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Ketamine*

Open AccessPublished:June 18, 2015DOI:https://doi.org/10.1016/j.jpainsymman.2015.06.002
      Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. The content is also available on www.palliativedrugs.com and will feature in future editions of the Hospice and Palliative Care Formulary USA and its British and Canadian counterparts. The series editors welcome feedback on the articles ( [email protected] ).

      Abbreviations/Key

      Specialist use only
      Off-label indication
      AMPA
      α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
      ATP
      Adenosine triphosphate
      b.i.d.
      Bis in die, twice daily
      CIVI
      Continuous intravenous infusion
      CSCI
      Continuous subcutaneous infusion
      CSF
      Cerebrospinal fluid
      CT
      Computerized tomography
      CVA
      Cerebrovascular accident
      CYP
      Cytochrome P450
      ED
      Epidural
      HCN
      Hyperpolarization-activated cyclic nucleotide-gated
      LFTs
      Liver function tests
      MRI
      Magnetic resonance imaging
      NMDA
      N-methyl-D-aspartate
      IM
      Intramuscular
      IV
      Intravenous
      PO
      Per os, by mouth
      PR
      Per rectum
      p.r.n.
      Pro re nata, as required
      q.i.d.
      Quarta in die, four times daily
      RCT
      Randomized controlled trial
      SC
      Subcutaneous
      SL
      Sublingual
      t.i.d.
      Ter in die, three times daily
      WFI
      Water for injection
      The use of ketamine is associated with neuropsychiatric, urinary tract and hepatobiliary toxicity. Although most reports involve long-term recreational abusers, it has also arisen after only 1–2 weeks of therapeutic use (Box A). Accordingly, the use of ketamine should be restricted to specialists in pain or palliative care for patients who have failed to obtain relief from standard drug and non-drug treatments.
      Ketamine and neuropsychiatric, urinary and hepatobiliary toxicity
      Neuropsychiatric
      There are no studies of neuropsychiatric effects in patients receiving therapeutic ketamine long-term. Most participants in the studies below also abused multiple other drugs.
      Long-term ketamine abusers have a dose-related increase in subclinical psychotic symptoms, e.g. delusions, dissociation and schizotypy. The relevance is uncertain; no definite link exists between ketamine abuse and psychosis.
      • Morgan C.J.
      • Curran H.V.
      Ketamine use: a review.
      In frequent abusers of ketamine (≥5 days/week), both short- and long-term memory are affected with dose-related impairments in visual recognition memory (tested by remembering patterns) and spatial working memory (tested by remembering which boxes contained hidden tokens).
      • Morgan C.J.
      • Curran H.V.
      Ketamine use: a review.
      • Morgan C.J.
      • Muetzelfeldt L.
      • Curran H.V.
      Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: a 1-year longitudinal study.
      MRI changes were evident with total estimated lifetime doses of ≤3g.
      • Liao Y.
      • Tang J.
      • Fornito A.
      • et al.
      Alterations in regional homogeneity of resting-state brain activity in ketamine addicts.
      • Liao Y.
      • Tang J.
      • Ma M.
      • et al.
      Frontal white matter abnormalities following chronic ketamine use: a diffusion tensor imaging study.
      Functional MRI show dose-related alterations in the anterior cingulate cortex (decrease) and in the left precentral frontal gyrus (increase).
      • Liao Y.
      • Tang J.
      • Fornito A.
      • et al.
      Alterations in regional homogeneity of resting-state brain activity in ketamine addicts.
      These effects may be the consequence of long-term NMDA-receptor-channel blockade. Dopamine depletion in the prefrontal cortex, a key area involved in working memory, is also reported in those abusing ≥200mg/week.
      • Narendran R.
      • Frankle W.G.
      • Keefe R.
      • et al.
      Altered prefrontal dopaminergic function in chronic recreational ketamine users.
      Ketamine is also directly neurotoxic, with dose-related MRI changes suggestive of disruption or damage to the white matter in the frontal and left temporoparietal regions.
      • Liao Y.
      • Tang J.
      • Ma M.
      • et al.
      Frontal white matter abnormalities following chronic ketamine use: a diffusion tensor imaging study.
      Memory impairments appear to improve with abstinence, but former abusers continue to score higher than controls on delusional symptoms.
      • Morgan C.J.
      • Curran H.V.
      Ketamine use: a review.
      Urinary tract
      In three patients with chronic pain, urinary symptoms developed after receiving ketamine PO 650–800mg/24h for 5–18 months.
      • Storr T.M.
      • Quibell R.
      Can ketamine prescribed for pain cause damage to the urinary tract?.
      In another patient, severe damage necessitated cystectomy after three years of ketamine PO 240mg/24h for chronic back pain.
      • Shahzad K.
      • Svec A.
      • Al-koussayer O.
      • et al.
      Analgesic ketamine use leading to cystectomy: a case report.
      However, urinary symptoms developed after only 9 days in a 16 year-old receiving ketamine PO 8mg/kg/24h.
      • Grégoire M.C.
      • MacLellan D.L.
      • Finley G.A.
      A pediatric case of ketamine-associated cystitis (Letter-to-the-Editor Re: Shahani R, Streutker C, Dickson B, et al.: ketamine-associated ulcerative cystitis: a new clinical entity. Urology 2007;69: 810–812).
      Urinary symptoms have been reported in abusers of ‘street’ ketamine, generally taken as powdered ketamine via nasal insufflation. The risk appears related to both dose and frequency of use.
      • Winstock A.R.
      • Mitcheson L.
      • Gillatt D.A.
      • Cottrell A.M.
      The prevalence and natural history of urinary symptoms among recreational ketamine users.
      Symptoms include frequency, urgency, urge incontinence, dysuria, hematuria and lower abdominal pain.
      • Winstock A.R.
      • Mitcheson L.
      • Gillatt D.A.
      • Cottrell A.M.
      The prevalence and natural history of urinary symptoms among recreational ketamine users.
      • Chu P.S.
      • Ma W.K.
      • Wong S.C.
      • et al.
      The destruction of the lower urinary tract by ketamine abuse: a new syndrome?.
      • Shahani R.
      • Streutker C.
      • Dickson B.
      • Stewart R.J.
      Ketamine-associated ulcerative cystitis: a new clinical entity.
      The exact mechanism of the damage is unclear, but ketamine has a direct irritant effect on the upper and lower urinary tract.
      • Wood D.
      • Cottrell A.
      • Baker S.C.
      • et al.
      Recreational ketamine: from pleasure to pain.
      Investigations (e.g. cystoscopy and biopsy, CT urogram) may show interstitial cystitis, detrusor overactivity, decreased bladder capacity, vesico-ureteric reflux, hydronephrosis, papillary necrosis, and renal impairment. Irreversible damage leading to renal failure has occurred.
      Animal studies have found an increased expression of P2X1 purinergic receptors (activated by ATP) but not muscarinic receptors on bladder smooth muscle, which may explain the reports of limited benefit from antimuscarinic antispasmodics.
      • Meng E.
      • Chang H.Y.
      • Chang S.Y.
      • et al.
      Involvement of purinergic neurotransmission in ketamine induced bladder dysfunction.
      Consequently, when patients receiving therapeutic ketamine experience urinary symptoms without evidence of bacterial infection, practitioners should consider stopping the ketamine and seeking the advice of a urologist.
      Symptoms generally settle several weeks after stopping ketamine. However, in some abusers, symptoms have persisted despite abstinence.
      • Winstock A.R.
      • Mitcheson L.
      • Gillatt D.A.
      • Cottrell A.M.
      The prevalence and natural history of urinary symptoms among recreational ketamine users.
      • Cheung R.Y.
      • Chan S.S.
      • Lee J.H.
      • et al.
      Urinary symptoms and impaired quality of life in female ketamine users: persistence after cessation of use.
      Hepatobiliary
      Abnormal LFTs have been associated with both ketamine abuse and therapeutic use, e.g. IV for maintenance anesthesia (>10h) or infusions for pain relief (≥4 days).
      • Ng S.H.
      • Tse M.L.
      • Ng H.W.
      • Lau F.L.
      Emergency department presentation of ketamine abusers in Hong Kong: a review of 233 cases.
      • Wong S.W.
      • Lee K.F.
      • Wong J.
      • et al.
      Dilated common bile ducts mimicking choledochal cysts in ketamine abusers.
      • Dundee J.W.
      • Fee J.P.
      • Moore J.
      • McIlroy P.D.
      • Wilson D.B.
      Changes in serum enzyme levels following ketamine infusions.
      • Noppers I.M.
      • Niesters M.
      • Aarts L.P.
      • et al.
      Drug-induced liver injury following a repeated course of ketamine treatment for chronic pain in CRPS type 1 patients: a report of 3 cases.
      In the latter, although abnormal LFTs were sometimes apparent after 4–5 days, in others it occurred only with a second infusion some 2 weeks later.
      • Noppers I.M.
      • Niesters M.
      • Aarts L.P.
      • et al.
      Drug-induced liver injury following a repeated course of ketamine treatment for chronic pain in CRPS type 1 patients: a report of 3 cases.
      In abusers, abdominal pain has been reported and, in some, dilation or strictures of the common bile duct.
      • Wong S.W.
      • Lee K.F.
      • Wong J.
      • et al.
      Dilated common bile ducts mimicking choledochal cysts in ketamine abusers.
      • Ng S.H.
      • Lee H.K.
      • Chan Y.C.
      • Lau F.L.
      Dilated common bile ducts in ketamine abusers.
      • Seto W.K.
      • Ng M.
      • Chan P.
      • et al.
      Ketamine-induced cholangiopathy: a case report.
      The cause is unknown, but possibilities include a direct toxic effect of ketamine or a metabolite, or ketamine-related dysfunction of the sphincter of Oddi.
      • Ng S.H.
      • Tse M.L.
      • Ng H.W.
      • Lau F.L.
      Emergency department presentation of ketamine abusers in Hong Kong: a review of 233 cases.
      • Lee S.T.
      • Wu T.T.
      • Yu P.Y.
      • Chen R.M.
      Apoptotic insults to human HepG2 cells induced by S-(+)-ketamine occurs through activation of a Bax-mitochondria-caspase protease pathway.
      With abstinence, the LFTs, abdominal pain and biliary duct dilation generally improve. Some recommend regular monitoring of LFTs during the long-term therapeutic use of ketamine.
      • Noppers I.M.
      • Niesters M.
      • Aarts L.P.
      • et al.
      Drug-induced liver injury following a repeated course of ketamine treatment for chronic pain in CRPS type 1 patients: a report of 3 cases.
      Class: General anesthetic.
      Indications: Induction and maintenance of anesthesia; †neuropathic, inflammatory, ischemic limb and procedure-related pain unresponsive to standard treatments.
      • Persson J.
      • Hasselström J.
      • Wiklund B.
      • et al.
      The analgesic effect of racemic ketamine in patients with chronic ischemic pain due to lower extremity arteriosclerosis obliterans.
      • Persson J.
      Ketamine in pain management.
      Contra-indications: Any situation in which an increase in blood pressure would constitute a hazard.

