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This is the first in a series of arti-

cles that highlight some of theimportant issues for GPs to con-sider when their patients arestarted on specialist palliative-caremedicines. The articles will helpGPs understand the purpose of some of these specialist-initiatedmedicines and how to safely moni-tor and (if necessary) prescribethem.

Our recommendations arebased on evidence from the litera-ture wherever possible. Wherethere is insufficient information inthe literature, our recommenda-tions are based on the practice of one of the authors (PH).

Neuropathic pain of varioustypes is estimated to occur in at least 0.6 per cent of patients regis-tered in UK general practices. 1Therefore it is an important causeof difficult-to-treat pain that isrecognised to reduce patient-reported quality of life. 2

Ketamine is a specialist drug

used to treat central sensitisation, apain syndrome that commonly complicates neuropathic pain andother difficult pain syndromes.

This article will review the useof ketamine in the primary-care set-ting, making recommendations onmanagement.

Recent developments inthe understanding ofintractable painPain is not transmitted along hard-

wired pathways . Throughout itslength, from the pain receptor tothe cerebral cortex, numerous fac-tors can increase or decrease apains intensity. For example,inflammation can increase the sig-nal intensity from a peripheral nerve spain receptor (peripheral sensiti-sation).

Further, persistent painimpulses from peripheral nerves,eg from severe tissue or peripheral

nerve injury, can trigger changes

upstream in the central nervous sys- tem (central sensitisation). Suchpatients develop hyperexcitability in the central pain pathways of thespinal cord and brain.

The exaggerated response of these latter pathways results in painthat is more severe , more widespread ,eg extends beyond dermatomeboundaries, and opioid poorly respon- sive . The commonest cause of centralsensitisation is neuropathic pain.

Central sensitisation has impli-cations for both pain prevention and

pain treatment . Limiting the magni-tude of an initial painful event might reduce the risk and/or sever-ity of subsequent chronic pain.Some studies appear to demon-strate this in the postoperative set-ting, 4,5 but other studies areinconclusive.

Further, the recognition that changes in NMDA (N-methyl-D-aspartate, a subset of glutamate)

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Drug points

What GPs need to know about

palliative-care drugs: ketamineRachel Howard PhD, MRPharmS, DipClinPharm and Paul Howard BMedSci, MRCP

This is the first in a short

series of articles that focus

on what GPs should consider

when monitoring and pre-

scribing specialist-initiated

palliative-care drugs. This

first article summarises the

key issues for patients

receiving ketamine.

KEY POINTS ketamine is a specialist-initiated analgesic for neuropathic pain initiation by pain or palliative-care specialists reflects its limited evi-

dence base, unlicensed use in pain and potential adverse effects

its principal action is blockade of NMDA receptors that are associatedwith central sensitisation

ketamine can be administered orally or subcutaneously; the oral solu-tion is only available as an unlicensed special

prescribers need to be familiar with the management of adverseeffects, which should be monitored for; indirect opioid toxicity canalso develop

in patients without advanced life-limiting disease, discontinuation canbe considered in patients with adverse effects or struggling with tabletburden, or after six months if pain well controlled; gradual withdrawalis advised

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receptors are partly responsible forthe hyperexcitability has led to new treatment options such as ketamineand methadone (subject of thenext article in this series).

The use of ketamine inpain management

Where central sensitisation does not respond to conventional analgesia,ketamine can be used to block theNMDA receptors responsible.

Table 1 describes some of thekey pharmacological features of ketamine that make it useful for

treating pain associated with cen-tral sensitisation.

Ketamines place relative to other approaches for neuropathic pain

Ketamine is a specialist-initiatedthird-line option for a variety of dif-ficult pains. 6 For example, keta-mine would be reserved forneuropathic pain that failed torespond to an antidepressant, oneor more antiepileptics and an opi-oid. Ketamines limited placereflects its: limited evidence base (ran-domised trials are often small andsome have methodological con-

cerns) lack of licence for use in pain potentially problematic adverseeffects when first initiated (titrationrequires experience).

Other specialist-initiated third-line options include methadone,nerve blocks, iv lidocaine and lesscommonly used antiepileptics.

Can GPs prescribe keta-mine?Many palliative-care patients aremanaged at home, which requiresGPs to retain a central overseeingrole, and although ketamine isonly initiated by pain or palliative-care specialists, GPs will inevitably encounter patients prescribedketamine.

They may also take over pre-scribing ketamine where this is con-sidered to be in the patients best interests. This is supported by theGeneral Medical Councils

(GMCs) guidance on good prac-tice in prescribing medicines. 3 Tguidance relevant to prescribingketamine in general practice isshown in Table 2.

