Palliative Care Guidelines: Ketamine Ketamine in Palliative Care Description Anaesthetic agent used with specialist supervision as a third line analgesic to manage very complex pain. It is an N-methyl-D-aspartate (NMDA) receptor inhibitor. This use is outside the UK marketing authorisation and ketamine is ordered on a named patient basis. Preparations Ketamine injection Ketamine oral solution 50mg/5ml Used by subcutaneous injection/ infusion. Specialists occasionally give ketamine IV – see below 500ml bottle Martindale Pharmaceuticals A ketamine oral solution can be prepared by the pharmacist from the injection preparation using purified water + flavouring to mask ketamine’s bitter taste. (Can be stored in a fridge for up to 1 week.) Indications • Neuropathic pain poorly responsive to titrated opioids and oral adjuvant analgesics (eg. antidepressant and/or anticonvulsant) particularly when there is abnormal pain sensitivity allodynia, hyperalgesia or hyperpathia. • Complex ischaemic limb pain or phantom limb pain. • Poorly controlled incident bone pain (often has a neuropathic element). • Complex visceral / abdominal neuropathic pain. Contraindications • Do not use ketamine if patient has raised intracranial pressure; uncontrolled hypertension, delirium or recent seizures; history of psychosis. Cautions • Use low doses, carefully monitored, in cardiac failure, cerebrovascular disease, ischaemic heart disease. • If used for over 3 weeks, discontinue ketamine gradually. Drug interactions • Ketamine interacts with theophylline (tachycardia, seizures) and levothyroxine (monitor for hypertension, tachycardia). • Diazepam increases the plasma concentration of ketamine. Side effects • • • • Hallucinations, dysphoria and vivid dreams – see p2. Hypertension, tachycardia, raised intracranial pressure. Sedation at higher doses. Erythema and pain at infusion site. Starting ketamine • Ketamine is started on the recommendation of a palliative medicine consultant. This is usually done in an inpatient setting. • Very occasionally, a patient may need to start ketamine in the community. The route of choice is generally oral ketamine. The palliative medicine consultant will liaise closely with the GP, district nurse, and unscheduled care service. • 24 hour palliative medicine advice will be available. © NHS Lothian Re-issue date: August 2010 Review date: August 2013 1 Palliative Care Guidelines: Ketamine Dose & Administration • Patients starting ketamine will be taking a regular opioid. Ketamine may restore the patient’s opioid sensitivity and lead to opioid toxicity. • The specialist may recommend changing to a short acting, regular opioid before starting ketamine, particularly if the patient has side effects from the current opioid dose. • Monitor closely for signs of opioid toxicity (eg. sedation, confusion); reduce opioid dose by one third if the patient is drowsy and seek advice. • Hallucinations/ dysphoria: if the patient is not drowsy this is more likely to be a ketamine side effect than due to opioids. • Give haloperidol oral 0.5-1mg twice daily or SC 1mg-2.5mg once daily. Midazolam SC 2.5mg as needed can also be used. • Preventing ketamine dysphoria – consider oral haloperidol 0.5-1mg daily when starting ketamine. It can be stopped when the patient is stable. Oral ketamine • Ketamine can be started using the oral route or patients may be changed from a subcutaneous infusion when pain is controlled. • Starting dose: 5-10mg four times daily. • Increase dose in 5-10mg increments. • Usual dose range: 10mg-60mg four times daily. Subcutaneous ketamine infusion • Starting dose: 50-150mg/24 hours. • Review daily; increase dose in 50-100mg increments. • Usual dose range: 50mg- 600mg/24 hours (higher doses are occasionally used in specialist units). Administration • Prepare a new syringe every 24 hours. • Dilute ketamine with sodium chloride 0.9%. • Check the syringe is not cloudy and protect it from light. • Ketamine stability and compatibility – see table below. • Discard the ketamine vial immediately after preparing the syringe. • Rotate the subcutaneous infusion site daily to prevent site reactions. If these occur, increase the volume of sodium chloride 0.9% used to dilute the ketamine and/or add dexamethasone injection 1mg to the ketamine infusion. Only low dose dexamethasone can be mixed with ketamine in this way. Converting from a 24 hour SC ketamine infusion to oral ketamine • Oral ketamine is more potent than SC ketamine (due to liver metabolism). Many patients require a dose reduction of 25-50% when changing to oral ketamine. • Prescribe the oral ketamine in divided doses - four times daily. • Titrate dose in 5-10mg increments. • Some specialists stop the SC infusion when the first dose of oral ketamine is given. Others gradually reduce the infusion dose as the oral dose is increased. Parenteral administration Palliative medicine consultants or anaesthetists occasionally administer SC or IV