• Ketamine oral solution for complex pain should only be commenced, prescribed, titrated, and discontinued by the clinicians specifically trained in its use such as the Acute Pain Consultants, Consultant Anaesthetists, Intensivist or a Nurse Consultant in Pain management.

• This guideline does not cover the administration of ketamine as an anaesthetic agent or for the relief of procedural pain in areas such as Accident and Emergency. It does not cover the use of ketamine in palliative care or in chronic pain.

• Please note there is a separate guideline for intravenous ketamine infusion for acute pain in adult patients in high dependency areas. Automatic transition from intravenous (IV) ketamine infusion to oral administration is not recommended unless there is a specific clinical indication to continue treatment.

This is a controlled document. If you are using a printed copy, check it against the guidelines site to ensure you are using the latest edition. Print copies must be destroyed after use.

Abbreviations

1.1 The purpose of this document is to provide guidance on administering oral ketamine solution to adult inpatients with uncontrolled complex pain. Ketamine must be stored in accordance with Trust’s medicines management policy on controlled drugs and requires a two-person signature on the MAR.

1.2 All ketamine prescriptions for pain will be off-label or unlicensed and to have formulary approved for pain management. Use of Ketamine for analgesia is restricted and must, therefore, be agreed by the Acute Pain Consultant or a Consultant Anaesthetist/Intensivist or the Nurse Consultant in Pain Management.

1.3 This guideline explains how nurses can administer ketamine oral solution in the inpatient setting. Patients with severe opioid resistant neuropathic pain that is not alleviated by conventional analgesia, such as paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), regional anaesthetic blocks/catheters and neuropathic pain medications, may be considered for oral Ketamine solution.

2.1 Complex pain refers to chronic or persistent pain that is challenging to manage due to its multifaceted nature, often involving:

• Multiple contributing factors (e.g., physical, psychological, emotional)

• Complex underlying mechanisms (e.g., neuropathic, inflammatory)

• Significant impact on daily life and functioning

• Resistance to conventional treatments such as strong opioids

Complex pain often requires a multidisciplinary approach, incorporating various healthcare professionals and treatment modalities to address the patient's unique needs. In most cases, this is caused by complex pathophysiology, resulting in a mixture of neuropathic and nociceptive pain.

• Allodynia - pain caused by a stimulus that normally would not cause pain ^(1).

• Hyperalgesia - the perception of increased pain triggered by a stimulus normally provoking ^(1).

• Opioid-induced hyperalgesia – an abnormal sensitivity to pain associated with opioid use ⁽²⁾.

3.1 Ketamine should not be used routinely for all patients. Ketamine is an anaesthetic agent, but in low doses can be effective as an analgesic without inducing anaesthesia. It is used to manage pain in complex patients and works by blocking the NMDA receptor, antagonising the effects of the excitatory neurotransmitter glutamate. ^(3,4)

3.2 Before prescribing ketamine analgesia consider:

• Adjunctive analgesics if appropriate: such as Paracetamol, Non-Steroidal Anti-inflammatory Drugs (NSAIDs), (if appropriate), Opioids, Regional anaesthetic blocks/catheter, Conventional neuropathic pain medications, [Gabapentin/ pregabalin, Anti-depressant medications (Tricyclic antidepressants, Selective Serotonin, Reuptake Inhibitor, Serotonin and Norepinephrine Reuptake Inhibitors)], TENS.

Other causes of the pain:

• Surgical cause requiring intervention (e.g. compartment syndrome)

• Anxiety and fear (consider reassurance, family/friends, anxiolytic)

• Smooth muscle spasm (consider hyoscine butyl bromide, Mebeverine)

• Full bladder/ urinary retention / blocked catheter

• Ischaemic pain (e.g. cardiac, limb)

3.3 The use of oral ketamine solution should only be considered if the following criteria are met ⁽⁵⁾.

• Patients with hyperalgesia or allodynia.

• Patients who have had poor responses to opioids.

• Patients with a history of opioid use prior to injury or surgery.

• Neuropathic pain, including phantom limb pain.

Most of the contraindications are noted in the Summary of Product Characteristics and are related to giving IV ketamine in high doses. The following contraindications should apply to the administration of oral ketamine:

4.1 Absolute:

• Allergy to ketamine.

• Acute porphyria

• Schizophrenia, even if stable or controlled with medications (can exacerbate condition) ⁽⁶⁾.

• Psychosis

• Pregnancy ⁽⁶⁾

• History of Ketamine abuse

• Patient not consenting

4.2 Relative: (benefits may outweigh risks)

• Raised intracranial pressure (increased intracranial pressure with ketamine), epilepsy, delirium

• Cardiovascular disease (ischaemic heart disease, hypertension)

• Known difficult airway (presumed higher risk of airway complications)

• Active pulmonary infection or disease, upper respiratory tract infection (greater risk of laryngospasm)

• Raised intraocular pressure

• Thyroid disorder or thyroid medication (enhanced sympathomimetic effect)

• Bipolar disorder (avoid using in manic phase)

• In high dependency areas (such as ICU, SADU, PACU, MADU) it is recommended to perform an intravenous ketamine trial before starting on oral ketamine. This will help to determine whether the patient is likely to respond to ketamine and allows pain to be treated quickly.

