably between different individuals.

NB: Intramuscular or subcutaneous routes should not be used for analgesia in major trauma as the rate of absorption is variable and physiological changes occurring as resuscitation proceeds makes time of onset unreliable, and the effect unpredictable.

Maintenance of pain control The maximum dose of morphine for patients with major trauma is that which is required to relieve the pain. As patients with major trauma are under close observation, give repeated small doses intravenous morphine as required to maintain relief from pain. Pethidine should not be used for repeated maintenance treatment.

Major trauma with altered conscious state, with or without head injury

Initial management involves ensuring the airway is secure, breathing is adequate, circulatory resuscitation is obtained and the neurological disability is recorded using the Glasgow Coma Scale and examination of the patient’s pupils. In patients with altered conscious state, ie a Glasgow Coma Score of 9 to 14, analgesia is a difficult problem as it is often withheld for fear of hiding pupillary changes and obscuring a deteriorating conscious state.

Despite the pupillary constriction due to administration of morphine, pupils will dilate if there is an expanding intracranial haematoma. 52

The Glasgow Coma Score may decrease by as much as 2 points after analgesia, but will return to preanalgesic levels if the patient is stimulated.

Note: The Glasgow Coma Score is determined by the best motor response, best verbal response and best eye opening.

In a comatose injured patient requiring controlled ventilation, analgesia may still be necessary if their agitated state suggests the influence of nociceptive stimuli.

Burn pain Pain relief is important in the treatment of burns, but should not take precedence over establishing adequate airway and venous access when necessary.

Irrigation with cool water provides substantial relief of painful burns or scalds to small areas of the limbs which may on occasions be just as painful as more extensive burns. The application of ice cold water or ice packs to large areas may produce hypothermia, especially in children.

For minor burns a simple oral analgesic may be adequate.

Give; paracetamol (to a max daily dose of 4 g) orally, in the recommended regimen. If this is inadequate intravenous morphine may be required. This should be given only after initial assessment of the airways and the need for urgent IV volume expansion.

NB: Patients with severe burns are as a rule hypovolaemic, and a greater proportion of cardiac output is delivered to the major organs, including brain. Such patients are more susceptible to the respiratory effects of opioids.

Morphine should be given as small repeated bolus doses;

Give; morphine 2 to 4 mg (children: 30 microgram/kg) intravenously, administered slowly over a few minutes. The dose may be repeated up to 3 or 4 times if pain relief is inadequate, provided there is no

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central depression.

Accurate body weight will not be available in such an emergency.

For children between 6 to 12 years: A useful ‘rule of thumb’ to estimate body weight (in kg) is: weight = (age in years) x 3. In younger infants, a useful ‘rule of thumb’ to estimate body weight (in kg) is: weight = [(age in years) x 2] + 9.

Equipment for assisted ventilation should always be kept closely available.

Note: Intramuscular or subcutaneous morphine is contraindicated in severe burns. The drug is very slowly absorbed in shocked patients resulting in poor analgesia. This may lead to repeated dosing. Later, when the patient is resuscitated, the depot of morphine can be rapidly absorbed!

Management of pain for burned patients in hospital care.

After stabilisation of the pain with bolus doses, morphine infusions remain the mainstay for the relief of severe pain.

Give; Morphine 30 to 40 microgram/kg/hour by intravenous infusion. Supplemented with bolus doses of 20 to 30 microgram/kg to control breakthrough pain.

Note: Pethidine is not suitable for long-term use in burns patients, because the metabolite norpethidine accumulates and may cause seizures.

If oral medication is tolerated, paracetamol can be used in addition to the opioid, which may reduce the morphine requirement.

Give; Paracetamol (to a maximum daily dose of 4 g) orally, in the standard dose.

For children, use; paracetamol 15 mg/kg/dose orally, every 4 to 6 hours. The maximum dose is 90 mg/kg/day.

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Burns dressings and debridement Dressings and debridement can be very painful and distressing.

There are several options for analgesia, depending upon the anticipated pain severity and duration.

Give; Midazolam 0.5 mg/kg orally, up to a maximum of 15 mg orally, 15 to 30 minutes before the procedure. The duration of effect is more than 1 hour.

Or; Nitrous oxide/oxygen mixture inhalation during the procedure.

Obstetric pain See the Module “Reproductive Health”

Gynaecological pain See the Module “Reproductive Health”

Headache See the Module “Neurology”.

Special cases of pain caused by viral infections

Herpes zoster pain Pain due to herpes zoster may occur before, along with or after the skin rash. Pain persisting for longer than 4 weeks after the vesicles, is considered a postherpetic neuralgia. Overall, about 10 percent of patients with herpes zoster will get a postherpetic neuralgia. Older patients are more likely to experience severe pain and complications.

Early antiviral treatment significantly reduces acute pain, duration of the rash, viral shedding and reduces the risk for ophthalmological complications.

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Acute herpes zoster is a greater risk in immunocompromised patients. Antiviral therapy should be considered in patients who are immunosuppressed, more than 60 years old, with severe pain, with involvement of critical areas such as eyes, face, perineum.

If antiviral therapy is indicated, start treatment as early as possible;

Give; Famciclovir 250 to 750 mg orally, every 8 hours for 7 days Or; Aciclovir 800 mg (children: 100 mg/kg up to adult dose in 5 divided doses) orally, 5 times daily for 7 days, Or; Valaciclovir 1 g orally, 3 times daily for 7 days.

Famciclovir has better bioavailability than aciclovir. Valaciclovir is a prodrug for aciclovir with better bioavailability.

Note: There is no proven value of antiviral therapy in the immunocompetent patient if it is commenced more than 72 hours after onset of rash.

Acute pain of herpes zoster Herpetic lesions are usually painful, but occasionally pain precedes the rash. The pain of acute herpes zoster is usually mild, but can be intense, especially on the face.

Give; aspirin or paracetamol (to a maximum daily dose of 4 g) per orally. A variety of topical therapies have been recommended.

Give; Calamine lotion topically, to the painful areas Or; Lignocaine 5% gel topically, with an occlusive dressing if possible, to the painful areas Or; Aspirin 750 to 1500 mg in 20 to 30 mL ether topically, to the painful areas

If the pain is severe, add codeine 30 to 60 mg orally, every 4 hours as necessary.

There is no proof that systemic corticosteroids alone prevent postherpetic neuralgia.

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But one large study has shown that pain and abnormal sleep patterns resolved faster if prednisolone was given, at dose level 40 mg daily over 21 days in combination with aciclovir.

Postherpetic neuralgia Pain of postherpetic neuralgia is usually severe and has a variety of characteristics. It may present as burning, aching and monotonous pain, or it may present as paroxysmal ‘shock-like’ stabbing or lancinating pain.