ketamine as single doses for severe pain or to cover painful procedures. Specialists have used IV ketamine infusions to manage ischaemic limb pain. 2 Re-issue date: August 2010 Review date: August 2013 © NHS Lothian Palliative Care Guidelines: Ketamine Patient monitoring • Patients who are at risk of hypertension, tachycardia, respiratory depression or opioid toxicity should only start ketamine in a clinical area able to monitor them 2-4 hourly for the first 24 hours. • All patients should be reviewed at least once daily until stable, and then weekly. • Once the pain is controlled, the palliative medicine specialist may recommend a gradual reduction in the dose of opioid and /or ketamine. Blood pressure • Check BP is normal or well controlled before starting ketamine. Record a baseline BP. • Check BP an hour after the first dose of oral ketamine or starting a SC infusion. • Check BP 24 hours after the first dose of ketamine, then daily. • If blood pressure increases 20 mmHg above baseline inform the patient’s doctor. • If blood pressure remains elevated 20mmHg above baseline on repeated measurement, stop the ketamine and seek advice from a palliative medicine specialist. Pulse • Record a baseline pulse rate. • Check pulse an hour after the first dose of ketamine or starting SC infusion. • Check pulse 24 hours after the first dose of ketamine, then daily. • If pulse rate increases 20bpm above baseline or rises above 100bpm inform the patient’s doctor. If there is no other cause of tachycardia, seek advice from a palliative medicine specialist. Respiratory rate • Record a baseline respiratory rate. • The palliative medicine specialist will advise on frequency of monitoring. • If respiratory rate decreases to 10 breaths/min inform medical staff. Seek advice from a palliative medicine specialist. • Naloxone (in small titrated doses) is only required for reversal of life-threatening respiratory depression due to opioid analgesics, indicated by • A low respiratory rate < 8 respirations/minute • Oxygen saturation <85%, patient cyanosed • Naloxone should not be given in large bolus doses as it can precipitate an acute opioid withdrawal reaction. See: Naloxone guideline Dysphoria, hallucinations, vivid dreams Assess patient daily until ketamine dose is stable; then stop any regular haloperidol or midazolam. Further information Specialist palliative care services/ Palliative medicine on-call advice service Palliative Care Drug Information online: http://www.palliativedrugs.com/ © NHS Lothian Re-issue date: August 2010 Review date: August 2013 3 Palliative Care Guidelines: Ketamine References • Fallon M, Welsh J. The role of ketamine in pain control. European Journal of Palliative Care 1996; 3:143-146. • Mercadante S. Ketamine in cancer pain: an update. Palliative Medicine 1996; 10: 225-230. • Edmonds P. The role of ketamine in the management of chronic pain. CME Bulletin Palliative Medicine 1998; 1:3-5. • Grant I, Nimmo W, Clements J. Pharmacokinetics and analgesic effects of IM and oral ketamine. British Journal of Anaesthesia 1981; 53:805-809. • Enarson M, Hays H, Woodroffe M. Clinical experience with oral ketamine. Journal Pain & Symptom Management 1999; 5: 384-386. • Bell RF. Low-dose subcutaneous ketamine infusion and morphine tolerance. Pain 1999; 83: 101-103 • Fitzgibbon E, Hall P, Schroder C et al. Low Dose Ketamine as an Analgesic Adjuvant in Difficult Pain Syndromes: A Strategy for Conversion from Parenteral to Oral Ketamine. Journal Pain & Symptom Management 2002; 23(2): 165-170. • Beitez-Rosario M, Feria M, Salinas-Martin A. A retrospective comparison of the dose ratio between subcutaneous and oral ketamine. Journal Pain & Symptom Management 2003; 25: 400-402. • Kannan T, Saxena A, Bhatnagar, Barry A. Oral ketamine as an adjuvant to oral morphine for neuropathic pain in cancer patients. Journal Pain & Symptom Management 2002; 23: 6065. • Bell R, Eccleston C, Kalso E. Ketamine as an adjuvant to opioids for cancer pain (Cochrane Review). In: The Cochrane Library. Issue 3, 2004. Oxford: Update Software • Hocking G, Cousins M. Ketamine in chronic pain management: an evidence-based review. Anaesth Analg. 2003; 97: 1730-9 • Visser E, Schug S. The role of ketamine in pain management. Biomedicine and Pharmacotherapy 2006; 60: 341-348 • Webster L, Walker M. Safety and efficacy of prolonged outpatient ketamine infusions for neuropathic pain. American Journal of Therapeutics 2006; 13: 300-5 Stability References • Watson D, Lin M, Morton A et al. Compatibility and stability of dexamethasone sodium phosphate and ketamine hydrochloride subcutaneous infusions in polypropylene syringes. Journal Pain & Symptom Management 2005; 30: 80-86 • Twycross R and Wilcock A. Palliative Care Formulary (Third Edition). Palliativedrugs.com Ltd 2007. • Dickman A, Schneider J and Varga J. The Syringe Driver (Second Edition). Oxford University Press 2005. 4 Re-issue date: August 2010 Review date: August 2013 © NHS Lothian