• The decision to prescribe ketamine for patients in ward areas should be made by the Acute Pain Consultants, Consultant Anaesthetists or Intensivist or the Nurse Consultant in Pain Management, in conjunction with the parent team.

• In the ward areas if an IV trial is difficult to achieve due to unavailability of a competent clinician, then consider an oral ketamine trial. If there is no difference in pain score and there is no analgesic effect achieved after 1-2 doses of oral ketamine, then this will indicate that the pain is not responsive to ketamine.

• The IV ketamine trial can be undertaken by a clinician who has been trained and deemed competent.

5.1 Process of giving IV ketamine trial

• Make up a syringe of IV ketamine to a concentration of 1mg/ml (total of 10mg/10ml)

• The 10mL syringe of IV ketamine should be clearly labelled.

• A syringe of 20mL of saline, which will be used for flushing the intravenous line, should also be drawn up and clearly labelled.

• Obtain consent and explain the IV ketamine trial to the patient including indication, side effects and possible expected outcomes. Document pain score before the trial of IV ketamine at rest and on functional movement.

• The clinician can give a bolus of 2.5mg of IV ketamine, no quicker than every 5 minutes to a maximum of 10mg or until pain improves significantly.

• If the patient’s pain responds to the IV ketamine trial, they may be prescribed ketamine oral solution.

• All ketamine prescriptions are to be agreed by the Acute Pain Consultant or a Consultant Anaesthetist/Intensivist or the Nurse Consultant in Pain Management.

• Ketamine oral solution can be prescribed to patients and is obtainable from the pharmacy.

• Ketamine oral solution can be given to patients in ward settings and administered by nursing staff on the wards. It is a Schedule 2 controlled drug; therefore, the Trust’s medicines management policy on controlled drugs should be followed and requires a two-person signature.

• It is preferable to allow the oral ketamine solution to absorb through the buccal mucosa, by holding the solution in the mouth for a few minutes, as opposed to swallowing immediately. In buccal route, the transmucosal drug absorption enters the general circulation without passing through the liver, thus avoiding first-pass metabolism ⁽⁷⁾

• Ketamine Oral Solution 100 mg/10 ml (10mg/ml,) special manufactured solution.

• Recommended starting dose is 25mg ketamine, 6 hourly.

• Consider starting at 10mg 6 hourly for patients who may have increased sensitivity to opioids e.g. elderly, frail or previous history of opioid sensitivity.

• If the desired effect is not achieved after minimum of 4 doses, and there are no side effects, consider increasing the dose. Ketamine can be titrated further to a maximum of 400mg per day (100mg 6 hourly). This must be discussed with the authorising consultant or by the inpatient pain team.

• It is possible for some patients to experience breakthrough pain when they receive ketamine every six hourly, as it wears off within six hours. These patient benefit from ketamine administered four hourly as a regular prescription. The dose can be titrated up to a maximum of 75 mg every 4 hourly regular if indicated (a total of 450 mg of ketamine per day).

It is unlikely that the above-mentioned doses of ketamine will affect vital signs, as its sympathomimetic effect of hypertension and tachycardia occurs with anaesthetic doses. The administration of oral ketamine solution does not require any additional monitoring of the patient’s vital signs.

• At the doses recommended by this oral ketamine protocol, the dysphoric effects of ketamine (hallucinations, abnormal dreams, confusion, light-headedness) are expected to be minimal. The prescription can be discontinued if there are any unpleasant side effects.

• The most reported adverse events of ketamine use are nausea, vomiting, vivid dreams, and hallucinations. However, in most studies, the incidence of adverse events is minimal ^{(8), (9).}

• Ketamine is recognized for its potential for abuse ⁽¹⁰⁾. Chronic abuse can lead to serious adverse effects, such as haemorrhagic cystitis ⁽¹¹⁾, cholestasis and biliary dilatation ⁽¹²⁾, ⁽¹³⁾. These symptoms typically do not manifest in patients who use ketamine in small doses for a brief period. However, these concerns must be considered when starting ketamine, as they may restrict its indications ⁽¹⁴⁾. Therefore, patients who have been administered ketamine in an acute setting must not be sent home with it. As previously stated, ketamine administration is only for a short period of time (maximum 5-7 days) for inpatient use only and must be stopped before the patient is discharged from the hospital, and an alternative treatment for neuropathic pain should be initiated if necessary.

• Managing some complex pain patients may require initiating additional medication for neuropathic pain, (e.g., gabapentin or pregabalin, duloxetine), alongside the ketamine regimen. These medications can be adjusted to therapeutic levels while the patient is concurrently on ketamine.

• Ketamine is only suitable to be used while the patient is an inpatient. Patients MUST NOT be discharged on ketamine.

• It is recommended to cease the use of strong opioids before discontinuing ketamine to avoid rebound opioid-induced hyperalgesia, which can occur if ketamine is stopped first ⁽¹⁵⁾.

• When patients are on therapeutic doses of neuropathic medications, ketamine may be discontinued before ceasing strong opioids.

• Ketamine can be discontinued suddenly, but, when possible, it is advisable to taper off to prevent the recurrence of pain ⁽¹⁶⁾