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Drug-induced liver injury following a repeated course of ketamine treatment for chronic pain in crps type 1 patients: a report of 3 cases

PAINÒ 152 (2011) 2173–2178 Drug-induced liver injury following a repeated course of ketamine treatmentfor chronic pain in CRPS type 1 patients: A report of 3 cases Ingeborg M. Noppers Marieke Niesters Leon P.H.J. Aarts Martin C.R. Bauer Asbjørn M. Drewes Albert Dahan , Elise Y. Sarton a Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlandsb Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg Hospital, Aarhus University Hospital, 9000 Aalborg, Denmark Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Studies on the efficacy of ketamine in the treatment of chronic pain indicate that prolonged or repetitive Received 18 October 2010 infusions are required to ensure prolonged pain relief. Few studies address ketamine-induced toxicity.
Received in revised form 20 March 2011 Here we present data on the occurrence of ketamine-induced liver injury during repeated administrations Accepted 21 March 2011 of S(+)-ketamine for treatment of chronic pain in patients with complex regional pain syndrome type 1 aspart of a larger study exploring possible time frames for ketamine re-administration. Six patients werescheduled to receive 2 continuous intravenous 100-hour S(+)-ketamine infusions (infusion rate 10– 20 mg/h) separated by 16 days. Three of these patients developed hepatotoxicity. Patient A, a 65-year- old woman, developed an itching rash and fever during her second exposure. Blood tests revealed elevated Side effectsLiver injury liver enzymes (alanine transaminase, alkaline phosphatase, aspartate transaminase, and c-glutamyl trans- ferase, all P3 times the upper limit of normal) and modestly increased eosinophilic leukocytes. Patient E, a48-year-old woman, developed elevated liver enzymes of similar pattern as Patient A during her secondketamine administration and a weakly positive response to antinuclear antibodies. In a third patient,Patient F, a 46-year-old man, elevated liver enzymes (alanine transaminase and c-glutamyl transferase)were detected on the first day of his second exposure. In all patients, the ketamine infusion was promptlyterminated and the liver enzymes slowly returned to reference values within 2 months. Our data suggestan increased risk for development of ketamine-induced liver injury when the infusion is prolonged and/orrepeated within a short time frame. Regular measurements of liver function are therefore required duringsuch treatments.
Ó 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
Most of the published randomized controlled trials (36/38) are ofpoor-to-moderate quality. Despite the absence of good quality It is well established that the N-methyl-D-aspartate receptor studies, ketamine treatment seems to get a definite place in the (NMDAR) plays an important role in the etiology and duration of treatment of chronic pain in clinical practice The use of keta- chronic pain . Chronic pain activates and upregulates mine has raised the concern for toxicity . Animal studies indi- the NMDAR in the dorsal horn of the spinal cord, which causes en- cate that ketamine use is associated with neurotoxicity and hanced signal transmission in the pain circuitry and leads to learning disabilities, while human studies indicate abuse potential chronic pain, often coupled with allodynia and hyperalgesia and a high frequency of psychotropic side effects. Case reports on Consequently, drugs that block the NMDAR are able to re- the side effects and toxicity of the recreational abuse of ketamine lieve chronic pain and possibly modulate the underlying disease indicate a pattern of renal and liver toxicity During the process . The most potent NMDAR antagonist currently course of a study on repeated administrations of ketamine for available is ketamine, and the number of studies on the efficacy treatment of chronic pain in patients with complex regional pain of ketamine increases rapidly. Since 1992 there are 38 published syndrome type 1 (CRPS), we encountered hepatotoxicity in a sub- randomized controlled trials on ketamine use in chronic (noncan- set of patients that received 2 100-hour infusions of S(+)-ketamine cer) pain patients and even more open-label and case studies .
at a 16-day interval. Six subjects were enrolled in that study armand liver damage was observed in 3 of them. This prompted usto end the trial prematurely. Liver damage is considered a rare side ⇑ Corresponding author. Address: Department of Anesthesiology, Leiden Univer- effect of ketamine use, but since repeated dosing is often neces- sity Medical Center, P5-Q, 2300 RC Leiden, The Netherlands.
