Ketamine's second life : Treatment of acute and chronic pain Sigtermans, M.J.

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Ketamine's second life : Treatment of acute and chronic pain

Sigtermans, M.J.

Citation

Sigtermans, M. J. (2010, October 5). Ketamine's second life : Treatment of acute and chronic pain. Retrieved from https://hdl.handle.net/1887/16009

Version: Corrected Publisher’s Version

License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden

Downloaded from: https://hdl.handle.net/1887/16009

Note: To cite this publication please use the final published version (if applicable).

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Section IV

CRPS-1 patients

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Chapter 5

An observational study on the eﬀect of S(+)-ketamine on chronic pain versus experimental acute pain in CRPS type 1 patients

Marnix Sigtermans, Ingeborg Noppers, Elise Sarton, Martin Bauer, Ren´e Mooren, Erik Olofsen & Albert Dahan European Journal of Pain 2009; 14: 302 – 307

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An observational study on the effect of S(+)-ketamine on chronic pain versus experimental acute pain in CRPS type 1 patients

5.1 Introduction

Ketamine is a phenylcycline derivative introduced in clinical practice in the early 1960s as intravenous anesthetic agent. While high-dose ketamine continues to be used as an anesthetic there is currently an increased interest in its application at low-dose as an analgesic for treatment and/or prevention of acute and chronic pain.^1,2 Ketamine acts at several receptors expressed on pain processing neurons in the spinal cord and brain such as sodium and other cation channels and G-coupled receptors, including opioid receptors, but its eﬀects arise predominantly via non-competitive antagonism of the ionotropic glutamate N-methyl-D-aspartate receptor (NMDAR).^1,2 The NMDAR plays an important role in the etiology and perseverance of chronic (neuropathic) pain.

In chronic pain states the NMDAR is activated and upregulated in the spinal cord (central sensitization), resulting in enhanced signal transmission in the pain circuitry from the spinal cord to the cortex leading to spontaneous pain, allodynia and hyperalgesia.^3–5 Low-dose ketamine has been used successfully in treatment of chronic pain patients, including cancer pain patients, with and without neuropathic pain, and patients with ﬁbromyalgia and Complex Regional Pain Syndrome type 1 (CRPS-1).^6–10 In the treatment of acute pain, low-dose intravenous ketamine has been shown to enhance opioid-induced analgesia by reducing opioid consumption.^11,12

The ability of ketamine to be effective in pain states with different mechanisms of pain processing (e.g., acute nociceptive versus chronic neuropathic pain) suggests a common role for the NMDAR in the processing of pain of various etiologies. However, ketamine’s effectiveness in different pain states may arise through different pathways and/or via activities at different receptor systems. In a first attempt to explore ketamine’s behavior in acute versus chronic pain we tested intravenous ketamine effect on experimental heat pain versus spontaneous pain in CRPS-1 patients. We were not only interested in ketamine’s effectiveness in producing pain relief but also in its dynam- ics (i.e., temporal profile) and therefore applied seven 5-min infusions with increasing doses at 20-min intervals and continued pain measurements for 3-h following infusion.

Our current study was not designed to assess an effect of S(+)-ketamine per se on pain relief. We therefore did not include placebo controls. In the current study design the patients serve as their own control (when testing spontaneous versus experimental pain). We further measured ketamine’s side effects focusing on psychomimetic effects by measuring drug high.

5.2 Methods

Subjects

Ten patients diagnosed with CRPS-1 were recruited for participation in the study.

Informed consent was obtained according to the Declaration of Helsinki from all participants and the local medical ethics committee approved the study. The study was registered (www.trialregister.nl) under number ISRCTN20522161. The diagnosis of CRPS-1 was based on the International Association for the Study of Pain criteria:^13,14

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(i) The presence of an initiating noxious event, or cause of immobilization; (ii) Con- tinuing pain, allodynia or hyperalgesia, with the pain being disproportionate to any inciting event; (iii) Evidence at some time of edema, changes in skin blood ﬂow and/or abnormal sudomotor activity in the region of pain; (iv) Exclusion of other conditions that would otherwise account for the degree of pain and dysfunction.

Before participation all subjects received a physical examination and their medical history was taken. Exclusion criteria were: age<18 years, pregnancy/lactation, a history of alcohol or drug abuse, a history of psychosis and a serious medical disease (e.g., car- diovascular, renal or liver disease), a pain score of less than 5 (out of 10) and the use of strong opioid medication. Patients were allowed to continue the following pain med- ications: paracetamol, non-steroid anti-inﬂammatory drugs, tramadol, amitryptiline, selective serotonin reuptake-inhibitors, gabapentin and pregabalin.