      Pharmacology

      Ketamine, a derivative of phencyclidine (PCP), is a dissociative anesthetic which has analgesic properties in sub-anaesthetic doses.
      • Persson J.
      Ketamine in pain management.
      • Mion G.
      • Villevieille T.
      Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings).
      Ketamine is the most potent NMDA-receptor-channel blocker available for clinical use, binding to the PCP site when the channels are in the open activated state (Fig. 1).
      • Mion G.
      • Villevieille T.
      Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings).
      It also binds to a second membrane-associated site which decreases the frequency of channel opening.
      • Mion G.
      • Villevieille T.
      Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings).
      Figure thumbnail gr1
      Fig. 1Diagram of the NMDA (excitatory) receptor-channel complex. The channel is blocked by magnesium (Mg2+) when the membrane potential is at its resting level (voltage-dependent block) and by drugs which act at the phencyclidine (PCP) binding site in the glutamate-activated channel, e.g. dextromethorphan, ketamine, methadone (use-dependent block).
      • Richens A.
      The basis of the treatment of epilepsy.
      The NMDA receptor-channel complex is closely involved in the development of central sensitization of dorsal horn neurons which transmit pain signals.
      • Richens A.
      The basis of the treatment of epilepsy.
      At normal resting membrane potentials, the channel is blocked by magnesium and is inactive.
      • Mion G.
      • Villevieille T.
      Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings).
      When the resting membrane potential is changed as a result of prolonged excitation, the channel unblocks and calcium moves into the cell. This leads to neuronal hyperexcitability and results in hyperalgesia and allodynia, and a reduction in opioid-responsiveness. These effects are probably mediated by the intracellular formation of nitric oxide and cyclic guanosine monophosphate.
      • Mion G.
      • Villevieille T.
      Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings).
      The reduction in opioid-responsiveness arises from cross-talk between opioid receptors and the NMDA receptor-channel. Opioid receptor activation results in phosphorylation and opening of the NMDA receptor-channel leading to a cascade of events which ultimately down-regulates the opioid receptor and its effects, thereby contributing towards tolerance and hyperalgesia.
      • Mion G.
      • Villevieille T.
      Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings).
      In addition to blocking the NMDA receptor-channel, ketamine has other actions, some of which may contribute to its analgesic effect.
      • Persson J.
      Ketamine in pain management.
      These include opioid-like and anti-inflammatory effects,
      • De Kock M Loix S.
      Lavand'homme P.Ketamine and peripheral inflammation.
      and interactions with, e.g.:
      • other calcium, potassium and sodium channels, e.g. HCN, AMPA
      • cholinergic, dopaminergic and noradrenergic transmission
      • descending inhibitory pathways.
      Resultant changes in cellular processes, e.g. in gene expression and protein regulation, could explain ongoing benefit even after discontinuation of ketamine.
      • Sleigh J.
      • Martyn H.
      • Voss L.
      • Denny B.
      Ketamine - more mechanisms of action than just NMDA blockade.
      Ketamine is generally administered PO or SC/CSCI.
      • Luczak J.
      • Dickenson A.H.
      • Kotlinska–Lemieszek A.
      The role of ketamine, an NMDA receptor antagonist, in the management of pain.
      • Kotlinska-Lemieszek A.
      • Luczak J.
      Subanesthetic ketamine: an essential adjuvant for intractable cancer pain.
      It can also be administered IM, IV, SL, intranasally, PR and spinally (preservative-free formulation).
      • Lin T.C.
      • Wong C.S.
      • Chen F.C.
      • Lin S.Y.
      • Ho S.T.
      Long-term epidural ketamine, morphine and bupivacaine attenuate reflex sympathetic dystrophy neuralgia.
      • Haines D.
      • Gaines S.
      N of 1 randomised controlled trials of oral ketamine in patients with chronic pain.
      • Batchelor G.
      Ketamine in neuropathic pain.
      • Beltrutti D.P.
      • Trompeo A.C.
      • Di Santo S.
      The epidural and intrathecal administration of ketamine.
      • Mercadante S.
      • Arcuri E.
      • Tirelli W.
      • Casuccio A.
      Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study.
      • Carr D.B.
      • Goudas L.C.
      • Denman W.T.
      • et al.
      Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study.
      • Mercadante S.
      • Arcuri E.
      • Ferrera P.
      • Villari P.
      • Mangione S.
      Alternative treatments of breakthrough pain in patients receiving spinal analgesics for cancer pain.
      • Yeaman F.
      • Oakley E.
      • Meek R.
      • Graudins A.
      Sub-dissociative dose intranasal ketamine for limb injury pain in children in the emergency department: a pilot study.
      However, for spinal routes, concerns have been raised about the potential for neurotoxicity.
      • Vranken J.H.
      • Troost D.
      • Wegener J.T.
      • Kruis M.R.
      • van der Vegt M.H.
      Neuropathological findings after continuous intrathecal administration of S(+)-ketamine for the management of neuropathic cancer pain.
      Ketamine has been given by CIVI in adults and children in combination with opioids (fentanyl, morphine) ± midazolam to control intractable pain and agitation.
      • Berger J.M.
      • Ryan A.
      • Vadivelu N.
      • et al.
      Ketamine-fentanyl-midazolam infusion for the control of symptoms in terminal life care.
      • Enck R.
      A ketamine, fentanyl, and midazolam infusion for uncontrolled terminal pain and agitation.
      • Conway M.
      • White N.
      • Jean C.S.
      • Zempsky W.T.
      • Steven K.
      Use of continuous intravenous ketamine for end-stage cancer pain in children.
      Although in some countries both racemic ketamine and the S−enantiomer are available for clinical use, in the USA only the racemic mixture is marketed. Because of its greater affinity and selectivity for the NMDA-receptor, the S−enantiomer as a parenteral analgesic is about 4 times more potent than the R−enantiomer, and twice as potent as the racemic mixture.
      • Oye I.
      • Hustveit O.
      • Moberg E.R.
      • Pausen O.
      • Skoglund L.A.
      The chiral forms of ketamine as probes for NMDA receptor function in humans.
      • White P.F.
      • Ham J.
      • Way W.L.
      • Trevor A.J.
      Pharmacology of ketamine isomers in surgical patients.
      • Mathisen L.C.
      • Skjelbred P.
      • Skoglund L.A.
      • Oye I.
      Effect of ketamine, an NMDA receptor inhibitor, in acute and chronic orofacial pain.
      When equi-analgesic doses are compared, the S−enantiomer is also associated with lower levels of undesirable effects, e.g. anxiety, tiredness, cognitive impairment.
      • White P.F.
      • Ham J.
      • Way W.L.
      • Trevor A.J.
      Pharmacology of ketamine isomers in surgical patients.
      • Pfenninger E.G.
      • Durieux M.E.
      • Himmelseher S.
      Cognitive impairment after small-dose ketamine isomers in comparison to equianalgesic racemic ketamine in human volunteers.
      About 90% of a parenteral dose of ketamine is excreted in the urine, mostly as conjugates of hydroxylated metabolites. Less than 5% is excreted unchanged via the faeces and urine. Ketamine undergoes hepatic metabolism mainly to norketamine. Because of extensive first-pass metabolism, a greater proportion of a PO dose of ketamine is converted to norketamine compared to one administered by injection.
      • Clements J.A.
      • Nimmo W.S.
      • Grant I.S.
      Bioavailability, pharmacokinetics and analgesic activity of ketamine in humans.
      Norketamine has a lower affinity for the NMDA-receptor-channel than ketamine. Although norketamine (particularly S-norketamine) is analgesic in rodents, this remains to be clarified in humans.
      • Hijazi Y.
      • Boulieu R.
      Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes.
      • Holtman Jr., J.R.
      • Crooks P.A.
      • Johnson-Hardy J.K.
      • et al.
      Effects of norketamine enantiomers in rodent models of persistent pain.
      • Olofsen E.
      • Noppers I.
      • Niesters M.
      • et al.
      Estimation of the contribution of norketamine to ketamine-induced acute pain relief and neurocognitive impairment in healthy volunteers.
      Norketamine is further metabolized to the inactive dehydronorketamine.
      Ketamine causes hepatic enzyme induction and enhances its own metabolism. The implications of this for the efficacy or tolerability of therapeutic ketamine is unknown. However, in abusers, it may contribute towards the relatively rapid tolerance to the desired ‘high’, with those taking it most days of the week reporting about a 7-fold increase in dose after the first 2 months of use.
      • Muetzelfeldt L.
      • Kamboj S.K.
      • Rees H.
      • et al.
      Journey through the K-hole: phenomenological aspects of ketamine use.
      Ketamine increases sympathetic nervous system activity and causes tachycardia and intracranial hypertension. When ketamine is used for procedural anesthesia, a quarter of patients experience vivid dreams, misperceptions, hallucinations and alterations in body image and mood as emergent (psychotomimetic) phenomena, i.e. as the effects of a bolus dose wear off. The incidence is reduced to <10% by the concurrent use of midazolam.
      • Sener S.
      • Eken C.
      • Schultz C.H.
      • Serinken M.
      • Ozsarac M.
      Ketamine with and without midazolam for emergency department sedation in adults: a randomized controlled trial.
      Emergent phenomena occur to a lesser extent with the sub-anaesthetic analgesic doses given PO or CSCI, and generally can be controlled by concurrent administration of a benzodiazepine (e.g. diazepam, midazolam) or haloperidol.
      • Mercadante S.
      • Arcuri E.
      • Tirelli W.
      • Casuccio A.
      Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study.
      • Hughes A.
      • Crosby V.
      • Wilcock A.
      • Corcoran R.
      Ketamine.
      • Giannini A.J.
      • Underwood N.A.
      • Condon M.
      Acute ketamine intoxication treated by haloperidol: a preliminary study.
      Sub-anaesthetic doses of ketamine are associated with impaired attention, memory and judgement, and it is used as a pharmacological model for acute schizophrenia.
      • Mion G.
      • Villevieille T.
      Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings).
      Although it is used as an analgesic in various clinical settings (including postoperatively
      • Subramaniam K.
      • Subramaniam B.
      • Steinbrook R.A.
      Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic review.
      • Bell R.F.
      • Dahl J.B.
      • Moore R.A.
      • Kalso E.
      Perioperative ketamine for acute postoperative pain.
      ), the increasing concern about the potential for neuropsychiatric, urinary tract and hepatobiliary toxicity (Box A) will probably result in a decline in the use of ketamine for chronic non-cancer pain, and possibly cancer pain. In the palliative care setting, ketamine should generally be reserved for pain which has failed to respond to standard analgesic drugs, including opioids and adjuvants.

