Dr Kirsty Lowe ST6 in Palliative Medicine NHS Grampian Ketamine Dr Kirsty Lowe ST6 in Palliative Medicine NHS Grampian

Overview Case study What is ketamine? Indications Cautions, contraindications, interactions Side effects Dose and administration Monitoring Questions

Case study Tom is a 40 year old man with metastatic renal cancer Bone metastasis in R hip causing neuropathic pain down R leg. Allodynia over R thigh. Reduced mobility due to pain. Current analgesia: MST 60mg BD, oramorph 20mg PRN (doesn’t help much) Amitriptyline 50mg nocte Pregabalin 200mg BD Dexamethasone 6mg OD Previous radiotherapy to R hip metastasis – no effect.

What now?

What is Ketamine? Anaesthetic agent used with specialist supervision as a third line analgesic to manage complex pain. It is an N-methyl-D-aspartate (NMDA) receptor inhibitor. Ketamine is a Schedule 2 CD therefore all prescriptions must satisfy CD prescription requirements to be valid and include details of the dose, form, strength, directions for use and total quantity (in both words and figures).

NMDA receptor The antagonism of the NMDA receptor is responsible for: Amnesic Psychosensory Analgesic effects of ketamine NMDA receptors are present on nearly all the cells of the CNS especially those involved with nociception. When resting membrane potential is changed, as a result of prolonged excitation, the NMDA channel unblocks. Neuronal hyperexcitability develops causing hyperalgesia/ allodynia and a reduction in opioid responsiveness. Ketamine: decreases the NMDA channel opening time decreases the amplification of the response to a repeated stimulus (wind-up) binds to a second site to reduce the frequency of the channel opening.

More fun facts about ketamine! Ketamine also has actions away from the NMDA receptor: Calcium and Na channels Dopamine receptors Cholinergic transmission Noradrenergic and serotinergic re-uptake 90% excreted in the urine (conjugated, hydroxylated metabolites). Oral ketamine undergoes extensive first-pass hepatic metabolism to Norketamine via CYP3A4. Norketamine is also an NMDA receptor blocker Equipotent analgesic but not anaesthetic agent Ketamine causes hepatic enzyme induction and enhances its own metabolism

Indications Neuropathic pain poorly responsive to titrated opioids and oral adjuvant analgesics (e.g. antidepressant and/or anticonvulsant) particularly when there is abnormal pain sensitivity – allodynia or hyperalgesia. Complex ischaemic limb pain or phantom limb pain. Poorly controlled incident bone pain (often has a neuropathic element). Complex visceral / abdominal neuropathic pain.

Cautions, contraindications, interactions Use low doses, carefully monitored, in cardiac failure, cerebrovascular disease, ischaemic heart disease. If used for over 3 weeks and there is a need to stop treatment, discontinue ketamine gradually. Consider dose reduction in severe hepatic impairment Contraindications Do not use ketamine if patient has raised intracranial pressure; uncontrolled hypertension, delirium or recent seizures; history of psychosis.  Drug interactions Ketamine interacts with theophylline (tachycardia, seizures) and levothyroxine (monitor for hypertension, tachycardia). Diazepam increases the plasma concentration of ketamine. See relevant BNF section for further information. Inhibitors and inducers

Side effects Hallucinations, dysphoria and vivid dreams. Hypertension, tachycardia, raised intracranial pressure. Sedation at higher doses. Erythema and pain at infusion site. Urinary tract symptoms e.g. frequency, urgency, urge incontinence, dysuria and haematuria (where is there no evidence of bacterial infection consider discontinuing ketamine and seeking urology advice). Hepatotoxicity

Starting ketamine Ketamine is started on the recommendation of a palliative medicine consultant. This is usually done in an in-patient setting. 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. 24 hour palliative medicine advice will be available. Patients starting ketamine are usually taking a regular opioid. Ketamine may restore the patient’s opioid sensitivity and lead to opioid toxicity. Monitor closely for signs of opioid toxicity (e.g. 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. Haloperidol can be helpful. Preventing ketamine dysphoria – consider oral haloperidol 500 micrograms to 1mg daily when starting ketamine. It can be stopped when the patient’s ketamine dose is stable.

Dose and Administration 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 to 10mg QDS. Increase dose in 5 to 10mg increments. Usual dose range: 10mg to 60mg QDS, can go up to 100mg QDS. Subcutaneous ketamine infusion: Starting dose: 50 to 150mg/24 hours. Review daily; increase dose in 50 to 100mg increments. Usual dose range: 50mg to 600mg/24 hours (higher doses are occasionally used in specialist units).

Converting from SC to oral ketamine Oral ketamine is more potent than SC ketamine (due to liver metabolism). Many patients require a dose reduction when changing to oral ketamine. Prescribe the oral ketamine in divided doses - four times daily. Titrate dose in 5 to 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.

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 for the first 24 hours. All patients should be medically 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.

Patient monitoring 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. If respiratory rate falls to <10/min seek medical advice. 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.

Case study Tom is commenced on oral ketamine 10mg QDS and this is titrated over the next few days to 20mg QDS. Tom’s pain improves markedly! However... Tom starts to become drowsy, myoclonic and tells you there are spiders crawling over his bed.. What should you do?

Any questions?