Protocol and measurements

A venous line for drug infusion and an arterial line for blood sampling were placed in a brachial vein and the radial artery, respectively. All lines were inserted preferentially in the non-aﬀected arm. The S(+)-ketamine infusion scheme was as follows (doses are per 70 kg; ﬁgure 5.1a): min 0-5: 1.5 mg (given in 5 min), min 20-25: 3.0 mg, min 40-45:

4.5 mg, min 60-65: 6.0mg, min 80-85: 7.5 mg, min 100-105: 9.0 mg, min 120-125: 10.5 mg.

Heat pain was induced using the Thermal Sensory Analyzer II (Medoc Ltd., Ramat Yishai, Israel). Using a 3 x 3 cm thermode, the skin on the volar side of the forearm was stimulated with a gradually increasing stimulus (0.5 ℃/s; baseline temperature 32℃). The volar side of the arm was divided into six zones and marked as previously described.¹⁵ The thermode was moved from zone to zone between stimuli. The visual analogue scale (VAS) was recorded by the subjects on a 10-cm paper scale that ranged from 0 (no pain) to 10 (worst pain). The subjects rated pain intensity. The thermode peak temperature depended on an initial trial phase in which the subject rated the pain to four peak temperatures: 46, 48, 49 and 49.5 ℃. The lowest stimulus causing a VAS greater than 6.0 was used in the remainder of the study. The test data were discarded. Next, baseline values (= pre-drug VAS) were obtained. Pain assessments were performed at times t = 5, 20, 25, 40, 45, 60, 65, 80, 85, 100, 105, 120 and 125 during S(+)-ketamine treatment (infusion phase), and at times t = 2, 5, 10, 15, 25, 35, 50, 65, 85, 105, 135 and 175 min following ketamine infusion (elimination phase).

Directly after each pain assessment the subjects were instructed to rate their high feeling (drug high) on an 11-point scale ranging from 0 (absence of drug high) to 10 (maximal drug high rating). Patients and healthy volunteers underwent the same protocol except that patients also scored their spontaneous pain (VAS) just before the experimental pain tests were performed.

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Blood sampling and S(+)-ketamine and S(+)-norketamine anal- ysis

Arterial blood sampling was performed at times t = 0 (predrug baseline), 5, 20, 25, 40, 45, 60, 65, 80, 85, 100, 105, 120, 125, 127, 130, 135, 140, 150, 160, 175, 190, 210, 230, 260 and 300 min. Two to three ml plasma was separated within 15-min of blood collection and stored at -25℃until analysis. For the construction of S(+)-ketamine and S(+)-norketamine calibration lines, solid substances were obtained from Parke-Davis (Dallas, TX, USA) and Tocris (St. Louis, MO, USA), respectively. After extraction from the speciﬁc sample, S(+)-ketamine and S(+)-norketamine were determined by HPLC on a Gemini C18 column (Phenomenex, Utrecht, The Netherlands) at 40 ℃.

Monitoring of the eluent was performed at 195 nm with a photodiode-array-detector (PDA 100, Dionex, Amsterdam, The Netherlands). The lower limit of quantitation was 10 ng/ml for both drugs.

Statistical analysis

Statistical analysis was by repeated measures analysis of variance or t-test. All tests were performed using the statistical package SPSS 16.0 (Chicago, IL). P-values <0.05 were considered signiﬁcant. Data are presented as mean ± SEM unless otherwise stated.

5.3 Results

Patient and volunteer characteristics are listed in table 5.1. All subjects concluded the study without major side eﬀects.

Table 5.1: Patient characteristics CRPS-1 patients Number [M/F] 10 [0 / 10]

Age (year) 43.2 ± 13.0 Weight (kg) 68.9 ± 10.8 Height (cm) 170.9 ± 6.6 BMI 23.6 ± 3.9 Duration (years) [range] 8.4 ± 6.1 [1.1-20.7]

Ketamine concentrations

During the infusion phase of the study, seven increasing peaks in ketamine concentrations coincided with the end of each 5-min infusion period (ﬁgures 5.1a and b). In the elimination phase the ketamine concentration dropped rapidly from 425.4± 30.9 ng/ml

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Chapter 5

0 300

Time (h)

Ketamine infusion (mg/70kg)

0 2 4 6 8 10 12

0 25 50 75 100 125 150 175 200 225 250 275 300

I I I I I I I I I I I I I II I I I I I I I I I I I

infusion phase elimination phase

(a)

0 300

Time (h)

concentration (ng/ml)

0 100 200 300 400 500

0 25 50 75 100 125 150 175 200 225 250 275 300

S(+)−ketamine S(+)−norketamine

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Figure 5.1: Ketamine infusion and ketamine and norketamine plasma concentrations.

(a) Infusion and pain measurement schemes: Ketamine infusion scheme in mg/70kg. Each infusion was carried out over a 5 min period.