      Chronic non-cancer pain

      A review of sub-anaesthetic doses of ketamine for chronic non-cancer pain (mostly neuropathic but also ischemic, fibromyalgia, post-whiplash, etc.) identified 29 RCTs and concluded that:
      A systematic review of analgesics for phantom limb pain reached similar conclusions.
      • Alviar M.J.M.
      • Hale T.
      • Dungca M.
      Pharmacological interventions for treating phantom limb pain.
      There is RCT evidence of benefit in complex regional pain syndrome type 1, with relief persisting 4–6 weeks beyond the duration of the ketamine infusion.
      • Sigtermans M.J.
      • van Hilten J.J.
      • Bauer M.C.
      • et al.
      Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1.
      • Schwartzman R.J.
      • Alexander G.M.
      • Grothusen J.R.
      • et al.
      Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study.
      • Niesters M.
      • Martini C.
      • Dahan A.
      Ketamine in chronic pain: risks and benefits.

      Cancer pain

      A systematic review of ketamine as an adjunct to opioids in cancer pain found only two studies of sufficient quality
      • Mercadante S.
      • Arcuri E.
      • Tirelli W.
      • Casuccio A.
      Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study.
      • Yang C.Y.
      • Wong C.S.
      • Chang J.Y.
      • Ho S.T.
      Intrathecal ketamine reduces morphine requirements in patients with terminal cancer pain.
      and concluded that there is insufficient robust evidence to assess potential benefits and harms.
      • Bell R.F.
      • Eccleston C.
      • Kalso E.A.
      Ketamine as an adjuvant to opioids for cancer pain.
      Thus, in patients with cancer, evidence of ketamine's efficacy as an analgesic is mostly from case reports, retrospective surveys or uncontrolled studies in patients with refractory neuropathic, bone, and mucositis-related pain.
      • Luczak J.
      • Dickenson A.H.
      • Kotlinska–Lemieszek A.
      The role of ketamine, an NMDA receptor antagonist, in the management of pain.
      • Kotlinska-Lemieszek A.
      • Luczak J.
      Subanesthetic ketamine: an essential adjuvant for intractable cancer pain.
      • Mercadante S.
      • Arcuri E.
      • Tirelli W.
      • Casuccio A.
      Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study.
      • Yang C.Y.
      • Wong C.S.
      • Chang J.Y.
      • Ho S.T.
      Intrathecal ketamine reduces morphine requirements in patients with terminal cancer pain.
      • Oshima E.
      • Tei K.
      • Kayazawa H.
      • Urabe N.
      Continuous subcutaneous injection of ketamine for cancer pain.
      • Cherry D.A.
      • Plummer J.L.
      • Gourlay G.K.
      • Coates K.R.
      • Odgers C.L.
      Ketamine as an adjunct to morphine in the treatment of pain.
      • Mercadante S.
      Ketamine in cancer pain: an update.
      • Bell R.
      Low-dose subcutaneous ketamine infusion and morphine tolerance.
      • Fitzgibbon E.J.
      • Hall P.
      • Schroder C.
      • Seely J.
      • Viola R.
      Low dose ketamine as an analgesic adjuvant in difficult pain syndromes: a strategy for conversion from parenteral to oral ketamine.
      • Kannan T.R.
      • Saxena A.
      • Bhatnagar S.
      • Barry A.
      Oral ketamine as an adjuvant to oral morphine for neuropathic pain in cancer patients.
      • Benítez-Rosario M.A.
      • Feria M.
      • Salinas-Martín A.
      • Martínez-Castillo L.P.
      • Martín-Ortega J.J.
      A retrospective comparison of the dose ratio between subcutaneous and oral ketamine.
      • Fitzgibbon E.J.
      • Viola R.
      Parenteral ketamine as an analgesic adjuvant for severe pain: development and retrospective audit of a protocol for a palliative care unit.
      • Lauretti G.R.
      • Lima I.C.
      • Reis M.P.
      • Prado W.A.
      • Pereira N.L.
      Oral ketamine and transdermal nitroglycerin as analgesic adjuvants to oral morphine therapy and amitriptyline for cancer pain management.
      • Lossignol D.A.
      • Obiols-Portis M.
      • Body J.J.
      Successful use of ketamine for intractable cancer pain.
      • James P.J.
      • Howard R.F.
      • Williams D.G.
      The addition of ketamine to a morphine nurse- or patient-controlled analgesia infusion (PCA/NCA) increases analgesic efficacy in children with mucositis pain.
      Results from a large RCT of PO racemic ketamine in cancer-related neuropathic pain are pending.

      Fallon M. Personal communication, 2015.

      Short-term ‘burst’ treatment with ketamine may sometimes have a relatively long-lasting effect (i.e. several days to weeks and occasionally for months).
      • Jackson K.
      • Ashby M.
      • Howell D.
      • et al.
      The effectiveness and adverse effects profile of “burst” ketamine in refractory cancer pain.
      • Jackson K.
      • Ashby M.
      • Martin P.
      • et al.
      'Burst' ketamine for refractory cancer pain: an open-label audit of 39 patients.
      For example, ketamine 100mg/24h by CIVI for 2 days in a cancer patient, repeated a month later, reduced opioid requirements by 70%.
      • Mercadante S.
      • Villari P.
      • Ferrera P.
      Burst ketamine to reverse opioid tolerance in cancer pain.
      Similarly, in non-cancer pain, patients taking regular strong opioids for ischemic limb pain, a single 4h IV infusion of ketamine 600microgram/kg reduced opioid requirements during the next week.
      • Mitchell A.C.
      • Fallon M.T.
      A single infusion of intravenous ketamine improves pain relief in patients with critical limb ischaemia: results of a double blind randomised controlled trial.
      However, in a large case series, about a quarter of patients experienced severe undesirable effects from higher-dose ‘burst’ CSCI ketamine involving rapid dose escalation 100 → 300 → 500mg/24h over 3–5 days.
      • Jackson K.
      • Ashby M.
      • Howell D.
      • et al.
      The effectiveness and adverse effects profile of “burst” ketamine in refractory cancer pain.
      Further, in a 5-day RCT in cancer patients using the same regimen, there was no difference in the proportion responding in the ketamine and placebo arms (about 50% in each, based on average pain score).
      • Hardy J.
      • Quinn S.
      • Fazekas B.
      • et al.
      Randomized, double-blind, placebo-controlled study to assess the efficacy and toxicity of subcutaneous ketamine in the management of cancer pain.
      There were fewer treatment failures at the maximum dose (25 vs. 50%) but more undesirable effects and withdrawals due to toxicity (19 vs. 2%).
      • Hardy J.
      • Quinn S.
      • Fazekas B.
      • et al.
      Randomized, double-blind, placebo-controlled study to assess the efficacy and toxicity of subcutaneous ketamine in the management of cancer pain.
      These results suggest that rapid titration involving such doses of CSCI ketamine is generally inadvisable.