Treatment; Some cases are very difficult to treat. Some cases need only simple analgesics such as ibuprofen for a few days.

Tricyclic antidepressant drugs are the most effective drug therapy for management of post-herpetic neuralgia, with response in 40 to 65 %.

Give; Amitriptyline or desipramine if adverse effects of amitriptyline are unacceptable. Success is more likely if the treatment starts early.

The antidepressant should be taken for 3 to 6 months after pain is reduced or abolished.

Give; amitriptyline 10 to 50 mg orally, at night Or; desipramine 25 to 50 mg orally, at night.

For elderly patients, a low initial dose of antidepressant should be prescribed and the dose increased weekly until pain relief. To reach maximal effect may take weeks. In a patients with lancinating pain, addition of carbamazepine may be useful.

Give; carbamazepine 100 mg orally, twice daily initially. Increase the dose gradually until relief is obtained, to avoid drowsiness. Doses of 400 mg orally, twice a day may be required.

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Mental Health services, referral hospitals.

The acutely confused, aggressive patient - delirium. Only a small proportion of the patients who exhibit disturbed or aggressive behaviour, suffers from an actual mental illness. Medical psychiatric intervention is indicated only when the disturbed behaviour is due to an underlying abnormal mental state. People with mental illnesses, delirium or mania may be confused and with poor reality contact, expressing overactivity and disorganised behaviour placing themselves at risk, or reacting aggressively. Others, with idiopathic disorders such as paranoid illnesses or schizophrenia, remain capable of organised activity but can become acutely disturbed and aggressive on the basis of some delusion. Delirium is a state of confusion with impaired awareness and memory and disorientation. Delirium should not be mistaken for psychiatric disorders like schizophrenia or a manic phase of a bipolar disorder. A wide range of possible causes must be included in the assessment.

Diagnosis Checklist; DIMTOP

D – drugs

I – infections

M – metabolic

T – trauma

O – oxygen deficit

P – psychological and perceptual

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Dilirium due to substance withdrawal

Treatment; If the diagnoses is delirium caused by substance withdrawal; Give; Diazepam, IV, 10–20 mg for immediate sedative or action. Do not inject faster than maximum by 5 mg/minute.

secure airways

exclude presence of a hypoglycaemia

monitor the patient for possible respiratory depression

If delirium is caused by a medical disorder, and if the patient is very restless;

Give; Haloperidol, IM; first give 2-5 mg as starting dose, then 5–10 mg, after assessing the response and possible side effects for 4 hours after the first dose.

Especially for young patients, always also;

Give; Benztropin, 1-2 mg as intramuscular injection Benztropin is given to prevent risk for adverse reactions: laryngeal spasm, dyskinesia which otherwise can be induced by haloperidol, especially in young male pts. Refer the patient to specialist as soon as possible

Sedation of the acutely disturbed patient

An acutely disturbed patients may need safe sedation : • To reduce the risk of harm to him/herself, or others • To allow diagnostic assessment to proceed • To allow transport to an appropriate treatment setting.

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Key points during the use of medicine.

• Vital signs should be monitored closely during and after sedative administration. • Do not give diazepam by intramuscular injection, absorption is poor and erratic. • Intravenous midazolam should be avoided due to the risk of respiratory depression. • Benzodiazepines should not be used in patients with respiratory impairment. • If repeated dosing is carried out, the patient should be intensively monitored. • Elderly patients require lower doses of medications; repeated doses are likely to result in cumulative effects that may prove dangerous to the patient, see elderly patients and psychotropic medication. • Benzodiazepines should be used cautiously in children due to paradoxical behavioural disinhibition. Otherwise the treatment of children is the same as adults. See separate Table over doses in children and adolescents. • A record of medications administered to the patient should be kept and it should travel with the patient if they move to another facility.

Per oral drug administration for sedation.

Give; Diazepam per oral, 10 to 20mg orally as a single dose. The dose can be repeated every 2 to 6 hours, up to 120mg daily, depending on response Or; Chlorpromazine 50 to 100mg (tablet or syrup) per orally, repeat every 2 hours, up to a maximum of 300mg in 24 hours

NB; Chlorpromazine may cause postural hypotension. NB; If high doses are needed, the patient should be nursed in bed.

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Substance abuse; Alcohol and narcotic drug addiction When a case of addiction is identified, it is important to investigate the patients complete drug-use habits. A range of psychiatric disorders occur with higher than average frequency among patients with a history of addiction, which includes depression, psychoses, anxiety disorders (particularly social phobias) and personality disorders.

For the patients who are likely to continue injecting drugs, counseling and advice should include safe injection procedures, not sharing needles and syringes. Refer further to the National Mental Health program guidelines. Refer to specialist for detoxication integrated with somatic care and mental health support.

Alcoholism. Alcohol overdose

Alcohol overdose is potentially fatal. The average lethal blood concentration for ethanol is between 0.45 to 0.5 percent. Death may however result from much lower concentrations, if other sedative drugs also have been consumed.

Ideally, blood alcohol concentration should be monitored. Blood alcohol concentration will normally decline by 0.015 to 0.02 percent per hour.

Alcohol which still is present in the may continue to be absorbed, and hence the blood alcohol concentration could rise even if there is no further ingestion. Treatment should be supportive with careful monitoring of level of consciousness and responsiveness.

Stimulants should NOT be given.

Acute alcohol withdrawal

Alcohol withdrawal is characterised by a wide range of symptoms; tremor, paroxysmal sweating, nausea and vomiting, anxiety, agitation, headache, perceptual disturbances and occasiolally also seizures.

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Some patients (severe withdrawal) may develop delirium tremens. Symptoms usually appear within 6 to 24 hours since the last consumption of alcohol, and typically persist for 72 hours. In some patients, symptoms may persist longer. In case of seizures, give diazepam until symptoms are reduced to acceptable level.

Give; Diazepam 10 to 20mg per orally, every 2 hours until symptoms subside. A total cumulative dose of 60mg is usually enough. Do not exceed 120mg.

Diazepam should be given over the following 2 to 7 days if symptoms return. After long time of alcohol addiction, patiens are often deficient in thiamine,

Give; Thiamine 100mg by intramuscular or intravenous injection, once daily for 3 to 5 days. Follow with 100mg per oral dose, once daily.

Delirium tremens

Delirium tremens is the most severe manifestation of alcohol withdrawal.

It is usually seen 72 to 96 hours after stop of drinking; gross tremors and agitation, hallucinations, disorientation and confusion, fever, tachycardia and dehydration.

This is a medical emergency with risk for mortality, principally from patients with heart failure. Refer to hospital. Key principles of treatment includes supportive care, thiamine and diazepam.

