Drug points

What GPs need to know about palliative-care drugs: ketamine

Rachel Howard PhD, MRPharmS, DipClinPharm and Paul Howard BMedSci, MRCP

KEY POINTS
initiation by pain or palliative-care specialists reflects its limited eviketamine is a specialist-initiated analgesic for neuropathic pain dence base, unlicensed use in pain and potential adverse effects with central sensitisation

This is the first in a short series of articles that focus on what GPs should consider when monitoring and prescribing specialist-initiated palliative-care drugs. This first article summarises the key issues for patients receiving ketamine.

its principal action is blockade of NMDA receptors that are associated ketamine can be administered orally or subcutaneously; the oral solution is only available as an unlicensed special prescribers need to be familiar with the management of adverse
effects, which should be monitored for; indirect opioid toxicity can also develop be considered in patients with adverse effects or struggling with tablet burden, or after six months if pain well controlled; gradual withdrawal is advised

in patients without advanced life-limiting disease, discontinuation can

his is the first in a series of articles that highlight some of the important issues for GPs to consider when their patients are started on specialist palliative-care medicines. The articles will help GPs understand the purpose of some of these specialist-initiated medicines and how to safely monitor and (if necessar y) prescribe them. Our recommendations are based on evidence from the literature wherever possible. Where there is insufficient information in the literature, our recommendations are based on the practice of one of the authors (PH). Neuropathic pain of various types is estimated to occur in at least 0.6 per cent of patients registered in UK general practices. 1 Therefore it is an important cause of difficult-to-treat pain that is recognised to reduce patientreported quality of life.2
www.prescriber.co.uk

Ketamine is a specialist drug used to treat central sensitisation, a pain syndrome that commonly complicates neuropathic pain and other difficult pain syndromes. This article will review the use of ketamine in the primary-care setting, making recommendations on management.
Recent developments in the understanding of intractable pain

Pain is not transmitted along hardwired pathways. Throughout its length, from the pain receptor to the cerebral cortex, numerous factors can increase or decrease a pains intensity. For example, inflammation can increase the signal intensity from a peripheral nerves pain receptor (peripheral sensitisation). Further, persistent pain impulses from peripheral nerves, eg from severe tissue or peripheral

nerve injury, can trigger changes upstream in the central nervous system (central sensitisation). Such patients develop hyperexcitability in the central pain pathways of the spinal cord and brain. The exaggerated response of these latter pathways results in pain that is more severe, more widespread, eg extends beyond dermatome boundaries, and opioid poorly responsive. The commonest cause of central sensitisation is neuropathic pain. Central sensitisation has implications for both pain prevention and pain treatment. Limiting the magnitude of an initial painful event might reduce the risk and/or severity of subsequent chronic pain. Some studies appear to demonstrate this in the postoperative setting, 4,5 but other studies are inconclusive. Further, the recognition that changes in NMDA (N-methyl-Daspartate, a subset of glutamate)
Prescriber 19 June 2012 43

Drug points

predominant action: NMDA (glutamate) receptor blockade other actions of uncertain significance: monoamine reuptake inhibition; sodium and calcium channel blockade; opioid agonist; altered cholinergic and dopamine transmission oral route may be advantageous: extensive first-pass hepatic metabolism to the active metabolite, norketamine, retains the analgesic benefit but with reduced undesirable anaesthetic properties half-life: 3h (ketamine), 12h (norketamine)
Table 1. Pharmacology of ketamine

receptors are partly responsible for the hyperexcitability has led to new treatment options such as ketamine and methadone (subject of the next article in this series).
The use of ketamine in pain management

treating pain associated with central sensitisation. Ketamines place relative to other approaches for neuropathic pain Ketamine is a specialist-initiated third-line option for a variety of difficult pains. 6 For example, ketamine would be reser ved for neuropathic pain that failed to respond to an antidepressant, one or more antiepileptics and an opioid. Ketamines limited place reflects its: limited evidence base (randomised trials are often small and some have methodological concerns) lack of licence for use in pain potentially problematic adverse effects when first initiated (titration requires experience). Other specialist-initiated thirdline options include methadone, nerve blocks, iv lidocaine and less commonly used antiepileptics.
Can GPs prescribe ketamine?