The vertical bars indicate the times of a pain assessment. (b) Measured S(+)-Ketamine and S(+)-norketamine plasma concentrations in CRPS type 1 patients. Values are mean± SEM. Concentrations below the detection limit (10ng/ml) are not included in the graph.

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0 50 100 150 200 250 300 0

2 4 6 8 10

Time (h)

Pain scores (NRS)

0 1 2 3 4 5 6 7 8 9 10

0 50 100 150 200 250 300

experimental heat pain

CRPS pain

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Figure 5.2: Eﬀect of ketamine infusion on pain responses

Mean responses before, during and after ketamine infusion in CRPS-1 patients. Both spontaneous CRPS pain (squares) and the pain response to an experimental heat pain stimulus (circles) are shown. Open symbols indicate signiﬁcant diﬀerenceversus baseline (t = 0) value (P<0.05; repeated measures anova). Values are mean ± SEM.

to levels well below 80 ng/ml within minutes. Norketamine concentrations remained below ketamine concentrations during infusion phase, but were higher, albeit modestly, thereafter. Peak norketamine concentration was reached at t = 135 min (86.0 ± 16.4 ng/ml).

Pain response

Mean baseline CRPS pain was 6.2± 0.2 cm (squares in ﬁgure 5.2). Ketamine produced a signiﬁcant reduction in CRPS pain from t = 60 min until the end of the study (P

<0.05). Lowest VAS was reached at t = 125 min (0.4 ± 0.3 cm). The reduced VAS persisted even during the valleys in ketamine concentration. Although the VAS tended to increase in the elimination phase, VAS remained more than 50% below baseline values until the end of the study (VAS at 5 h = 2.8± 1.0 cm). There was no inﬂuence of disease duration on pain reduction by ketamine.

In the heat pain experiments the temperature of the thermode was 49.0 ± 2.3℃; mean baseline VAS was 7.7 ± 0.3 cm (circles in figure 5.2). Plasma ketamine concentrations causing a significant analgesia effect were > 300 ng/ml (i.e., the analgesia threshold for acute pain = 300 ng/ml). Consequently, only the last three ketamine peaks (at 85, 105 and 125 min) were associated with a significant decrease in VAS (P <0.05) with a maximum decrease after the highest infusion (t =125 min; VAS = 3.1 ± 1.4 cm).

In-between infusions, VAS values returned to levels not diﬀerent from baseline. In the elimination phase VAS returned rapidly towards baseline values and remained below baseline only during the ﬁrst 5 min of this part of the study.

When comparing the two pain assessments, ketamine aﬀected the course of CRPS pain

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Chapter 5

0 50 100 150 200 250 300 0

2 4 6 8 10

Time (min) Numerical Rating Scale (NRS) 0

1 2 3 4 5 6 7 8 9 10

0 50 100 150 200 250 300

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Figure 5.3: Eﬀect of ketamine infusion on drug high

Values are mean± SEM.

more favorably than that of experimental pain (time*VAS, P <0.001). In contrast to baseline pain scores (ρ = 0.64, P = 0.04), there was no signiﬁcant correlation between the eﬀect of S(+)-ketamine on experimental and CRPS pain as measured relative to baseline at t = 125 min (end of infusion; ρ = 0.03, P = 0.87).

Drug high

In the infusion phase, the pattern of drug high was similar to that observed for CRPS pain scores. Peak drug high occurred at t = 125 min and averaged 9.7 ± 0.2. In the elimination phase the side eﬀect rapidly dissipated (see ﬁgure 5.3).

5.4 Discussion

S(+)-ketamine produced potent analgesia in CRPS-1 patients with a signiﬁcant reduction in CRPS pain during a short-term infusion paradigm. These analgesic eﬀects persisted for at least 3-h beyond the infusion period when plasma concentrations of S(+)-ketamine and its metabolite S(+)-norketamine had dropped below 100 ng/ml.

In both patients and volunteers, S(+)-ketamine’s effect on acute experimental pain differed markedly from its effect on chronic pain. While S(+)-ketamine produced dose- dependent antinociception, this effect ended immediately upon the termination of infusion. This indicates that in contrast to its effect on chronic pain, S(+)-ketamine’s effect on acute pain is driven by pharmacokinetics (i.e., little or no hysteresis in the plasma concentration-effect data). To visualize the presence or absence of hysteresis in the data, we plotted plasma ketamine concentrations versus effect (acute and CRPS pain) in figure 5.4. The plots show a large clock-wise hysteresis loop for chronic pain

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0 100 200 300 400 500

0 2 4 6 8 10

Plasma ketamine concentration (ng/ml)

Pain scores (cm)