Give; Diazepam 10 to 20mg orally, every 2 hours until symptoms subside. If per oral administration is not possible, Or give; Diazepam 5mg intravenously, every 30 min until symptoms subside. Inject slowly, over several minutes, to minimise the risk of respiratory depression.

Give Flumazenil as antidote if it is needed to reverse excessive

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benzodiazepine effects.

If an antipsychotic agent is required;

Give; Haloperidol 1.5 to 10mg per orally, titrated to clinical response. For treatment of severe psychotic symptoms, if per oral administration is not possible,

Give; Haloperidol 5mg by intramuscular injection, as a single dose.

To avert/prevent extra-pyramidal adverse effects caused by haloperidol; Give; Benztropine per 2mg orally or intramuscularly.

NB: Diazepam, haloperidol and droperidol may worsen symptoms of hepatic encephalopathy.

Barbiturate abuse and overdose A key principle to limit this problem, is to limit the use of barbiturates as restrictively as possible, and only to make barbiturates available on prescription.

Barbiturates should not be sold without prescription and barbiturates should not be used as or . Phenobarbital has a role mainly in treatment and control of epilepsy, seizures.

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Treatment of barbiturate overdose. The symptoms of overdose and intoxication are similar to those for alcohol. Overdose effects are mainly due to a dose-related depression of the central nervous system (CNS) with risk for coma, respiratory depression and death at high doses. In Timor Leste, it is not unheard of to combine alcohol and phenobarbital, which causes added risk. Hyperexcitability may also be observed. Barbiturate overdose is a medical emergency and requires immediate treatment.

1. Airway protection and ventilation

Barbiturate poisoning causes severe CNS depression with loss of airway drive and protective reflexes with at least 40% risk of aspiration pneumonitis.

Secure airways is an early priority, and mechanical ventilation with oxygenation may be needed immediately. Positive pressure ventilation should be used with caution to maintain adequate oxygenation because barbiturates impair reflex cardiovascular adjustments to inflation of the lungs

2. Cardiovascular support

Hypotension, due to and direct myocardial depressant effects is treated with crystalloid bolus infusions. It rarely requires vasopressors.

If the patient remains hypotensive after 2 L of crystalloid I.V. solution has been infused and, give vasopressors (dopamine, or norepinephrine).

3. Metabolic support:

Give infusion of 25-50 g dextrose, 2 mg of naloxone, and 100 mg of thiamine.

4. Gastric decontamination and accelerated elimination

Once the patient is stabilized, give repeated per oral suspension of active charcoal and gastric lavage. Gastric intubation and lavage is indicated for life-threatening overdoses. This should only be performed in patients with protected airways! Since phenobarbital has significant enterohepatic recirculation, gastrointestinal elimination is also enhanced with help of multiple doses of activated charcoal. (Repeated intake of activated charcoal has been documented to reduce the elimination half-life of phenobarbital from 148 hours to 19 hr). Repeated charcoal is likely more effective than forced alkaline diuresis to force clearance of phenobarbital. With repeated oral activated charcoal, elimination half-life of phenobarbital can be reduced from 148 to 19 hours. Alkaline diuresis alone reduces the half-life only from 148 to 47 hours.

5. Enhancement of renal excretion by forced alkaline diuresis

Forced renal elimination is achieved through forced alkaline diuresis. Because Barbiturates are weak acids, urinary elimination can be enhanced with the help of alkalinization of the urine. Add 2-3 ampules of sodium bicarbonate (44.6 mEq per ampule) to 1 L of 5% Glucose (dextrose). Start infusion with 200 mL/h. Resulting urinary pH should be between 7.5 and 8.

Give also potassium replacement in this situation, because hypokalemia prevents bicarbonate excretion, and interferes with alkalinization of the urine.

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Barbiturate withdrawal.

Physical barbiturate dependence is manifested by withdrawal symptoms similar to those for alcohol; with anxiety, tremor, perceptual disturbances, nausea and vomiting and, in more severe cases, seizures and delirium.

Abrupt withdrawal after long time use of high doses of barbiturates may even cause life-threatening seizures and should always be managed in hospital.

Withdrawal treatment is best accomplished with phenobarbital because of its long half-life. Give as loading dose; Phenobarbital 120mg per orally, once per hourl until sedation has been achieved. Because of the long half-life further doses are not usually required.

Benzodiazepine abuse

The risk for benzodiazepine dependence is low, as long the patients take only normal therapeutic doses and use benzodiazepines only for short periods of time, eg 1 to 2 weeks. Long-term benzodiazepine use, particularly with high doses, cause a risk for addiction.

The risk increases with dose and duration of treatment. A small group of patients may develop serious benzodiazepine dependence with impaired dosage control, self-administration and continued use despite adverse consequences. A history of other substance addiction, are indicates risk for benzodiazepine dependence.

Benzodiazepine overdose

Benzodiazepine overdose can be treated with the antagonist Flumazenil. If benzodiazepine has been combined with other sedative drugs, additional measures may be required.. Flumazenil can not reverse the action of antidepressants, alcohol, barbiturates or opioids.

For treatment of acute benzodiazepine overdose:

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Give; Flumazenil 0.2 to 0.3mg by intravenous injection lasting over 15 seconds.

Repeat the dose each following minute, until the desired degree of consciousness and breathing rate is obtained, or a total maximum dose of 2mg has been given.

After intravenous flumazenil, overdose effects are reversed within 30 to 60 seconds. The overdose effects may however gradually reappear within the next few hours.

This is because the elimination half-life of flumazenil is 50 minutes, which is much shorter than the half-life of any of the benzodiazepines. Repeated doses of flumazenil may be needed.

NB; Flumazenil may induce withdrawal reactions or convulsions in patients with history of chronic long-term benzodiazepine use. NB: Patients must be observed for several hours after administration of flumazenil because of possible re-emergence of over-dose symptoms.

Benzodiazepine withdrawal

The risk for benzodiazepine withdrawal is highly variable between patients. Common symptoms include anxiety, insomnia, irritability, palpitations and sensory disturbances. Abrupt discontinuation in patients who has been taking high doses, eg more than 50mg diazepam per day, may cause seizures.

After short-term use, benzodiazepines can usually be ceased without problems. If a person has used a benzodiazepine dose only slightly above the therapeutic range for several months or more, reduce dose with 15 percent per week. For persons using higher doses, stabilisation on an equivalent dose of diazepam is recommended.

Patients with severe benzodiazepine withdrawal should be treated with diazepam, using a dose equivalent to their total (other) benzodiazepine consumption. If this is not known;

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Give; Diazepam 20mg orally, every 2 hours until withdrawal symptoms are controlled. Gradually step-down dose during the following 14 days.