E-mail address: (A. Dahan).
sary, we believe that awareness of this side effect is needed. We 0304-3959/$36.00 Ó 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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I.M. Noppers et al. / PAINÒ 152 (2011) 2173–2178 therefore present the course of events of the 6 subjects enrolled in 0–17 U/L], c-glutamyl transferase [cGT; reference values 5–40 U/ the 16-day interval study arm.
L]) were measured during ketamine treatment (in weeks 1 and4) on days 1 (before the start of drug infusion), 3, and 5. In case of liver enzyme elevation, the frequency of testing increased totwice daily. Heart rate, blood pressure, and tympanic temperature The patients presented were involved in a study registered in were obtained 3 times per day.
the Netherlands Trial Register (under num-ber NTR1550. This pilot study was aimed at generating exploratory data on the effect of two 5-day (i.e., 100 h) ketamine treatments(treatment 1 in week 1, treatment 2 in week 4) on pain relief in The total number of subjects in this pilot study was arbitrarily CRPS 1 patients.
set at 30 (10 per group). No comparative analysis was planned,and the data are presented in a descriptive manner only.
Patients eligible for the study were those referred to our outpa- tient pain clinic and who were diagnosed with CRPS-1, as based on Patient admissions took place between December 2008 and the International Association for the Study of Pain CRPS-1 criteria February 2010. The inclusion of patients in the study was ended , and who had pain scores of 5 or higher (on a numerical rating prematurely after 13 subjects had been admitted. Five of the 6 sub- scale [NRS] from 0 to 10 where 0 = no pain and 10 = worst pain).
jects randomized to Group 1 developed side effects: one developed Exclusion criteria included age <18 years, inability to give informed severe hypertension and another psychotropic side effects during consent, serious medical disease (e.g., cardiovascular, renal, or liver their first exposure to S(+)-ketamine, and 3 developed elevated disease), use of strong opioids or baclofen, pregnancy/lactation, hepatotoxicity prior to or during their second exposure to S(+)-ket- and history of psychosis. Patients were asked not to change their amine. The development of hepatotoxicity was such that we pain medication from the start of the study until completion of fol- decided that continuation of the trial was unjustifiable. See for a flow chart of the study. None of the subjects randomized toGroups 2 (n = 2) and 3 (n = 5) developed severe side effects. In 2.2. Trial design , the characteristics of patients randomized to Group 1 aregiven.
The study design was single blind. Patients were admitted twice for 5 days and randomly allocated to 1 of 3 groups: Group 1 was 3.1. Patient A: a 65-year-old woman with CRPS in her left foot admitted in weeks 1 and 4 and received ketamine on both occa-sions (ie, they had a 16-day ketamine-free interlude); Groups 2 During treatment in week 1, pain score reduced from 7 to 2 on and 3 were admitted in weeks 1 and 13 and received ketamine day 2 of the ketamine infusion. Due to the development of severe on both occasions (Group 2) or midazolam on the first occasion psychotropic side effects, nausea, and dizziness, the infusion was and ketamine on the second (Group 3). Follow-up was performed reduced to 2.1 lg kg 1 h 1 on day 2. At this infusion rate, side ef- during the 12 weeks after the second admission. Since the focus fects were bearable. An increase in infusion rate was not possible, of this report is on the side effects observed in the Group 1 subset and the pain score increased to 5 at the end of the infusion. No in- of patients, we restrict our presentation to these patients.
crease in liver enzymes was detected in treatment week 1 Upon admission in week 4, pain had returned to prestudy baseline level and on day 2 of the treatment, similar side effects occurred ashad been seen in week 1 (ketamine infusion rate 2.7 lg kg 1 h 1, S(+)-ketamine (Ketanest S, Pfizer BV, Capelle a/d IJssel, The pain score 2). After 72 h of ketamine infusion, the patient devel- Netherlands) was administered continuously by intravenous route oped an itching rash on legs, abdomen, back, and upper arms, for 5 days according to an infusion scheme of Sigtermans et al. combined with an increase in tympanic temperature to 38.3 °C.