Where central sensitisation does not respond to conventional analgesia, ketamine can be used to block the NMDA receptors responsible. Table 1 describes some of the key pharmacological features of ketamine that make it useful for
Prescribing unlicensed medicines (excerpts from paragraph 18) be satisfied that an alternative, licensed medicine would not meet the patients needs be satisfied that there is a sufficient evidence base and/or experience of using the medicine to demonstrate its safety and efficacy take responsibility for prescribing the unlicensed medicine and for overseeing the patients care, including monitoring and any follow-up treatment (see also paragraphs 25-27 on prescribing for hospital outpatients) record the medicine prescribed and, where you are not following common practice, the reasons for choosing this medicine in the patients notes Hospital outpatient prescriptions (excerpt from paragraph 27) the decision about who should take responsibility for continuing care or treatment after initial diagnosis or assessment should be based on the patients best interests rather than on the healthcare professionals convenience or the cost of the medicine
Table 2. Excerpts from the GMCs Good Practice in Prescribing Medicines relevant to prescribing ketamine in general practice; after reference 3
44 Prescriber 19 June 2012

Many palliative-care patients are managed at home, which requires GPs to retain a central overseeing role, and although ketamine is only initiated by pain or palliativecare specialists, GPs will inevitably encounter patients prescribed ketamine. They may also take over prescribing ketamine where this is considered to be in the patients best interests. This is supported by the General Medical Councils

(GMCs) guidance on good practice in prescribing medicines.3 The guidance relevant to prescribing ketamine in general practice is shown in Table 2. If a GP is considering taking over the prescribing of ketamine, they should: be confident that they will receive ongoing support from the specialist initiating the drug determine whether the benefits to the patient outweigh the risks of taking over prescribing understand that, irrespective of the route used, ketamine is either unlicensed or used off-label: oral solutions of ketamine (usually 50mg per 5ml) are unlicensed Ketalar ampoules for injection can be administered subcutaneously, but both indication and route are off-label; their contents can also be administered orally, but this is more cumbersome for patients than a premade oral solution be familiar with which adverse effects to monitor for and how to manage them should they arise (see Tables 3 and 4) be clear about their responsibility in the shared care of the patient; this can be achieved through written shared-care agreements (examples are available from www.palliativedrugs.com) only take over prescribing if there is enough information for safe management; if a GP needs more information they should contact the referring specialist be confident that the recommended dose is safe doses vary widely from 10mg three times daily to 100mg four times daily or more; compare the doses stated in the discharge/outpatient letter and on the bottle with the dose the patient is actually taking; if a GP is concerned they should contact the original prescriber for clarification before prescribing (hospital conwww.prescriber.co.uk

Drug points

Problem Drowsiness

Explanation ketamine both potentiates opioid responsiveness and reduces underlying pain (see Table 4) direct psychotropic effect of ketamine

Management initially, reduce the opioid, leaving the ketamine unaltered; if drowsiness persists, give less ketamine more frequently, eg 20mg tds 15mg qds give haloperidol 0.51.5mg nocte or lorazepam 0.5mg bd; if psychotropic effects persist, give less ketamine more frequently, eg 20mg tds 15mg qds consider in those with culture-negative urinary symptoms; in those with a prognosis of weeks, analgesic benefit may outweigh milder symptoms; otherwise, ketamine discontinuation and urological advice are required

Psychotropic effects, eg derealisation, depersonalisation, nightmares Urinary irritation, eg dysuria, haematuria

chemical (noninfective) cystitis; usually with longer-term (>months) use of higher doses (>500mg/day); initially settles within weeks of discontinuation, but if ketamine is continued it eventually progresses to irreversible bladder fibrosis and finally obstructive uropathy a reversible rise in most liver enzymes is reported9

Hepatotoxicity

in those with a prognosis of weeks, analgesic benefit may outweigh milder symptoms; otherwise, if abnormal LFTs persist after ketamine discontinuation, seek hepatological advice clinicians should exercise the same vigilance as with opioids not a common clinical problem in palliation, but consider ketamine as a cause of new cardiac symptoms

Aberrant use

like opioids and other analgesics, ketamine is sometimes used recreationally direct sympathomimetic effect of ketamine

Hypertension or tachyarrhythmia

Table 3. Adverse effects of ketamine that should be monitored for and their management

sultants have been found to make errors in 6 per cent of their prescriptions7).
Cost of prescribing ketamine

Common problems and monitoring issues

Oral ketamine solution is available as an unlicensed special. The cost varies widely because it is not yet included in the new unlicensed specials tariff: prices per 100ml range from 20 to over 100. The specialist prescriber should be able to advise on procuring the most cost-effective preparation, although community pharmacists are not obliged to purchase from the recommended manufacturer and may add a handling fee.
www.prescriber.co.uk

Although specialists initiating medicines unfamiliar to others have a responsibility to be available for advice and for timely patient reviews as needed, GPs may find it helpful to be familiar with the management of adverse effects of ketamine shown in Tables 3 and 4. Monitoring for these adverse effects is an essential part of the safe management of ketamine.
Losing the oral route: converting to subcutaneous ketamine

subcutaneous ketamine because its effects sometimes persist. If pain recurs, however, ketamine can be given by subcutaneous syringe driver under the guidance of a specialist prescriber. The author (PH) uses a 1:1 ratio when converting from oral to subcutaneous ketamine, eg ketamine 20mg three times daily orally ketamine 60mg per 24h via subcutaneous syringe driver.8 Adding ketamine to syringe drivers Obser vational data are available regarding which drugs can safely be mixed with ketamine in a syringe driver and which diluents may be used. A summar y of the
Prescriber 19 June 2012 45