Opiate / opioid abuse and addiction Heroin is the opioid most frequently associated with problems of abuse and dependence. But other opiates such as codeine, pethidine and morphine may also be used. It should also be remembered that injecting drug use (IDU) also is a risk for transmission of HIV-AIDS. A holistic approach is needed in support to intravenous drug users, integrating mental health, detoxication and management of associated illnesses such as HIV-AIDS, tuberculosis, hepatitis, sexually transmitted diseases.

Use of medication to ease adverse symptoms during detoxication includes against the hypersy,mpathetic “cold turkey” syndrome, along with step-wise reduction of daily dose of opoid during detoxication. Use of a substitute opoid methadone helps the patient in transition from heroin addiction and drug-seeking, to attain a non-drug dependent existence.

Acute opiate / opioid overdose Opioid overdose causes acute respiratory depression, a stuporous or comatose state and constricted pupils. Pulmonary oedema may also occur. Treat by injection of the opioid antagonist naloxone;

Give; Naloxone 0.4 to 2mg intravenously or intramuscularly, repeated every 2 to 3 minutes, as needed, up to 10mg.

The initial dose should be determined by symptom severity, using 2mg when significant respiratory depression is present.

NB: Patients should be kept under surveillance and repeated doses need to be given again at a later time, because naloxone has a shorter half-life than heroin or other commonly used opioids. NB: Overdosed on buprenorphine requires considerably higher doses of Naloxone, eg up to 10 times the standard dose, used for heroin or methadone overdose. 67

NB; In opioid-dependent persons naloxone will precipitate a severe withdrawal syndrome, often with result that the patient becomes agitated and aggressive.

Opioid / opiate detoxication and withdrawal The marked tolerance that develops during opioids treatment often results in significant dose escalation, and a high degree of physical dependence.

When the dose shall be tapered or opioid treatment be stopped, a withdrawal syndrome then occurs. The symptoms include hyper- sympathetic agitation, sweating, musculo-skeletal pain, abdominal cramps, diarrhoea, nausea and vomiting, seizure and goose flesh.

Following the cessation of heroin use, these effects are most intense around day 2 after the last heroin dose, and the symptoms disappear after 10 days.

This is not life-threatening. Uncomfortable symptoms can be reduced with help of a drug counteracting the central nervous sympathic system hyperactivity.

Control of autonomous nervous system symptoms during opioid withdrawal;

Give; Clonidine 5 to 15 microgram/kg/day orally, in 3 divided doses for 7 to 10 days with gradual dose tapering over 3 further days.

Start with an initial test dose of 6 microgram/kg. Ongoing blood pressure monitoring to adjust dosing are recommended.

Sedation and hypotension are the most common adverse effects of clonidine.

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Treatment of anxiety and agitation during opoid withdrawal Give; Diazepam 5 to 20mg orally, 4 times a day.

Caution should be exercised in prescribing benzodiazepines, because abuse of benzodiazepines is also common amongst opioid addicted patients.

Over-use of benzodiazepines in combination with heroin increases the risk of fatal overdose. Other treatments can include atropine to help control diarrhoea.

Metoclopramide can be given to reduce nausea and vomiting. Paracetamol or ibuprofen can give relief from hyperalgesia and musculoskeletal pain.

An alternative approach to opioid withdrawal involves the use of methadone. Methadone withdrawal is then used as short-term replacement-treatment, to prevent emergence of acute-phase withdrawal syndrome. This is different from use of methadone for long-term opioid replacement-maintenance, where methadone treatment is continued long time.

All such treatment must be under close supervision of a physician who is well experienced in the assessment of opioid dependence and in detoxication.

As initial dose, Give; Methadone 20 to 30mg orally, given as a single daily dose or in 2 divided doses. Then reduce the methadone-dose gradually, over a period of 7 days.

For outpatients, dose reductions may be carried out over 21 days. Withdrawal from opioids needs to be followed by an appropriate counseling and psychosocial support program to reduce the risk of relapse.

Opioid-dependent individuals who are admitted to hospitals as inpatients for treatment of other disorders, may also need to be stabilised with the help of methadone, in order to prevent them from developing acute opioid withdrawal symptoms,

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Give; Methadone 20 to 30mg orally, daily as 2 equal divided doses. Adjust dosage according to symptoms of opioid intoxication or withdrawal.

NB; A higher dose or an additional opioid may need to be administered if analgesia is required. NB; At discharge, the patient should be referred for treatment of her/his opioid dependence. NB; Observe statutory health regulations in regard to prescription of methadone.

Long-term treatment of patient with history of opioid dependence Methadone as maintenance opioid replacement; Methadone is an opioid agonist.

The principle of long-term methadone is to shift the patient from heroin to instead use per oral methadone. Methadone maintenance has the advantages of high acceptability (particularly in comparison to withdrawal- and abstinence-based approaches) with a well proven effectiveness in its ability to reduce illicit opioid/heroin use.

Shifting from intravenous to per oral use also interrupt and stop the risk for transmission of HIV, hepatitis etc.

The methadone dose needs to be determined individually. As starting dose;

Give; Methadone approximately 20mg per orally, once daily. Stabilisation of the dose is normally achieved over 3 weeks. Research suggests that outcomes are better when most patients receive a maintenance doses in the range of 50 to 80mg daily.

NB; Liver function tests and hepatitis B, hepatitis C and HIV serology are useful tests to consider.

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CNS stimulant addiction and abuse The psychomotor include amphetamines and their analogues, ephedrine, pseudoephedrine, cocaine.

Amphetamine and cocaine Overdose of amphetamine, cocaine and other stimulant drugs can produce a wide range of symptoms; This includes anxiety, insomnia, confusion, paranoid psychosis, tremors, convulsions, rapid respiration, hyperthermia, rhabdomyolysis, hypertension, tachycardia, cardiac arrhythmias. There are reports of cerebrovascular accidents, and death can be due to cardiac arrest.

Diazepam reduces the risk of seizures and is the drug of first choice here; Haloperidol reduces the risk of hyperthermia, and is given if required. Doses should be the same as those described for treatment of “The acutely disturbed patient”.

Hypertension can be treated with an alpha-blocker, eg phentolamine, or a direct vasodilator, such as nitroprusside.

Observe that beta-blockers, such as propranolol, are not effective and may in fact instead produce an increased blood pressure. Calcium channel blockers should also not be used, because of risk of seizures when they have been used after ovrdose of a stimulant such as amphetamine. Attention should be given to hydration and nutrition.

Amphetamine derivative overdose toxicity Overdose of an amphetamine or amphetamine derivative such is potentially fatal.

While the signs and symptoms are similar to those described for amphetamine, hyperthermia may be far more pronounced after high doses of these drugs.

Core body temperature may exceed 42°C. Treatment must be given against secondary pathological events, rhabdomyolysis, disseminated intravascular , acute renal failure and metabolic disturbances.