On day 1, infusion started at 8 am at 1.2 lg kg 1 h 1. Three times aday (at 8 am, noon, and 4 pm), the infusion rate could be increasedin steps of 0.6 lg kg 1 h 1 until a maximum infusion rate of7.2 lg kg 1 h 1 was reached. When the patient reached a painrating of zero, the infusion rate was not further changed. In caseof severe side effects, the infusion rate was lowered in steps of0.6 lg kg 1 h 1 and later increased again if possible. On day 5, atnoon, the infusion ended. In case of nausea, 10 mg oral domperi-done could be given, with a maximum of 40 mg per day.
2.4. Measurements The primary outcome measure of the study was pain relief as measured by the 10-point NRS ranging from 0 (no pain) to 10(worst pain), measured 3 times daily (8 am, 12 pm, and 4 pm)during treatment, and weekly in between treatments and duringfollow-up. Secondary outcome parameters were psychotropic sideeffects, nausea, and headache, all scored on a range from 0 (notpresent) to 10 (maximal presence). Liver enzymes (alkaline phos-phatase [ALP; reference values 40–120 U/L], alanine transaminase[ALT; reference values 5–34 U/L], aspartate transaminase [AST;reference values 5–30 U/L], total bilirubin [TBIL; reference values Fig. 1. Flow chart of Group I of the study at the time of study termination.

I.M. Noppers et al. / PAINÒ 152 (2011) 2173–2178 Table 1Patient characteristics, NRS and ketamine treatment.
Patient Age (y); Sex BMI Duration of Affected Ketamine amount Ketamine amount baseline in week 1 Tramadol 3 dd 50 mg Paracetamol/codeine od Both arms Ibuprofen 600 mg od i.v. Line placement 144 Right arm Tramadol 3 dd 100 mg Gabapentin 4 dd 600 mgIbuprofen 2 dd 800 mgOral contraceptive Tramadol 1 dd 150 mg tramadol/paracetamol 4 dd 325/37.5 mgAmitriptyline 1 dd 20 mg Naproxen 2 dd 500 mg Cannabis tea 1–2/wk BMI, body mass index; CRPS, complex regional pain syndrome type 1; NRS, numerical rating scale; i.v., intravenous; od, on demand; dd, times daily.
The blood tests performed on day 3 revealed elevated liver en- she experienced severe psychotropic side effects: fearsome halluci- zymes (see ; ALP, ALT, AST, TBIL, and cGT exceeded the upper nations and a panic attack. She refused further treatment and was reference values). A diagnosis of drug-induced liver injury (DILI) discharged with a pain score of 4. Pain relief lasted for another was made and the ketamine infusion was terminated (total 13 weeks. No increase in liver enzymes was detected during keta- amount of ketamine infused at that time was 1.3 g). Also, all other mine treatment.
medication was stopped. Jaundice and tenderness or enlargementof the liver were absent on physical examination. No further abnor- 3.3. Patient C: A 39-year-old woman with CRPS in both arms malities were observed in blood hematology or chemistry, apartfrom a small increase in eosinophilic and neutrophilic leukocytes In treatment week 1 there was a slow and modest reduction in (to 8% and 77%, respectively). The patient received topical cortico- CRPS pain score from 9 to 6 on day 3. She developed a gradual in- steroid and oral clemastine to treat the pruritis. Liver enzymes de- crease in mean arterial blood pressure from 93 to 135 mm Hg on creased upon termination of the ketamine infusion, except for ALP day 3. Decreasing the infusion rate did not lower the blood pres- and cGT, which increased for another day. The patient was dis- sure and the treatment was terminated on day 4 (pain score 6, charged on day 5 with an NRS of 3. After discharge the rash slowly mean arterial pressure 130 mm Hg). The decision was made by improved, disappearing completely within 2 weeks. Liver enzymes the investigators and patient to not participate in the second keta- returned to normal within 1 month, except for cGT, which normal- mine session. The high blood pressure was successfully treated ized within 2 months. The patient continued to experience a lack of with antihypertensive medication that is continued to date. No in- energy following discharge for 6 months. The pain score returned crease in liver enzymes was detected during ketamine treatment.
to baseline 5 weeks after discharge.