If a GP is considering takinover the prescribing of ketamine,they should: be confident that they will receiveongoing support from the specialistinitiating the drug determine whether the benefitsto the patient outweigh the risks oftaking over prescribing understand that, irrespective ofthe route used, ketamine is either

unlicensed or used off-label: oral solutions of ketamine (usu

ally 50mg per 5ml) are unlicensed Ketalar ampoules for injection

can be administered subcutaneously, but both indication androute are off-label; their contents can also be administeredorally, but this is more cumbersome for patients than a premadeoral solution be familiar with which advers

effects to monitor for and how tomanage them should they arise(see Tables 3 and 4) be clear about their responsibil-ity in the shared care of thepatient; this can be achievedthrough written shared-care agree-ments (examples are availablfrom www.palliativedrugs.com) only take over prescribing if thereis enough information for safemanagement; if a GP needs moreinformation they should contactthe referring specialist be confident that the recom-mended dose is safe doses var

widely from 10mg three times dailto 100mg four times daily or morecompare the doses stated in the dis-charge/outpatient letter and onthe bottle with the dose the patient is actually taking; if a GP is cocerned they should contact theoriginal prescriber for clarificationbefore prescribing (hospital con-

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Table 1. Pharmacology of ketamine

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 withreduced undesirable anaesthetic properties

half-life: 3h (ketamine), 12h (norketamine)

Table 2. Excerpts from the GMCs Good Practice in Prescribing Medicines relevant to prescribing ketamine in gen-eral practice; after reference 3

Prescribing unlicensed medicines (excerpts from para-

graph 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 demon-strate its safety and efficacy

take responsibility for prescribing the unlicensed medi-cine and for overseeing the patients care, includingmonitoring and any follow-up treatment (see also para-graphs 25-27 on prescribing for hospital outpatients)

record the medicine prescribed and, where you arenot following common practice, the reasons forchoosing this medicine in the patients notes

Hospital outpatient prescriptions (excerpt from para- graph 27) the decision about who should take responsibility for

continuing care or treatment after initial diagnosis orassessment should be based on the patients bestinterests rather than on the healthcare professionalsconvenience or the cost of the medicine

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sultants have been found to makeerrors in 6 per cent of their pre-scriptions 7).

Cost of prescribingketamineOral ketamine solution is availableas an unlicensed special. The cost varies widely because it is not yet included in the new unlicensedspecials tariff: prices per 100mlrange from 20 to over 100.

The specialist prescriber shouldbe able to advise on procuring themost cost-effective preparation,although community pharmacistsare not obliged to purchase fromthe recommended manufacturerand may add a handling fee.

Common problems andmonitoring issues

Although specialists initiating med-icines unfamiliar to others have aresponsibility to be available foradvice and for timely patient reviews as needed, GPs may find it helpful to be familiar with the man-agement of adverse effects of keta-mine shown in Tables 3 and 4.Monitoring for these adverseeffects is an essential part of thesafe management of ketamine.

Losing the oral route:converting to subcutan -eous ketaminePatients losing the oral route do not need to be routinely converted to

subcutaneous ketamine because itseffects sometimes persist. If painrecurs, however, ketamine can begiven by subcutaneous syringedriver under the guidance of a spe-cialist prescriber.

The author (PH) uses a 1:1 ratio when converting from oral to sub-cutaneous ketamine, eg ketamine20mg three times daily orally ket-amine 60mg per 24h via subcuta-neous syringe driver. 8

Adding ketamine to syringe drivers Observational data are availableregarding which drugs can safely be mixed with ketamine in asyringe driver and which diluentsmay be used. A summary of the

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Drug points

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

Drowsiness ketamine both potentiates opioid initially, reduce the opioid, leaving the ketamine

responsiveness and reduces underlying unaltered; if drowsiness persists, give less keta-pain (see Table 4) mine more frequently, eg 20mg tds 15mg qds

Psychotropic effects , direct psychotropic effect of ketamine give haloperidol 0.51.5mg nocte or lorazepameg derealisation, 0.5mg bd ; if psychotropic effects persist, givedepersonalisation, less ketamine more frequently, eg 20mg tdsnightmares 15mg qds

Urinary irritation , chemical (noninfective) cysti tis; usual ly consider in those with cul ture-negat ive urinaryeg dysuria, with longer-term (>months) use of higher symptoms; in those with a prognosis of weeks,haematuria doses (>500mg/day); initially settles analgesic benefit may outweigh milder symptoms;

within weeks of discontinuation, but if otherwise, ketamine discontinuation and

ketamine is cont inued it eventually urological advice are requiredprogresses to irreversible bladder fibrosisand finally obstructive uropathy