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Hallucinogen addiction and abuse The include a number of substances. Psychotic behaviour result with the use of these drugs. The duration of action depends on which drug and which dose has been taken.

While the patient is under the influence of hallucinogenic substances, treatment with benzodiazepines may be helpful against fear and anxiety;

Give; Diazepam 10 to 20mg per orally Repeat with the same dose every 2 hours if necessary, up to a maximum of 120mg daily.

Cannabis or Hashisch Cannabis intoxication is characterised by elevated heart rate, red eyes, cognitive and psychomotor impairment and altered time perception.

Anxiety, paranoia and psychosis can be precipitated. With chronic use, cannabis has a long duration of action, causing persistent effects. Psychological dependence may become marked and the user becomes detached and uninvolved in the surrounding world.

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Schizophrenia Schizophrenia is a severe psychiatric illness characterised by disturbances in language, perception, cognition, volition and emotions and this is one of the most disabling disorders. Males and females are equally affected.

Peak age of onset is in the late teens and early twenties; women tend to have a later onset and a better prognosis than men.

Signs and symptoms of schizophrenia Positive Negative Cognitive

• Hallucinations (hearing • Lack of motivation • Impaired planning voices) • Poor self-care • Reduced mental flexibility • Delusions (persecutory, • Blunted affect • Impaired memory bizarre, religious) • Reduced speech output • Disorganised communication, thinking and behaviour

Many patients with schizophrenia have physical and psychiatric comorbid conditions which also require specific treatment. Major depression is common, with a high proportion of people with schizophrenia experiencing at least one major depressive episode.

Delusional paranoid disorders usually appear in middle or late adult life. It is characterised by delusions and there may be auditory or visual hallucinations. Patients have less general impairment than in case of schizophrenia. The course of delusional disorder is variable.

Management usually involves the combination of antipsychotic medication with antidepressants (when depressed) and lithium (when manic and as a mood stabiliser).

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Principles of treatment for schizophrenia Psychosis needs prompt identification and treatment. Evidence show a clear association between delayed diagnosis-treatmen of psychosis and worse long-term outcomes.

Treatment of a first episode of schizophrenia As with all serious mental illnesses, it is important to assess risk of self-harm or danger to others. The need for hospitalisation needs to be assessed. With first episode psychosis, there is a particular need to be mindful of possible drug-induced complications.

Patients with their first psychotic episode may respond to treatment at lower-than-usual doses of medication.

Newer antipsychotics are better in terms of tolerability, but not better in terms of treatment efficacy.

Treatment of schizophrenia when low degree of sedative effect is required: Adult patients; Give: Haloperidol, per oral initial dose 2.5 mg twice daily Gradually increase dose until symptoms are controlled or until a maximum of 12.5 mg per day. Once the patient is stabilised, administer as a single dose at bedtime

Elderly patients; Give haloperidol, lower per oral initial dose 1.5 mg twice daily

Increase the dose in smaller steps and more gradually until symptoms are controlled or until a maximum of 12.5 mg daily is reached

Once the patient is stabilised, administer as a single dose at bedtime

Treatment of schizophrenia if a more sedative effect is needed: Give: Chlorpromazine, per oral, initial dose 25 mg three times daily Gradually increase dose until symptoms are controlled

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Once the patient is stabilised, administer as a single dose at bedtime. Maintenance dose: 75–300 mg at night, but may need up to high dsoes as 1 000 mg in some patients.

Only specialists should attempt combined use of antipsychotic drug and Benzodiazepines.

Management of acute psychosis (including mania): Give; Diazepam, IM or IV, 10–20 mg. Do not inject faster than maximum by 5 mg/minute. And; Haloperidol, IM, 2–5 mg Doses may be repeated at hourly intervals, usually 4–8 hourly, if needed The maximum dose 20 mg in 24 hours Refer to hospital if higher doses are required

After the acute phase: Give Haloperidol, per oral 2.5–12.5 mg 2–3 times daily in divided doses. Maintenance dose: 2.5–10 mg daily.

If there is no response after 3 weeks it may be necessary to gradually increase the above doses over the next 2 weeks.

Monitor the patient very closely for extrapyramidal adverse effects such as dystonia, especially laryngeal dystonia can become life threatening and is particularly common in young adult patients, stiffness, shaking, restlessness. Give benztropin and reduce antipsychotic medicine doses if necessary.

To treat anxiety, agitation and insomnia, use short-term benzodiazepine treatment. Give; Diazepam 5 to 10mg orally, as required (up to 40mg per day).

Continue antipsychotic drug-treatment alongside other treatment for about 1 year.I f the patient has been symptom-free over that period, consider slow discontinuation under close observation for signs of relapse.

If extrapyramidal side-effects, dystonia, occur with the use of haloperidol or other antipsychotic medication; 75

Give; Benztropin 0,5-1mg per day per oral, max 6 mg/day, if by IV or IM injection, 1-2 mg, repeated if symptoms so requires.

Or; Biperiden per oral 1 mg two times per day, up to 2mg 3 times per day, usual maintenance 3-12 mg per day in divided doses, elderly lower dose. By I.M. injection or slowI.V. injection, biperiden lactate 2,5 – 5 mg up to 4 times per day. Elderly, lower doses. Or; orphenadrine 50-150 mg per day in divided doses. 50 mg is usually enough, maximum dose is 400 mg per day, per oral as tablets. Use lower dose in elderly.

Treatment of acute dystonic reactions, laryngeal dystonia: Give; Benztropin 1-2 mg by intravenous slow injection, repeated if symptoms reappear. Or :biperiden, IM, 2 mg Refer to specialist • patients with first psychotic episode • patients with no response to treatment • patients who show intolerance to drug treatment • patients with high suicidal risk • patients with concurrent medical or other psychiatric illness • children, adolescents and the elderly patient • pregnant and lactating women • patients with both epilepsy and psychosis

Long-term antipsychotic medication is needed to prevent relapse in chronic schizophrenia. Treatment should be tailored to each patients need, and supervised by specialist psychiatrist in collaboration with a primary care physician available close to the patient.

Treatment of relapse of schizophrenia Patients who will take per oral medication; Higher doses of antipsychotic medications may be required for subsequent acute exacerbations; but this is not always the case.

If the patient needs parenteral medication; Give; Haloperidol 5mg intramuscularly, initially, up to 20mg in 24 hours, depending on the response, switching to oral olanzapine,

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risperidone or quetiapine (as previously used) unless depot antipsychotic is needed There is no evidence that doses of haloperidol over 20mg in 24 hours are of any additional benefit in controlling acute schizophrenia.

With the use of parenteral haloperidol, always also give an anticholinergic agent to prevent serious side effects during days of parenteral administration, and for several days after, Give; Benztropine 1 to 2mg orally, twice daily.