3.4. Patient D: A 20-year-old woman with CRPS of the left leg 3.2. Patient B: A 53-year-old woman with CRPS in her right arm Upon admission in week 1, CRPS pain score was 9. The ketamine Ketamine produced a reduction in CRPS pain score from 8 to 2 infusion rate was increased to the maximum dose without any on treatment day 2. On day 3 the patient was pain free. On day 4 effect on the pain score. The patient experienced no side effects.
Fig. 2. Serum liver enzymes in the first (left) and second (right) S(+)-ketamine treatment week (= study week 4) of patient A. Alkaline phosphatase, alanine transaminase,aspartate transaminase, total bilirubin, and c-glutamyl transferase exceeded the upper reference values. Reference values: alkaline phosphatase (orange open square) 40–120 U/L, alanine transaminase (blue closed circle) 5–34 U/L, aspartate transaminase (red closed square) 5–30 U/L, total bilirubin (black star) 0–17 U/L, and c-glutamyltransferase (green open circle) 5–40 U/L. The gray bar indicates the ketamine infusion.

I.M. Noppers et al. / PAINÒ 152 (2011) 2173–2178 Fig. 3. Serum liver enzymes in the first (left) and second (right) S(+)-ketamine treatment week (= study week 4) of patient E. Alkaline phosphatase, alanine transaminase,aspartate transaminase, total bilirubin, and c-glutamyl transferase exceeded the upper reference values (for reference values see legend). The gray bar indicates theketamine infusion.
On day 5 the patient was discharged with pain score 9. A similar terminated on the same day after 6 h of infusion, when the results course was observed during treatment in week 4. The pain score of the blood screening became available: ALT was elevated to 77 was 9 upon discharge and remained between 8 and 9 during the U/L (normal range 5–34 U/L) and cGT was elevated to 267 U/L follow-up period. No increase in any of the liver enzymes was de- (5–40 U/L). The other enzymes remained within the range of normal.
tected during ketamine treatment in weeks 1 and 4.
A second sample 8 h after the initiation of treatment gave similarvalues. The patient denied the use of alcohol, intake of any medica- 3.5. Patient E: a 48-year-old woman with CRPS of the right foot tion, or any episodes of epigastric pain in the period prior to hissecond admission. Blood hematology tests revealed the absence of Ketamine induced gradual pain relief, with CRPS pain NRS 6 to 0 gallstones or signs of infection. Since we discontinued ketamine on day 4. During treatment the patient experienced various side treatment, the patient refused any follow-up blood measurements.
effects, including psychotropic effects, sedation, dizziness, and Two additional blood samples were taken 1 week and 4 months nausea. No increase in liver enzymes was detected during the first later, by the patient's family doctor: cGT remained elevated ketamine treatment week. Upon the start of treatment in week 4, (92 U/L) in the first sample but was normalized in the second.
CRPS pain score was 3. Within 1 day of ketamine treatment, the The course of pain relief and ketamine infusion scheme, an pain score was reduced to 1. Side effects were again present, but average plot of the pain scores and ketamine infusion rates is given they seemed of lesser intensity compared to the first admission.
in for 5 patients of Group 1 (data from patient D are excluded For nausea, domperidone was given. Routine blood screening on in this graph). Since the study was single blind and not placebo- day 3 revealed elevated liver enzymes ALP, ALT, AST, TBIL, controlled, these data do not constitute efficacy data, but do give and cGT exceeded the upper reference values). The ketamine infu- an impression of the effect of treatment on pain scores.