      Miscellaneous

      PO/IV ketamine (generally in combination with morphine or midazolam) can provide analgesia in severe cancer treatment-related mucositis,
      • White M.C.
      • Hommers C.
      • Parry S.
      • Stoddart P.A.
      Pain management in 100 episodes of severe mucositis in children.
      during painful procedures, e.g. change of dressings,
      • Arroyo-Novoa C.M.
      • Figueroa-Ramos M.I.
      • Miaskowski C.
      • et al.
      Efficacy of small doses of ketamine with morphine to decrease procedural pain responses during open wound care.
      • Kundra P.
      • Velayudhan S.
      • Krishnamachari S.
      • Gupta S.L.
      Oral ketamine and dexmedetomidine in adults' burns wound dressing–A randomized double blind cross over study.
      • Norambuena C.
      • Yañez J.
      • Flores V.
      • et al.
      Oral ketamine and midazolam for pediatric burn patients: a prospective, randomized, double-blind study.
      and orthopaedic emergencies.
      • Cevik E.
      • Bilgic S.
      • Kilic E.
      • et al.
      Comparison of ketamine-low-dose midozolam with midazolam-fentanyl for orthopedic emergencies: a double-blind randomized trial.
      Topical ketamine has been applied to the skin in various non-cancer pains,
      • Finch P.M.
      • Knudsen L.
      • Drummond P.D.
      Reduction of allodynia in patients with complex regional pain syndrome: a double-blind placebo-controlled trial of topical ketamine.
      • Gammaitoni A.
      • Gallagher R.M.
      • Welz-Bosna M.
      Topical ketamine gel: possible role in treating neuropathic pain.
      and used as an oral rinse in radiation-induced mucositis.
      • Slatkin N.E.
      • Rhiner M.
      Topical ketamine in the treatment of mucositis pain.
      Ketamine has a rapid antidepressant effect in patients with major depression and bipolar disorder, including a reduction in suicidal ideation.
      • Fond G.
      • Loundou A.
      • Rabu C.
      • et al.
      Ketamine administration in depressive disorders: a systematic review and meta-analysis.
      Following a single IV dose (typically 500microgram/kg over 40min), up to 70% of patients respond, with improvements seen within hours. However, duration of benefit is generally ≤1 week.
      • Fond G.
      • Loundou A.
      • Rabu C.
      • et al.
      Ketamine administration in depressive disorders: a systematic review and meta-analysis.
      • Salvadore G.
      • Singh J.B.
      Ketamine as a fast acting antidepressant: current knowledge and open questions.
      These effects are accompanied by a more rapid restoration of neuroplasticity than that seen with conventional antidepressants. The exact mechanism is unclear but includes the release of brain-derived neurotrophic factor which helps to restore neuroplasticity, e.g. through the formation of new synapses.
      • Salvadore G.
      • Singh J.B.
      Ketamine as a fast acting antidepressant: current knowledge and open questions.
      Although case reports of benefit are emerging from the palliative care setting,
      • Stefanczyk-Sapieha L.
      • Oneschuk D.
      • Demas M.
      Intravenous ketamine “burst” for refractory depression in a patient with advanced cancer.
      • Irwin S.A.
      • Iglewicz A.
      Oral ketamine for the rapid treatment of depression and anxiety in patients receiving hospice care.
      • Zanicotti C.G.
      • Perez D.
      • Glue P.
      Mood and pain responses to repeat dose intramuscular ketamine in a depressed patient with advanced cancer.
      • Grott Zanicotti C.
      • Perez D.
      • Glue P.
      Case report: long-term mood response to repeat dose intramuscular ketamine in a depressed patient with advanced cancer.
      • Irwin S.A.
      • Iglewicz A.
      • Nelesen R.A.
      • et al.
      Daily oral ketamine for the treatment of depression and anxiety in patients receiving hospice care: a 28-day open-label proof-of-concept trial.
      the use of ketamine to treat major depression is experimental, and should ideally be restricted to RCTs. Other drugs which act on the NMDA receptor-channel complex are undergoing clinical trials in depression.
      • Dolgin E.
      Rapid antidepressant effects of ketamine ignite drug discovery.
      The use of CIVI ketamine has been explored in the treatment of refractory status epilepticus, but its place in clinical practice remains to be determined.
      • Zeiler F.A.
      • Teitelbaum J.
      • Gillman L.M.
      • West M.
      NMDA antagonists for refractory seizures.
      Bioavailability 93% IM; 45% nasal; 30% SL; 30% PR; and 20% PO.
      • Chong C.C.
      • Schug S.A.
      • Page-Sharp M.
      • Ilett K.F.
      Bioavailability of ketamine after oral or sublingual administration.
      • Yanagihara Y.
      • Ohtani M.
      • Kariya S.
      • et al.
      Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers.
      Onset of action 5min IM; 15–30min SC; 30min PO.
      Time to peak plasma concentration no data SC; 30min PO; 1h norketamine.
      • Grant I.S.
      • Nimmo W.S.
      • Clements J.A.
      Pharmacokinetics and analgesic effects of IM and oral ketamine.
      Plasma halflife 1–3h IM; 3h PO; 12h norketamine.
      • Domino E.F.
      • Domino S.E.
      • Smith R.E.
      • et al.
      Ketamine kinetics in unmedicated and diazepam premedicated subjects.
      Duration of action 30min–2h IM; 4–6h PO, sometimes longer.
      • Rabben T.
      • Skjelbred P.
      • Oye I.
      Prolonged analgesic effect of ketamine, an N-methyl-D-aspartate receptor inhibitor, in patients with chronic pain.

      Cautions

      History of psychiatric disorder; epilepsy, glaucoma, hypertension, heart failure, ischemic heart disease, CVAs, acute intermittent porphyria.
      • Ward J.
      • Standage C.
      Angina pain precipitated by a continuous subcutaneous infusion of ketamine.
      Hyperthyroidism (increased risk of hypertension and tachycardia). Conditions causing excessive upper airway secretions; ketamine both increases salivation and sensitizes the gag reflex, leading on rare occasions to laryngospasm. Severe hepatic impairment (consider dose reduction).
      Because of reports of ketamine increasing CSF pressure, raised intracranial pressure (e.g. as a result of head injury, intracranial tumour, hydrocephalus) is a traditional caution. However, systematic reviews report no such concerns in ventilated patients with traumatic or non-traumatic brain injury.
      • Zeiler F.A.
      • Teitelbaum J.
      • West M.
      • Gillman L.M.
      The ketamine effect on ICP in traumatic brain injury.
      • Zeiler F.A.
      • Teitelbaum J.
      • West M.
      • Gillman L.M.
      The ketamine effect on intracranial pressure in nontraumatic neurological illness.

      Drug interactions

      Reports involving the CYP450 enzyme system are mostly limited to PO S-ketamine:
      • clarithromycin and grapefruit juice (potent CYP3A4 inhibitors) increase the plasma concentration of S−ketamine and reduce that of norketamine
        • Hagelberg N.M.
        • Peltoniemi M.A.
        • Saari T.I.
        • et al.
        Clarythromycin, a potent inhibitor of CYP3A, greatly increases exposure to oral S-ketamine.
        • Peltoniemi M.A.
        • Saari T.I.
        • Hagelberg N.M.
        • et al.
        S-ketamine concentrations are greatly increased by grapefruit juice.
      • ticlopidine (potent CYP2C19 and weak CYP2B6 inhibitor) increases the area under the plasma concentration-time curve
        • Peltoniemi M.A.
        • Saari T.I.
        • Hagelberg N.M.
        • et al.
        Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine.
      • rifampin and St. John's wort (potent CYP3A4 inducers) decrease the plasma concentration of S−ketamine; rifampin also following IV S−ketamine.
        • Peltoniemi M.A.
        • Saari T.I.
        • Hagelberg N.M.
        • et al.
        Rifampicin has a profound effect on the pharmacokinetics of oral S-Ketamine and less on intravenous S-ketamine.
        • Peltoniemi M.A.
        • Saari T.I.
        • Hagelberg N.M.
        • et al.
        St. John's wort greatly decreases the plasma concentrations of oral S-ketamine.
      The clinical relevance of these interactions is unclear. Other potent inhibitors or inducers of these enzymes could have similar effects.

      Undesirable effects

      Ketamine can be abused or diverted; careful monitoring is essential.
      Dose-related psychotomimetic phenomena occur in about 40% of patients with CSCI ketamine, less with PO: euphoria, dysphasia, blunted affect, psychomotor retardation, vivid dreams, nightmares, impaired attention, memory and judgement, illusions, hallucinations, altered body image.
      Delirium, drowsiness, dizziness, diplopia, blurred vision, nystagmus, altered hearing, hypertension, tachycardia, hypersalivation, nausea and vomiting. At higher anesthetic doses, tonic-clonic movements are very common (>10%) but these have not been reported after PO use or with analgesic parenteral doses.
      Erythema and pain at injection site. Neuropsychiatric, urinary and hepatobiliary toxicity (Box A).