If symptoms of a dystonic reaction develops, immediately, Give; Benztropine 1 to 2mg intravenously or intramuscularly.

Shift back to per oral medication as soon as the condition allows.

Management of treatment-resistant schizophrenia A significant proportion (up to 30 percent) of patients with schizophrenia do not respond fully to given antipsychotic medication. Research evidence has demonstrated that clozapine has good efficacy for management of treatment-resistant schizophrenia. But clozapine can only be used by specialists in facilities which can monitor risk for adverse reactions which includes risk for neutropenia, agranulocytosis and myocarditis.

Long-acting or depot antipsychotics for schizophrenia Poor compliance is often an issue in relapse prevention. Factors which can cause poor complicance include adverse events. It is therefore important to start treatment at low doses, and slowly step up in a way which can avoid unnecessary adverse effects. This will help to motivate the patient to maintain his/her compliance with prescribed treatment. The use of a small test dose is recommended as a start, especially if the patient has not been exposed to antipsychotic drugs before. After the test dose, it is important to monitor the patient for adverse reactions, extrapyramidal adverse effects and allergic reactions.

A depot preparation can offer treatment advantages; Haloperidol decanoate 50mg intramuscularly, as a test dose, then the dose titrated between 50 and 300mg intramuscularly, every 4 weeks

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Management of adverse reactions during use of antipsychotic medicine

Management of acute dystonia Acute dystonias especially develop after parenteral administration of traditional antipsychotics. They generally develop within hours to days and affect the face, neck and trunk. Oculogyric crisis, laryngeal spasm and opisthotonus occur, and from reported cases it can be concluded that young males are most at risk. Give; Benztropine 1 to 2mg intravenously or intramuscularly. Following immediate relief of the acute signs, per oral benztropine should be given. This treatment with benztropin is usually needed for several weeks, but can often be discontinued by dose-step-wise reduction after several weeks.

Management of akathisia Akathisia is a severe sense of agitation experienced in the limbs or as a mental perturbation. It generally occurs within a week from start of treatment. If this adverse symptom is missed, there is a risk that the dose of antipsychotic medication instead is increased inappropriately, because the patient show signs of increased agitation. Wherever possible, the antipsychotic drug dose should be reduced, until akathisia becomes less troublesome. Newer antipsychotics such as clozapine, olanzapine or risperidone are less likely to cause these extrapyramidal adverse events than the older, traditional agents. Alternatively, as short-term treatment against akathisia, Give; Propranolol 20 to 40mg per orally, 3 or 4 times a day Or; Diazepam 2 to 5mg orally, 3 times a day Or; Benztropine 0.5 to 4mg orally, daily.

NB; Propranolol should be avoided in patients with asthma or severe peripheral vascular disease and some patients with heart failure. It should be used cautiously in patients with diabetes.

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Management of drug-induced Parkinsonism Parkinsonism is typically seen early, weeks after start of treatment with traditional antipsychotic drugs. There is general poverty of movement, rigidity, growing tremor, drooling and hypersalivation. Akinesia is sometimes confused with drug-induced depression. If possible, the antipsychotic drug dose should be reduced.

Alternatively,

Give; Benztropine 0.5 to 4mg orally, daily Or; benzhexol 2 to 5mg orally, 3 times a day. After several weeks the anticholinergic agents should be reduced or ceased as possible.

Tardive dyskinesia In general there is no specific treatment for these abnormal movements.

Note: Because of the lack of suitable management for established tardive dyskinesia, prevention is strongly recommended. Antipsychotic drugs should only be used in the lowest possible dose and only in those patients where there is a strong clinical indication. Antipsychotic pharmacotherapy should be reviewed regularly and dosage reduced and ceased as soon as possible.

Neuroleptic (antipsychotic) malignant syndrome Treatment depends on the severity of the symptoms. In all cases, discontinue the antipsychotic medication. Monitor basic functions and ensure adequate hydration using intravenous fluids. For mild cases conservative management may be sufficient. Sometimes, per oral bromocriptine is indicated.

In a life-threatening situation, treatment in an intensive care unit is indicated.

Give; Bromocriptine 2.5mg per orally, twice per day initially, gradually increase to 5mg 3 times a day as needed. And; Dantrolene, 50mg intravenously, every 12 hours for up to 7 doses. In patients with suspected or documented neuroleptic malignant 79

syndrome, the continuing need for antipsychotic medications should be reviewed by a psychiatrist. Thirty percent of these patients will develop the syndrome again on rechallenge.

Mood disorders

This chapter outline principles for management of grief, acute and recurrent major depression, acute mania, bipolar depression, recurrent bipolar disorder, mixed episodes, dysphoric mania and rapid cycling bipolar disorder Drug treatment is only one component in the care for patients suffering these conditions.

Anxiety and associated disorders Anxiety may be primary or secondary to other disorders. In secondary anxiety, treatment of underlying problem is needed. Non- pharmacological therapy is often effective.

Note: A depressive disorder can be the cause of anxiety symptoms. It is important to review unresponsive patients, as depressed patients need antidepressant therapy

Anxiety adjustment disorder This diagnostic term describes the patients who responds within a few months after identified psychosocial stress, with anxiety symptoms which impair social or occupational function. Basic treatment is non-pharmacological, including counselling, relaxation, stress management and cognitive behavioural therapy. Short-term drug treatment for less than 2 weeks can be considered if the symptoms are severe, then Give; Diazepam 2 to 5mg orally, as a single dose, which may be repeated, if required, up to twice daily, for up to 2 weeks

Obsessive-compulsive disorder Obsessions are recurrent and persistent intrusive ideas, impulses or images which are recognised as the product of the own mind. Compulsions are repetitive, stereotyped behaviours in response to an obsession, to prevent discomfort or some dreaded event with which it is not connected in a realistic way. 80

The person with a obsessive-compulsive disorder generally recognises that their behaviour is excessive or unreasonable. These obsessions or compulsions may cause marked distress and significantly interfere with the person’s life. Refer to psychiatry specialist.

Treatment should be given with psychotherapy. Drug treatment can be a complement.

Consider treatment with a , Give; Clomipramine 50 to 75mg per orally, at night, increasing every 2 to 3 days (depending on adverse effects) to 150 to 250mg at night. If there is no response after 4 to 6 weeks, dosage can be increased at weekly intervals by increments of 25 to 50mg per day, up to 300mg at night.

NB; Lower doses are required in the elderly. NB; The risk of adverse effects, including convulsions, increases at higher doses.

Phobic disorders Phobias are marked fears of situations or objects which are recognised by the sufferer as unreasonable or excessive and which interfere with normal function by the resulting discomfort, or by measures taken to avoid the precipitating factors. These disorders may be named for the nature of the situation or object, eg agoraphobia, social phobia (social anxiety disorder), simple phobia.