sion was ended on that same day (total dose given, 800 mg). Thepatient had no fever, jaundice, abdominal tenderness, or enlarge- ment of the liver. The following tests were performed: renal func-tion; clotting time; serum concentrations of ammonia and lactate; Ketamine is increasingly used for the treatment of chronic pain.
serology for hepatitis A, B, and C; cytomegaly virus; Epstein-Barr Data from recent trials suggest that prolonged or repetitive admin- virus; and antinuclear, antimitochondrial, and antismooth muscle istrations of this agent are needed to induce long-term pain relief, antibodies. All tests were normal or negative except for the antinu- that is, pain relief outlasting the treatment period for a period long- clear antibody, which was weakly positive. An ultrasound of the er than 48 h . In a previous study we showed that a single con- liver, bile ducts, and related vasculature showed no abnormalities.
tinuous 100-hour infusion of ketamine produces the relief of CRPS On day 4 the patient developed a severe itch of both feet and pete- pain for up to 11 weeks, compared to placebo This is a some- chiae. The CRPS seemed to flare up with edema of the right foot what disappointing effect and prompted us to examine the effect of and an increase in pain score to 6. The patient was discharged on a second 100-hour infusion period on pain relief in CRPS-1 pa- day 5, after which liver enzymes slowly decreased and the itch tients. A pilot study was designed to explore possible time frames and petechiae disappeared over a course of days to weeks. The liver for ketamine re-administration (4 weeks vs 13 weeks). Apart from enzymes normalized within 2 months.
the expected psychotropic and hypertensive side effects, weencountered a problem that so far was considered a rare side effect 3.6. Patient F: a 46-year-old man with CRPS of the left arm of ketamine administration—elevation of serum liver enzymes—ata relatively high frequency. In 3 patients in study Group 1, the in- Before treatment, the CRPS pain score was 8. Upon ketamine crease in liver enzymes was detected just prior or during a second infusion, a slow decline in pain score occurred with no side effects ketamine administration, 16 days after an initial 100-hour apart from mild sedation. During the course of the week, the treatment. We relate the cause of elevated liver enzymes to patient experienced various episodes of sub-febrile temperature ketamine-induced hepatotoxicity in patients A and E, as there (37.9 °C) without any signs of illness, infection, or allergy. At dis- was an evident chronological relation between the ketamine infu- charge, pain score was 4. Upon admission in week 4, the CRPS pain sion and the development and resolution of the liver injury (e.g., score had increased to 7. The ketamine treatment was started but liver enzymes declined rapidly upon termination of treatment).

I.M. Noppers et al. / PAINÒ 152 (2011) 2173–2178 Fig. 4. Pain data and infusion rates of 5 subjects showing an analgesic response during treatment with ketamine (given in a single-blind fashion). (A) Numerical rating scoresfrom week 1 to the end of week 4. The continuous black line is the pretreatment baseline mean numerical rating score ± 95% confidence interval (dashed gray lines); thecontinuous gray line is the 50% effect line. The numbers indicate the number of patients from which the pain data was obtained. (B) Ketamine infusion rates (mg/h) for thefirst treatment week (week 1). (C) Ketamine infusion rates for the second treatment week (week 5). Values are mean ± SEM. In graphs A and B, the baseline mean ± 95%confidence interval is shown (continuous black line ± dashed gray lines); in graph A, the 50% effect line is given (continuous gray line).
The cause of the liver enzyme elevation in patient F is less clear and made thereafter . Sporadic reports of liver injury do appear is possibly related to the ketamine treatment. We made the deci- . For example, in refractory CRPS patients receiving keta- sion to end the trial, as we argued that repetitive long-term keta- mine in anesthetic dosages for 5 days, modest elevations in liver en- mine infusions within a short time frame is a risk factor for liver zymes were noted in 16 (of 20) patients on the last days of treatment cell damage and we therefore concluded that our study design Following treatment, the enzymes returned to reference values (in Group 1 patients) is not acceptable. These data contrast findings within 10 to 14 days. In another study, low-dose ketamine given to in our previous study: Patients in the Sigtermans et al. trial CRPS patients caused elevated liver enzymes in 4 (of 33) patients received a single 100-hour infusion of ketamine with an average during a first treatment period (duration of treatment ranged from ketamine dose of 2.5 g (range 1.7–3.3 g) without any signs of liver 4 to 20 days; ketamine infusion rate 10–50 mg/h) One of these toxicity or side effects beyond the duration of treatment. Some of patients who required additional treatments 3 months later devel- the patients in the current study use co-medication that may have oped immediate elevations of his liver-enzyme profile during 2 had an effect on liver function.