      Dose and use

      Because of the undesirable effects profile of ketamine, which includes neuropsychiatric, urinary tract and hepatobiliary toxicity, prescription of ketamine as an analgesic should be restricted to specialists in pain or palliative care for patients who have failed to obtain adequate relief from standard non-drug and drug treatments, including the optimal use of opioids, non-opioids and adjuvant analgesics. A toxicity monitoring form is available.

      Palliativedrugs.com. Ketamine monitoring chart. Document Library. Pain (neuropathic). 2013. Available at: www.palliativedrugs.com. Accessed June 14, 2015.

      In patients with a prognosis of more than a few weeks, once analgesia has been obtained, an attempt should be made to withdraw ketamine over 2–3 weeks. Benefit from a short course can last for weeks or even months, and can be repeated if necessary.

      Fallon M. Personal communication, 2015.

      Thus, apart from patients with a prognosis of just days–weeks, long-term continuous ketamine should be used only as a last resort, i.e. in those patients with unsatisfactory analgesia from a short course approach.
      Note: whole body hyperalgesia and allodynia may occur if ketamine is abruptly stopped after ≥3 weeks of use.
      • Mitchell A.C.
      Generalized hyperalgesia and allodynia following abrupt cessation of subcutaneous ketamine infusion.

      All doses in this section relate to racemic ketamine

      Dose recommendations vary widely, but ketamine is often started low dose PO (see below). In some centres, an initial test dose is given to assess tolerability and efficacy. The prophylactic concurrent administration of a benzodiazepine or an antipsychotic is also routine in some but not all centres, where it is reserved for more select circumstances (see below). Long-term success, i.e. both pain relief and tolerable undesirable effects, varies from <20% to about 50%.
      • Haines D.
      • Gaines S.
      N of 1 randomised controlled trials of oral ketamine in patients with chronic pain.
      • Batchelor G.
      Ketamine in neuropathic pain.
      • Kannan T.R.
      • Saxena A.
      • Bhatnagar S.
      • Barry A.
      Oral ketamine as an adjuvant to oral morphine for neuropathic pain in cancer patients.
      • Enarson M.C.
      • Hays H.
      • Woodroffe M.A.
      Clinical experience with oral ketamine.
      Some practitioners routinely reduce the background opioid dose by 25–50% when starting parenteral ketamine. If the patient becomes drowsy, the dose of opioid should be reduced. If a patient experiences dysphoria or hallucinations, the dose of ketamine should be reduced and a benzodiazepine prescribed, e.g. diazepam 5mg PO stat & at bedtime, lorazepam 1mg PO stat & b.i.d., midazolam 5mg SC stat and 5–10mg CSCI, or haloperidol, e.g. 2–5mg PO stat & at bedtime, or 2–5mg SC stat and 2–5mg CSCI.
      • Giannini A.J.
      • Underwood N.A.
      • Condon M.
      Acute ketamine intoxication treated by haloperidol: a preliminary study.
      In patients at greatest risk of dysphoria (those with high anxiety levels), these measures may be more effective if given before starting ketamine.
      When switching from CSCI to PO after just a few days, a conversion ratio of 1:1 should be used.
      • Benítez-Rosario M.A.
      • Feria M.
      • Salinas-Martín A.
      • Martínez-Castillo L.P.
      • Martín-Ortega J.J.
      A retrospective comparison of the dose ratio between subcutaneous and oral ketamine.
      • Benítez-Rosario M.A.
      • Salinas-Martín A.
      • González-Guillermo T.
      • Feria M.
      A strategy for conversion from subcutaneous to oral ketamine in cancer pain patients: efficacy of a 1:1 ratio.
      However, after weeks–months of use, some have found that a smaller total daily dose (25–50% of the parenteral dose) can maintain a similar level of analgesia, e.g. CSCI 400mg/24h → PO 150mg/24h.
      • Fitzgibbon E.J.
      • Hall P.
      • Schroder C.
      • Seely J.
      • Viola R.
      Low dose ketamine as an analgesic adjuvant in difficult pain syndromes: a strategy for conversion from parenteral to oral ketamine.
      In both instances, the patient should be monitored closely and the dose titrated accordingly. When switching from PO to CSCI or CIVI, it is advisable to commence on a small dose and titrate as required.

      By mouth
      • Luczak J.
      • Dickenson A.H.
      • Kotlinska–Lemieszek A.
      The role of ketamine, an NMDA receptor antagonist, in the management of pain.
      • Kotlinska-Lemieszek A.
      • Luczak J.
      Subanesthetic ketamine: an essential adjuvant for intractable cancer pain.
      • Clark J.L.
      • Kalan G.E.
      Effective treatment of severe cancer pain of the head using low-dose ketamine in an opioid-tolerant patient.
      • Broadley K.E.
      • Kurowska A.
      • Tookman A.
      Ketamine injection used orally.
      • Vielvoye-Kerkmeer A.P.
      • van der Weide M.
      • Mattern C.
      Re: clinical experience with ketamine.

      An oral solution can be prepared by a local pharmacy (Box B). When this option is not available, use direct from a vial or dilute for convenience (immediately before administration) to 50mg/5mL; add a flavouring of the patient's choice, e.g. fruit cordial, to mask the bitter taste:
      • start with 10–25mg t.i.d.–q.i.d. and p.r.n.
      • if necessary, increase dose in steps of 10–25mg up to 100mg q.i.d.
      • maximum reported dose 200mg q.i.d.
        • Clark J.L.
        • Kalan G.E.
        Effective treatment of severe cancer pain of the head using low-dose ketamine in an opioid-tolerant patient.
        • Vielvoye-Kerkmeer A.P.
        • van der Weide M.
        • Mattern C.
        Re: clinical experience with ketamine.
      • give a smaller dose more frequently if psychotomimetic phenomena or drowsiness occurs which does not respond to a reduction in opioid.
      Preparation of ketamine oral solution: pharmacy guidelines
      Use ketamine 100mg/mL 10mL vials because this is the cheapest concentration. Simple Syrup USP can be used for dilution but this is too sweet for some patients. Alternatively, use purified water as the diluent and ask patients to add their own flavouring, e.g. fruit cordial, just before use to disguise the bitter taste.

        To prepare 100mL of 50mg/5mL oral solution:

      • 10mL vial of ketamine 100mg/mL for injection
      • 90mL purified water.
      Store in a refrigerator with an expiry date of 1 week from manufacture.

      Subcutaneous
      • Kotlinska-Lemieszek A.
      • Luczak J.
      Subanesthetic ketamine: an essential adjuvant for intractable cancer pain.

      • typically 10–25mg p.r.n., some use 2.5–5mg
      • if necessary, increase dose in steps of 25–33%.

      CSCI
      • Luczak J.
      • Dickenson A.H.
      • Kotlinska–Lemieszek A.
      The role of ketamine, an NMDA receptor antagonist, in the management of pain.
      • Hughes A.
      • Crosby V.
      • Wilcock A.
      • Corcoran R.
      Ketamine.
      • Oshima E.
      • Tei K.
      • Kayazawa H.
      • Urabe N.
      Continuous subcutaneous injection of ketamine for cancer pain.
      • Cherry D.A.
      • Plummer J.L.
      • Gourlay G.K.
      • Coates K.R.
      • Odgers C.L.
      Ketamine as an adjunct to morphine in the treatment of pain.
      • Bell R.
      Low-dose subcutaneous ketamine infusion and morphine tolerance.
      • Lloyd-Williams M.
      Ketamine for cancer pain.

      Because ketamine is irritant, dilute to the largest volume possible, and consider the use of 0.9% saline as the diluent. Consider the use of prophylactic diazepam, lorazepam, midazolam or haloperidol (see text above).
      • start with 1–2.5mg/kg/24h
      • if necessary, increase by 50–100mg/24h
      • continue to titrate until adequate pain relief
      • usual maximum 500mg/24h
      • maximum reported dose 3.6g/24h.
      CSCI compatibility with other drugs: There are 2-drug compatibility data for ketamine in WFI with metoclopramide, midazolam and morphine sulfate. For more details see www.palliativedrugs.com.
      There are 2-drug compatibility data for ketamine in 0.9% saline with alfentanil, clonazepam, dexamethasone (low-dose), diamorphine (not USA), haloperidol, hydromorphone, levomepromazine, metoclopramide, midazolam, morphine sulfate and oxycodone (not USA). For more details see www.palliativedrugs.com.

      Intravenous
      • Kotlinska-Lemieszek A.
      • Luczak J.
      Subanesthetic ketamine: an essential adjuvant for intractable cancer pain.
      • Mason K.P.
      • Michna E.
      • DiNardo J.A.
      • et al.
      Evolution of a protocol for ketamine-induced sedation as an alternative to general anesthesia for interventional radiologic procedures in pediatric patients.

      For cancer pain:
      • typically 2.5–5mg p.r.n.
      To cover procedures which may cause severe pain:
      • 500microgram–1mg/kg (typically 25–50mg; some start with 5–10mg), given over 1–2min preceded by, e.g. IV lorazepam 1mg or IV midazolam 100microgram/kg (typically 5–10mg; some start with 1–2mg) to reduce emergent phenomena
      • use a maximum concentration of ketamine 50mg/mL; 0.9% saline or 5% glucose are suitable diluents.
      The right dose should provide analgesia within 1–5min lasting for 10–20min.
      There is a risk of marked sedation when ketamine and a benzodiazepine are given concurrently. Use only if competent in airway management and the patient can be adequately monitored.
      Procedures of longer duration may require ketamine CIVI; obtain advice from an anesthetist.