Patients losing the oral route do not need to be routinely converted to

Drug points

A previously well-tolerated opioid can produce new adverse effects, eg drowsiness or delirium, if a second analgesic, such as ketamine or gabapentin, is added. This occurs if the second analgesic works and thus reduces the patients opioid requirement. It can be difficult to distinguish from adverse effects directly attributable to the new drug. In such circumstances, consider reducing the opioid rather than the newer drug if: the adverse effects coincide with improved pain control and the pain is suspected to be incompletely opioid responsive Other explanations for new problems with a previously tolerated opioid include: reduced underlying pain, eg radiotherapy to a bone metastasis accumulation, eg renal impairment medication error or poor adherence, eg unintended change in brand, confusion with tablets
Table 4. Indirect opioid toxicity can occur when a more effective nonopioid analgesic is added to an existing opioid regimen

ketamine, including adverse effects that are not always self-evident such as persistent culture-negative urinary symptoms.
References

most commonly encountered drugs is given in Table 5.

When should ketamine be stopped?

Ketamine is thought to reset central sensitisation and thus not be required indefinitely. However, in advanced life-limiting disease, ketamine is often given for the remainder of life. Thus there is little clinical experience to guide the required duration of use in patients with longer prognoses. The authors (PH) practice is to consider a trial of discontinuation in patients: with adverse effects or struggling with tablet burden or after six months if pain is well controlled; restart ketamine or re-refer if pain recurs.

Abrupt cessation of ketamine is occasionally reported to cause generalised pain.6 Gradual withdrawal is advised, eg 30mg tds 20mg tds 10mg tds at two-weekly intervals, then stop.
Summary

Prescribing in palliative care, as in all specialties, is gradually changing. Thus GPs are constantly required to familiarise themselves with new medicines in order to carry out their central overseeing role effectively. It is hoped that this series of articles, combined with good relations with palliative-care colleagues, will help GPs to feel confident in managing such medicines. In particular, Table 3 summarises the key monitoring issues for patients receiving

1. Hall GC, et al. Pain 2006;122:15662. 2. Doth AH, et al. Pain 2010;149:33844. 3. General Medical Council. Good practice in prescribing medicines guidance for doctors. London: General Medical Council, 2008. 4. Sen H, et al. Anesth Analg 2009;109: 164550. 5. Brogly N, et al . Anesth Analg 2008; 107:17205. 6. Quibell R, et al. J Pain Symptom Manag 2011;41:6409. 7. Dornan T, et al. An in depth investigation into causes of prescribing errors by foundation trainees in relation to their medical education . EQUIP study . London: General Medical Council, 2009. 8. Benitez-Rosario MA, et al . J Pain Symptom Manag 2010;41:1098105. 9. Noppers IM, et al . Pain 2011;152: 21738. 10. Continuous subcutaneous infusions. Ch. 20. In: Twycross R, et al , eds. Palliative care formulary. 4th ed. Nottingham: Palliativedrugs.com, 2011. 11. Palliativedrugs.com. Syringe driver survey database 2012 . Available from: www.palliativedrugs.com/syringe-driv e r- d a t a b a s e - i n t r o d u c t i o n . h t m l (accessed 28 May 2012).

Conflicts of interest

Ketamine can be combined with the following drugs in a syringe driver:a one of: oxycodone, diamorphine or morphine sulphate and one of: haloperidol or midazolam using water or sodium chloride 0.9% as diluents
with many commonly used syringe driver combinations, these combinations are based predominantly on observational data, ie a lack of visible precipitation or skin reactions, either used by the author (PH) or reported;10,11 however, precipitation can occur without visible evidence; seek advice from a palliative-care specialist if symptoms recur unexpectedly Table 5. Ketamine and syringe driver combinations
46 Prescriber 19 June 2012
aas

Rachel Howard: none to declare; Dr Howard is editor of the Palliative Care Formular y and member of: Royal Berkshire Hospital Drugs and Therapeutics Committee, Berkshire West General Practice Medicines Management Group, Berkshire Primar y Care Trust Effective Prescribing Committee, and Berkshire West Palliative Care Ser vice Medicines Management Team. Rachel Howard is lecturer in pharmacy practice, School of Pharmacy, University of Reading, and Dr Howard is consultant in palliative medicine, Berkshire West
www.prescriber.co.uk