more treatment attempts. More frequent incidence of liver damageis observed following frequent recreational ketamine abuse 4.1. Ketamine-induced liver injury These patients often present with kidney injury,elevated liver enzymes, and bladder dysfunction. Some of these The first reports on an association between ketamine and liver in- patients have epigastric pain, but in most cases the elevated liver jury date from 1979–1980. In the isolated rat hepatocyte, supraclin- enzymes were discovered upon blood examination when the ical doses of ketamine inhibited gluconeogenesis, and urea patients came in for urinary tract symptoms .
formation from alanine caused a reduction in adenosine triphos- All of the above studies that reported liver injury in response to phate concentration and a dose-dependent leakage of L-lactate ketamine treatment used a racemic ketamine mixture. In our study dehyrogenase Dundee et al. described a higher incidence we administered the S(+) enantiomer indicating that the enantio- of significant elevations in liver enzyme levels in patients receiving selective use of ketamine will not protect the patient for possible 3–4 mg/kg ketamine for induction and maintenance of general anes- liver injury.
thesia compared to ‘‘standard'' techniques (involving halothane andthiopentone). Fourteen (of 34) patients receiving ketamine and 7 (of 4.2. Drug-induced liver injury (DILI) 34) receiving standard treatment had signs of liver injury. Moststudies on the use of ketamine for chronic pain treatment either Drug-induced liver injury is unpredictable (ie, not dose related, did not measure liver enzymes or found an absence of changes in and difficult to reproduce in animal models) and is considered to plasma liver enzymes . For example, in 30 patients receiv- have a rare incidence . Various forms have been described ing a 100-hour continuous infusion of ketamine (infusion rate be- (hepatitis, cholestasis, cirrhosis, granulomas, steatosis, neoplas- tween 10 and 20 mg/kg), no effect on liver enzymes was observed mas, vascular). DILI may have immune-mediated (allergic) and during the ketamine treatment period, but no measurements were non-immune-mediated (nonallergic) features. In the allergic form, I.M. Noppers et al. / PAINÒ 152 (2011) 2173–2178 the innate immune system responds to the drug or its metabolite fully monitoring the myriad of short- and long-term side effects as if it was a toxic foreign body or infectious organism causing a linked to ketamine treatment.
sterile inflammatory response. In the nonallergic form, mitochon-drial impairment, oxidative stress, and cellular adaptation failure Conflict of interest statement are causative factors. Allergic DILI has a latency period of 1–6 weeks, with a high incidence of fever, rash, and eosinophilia, is None of the authors report any competing interests relating to not dose related, and recurs upon drug re-challenge. Nonallergic the topic of this paper.
DILI has a latency of 1 month to 1 year and is possibly dose related,while the occurrence of rash, fever, and eosinophilia is uncommon.
On the basis of the liver enzyme level, DILI is classified into hep- atitis, cholestatis, or a mixed pattern . DILI is defined as hepa- This study was funded in part by the TREND (Trauma RElated titis when ALT P 3
ULN (where ULN = upper limit of the normal Neuronal Dysfunction) organization (Delft, The Netherlands), a (ALT/ULN)/(ALP/ULN) P 5; non-profit consortium of academic hospitals, technical research ALP P 2
ULN and (ALT/ULN)/(ALP/ULN) 6 2; and mixed when groups, and companies focused on the study of Complex Regional 2 < (ALT/ULN)/(ALP/ULN) < 5. In severe cases of DILI, the patient Pain Syndrome type 1.
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