      CIVI
      • Conway M.
      • White N.
      • Jean C.S.
      • Zempsky W.T.
      • Steven K.
      Use of continuous intravenous ketamine for end-stage cancer pain in children.
      • Hocking G.
      • Visser E.J.
      • Schug S.A.
      • Cousins M.J.
      Ketamine: does life begin at 40?.
      • Okamoto Y.
      • Tsuneto S.
      • Tanimukai H.
      • et al.
      Can gradual dose titration of ketamine for management of neuropathic pain prevent psychotomimetic effects in patients with advanced cancer?.

      Dilute to a concentration of 1mg/mL with 0.9% saline or 5% glucose.
      • give a single ‘burst’ of 600microgram/kg up to a maximum of 60mg over 4h (reduce dose by 1/3–1/2 in elderly/frail patients); monitor blood pressure at baseline and then hourly:
        • if necessary, repeat daily for up to 5 days
        • if no analgesic response to an infusion, increase the dose of the next one by 30%
        • further dose titrate according to response and/or undesirable effects
        • repeat the above if the pain subsequently recurs.

          Fallon M. Personal communication, 2015.

      Or
      • start with 50–150microgram/kg/h (typically 50–100mg/24h) and titrate as necessary (typical increments 25–50mg/24h)
      • in one series of 46 patients with cancer:
        • 20% responded to ≤100mg/24h
        • typical dose 100–300mg/24h
        • no psychotomimetic effects were seen with doses <300mg/24h.

      Supply

      Ketamine (generic)
      Injection 10mg/mL, 20mL vial = $18; 50mg/mL, 10mL vial = $6; 100mg/mL, 5mL vial = $10, 10mL vial = $14.
      Ketalar® (JHP Pharmaceuticals)
      Injection 10mg/mL, 20mL vial = $18; 50mg/mL, 10mL vial = $6; 100mg/mL, 5mL vial = $10, 10mL vial = $14.
      Although use as an analgesic is off-label, ketamine injection can be prescribed both in hospitals and in the community.

      References

        • Persson J.
        • Hasselström J.
        • Wiklund B.
        • et al.
        The analgesic effect of racemic ketamine in patients with chronic ischemic pain due to lower extremity arteriosclerosis obliterans.
        Acta Anaesthesiol Scand. 1998; 42: 750-758
        • Persson J.
        Ketamine in pain management.
        CNS Neurosci Ther. 2013; 19: 396-402
        • Mion G.
        • Villevieille T.
        Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings).
        CNS Neurosci Ther. 2013; 19: 370-380
        • Richens A.
        The basis of the treatment of epilepsy.
        (neuropharmacology)in: Dam M. A practical approach to epilepsy. Pergamon Press, Oxford1991: 75-85
        • De Kock M Loix S.
        Lavand'homme P.Ketamine and peripheral inflammation.
        CNS Neurosci Ther. 2013; 19: 403-410
        • Sleigh J.
        • Martyn H.
        • Voss L.
        • Denny B.
        Ketamine - more mechanisms of action than just NMDA blockade.
        Trends in Anaesthesia & Critical Care. 2014; 4: 76-81
        • Luczak J.
        • Dickenson A.H.
        • Kotlinska–Lemieszek A.
        The role of ketamine, an NMDA receptor antagonist, in the management of pain.
        Prog Palliat Care. 1995; 3: 127-134
        • Kotlinska-Lemieszek A.
        • Luczak J.
        Subanesthetic ketamine: an essential adjuvant for intractable cancer pain.
        J Pain Symptom Manage. 2004; 28: 100-102
        • Lin T.C.
        • Wong C.S.
        • Chen F.C.
        • Lin S.Y.
        • Ho S.T.
        Long-term epidural ketamine, morphine and bupivacaine attenuate reflex sympathetic dystrophy neuralgia.
        Can J Anaesth. 1998; 45: 175-177
        • Haines D.
        • Gaines S.
        N of 1 randomised controlled trials of oral ketamine in patients with chronic pain.
        Pain. 1999; 83: 283-287
        • Batchelor G.
        Ketamine in neuropathic pain.
        Pain Soc Newsl. 1999; 1: 19
        • Beltrutti D.P.
        • Trompeo A.C.
        • Di Santo S.
        The epidural and intrathecal administration of ketamine.
        Curr Rev Pain. 1999; 3: 458-472
        • Mercadante S.
        • Arcuri E.
        • Tirelli W.
        • Casuccio A.
        Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study.
        J Pain Symptom Manage. 2000; 20: 246-252
        • Carr D.B.
        • Goudas L.C.
        • Denman W.T.
        • et al.
        Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study.
        Pain. 2004; 108: 17-27
        • Mercadante S.
        • Arcuri E.
        • Ferrera P.
        • Villari P.
        • Mangione S.
        Alternative treatments of breakthrough pain in patients receiving spinal analgesics for cancer pain.
        J Pain Symptom Manage. 2005; 2005: 485-491
        • Yeaman F.
        • Oakley E.
        • Meek R.
        • Graudins A.
        Sub-dissociative dose intranasal ketamine for limb injury pain in children in the emergency department: a pilot study.
        Emerg Med Australas. 2013; 25: 161-167
        • Vranken J.H.
        • Troost D.
        • Wegener J.T.
        • Kruis M.R.
        • van der Vegt M.H.
        Neuropathological findings after continuous intrathecal administration of S(+)-ketamine for the management of neuropathic cancer pain.
        Pain. 2005; 117: 231-235
        • Berger J.M.
        • Ryan A.
        • Vadivelu N.
        • et al.
        Ketamine-fentanyl-midazolam infusion for the control of symptoms in terminal life care.
        Am J Hosp Palliat Care. 2000; 17: 127-132
        • Enck R.
        A ketamine, fentanyl, and midazolam infusion for uncontrolled terminal pain and agitation.
        Am J Hosp Palliat Care. 2000; 17: 76-77
        • Conway M.
        • White N.
        • Jean C.S.
        • Zempsky W.T.
        • Steven K.
        Use of continuous intravenous ketamine for end-stage cancer pain in children.
        J Pediatr Oncol Nurs. 2009; 26: 100-106
        • Oye I.
        • Hustveit O.
        • Moberg E.R.
        • Pausen O.
        • Skoglund L.A.
        The chiral forms of ketamine as probes for NMDA receptor function in humans.
        in: Kameyama T. Nabeshima T. Domino E.F. Biochemistry, pharmacology and behavior. NPP Books, Ann Arbor, MI1991: 381-389 (NMDA receptor related agents)
        • White P.F.
        • Ham J.
        • Way W.L.
        • Trevor A.J.
        Pharmacology of ketamine isomers in surgical patients.
        Anesthesiology. 1980; 52: 231-239
        • Mathisen L.C.
        • Skjelbred P.
        • Skoglund L.A.
        • Oye I.
        Effect of ketamine, an NMDA receptor inhibitor, in acute and chronic orofacial pain.
        Pain. 1995; 61: 215-220
        • Pfenninger E.G.
        • Durieux M.E.
        • Himmelseher S.
        Cognitive impairment after small-dose ketamine isomers in comparison to equianalgesic racemic ketamine in human volunteers.
        Anesthesiology. 2002; 96: 357-366
        • Clements J.A.
        • Nimmo W.S.
        • Grant I.S.
        Bioavailability, pharmacokinetics and analgesic activity of ketamine in humans.
        J Pharm Sci. 1982; 71: 539-542
        • Hijazi Y.
        • Boulieu R.
        Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes.
        Drug Metab Dispos. 2002; 30: 853-858
        • Holtman Jr., J.R.
        • Crooks P.A.
        • Johnson-Hardy J.K.
        • et al.
        Effects of norketamine enantiomers in rodent models of persistent pain.
        Pharmacol Biochem Behav. 2008; 90: 676-685
        • Olofsen E.
        • Noppers I.
        • Niesters M.
        • et al.
        Estimation of the contribution of norketamine to ketamine-induced acute pain relief and neurocognitive impairment in healthy volunteers.
        Anesthesiology. 2012; 117: 353-364
        • Muetzelfeldt L.
        • Kamboj S.K.
        • Rees H.
        • et al.
        Journey through the K-hole: phenomenological aspects of ketamine use.
        Drug Alcohol Depend. 2008; 95: 219-229
        • Sener S.
        • Eken C.
        • Schultz C.H.
        • Serinken M.
        • Ozsarac M.
        Ketamine with and without midazolam for emergency department sedation in adults: a randomized controlled trial.
        Ann Emerg Med. 2011; 57: 109-114.e102
        • Hughes A.
        • Crosby V.
        • Wilcock A.
        • Corcoran R.
        Ketamine.
        CME Bull Palliat Med. 1999; 1: 53
        • Giannini A.J.
        • Underwood N.A.
        • Condon M.
        Acute ketamine intoxication treated by haloperidol: a preliminary study.
        Am J Ther. 2000; 7: 389-391
        • Subramaniam K.
        • Subramaniam B.
        • Steinbrook R.A.
        Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic review.
        Anesth Analg. 2004; 99: 482-495
        • Bell R.F.
        • Dahl J.B.
        • Moore R.A.
        • Kalso E.
        Perioperative ketamine for acute postoperative pain.
        Cochrane Database Syst Rev. 2006; 1 (Updated 2009): CD004603
        • Bell R.F.
        Ketamine for chronic non-cancer pain.
        Pain. 2009; 141: 210-214
        • Alviar M.J.M.
        • Hale T.
        • Dungca M.
        Pharmacological interventions for treating phantom limb pain.
        Cochrane Database Syst Rev. 2011; 12: CD006380
        • Sigtermans M.J.
        • van Hilten J.J.
        • Bauer M.C.
        • et al.
        Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1.
        Pain. 2009; 145: 304-311
        • Schwartzman R.J.
        • Alexander G.M.
        • Grothusen J.R.
        • et al.
        Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study.
        Pain. 2009; 147: 107-115
        • Niesters M.
        • Martini C.
        • Dahan A.
        Ketamine in chronic pain: risks and benefits.
        Br J Clin Pharmacol. 2013; 77: 357-367
        • Yang C.Y.
        • Wong C.S.
        • Chang J.Y.
        • Ho S.T.
        Intrathecal ketamine reduces morphine requirements in patients with terminal cancer pain.
        Can J Anaesth. 1996; 43: 379-383
        • Bell R.F.
        • Eccleston C.
        • Kalso E.A.
        Ketamine as an adjuvant to opioids for cancer pain.
        Cochrane Database Syst Rev. 2012; 11: CD003351
        • Oshima E.
        • Tei K.
        • Kayazawa H.
        • Urabe N.
        Continuous subcutaneous injection of ketamine for cancer pain.
        Can J Anaesth. 1990; 37: 385-392
        • Cherry D.A.
        • Plummer J.L.
        • Gourlay G.K.
        • Coates K.R.
        • Odgers C.L.
        Ketamine as an adjunct to morphine in the treatment of pain.
        Pain. 1995; 62: 119-121
        • Mercadante S.
        Ketamine in cancer pain: an update.
        Palliat Med. 1996; 10: 225-230
        • Bell R.
        Low-dose subcutaneous ketamine infusion and morphine tolerance.
        Pain. 1999; 83: 101-103
        • Fitzgibbon E.J.
        • Hall P.
        • Schroder C.
        • Seely J.
        • Viola R.
        Low dose ketamine as an analgesic adjuvant in difficult pain syndromes: a strategy for conversion from parenteral to oral ketamine.
        J Pain Symptom Manage. 2002; 23: 165-170
        • Kannan T.R.
        • Saxena A.
        • Bhatnagar S.
        • Barry A.
        Oral ketamine as an adjuvant to oral morphine for neuropathic pain in cancer patients.
        J Pain Symptom Manage. 2002; 23: 60-65
        • Benítez-Rosario M.A.
        • Feria M.
        • Salinas-Martín A.
        • Martínez-Castillo L.P.
        • Martín-Ortega J.J.
        A retrospective comparison of the dose ratio between subcutaneous and oral ketamine.
        J Pain Symptom Manage. 2003; 25: 400-402
        • Fitzgibbon E.J.
        • Viola R.
        Parenteral ketamine as an analgesic adjuvant for severe pain: development and retrospective audit of a protocol for a palliative care unit.
        J Palliat Med. 2005; 8: 49-57
        • Lauretti G.R.
        • Lima I.C.
        • Reis M.P.
        • Prado W.A.
        • Pereira N.L.
        Oral ketamine and transdermal nitroglycerin as analgesic adjuvants to oral morphine therapy and amitriptyline for cancer pain management.
        Anesthesiology. 1999; 90: 1528-1533
        • Lossignol D.A.
        • Obiols-Portis M.
        • Body J.J.
        Successful use of ketamine for intractable cancer pain.
        Support Care Cancer. 2005; 13: 188-193
        • James P.J.
        • Howard R.F.
        • Williams D.G.
        The addition of ketamine to a morphine nurse- or patient-controlled analgesia infusion (PCA/NCA) increases analgesic efficacy in children with mucositis pain.
        Paediatr Anaesth. 2010; 20: 805-811
      1. Fallon M. Personal communication, 2015.