Hepatotoxicity a reversible rise in most liver enzymes is in those with a prognosis of weeks, analgesicreported 9 benefit may outweigh milder symptoms;

otherwise, if abnormal LFTs persist after ketaminediscontinuation, seek hepatological advice

Aberrant use like opioids and other analgesics, ketamine clinicians should exercise the same vigilance asis sometimes used recreationally with opioids

Hypertension or direct sympathomimetic effect of ketamine not a common clinical problem in palliation, buttachyarrhythmia consider ketamine as a cause of new cardiac

symptoms

Problem Explanation Management

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most commonly encountereddrugs is given in Table 5.

When should ketamine bestopped?Ketamine is thought to reset cen-tral sensitisation and thus not berequired indefinitely. However, inadvanced life-limiting disease, ket-amine is often given for the remain-

der of life. Thus there is littleclinical experience to guide therequired duration of use in patients

with longer prognoses.The authors (PH) practice is to

consider a trial of discontinuationin patients: with adverse effects or struggling

with tablet burden or after six months if pain is well con-trolled; restart ketamine or re-referif pain recurs.

Abrupt cessation of ketamine isoccasionally reported to cause gen-eralised pain. 6 Gradual withdrawalis advised, eg 30mg tds 20mg tds 10mg tds at two-weekly intervals,then stop.

Summary Prescribing in palliative care, as inall specialties, is gradually chang-

ing. Thus GPs are constantly required to familiarise themselves with new medicines in order tocarry out their central overseeingrole effectively.

It is hoped that this series of arti-cles, combined with good relations

with palliative-care colleagues, willhelp GPs to feel confident in man-aging such medicines. In particular,Table 3 summarises the key moni-toring issues for patients receiving

ketamine, including adverse effectsthat are not always self-evident sucas persistent culture-negative urinary symptoms.

References1. Hall GC, et al . Pain 2006;122:1562. Doth AH, et al . Pain 2010;149:3383. General Medical Council. Good pracin prescribing medicines guidance for docLondon: General Medical Council, 20084. Sen H, et al . Anesth Analg 2009;1164550.5. Brogly N, et al . Anesth Analg 20107:17205.6. Quibell R, et al . J Pain Symptom Man2011;41:6409.

7. Dornan T, et al . An in depth investition into causes of prescribing errors by fodation trainees in relation to their medieducation . EQUIP study . LondoGeneral Medical Council, 2009.8. Benitez-Rosario MA, et al . J PSymptom Manag 2010;41:1098105.9. Noppers IM, et al . Pain 2011;1521738.10. Continuous subcutaneous infusions.Ch. 20. In: Twycross R, et al , ePalliative care formulary . 4th ed. Noingham: Palliativedrugs.com, 2011.11. Palliativedrugs.com. Syringe drsurvey database 2012 . Available fro

www.palliativedrugs.com/syringe-dr ve r-database- in troduct ion .h tm(accessed 28 May 2012).

Conflicts of interestRachel Howard: none to declareDr Howard is editor of the PalliatCare Formulary and member oRoyal Berkshire Hospital Drugand Therapeutics Committee,Berkshire West General PracticeMedicines Management GroupBerkshire Primary Care TrusEffective Prescribing Committeeand Berk shire West Palliative CarService Medicines ManagemenTeam.

Rachel Howard is lecturer in phar- macy practice, School of Pharmacy,University of Reading, and Dr Howard is consultant in palliative medicine, Berkshire West

Table 4. Indirect opioid toxicity can occur when a more effective nonopioid analgesicis added to an existing opioid regimen

A previously well-tolerated opioid can produce new adverse effects, egdrowsiness or delirium, if a second analgesic, such as ketamine orgabapentin, is added. This occurs if the second analgesic works and thus

reduces the patients opioid requirement. It can be difficult to distinguish fromadverse 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 responsiveOther explanations for new problems with a previously tolerated opioidinclude: reduced underlying pain, eg radiotherapy to a bone metastasis accumulation, eg renal impairment medication error or poor adherence, eg unintended change in brand, confu-

sion with tablets

Table 5. Ketamine and syringe driver combinations

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 midazolamusing water or sodium chloride 0.9% as diluents

a as with many commonly used syringe driver combinations, these combinationsare based predominantly on observational data, ie a lack of visible precipitation orskin reactions, either used by the author (PH) or reported; 10,11 however, precipita-tion can occur without visible evidence; seek advice from a palliative-care special-ist if symptoms recur unexpectedly