Key points from the evidence

Key points from the evidence

The content of this evidence summary was up-to-date in February 2014. See summaries of product characteristics (SPCs), British national formulary (BNF), BNF for children (BNFc) or the MHRA or NICE websites for up-to-date information.

Summary

Two small, short-term, randomised, placebo-controlled trials and 1 small case series of n-of-1 trials provide no good quality evidence for the use of oral ketamine to treat chronic pain in adults. Only 1 phase I pilot study in young people was identified but this was too small and short-term to draw any firm conclusions about the efficacy and safety of oral ketamine for treating chronic pain in young people. In the studies that reported safety, oral ketamine was frequently associated with adverse effects that often resulted in treatment discontinuation.

Regulatory status: unlicensed if oral liquid preparations (as prepared by 'specials' manufacturers) are used, or off-label if the solution for injection or infusion is used orally (different indication and route to the licence). Ketamine is controlled as a class B drug under the Misuse of Drugs Act 1971, and as a schedule 4, part 1 drug under the Misuse of Drugs Regulations 2001, but its scheduling is currently subject to review (see regulatory status of oral ketamine).

The topic was prioritised because of the high volume of requests from the NHS for information on this topic and the potential for variation in practice.

Effectiveness

  • Two small, short-term, randomised, placebo-controlled trials and 1 small case series of n-of-1 trials provide insufficient evidence for using oral ketamine for treating chronic pain in adults.

  • Only 1 small, short-term phase I pilot study was identified that assessed the efficacy and safety of oral ketamine for treating chronic pain in young people. It found that oral ketamine improved pain scores without causing dose-limiting adverse effects in 5 out of 12 people taking between 0.25 and 1 mg/kg per dose. The small number of participants and short treatment duration (2 weeks) limit the conclusions that can be drawn.

Safety

  • Adverse effects were frequently reported with oral ketamine in the randomised controlled trials, and case series in adults.

  • In the pilot phase I study in young people, 2 participants out of 12 experienced a dose-limiting toxicity with oral ketamine at 1.5 mg/kg per dose.

  • Common adverse effects listed in the summary of product characteristics for ketamine hydrochloride injection (Ketalar, licensed as an anaesthetic agent for diagnostic and surgical procedures in children, young people and adults) include hallucination, abnormal dreams or nightmares, confusion, agitation, abnormal behaviour, nystagmus, hypertonia, tonic clonic movements, diplopia, increased blood pressure, heart rate or respiratory rate, nausea, vomiting, erythema and morbilliform rash.

  • Cases of cystitis, including haemorrhagic cystitis, have been reported in people being given ketamine on a long-term basis; therefore the summary of product characteristics states that 'ketamine is not indicated nor recommended for long term use'.

Patient factors

  • Withdrawal rates because of adverse effects are high. In the case series of n-of-1 trials, almost half of all participants withdrew from the study with oral ketamine because of adverse effects.

  • Ketamine is known as being a drug of abuse, with reports suggesting that it produces a variety of symptoms, including flashbacks, hallucinations, dysphoria, anxiety, insomnia and disorientation. If used on a daily basis for a few weeks, dependence and tolerance may develop, particularly in people with a history of drug abuse and dependence.

Resource implications

Ketamine hydrochloride solution for injection or infusion (Ketalar, Pfizer) costs:

  • 10 mg/ml, 1×20 ml vial=£5.06

  • 50 mg/ml, 1×10 ml vial=£8.77

  • 100 mg/ml, 1×10 ml vial=£16.10

The cost of ketamine oral liquid preparations varies depending on the strength, quantity and supplier. Standard costs are listed in Part VIIIB of the drug tariff for the 2 following formulations:

  • Ketamine 50 mg/5 ml oral solution: £215.90 for minimum volume of 200 ml plus £0.01 for each extra ml.

  • Ketamine 50 mg/5 ml oral suspension: £132.25 for minimum volume of 200 ml plus £0.01 for each extra ml.

Key points

Ketamine (in any preparation) is not currently licensed in the UK for treating chronic pain in children, young people or adults.

Ketamine hydrochloride solution for injection or infusion (Ketalar, Pfizer) is licensed in the UK as an anaesthetic agent for diagnostic and surgical procedures in children, young people and adults.

Oral liquid preparations of ketamine are not licensed in the UK, so use of these preparations, which are prepared by 'specials' manufacturers, is unlicensed. When ketamine solution for injection or infusion is used orally, this is off-label use.

Two small (n=26 and n=8), placebo-controlled randomised controlled trials (RCTs), and 1 small case series of n-of-1 trials (n=9) do not provide sufficient or reliable evidence of the short-term or long-term efficacy or safety of oral ketamine in adults with chronic pain. These studies were short-term (ranging from 3 days to 6 weeks), so the longer-term efficacy and safety of oral ketamine for treating chronic pain in adults cannot be determined.

No RCTs were identified that assessed oral ketamine for treating chronic pain in children or young people. One small phase I pilot study in young people found that 5 out of 12 people had reduced pain without dose-limiting adverse effects while receiving oral ketamine (0.25 to 1.0 mg/kg per dose).

Oral ketamine was frequently associated with adverse effects in a long-running case series. In the case series of n-of-1 trials assessing the short-term use of oral ketamine, 12 out of 21 participants discontinued treatment with oral ketamine during an initial 1-week open-label run-in because of no benefit and / or intolerable adverse effects.

In 2012 the Advisory Council on the Misuse of Drugs reviewed the misuse and harms of ketamine and in December 2013 it recommended that ketamine be upgraded to a class B and, subject to the outcome of a public consultation, a Schedule 2 drug, following increased evidence of bladder damage from frequent misuse (see regulatory status of oral ketamine).

On 10 June 2014, the Parliamentary Order reclassifying ketamine as a class B drug came into force. Ketamine is not being rescheduled immediately. In line with the Advisory Council on the Misuse of Drugs' (ACMD) advice, the Home Office will carry out a public consultation later this year to assess the impact of rescheduling ketamine to Schedule 2. A final decision on the appropriate schedule for ketamine will be made after the consultation. Until then ketamine will remain a Schedule 4 Part 1 drug (see the Medicines and Healthcare Products Regulatory Agency Medicines regulatory news on the control of lisdexamphetamine, tramadol, zaleplon, zopiclone and reclassification of ketamine for more information).

About this evidence summary

'Evidence summaries: unlicensed or off-label medicines' summarise the published evidence for selected unlicensed or off-label medicines that are considered to be of significance to the NHS, where there are no clinically appropriate licensed alternatives. The summaries provide information for clinicians and patients to inform their decision-making and support the construction and updating of local formularies.

The summaries support decision-making on the use of an unlicensed or off-label medicine for an individual patient, where there are good clinical reasons for its use, usually when there is no licensed medicine for the condition requiring treatment, or the licensed medicine is not appropriate for that individual.

The strengths and weaknesses of the relevant evidence are critically reviewed within this summary, but this summary is not NICE guidance.