NB:For all phobic disorders treatment should be generally with non- pharmacological measures, eg psychotherapy such as CBT.

If the phobia gives rise to severely disabling symptoms which suggest sympathetic overactivity, with tremors, palpitations, sweating are anticipated, then Give; propranolol 10 to 40mg orally, 30 to 60 minutes before the event. - unless beta-blockers are contraindicated, eg patients with asthma or severe peripheral vascular disease and some patients with heart failure.

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Acute stress disorder During the early weeks following exposure to a severe traumatic event, symptoms of re-experiencing, avoidance, detachment or being in a daze are common.

NB; Drug treatment is rarely needed for management of acute stress reactions.

Post-traumatic stress disorder Post-traumatic stress disorder should be distinguished from acute stress disorder. This condition is manifest by a set of symptoms which persist for more than one month after a traumatic event. Symptoms may include intrusive recollections, nightmares, avoidance of reminders of the trauma, irritability and emotional numbing.

NB; The mainstay of treatment of PTSD is cognitive psychotherapy usually including a component of exposure therapy.

The role of medication in acute post traumatic stress disorder is largely geared to the short-term relief of specific symptoms, in conjunction with psychotherapy. Carbamazepine has been shown to reduce re-experiencing and intrusive recollections in sufferers. Sleep disturbance may be relieved by short-term use of hypnotics. Refer to specialist for diagnosis and treatment.

Sleep disorders Assessing a complaint of sleep problems should include a review of the patient’s use of drugs, since many drugs and substances often disturbs sleep, eg coffee, tea, alcohol, hypnotics, antihistamines.

Insomnia Insomnia is diagnostic term allocated tocases when the patient express inability to function well with his/her amount and quality of sleep. The patient may have trouble getting to sleep, may suffer frequent nocturnal arousals, or awaken too early. Some patients, particularly the elderly, frequently have daytime naps that need to be included when calculating the total actual sleep duration per 24 hour period ! 82

Symptoms of insomnia are often secondary to some underlying medical, psychological or environmental problems. Insomnia can often be improved by management of any underlying problem, eg depression, anxiety, nocturnal asthma, angina, dyspnoea, oesophageal reflux, nocturia, pain, arthritis. Hypnotic drugs should not be first-line treatment. If hypnotics are prescribed, the duration of therapy should be limited to the shortest duration.

Sedating antihistamines are not recommended as hypnotics, because they can cause severe daytime sedation and many other side effects.

Hypnotics in the elderly When the elderly patient is given sedative and hynotic medicine, it is necessary to pay extra attention to the problems of dependence, risk to cause confusion and memory impairment. The old person may also risk to fall and break arms and legs, and additional problems with incontinence can also be caused by long-term use of drugs such as benzodiazepines. A key principle should therefore be to avoid such medication if at all possible. Cognitive-behavioural therapies such as stimulus control and sleep restriction are effective in late-life chronic persistent insomnia, whether alone or in combination with medicine. If medication is needed, give a short-acting benzodiazepine for as short time as possible.

General principles for the use of hypnotics in the elderly are: • exclude underlying causes of sleep disturbance • avoid hypnotics when possible • advise the patient that hypnotics are inappropriate if sleep timing is the problem • avoid combination of hypnotics with alcohol • be alert to the risk of drug accumulation in the elderly • be alert to risks of long-term use

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Index

A Benzodiazepine overdose ...... 65 Abbreviations and acronyms ...... 8 benzodiazepine withdrawal ...... 66 Acetylcysteine ...... 30, 31 Benzodiazepine withdrawal ...... 66 Acetylsalicylic acid – Aspirin ...... 31 benztropin ...... 75 Aciclovir ...... 24, 25, 56 Benztropin ...... 59, 76 Acknowledgements...... 8 Benztropine ...... 20, 63, 77, 78, 79 Acute alcohol withdrawal ...... 61 benzylpenicillin ...... 21 acute attack of migraine ...... 13 Benzylpenicillin ...... 21, 22, 23 Acute equipotency ratio for opioid bicarbonate ...... 64 analgesics ...... 33 Acute herpes zoster ...... 24 biperiden ...... 76 Acute joint pain ...... 44 Biperiden ...... 76 Acute low back pain ...... 43 Bromocriptine ...... 79 Acute opiate / opioid overdose ...... 67 buprenorphine ...... 67 Acute pain of herpes zoster ...... 25, 56 Burn pain ...... 53 Acute stress disorder ...... 82 Burns dressings and debridement ...... 55 acutely confused, aggressive patient ...... 58 After the acute phase ...... 75 C akathisia ...... 78 Alcohol and narcotic drug addiction ...... 61 Calamine...... 25 Alcohol overdose ...... 61 Calamine lotion ...... 56 Alcoholism ...... 61 Cannabis or Hashisch ...... 72 alpha-blocker ...... 71 carbamazepine ...... 57 amitriptyline ...... 57 Carbamazepine ...... 12, 16, 26, 82 Amitriptyline ...... 13, 26, 57 Cefotaxime ...... 21, 22, 23 Amoxicillin ...... 22 Ceftriaxone ...... 21, 22, 23 Amphetamine derivative overdose toxicity ...... 71 Central nervous system infection with Herpes zoster ampicillin ...... 22 ...... 24 Ampicillin ...... 21, 22 Cerebrovascular disorders...... 26 Anxiety adjustment disorder ...... 80 Chlorpromazine ...... 60, 74 Anxiety and associated disorders ...... 80 Chorea ...... 20 aspirin ...... 56 Chronic daily headache ...... 12 Aspirin ...... 13, 25, 28, 32, 36, 56 Chronic low back pain ...... 43 Clomipramine Atenolol ...... 13 ...... 81 Clonidine ...... 67, 68 B clozapine ...... 77 Cluster headache ...... 12 Barbiturate abuse ...... 63 CNS infections ...... 20 Barbiturate withdrawal ...... 65 CNS stimulant addiction and abuse ...... 71 Barbiturates ...... 64 Co‐analgesics ...... 35 benzhexol ...... 79 cocaine ...... 71 benzodiazepine ...... 65 codeine ...... 42 Benzodiazepine abuse ...... 65 Codeine ...... 25, 33, 34, 46 84 codeine phosphate ...... 39 Glasgow Coma Score ...... 53 Codeine phosphate ...... 37, 39 Control of trauma pain ...... 51 H corticosteroid ...... 11 Corticosteroids ...... 49 Haemophilus influenzae type b ...... 22 cotrimoxazole ...... 22 Hallucinogen addiction and abuse ...... 72 Cotrimoxazole ...... 22 haloperidol ...... 63, 74 Haloperidol ...... 20, 59, 63, 71, 74, 75, 76 D Haloperidol decanoate ...... 77 Headache ...... 12, 55 Dantrolene ...... 79 Headache, short overview ...... 12 delirium ...... 58 heroin ...... 69 Delirium tremens ...... 62 Herpes zoster pain ...... 55 desipramine ...... 57 hydroxychloroquine ...... 47 dextrose ...... 64 Hypertension...... 13 Diagnosis Checklist; DIMTOP ...... 58 Hypnotics in the elderly ...... 83 Diazepam ...... 59, 60, 62, 63, 67, 71, 72, 75, 78 Diclofenac ...... 32 I Directed treatment, against identified pathogens .... 22 disease-modifying antirheumatic drugs ...... 47 Ibuprofen ...... 32 DMARDs ...... 47 IMCI ...... 2 dopamine ...... 64 Immediate and early hospital management of droperidol...... 63 meningitis ...... 21 drug‐induced Parkinsonism ...... 79 Indomethacin...... 32 Drug‐treatment‐induced dystonia ...... 20 Initial analgesia ...... 52 dystonia...... 75 Insomnia ...... 82 Intramuscular opiate administration ...... 50 Intravenous opiate administration ...... 51 E Introduction ...... 2, 9 Empirical treatment of meningitis before organism is Involuntary movement disorders ...... 19 known ...... 21 Enhancement of renal excretion by forced J alkaline diuresis ...... 64 Juvenile chronic arthritis ...... 48 ephedrine ...... 71 Juvenile rheumatoid arthritis ...... 48 Epilepsy ...... 15 Ergotamine ...... 14 Essential Medicines List ...... 9 K Essential tremor ...... 19 Ketoprofen ...... 32 extrapyramidal adverse effects ...... 75 ketorolac ...... 50 Ketorolac ...... 50 F