        • Jackson K.
        • Ashby M.
        • Howell D.
        • et al.
        The effectiveness and adverse effects profile of “burst” ketamine in refractory cancer pain.
        J Palliat Care. 2010; 26: 176-183
        • Jackson K.
        • Ashby M.
        • Martin P.
        • et al.
        'Burst' ketamine for refractory cancer pain: an open-label audit of 39 patients.
        J Pain Symptom Manage. 2001; 22: 834-842
        • Mercadante S.
        • Villari P.
        • Ferrera P.
        Burst ketamine to reverse opioid tolerance in cancer pain.
        J Pain Symptom Manage. 2003; 25: 302-305
        • Mitchell A.C.
        • Fallon M.T.
        A single infusion of intravenous ketamine improves pain relief in patients with critical limb ischaemia: results of a double blind randomised controlled trial.
        Pain. 2002; 97: 275-281
        • Hardy J.
        • Quinn S.
        • Fazekas B.
        • et al.
        Randomized, double-blind, placebo-controlled study to assess the efficacy and toxicity of subcutaneous ketamine in the management of cancer pain.
        J Clin Oncol. 2012; 30: 11-17
        • White M.C.
        • Hommers C.
        • Parry S.
        • Stoddart P.A.
        Pain management in 100 episodes of severe mucositis in children.
        Peadiatr Anesth. 2011; 21: 411-416
        • Arroyo-Novoa C.M.
        • Figueroa-Ramos M.I.
        • Miaskowski C.
        • et al.
        Efficacy of small doses of ketamine with morphine to decrease procedural pain responses during open wound care.
        Clin J Pain. 2011; 27: 561-566
        • Kundra P.
        • Velayudhan S.
        • Krishnamachari S.
        • Gupta S.L.
        Oral ketamine and dexmedetomidine in adults' burns wound dressing–A randomized double blind cross over study.
        Burns. 2013; 39: 1150-1156
        • Norambuena C.
        • Yañez J.
        • Flores V.
        • et al.
        Oral ketamine and midazolam for pediatric burn patients: a prospective, randomized, double-blind study.
        J Pediatr Surg. 2013; 48: 629-634
        • Cevik E.
        • Bilgic S.
        • Kilic E.
        • et al.
        Comparison of ketamine-low-dose midozolam with midazolam-fentanyl for orthopedic emergencies: a double-blind randomized trial.
        Am J Emerg Med. 2013; 31: 108-113
        • Finch P.M.
        • Knudsen L.
        • Drummond P.D.
        Reduction of allodynia in patients with complex regional pain syndrome: a double-blind placebo-controlled trial of topical ketamine.
        Pain. 2009; 146: 18-25
        • Gammaitoni A.
        • Gallagher R.M.
        • Welz-Bosna M.
        Topical ketamine gel: possible role in treating neuropathic pain.
        Pain Med. 2000; 1: 97-100
        • Slatkin N.E.
        • Rhiner M.
        Topical ketamine in the treatment of mucositis pain.
        Pain Med. 2003; 4: 298-303
        • Fond G.
        • Loundou A.
        • Rabu C.
        • et al.
        Ketamine administration in depressive disorders: a systematic review and meta-analysis.
        Psychopharmacology (Berl). 2014; 231: 3663-3676
        • Salvadore G.
        • Singh J.B.
        Ketamine as a fast acting antidepressant: current knowledge and open questions.
        CNS Neurosci Ther. 2013; 19: 428-436
        • Stefanczyk-Sapieha L.
        • Oneschuk D.
        • Demas M.
        Intravenous ketamine “burst” for refractory depression in a patient with advanced cancer.
        J Palliat Med. 2008; 11: 1268-1271
        • Irwin S.A.
        • Iglewicz A.
        Oral ketamine for the rapid treatment of depression and anxiety in patients receiving hospice care.
        J Palliat Med. 2010; 13: 903-908
        • Zanicotti C.G.
        • Perez D.
        • Glue P.
        Mood and pain responses to repeat dose intramuscular ketamine in a depressed patient with advanced cancer.
        J Palliat Med. 2012; 15: 400-403
        • Grott Zanicotti C.
        • Perez D.
        • Glue P.
        Case report: long-term mood response to repeat dose intramuscular ketamine in a depressed patient with advanced cancer.
        J Palliat Med. 2013; 16: 719-720
        • Irwin S.A.
        • Iglewicz A.
        • Nelesen R.A.
        • et al.
        Daily oral ketamine for the treatment of depression and anxiety in patients receiving hospice care: a 28-day open-label proof-of-concept trial.
        J Palliat Med. 2013; 16: 958-965
        • Dolgin E.
        Rapid antidepressant effects of ketamine ignite drug discovery.
        Nat Med. 2013; 19: 8
        • Zeiler F.A.
        • Teitelbaum J.
        • Gillman L.M.
        • West M.
        NMDA antagonists for refractory seizures.
        Neurocrit Care. 2014; 20: 502-513
        • Chong C.C.
        • Schug S.A.
        • Page-Sharp M.
        • Ilett K.F.
        Bioavailability of ketamine after oral or sublingual administration.
        Pain Med. 2006; 7: 466-469
        • Yanagihara Y.
        • Ohtani M.
        • Kariya S.
        • et al.
        Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers.
        Biopharm Drug Dispos. 2003; 24: 37-43
        • Grant I.S.
        • Nimmo W.S.
        • Clements J.A.
        Pharmacokinetics and analgesic effects of IM and oral ketamine.
        Br J Anaesth. 1981; 53: 805-810
        • Domino E.F.
        • Domino S.E.
        • Smith R.E.
        • et al.
        Ketamine kinetics in unmedicated and diazepam premedicated subjects.
        Clin Pharmacol Ther. 1984; 36: 645-653
        • Rabben T.
        • Skjelbred P.
        • Oye I.
        Prolonged analgesic effect of ketamine, an N-methyl-D-aspartate receptor inhibitor, in patients with chronic pain.
        J Pharmacol Exp Ther. 1999; 289: 1060-1066
        • Ward J.
        • Standage C.
        Angina pain precipitated by a continuous subcutaneous infusion of ketamine.
        J Pain Symptom Manage. 2003; 25: 6-7
        • Zeiler F.A.
        • Teitelbaum J.
        • West M.
        • Gillman L.M.
        The ketamine effect on ICP in traumatic brain injury.
        Neurocrit Care. 2014; 21: 163-173
        • Zeiler F.A.
        • Teitelbaum J.
        • West M.
        • Gillman L.M.
        The ketamine effect on intracranial pressure in nontraumatic neurological illness.
        J Crit Care. 2014; 29: 1096-1106
        • Hagelberg N.M.
        • Peltoniemi M.A.
        • Saari T.I.
        • et al.
        Clarythromycin, a potent inhibitor of CYP3A, greatly increases exposure to oral S-ketamine.
        Eur J Pain. 2010; 14: 625-629
        • Peltoniemi M.A.
        • Saari T.I.
        • Hagelberg N.M.
        • et al.
        S-ketamine concentrations are greatly increased by grapefruit juice.
        Eur J Clin Pharmacol. 2012; 68: 979-986
        • Peltoniemi M.A.
        • Saari T.I.
        • Hagelberg N.M.
        • et al.
        Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine.
        Clin Pharmacol Ther. 2011; 90: 296-302
        • Peltoniemi M.A.
        • Saari T.I.
        • Hagelberg N.M.
        • et al.
        Rifampicin has a profound effect on the pharmacokinetics of oral S-Ketamine and less on intravenous S-ketamine.
        Basic Clin Pharmacol Toxicol. 2012; 111: 325-332
        • Peltoniemi M.A.
        • Saari T.I.
        • Hagelberg N.M.
        • et al.
        St. John's wort greatly decreases the plasma concentrations of oral S-ketamine.
        Fundam Clin Pharmacol. 2012; 26: 743-750
        • Morgan C.J.
        • Curran H.V.
        Ketamine use: a review.
        Addiction. 2012; 107: 27-38
        • Morgan C.J.
        • Muetzelfeldt L.
        • Curran H.V.
        Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: a 1-year longitudinal study.
        Addiction. 2010; 105: 121-133
        • Liao Y.
        • Tang J.
        • Fornito A.
        • et al.
        Alterations in regional homogeneity of resting-state brain activity in ketamine addicts.
        Neurosci Lett. 2012; 522: 36-40
        • Liao Y.
        • Tang J.
        • Ma M.
        • et al.
        Frontal white matter abnormalities following chronic ketamine use: a diffusion tensor imaging study.
        Brain. 2010; 133: 2115-2122
        • Narendran R.
        • Frankle W.G.
        • Keefe R.
        • et al.
        Altered prefrontal dopaminergic function in chronic recreational ketamine users.
        Am J Psychiatry. 2005; 162: 2352-2359
        • Storr T.M.
        • Quibell R.
        Can ketamine prescribed for pain cause damage to the urinary tract?.
        Palliat Med. 2009; 23: 670-672
        • Shahzad K.
        • Svec A.
        • Al-koussayer O.
        • et al.
        Analgesic ketamine use leading to cystectomy: a case report.
        Br J Med Surg Urol. 2012; 5: 188-191
        • Grégoire M.C.
        • MacLellan D.L.
        • Finley G.A.
        A pediatric case of ketamine-associated cystitis (Letter-to-the-Editor Re: Shahani R, Streutker C, Dickson B, et al.: ketamine-associated ulcerative cystitis: a new clinical entity. Urology 2007;69: 810–812).
        Urology. 2008; 71: 1232-1233
        • Winstock A.R.
        • Mitcheson L.
        • Gillatt D.A.
        • Cottrell A.M.
        The prevalence and natural history of urinary symptoms among recreational ketamine users.
        BJU Int. 2012; 110: 1762-1766
        • Chu P.S.
        • Ma W.K.
        • Wong S.C.
        • et al.
        The destruction of the lower urinary tract by ketamine abuse: a new syndrome?.
        BJU Int. 2008; 102: 1616-1622
        • Shahani R.
        • Streutker C.
        • Dickson B.
        • Stewart R.J.
        Ketamine-associated ulcerative cystitis: a new clinical entity.
        Urology. 2007; 69: 810-812
        • Wood D.
        • Cottrell A.
        • Baker S.C.
        • et al.
        Recreational ketamine: from pleasure to pain.
        BJU Int. 2011; 107: 1881-1884
        • Meng E.
        • Chang H.Y.
        • Chang S.Y.
        • et al.
        Involvement of purinergic neurotransmission in ketamine induced bladder dysfunction.
        J Urol. 2011; 186: 1134-1141
        • Cheung R.Y.
        • Chan S.S.
        • Lee J.H.
        • et al.
        Urinary symptoms and impaired quality of life in female ketamine users: persistence after cessation of use.
        Hong Kong Med J. 2011; 17: 267-273
        • Ng S.H.
        • Tse M.L.
        • Ng H.W.
        • Lau F.L.
        Emergency department presentation of ketamine abusers in Hong Kong: a review of 233 cases.
        Hong Kong Med J. 2010; 16: 6-11
        • Wong S.W.
        • Lee K.F.
        • Wong J.
        • et al.
        Dilated common bile ducts mimicking choledochal cysts in ketamine abusers.
        Hong Kong Med J. 2009; 15: 53-56
        • Dundee J.W.
        • Fee J.P.
        • Moore J.
        • McIlroy P.D.
        • Wilson D.B.
        Changes in serum enzyme levels following ketamine infusions.
        Anaesthesia. 1980; 35: 12-16
        • Noppers I.M.
        • Niesters M.
        • Aarts L.P.
        • et al.
        Drug-induced liver injury following a repeated course of ketamine treatment for chronic pain in CRPS type 1 patients: a report of 3 cases.
        Pain. 2011; 152: 2173-2178
        • Ng S.H.
        • Lee H.K.
        • Chan Y.C.
        • Lau F.L.
        Dilated common bile ducts in ketamine abusers.
        Hong Kong Med J. 2009; 15 (author reply 157): 157
        • Seto W.K.
        • Ng M.
        • Chan P.
        • et al.
        Ketamine-induced cholangiopathy: a case report.
        Am J Gastroenterol. 2011; 106: 1004-1005
        • Lee S.T.
        • Wu T.T.
        • Yu P.Y.
        • Chen R.M.
        Apoptotic insults to human HepG2 cells induced by S-(+)-ketamine occurs through activation of a Bax-mitochondria-caspase protease pathway.
        Br J Anaesth. 2009; 102: 80-89
      2. Palliativedrugs.com. Ketamine monitoring chart. Document Library. Pain (neuropathic). 2013. Available at: www.palliativedrugs.com. Accessed June 14, 2015.