Facial nerve (Bell's) palsy ...... 11 L Famciclovir ...... 56 laryngeal dystonia ...... 75, 76 Flumazenil ...... 62, 66 Levodopa/carbidopa ...... 19 lignocaine ...... 25 G Lignocaine ...... 56 Generic names ...... 10 Listeria monocytogenes meningitis ...... 22

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Long‐acting or depot antipsychotics for schizophrenia Nitrous oxide ...... 55 ...... 77 Nonsteroidal antiinflammatory drugs and analgesics ...... 48 M Nontraumatic acute joint pain ...... 45 norepinephrine ...... 64 Maintenance of pain control ...... 52 NSAID ...... 46 Major trauma ...... 52 NSAIDs Non‐steroidal antiinflammatory drugs ...... 32 Major trauma with normal conscious state ...... 51 Malaria ...... 2 O Management of acute dystonia ...... 78 Management of acute psychosis (including mania): . 75 Obsessive‐compulsive disorder ...... 80 Management of adverse reactions ...... 78 Obstetric pain ...... 55 Management of pain for burned patients in hospital Opiate / opioid abuse and addiction ...... 67 care ...... 54 Opiates ...... 33 Mechanical neck pain ...... 43 Opioid-dependent ...... 69 Meningitis ...... 20 Orofacial conditions and pain ...... 11 Mental Health ...... 58 orphenadrine ...... 76 methadone ...... 67, 69 Osteoarthritis ...... 46 Methadone ...... 33, 35, 69, 70 Oxycodone ...... 33 Methotrexate ...... 47 Metoclopramide ...... 13, 14, 37, 39, 69 P Metoprolol ...... 13 Midazolam ...... 55 Pain control ...... 29 Migraine ...... 12, 13 Pain control for adults ...... 36 Mild level of disease ...... 19 Pain control for children ...... 38 Mild pain in adults ...... 36 Pain syndromes ...... 40 Mild RA disease ...... 47 paracetamol ...... 42, 43, 46, 49, 53, 56 Moderate level of disease ...... 19 Paracetamol ...... 13, 25, 29, 36, 38, 39, 54 Moderate Pain in adults ...... 37 Paracetamol overdose...... 30 Moderate pain in children ...... 39 Parkinson's disease ...... 19 Moderate to severe RA disease ...... 47 Penicillin ...... 22 Module: Pain‐Control in Referral Hospitals ...... 29 Pethidine ...... 33, 34 Mood disorders ...... 80 phentolamine ...... 71 morphine ...... 45, 53 Phobic disorders ...... 81 Morphine ...... 33, 34, 37, 39, 46, 54 Piroxicam ...... 32 Musculoskeletal pain ...... 40 Pneumococci ‐ Streptococcus pneumoniae meningitis ...... 23 N Pneumococci meningitis with Strains relatively resistant to penicillin ...... 23 naloxone ...... 64, 67 Postherpetic neuralgia ...... 25, 57 Naloxone ...... 35, 37, 67 Postoperative pain control ...... 49 Naloxone ‐ Opiate antidote...... 35 Post‐traumatic stress disorder ...... 82 Naproxen ...... 32 Prednisolone ...... 11, 48 Neck pain with nerve root involvement ...... 44 Primary stroke‐prevention ...... 27 Neisseria meningitidis ...... 22 Promethazine ...... 13, 37 neuroleptic (antipsychotic) malignant syndrome ..... 79 Prophylaxis of migraine ...... 13 Neurology in referral hospitals ...... 11 propranolol ...... 71 Nimodipine ...... 27 Propranolol ...... 20, 78 nitroprusside ...... 71 pseudoephedrine ...... 71 86

PTSD ...... 82 T R Tardive dyskinesia ...... 79 Temporal arteritis ...... 13 Rheumatoid arthritis ...... 44, 47 Tension headache ...... 12 thiamine ...... 64 S Thiamine ...... 62 Tramadol ...... 38 Schizophrenia ...... 73 Traumatic acute joint pain ...... 46 Secondary stroke‐prevention ...... 28 treatment of acute dystonic reactions ...... 76 Sedation of the acutely disturbed patient ...... 59 Treatment of barbiturate overdose...... 64 Severe pain in adults ...... 37 Treatment of relapse of schizophrenia ...... 76 Severe pain in children ...... 39 Treatment of schizophrenia if a more sedative effect shingles ...... 24 is needed ...... 74 Sinusitis ...... 12 Treatment of schizophrenia when low degree of Sleep disorders...... 82 sedative effect is required ...... 74 Sodium Valproate ...... 16 treatment‐resistant schizophrenia ...... 77 Spinal pain ...... 42 Trigeminal neuralgia ...... 11 Stroke ...... 26 Subarachnoid haemorrhage ...... 13, 26 V Subcutaneous opiate administration ...... 50 Substance abuse ...... 61 Valaciclovir ...... 56 sulphasalazine ...... 47

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