        • Mitchell A.C.
        Generalized hyperalgesia and allodynia following abrupt cessation of subcutaneous ketamine infusion.
        Palliat Med. 1999; 13: 427-428
        • Enarson M.C.
        • Hays H.
        • Woodroffe M.A.
        Clinical experience with oral ketamine.
        J Pain Symptom Manage. 1999; 17: 384-386
        • Benítez-Rosario M.A.
        • Salinas-Martín A.
        • González-Guillermo T.
        • Feria M.
        A strategy for conversion from subcutaneous to oral ketamine in cancer pain patients: efficacy of a 1:1 ratio.
        J Pain Symptom Manage. 2011; 10: 1098-1105
        • Clark J.L.
        • Kalan G.E.
        Effective treatment of severe cancer pain of the head using low-dose ketamine in an opioid-tolerant patient.
        J Pain Symptom Manage. 1995; 10: 310-314
        • Broadley K.E.
        • Kurowska A.
        • Tookman A.
        Ketamine injection used orally.
        Palliat Med. 1996; 10: 247-250
        • Vielvoye-Kerkmeer A.P.
        • van der Weide M.
        • Mattern C.
        Re: clinical experience with ketamine.
        J Pain Symptom Manage. 2000; 19: 3-4
        • Lloyd-Williams M.
        Ketamine for cancer pain.
        J Pain Symptom Manage. 2000; 19: 79-80
        • Mason K.P.
        • Michna E.
        • DiNardo J.A.
        • et al.
        Evolution of a protocol for ketamine-induced sedation as an alternative to general anesthesia for interventional radiologic procedures in pediatric patients.
        Radiology. 2002; 225: 457-465
        • Hocking G.
        • Visser E.J.
        • Schug S.A.
        • Cousins M.J.
        Ketamine: does life begin at 40?.
        IASP Pain Clinical Updates. 2007; 15: 1-6
        • Okamoto Y.
        • Tsuneto S.
        • Tanimukai H.
        • et al.
        Can gradual dose titration of ketamine for management of neuropathic pain prevent psychotomimetic effects in patients with advanced cancer?.
        Am J Hosp Palliat Care. 2012; 30: 450-454