0 1 2 3 4 5 6 7 8 9 10

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0 100 200 300 400 500

0 2 4 6 8 10

Plasma ketamine concentration (ng/ml)

Pain scores (cm)

0 1 2 3 4 5 6 7 8 9 10

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Figure 5.4: Ketamine concentration-eﬀect data. All data are mean values

(a) Experimental pain data in CRPS-1 patients. (b) CRPS pain data in CRPS-1 patients. All data are mean values. Open circle indicates the starting point, open squares the ﬁnal data point. The largest hysteresis loop was observed for CRPS pain.

and absence or just a small hysteresis loop for acute pain. In addition, the lack of correlation between S(+)-ketamine’s eﬀect on experimental pain and CRPS pain at the end of the drug infusion is a further indication of a distinct mode of action of ketamine between the two pain states. Similar to experimental pain ketamine’s major side eﬀect in our study, drug high, was plasma concentration driven with a rapid return to baseline levels upon the termination of infusion.

The speciﬁc infusion design used in the study was chosen for two reasons. First and most important is that continuously changing plasma ketamine concentrations in- creases the ability to discriminate between responses driven by pharmacokinetics and responses that are less dependent on rapid changes in plasma drug concentrations but are additionally determined by secondary or modulatory processes. A second objective was to keep norketamine concentrations low enabling us to study a pure ketamine eﬀect (see below).

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Our observation that ketamine’s acute antinociceptive effects follow the plasma ketamine concentrations closely is in agreement with earlier observations on ketamine’s anesthetic effect. Schüttler et al.¹⁶ studied the effect of S(+)-ketamine on EEG slowing (changes in median frequency) and observed no hysteresis between venous ketamine concentration and effect. Using racemic ketamine, Herd et al.¹⁷ observed little or no hysteresis in children when studying arousal and recall memory. These data indicate that ketamine rapidly passes the blood-brain-barrier to sites in the CNS involved in pain processing, anesthesia and awareness, where it has an on-off effect. The acute antinociceptive effects are due to ketamine’s inhibition of the excitatory effect of glutamate at NMDAR sites in the CNS, although we cannot exclude actions via other receptor systems, most importantly the μ-opioid receptor system.^1,2 For example, in mice lacking opioid receptors Sarton et al.¹⁸showed that S(+)-ketamine antinociception is significantly reduced. Functional MRI studies indicate that S(+)-ketamine exhibits its acute pain inhibitory effect via deactivation of brain areas involved in the processing of somatosensory and affective components of pain, with a more pronounced effect on the affective component.¹⁹ Our data indicate that the effect of ketamine on acute antinociception was unaffected by chronic CRPS-1 development as we observed similar responses in healthy young volunteers (unpublished observation). This is true in qual- itative and quantitative terms as the analgesic threshold (300 ng/ml) and peak drug effect (VAS 2-3 cm at 450 ng/ml) are similar between CRPS-1 patients and healthy volunteers.

In contrast to acute pain, chronic CRPS pain remained relieved by ketamine, in- between and following infusion when plasma ketamine concentrations had dropped below the threshold for acute pain relief (figures 5.2 and 5.4). This suggests a modulatory effect of ketamine on neurons involved in the chronification of CRPS pain.

The most adhered theory for the mechanism of chronic (neuropathic and CRPS) pain development is NMDAR activation and upregulation in the spinal cord (i.e., central sensitization).^1,2,5 Our data show that ketamine, even a short infusion, is able to interfere with this process possibly by causing long-term central desensitization. However, this effect was only partial as we observed a slow increase in CRPS pain following ketamine infusion. It may well be that longer, repetitive or high(er)-dose infusion regimens will cause a more prolonged or even total pain relief. Indeed, in a separate placebo-controlled randomized and blinded trial we observed that a 4 day low-dose S(+)-ketamine infusion resulted in pain relief for 10 weeks or longer in CRPS-1 patients (unpublished observation). Several open-label and case studies corroborate our observations.^9,10,20,21 The fact that ketamine’s effect persisted when plasma concentrations and possibly also CNS concentrations are low or even absent indicates that NMDAR blockade did set a series of events in motion that is best described by pain dechronification.

Another possible interaction of ketamine with pain dechronification may be via restoration or activation of endogenous inhibitory modulation of pain perception. Such systems include noxious inhibitory control (DINC).²² DNIC is a pain-modulatory system and a representation of the top-down endogenous analgesia system.²² It dysfunctions or is less efficacious in various chronic pain disorders such as irritable bowel syndrome, fibromyalgia, chronic headache and temporomandibular disorder.^22–24 It may well be

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that also CRPS-1 patients suﬀer from a dysfunction of DNIC-like control that is re- stored by a central ¨reset¨from ketamine. Further studies are needed to examine this possibility. Finally, CRPS is associated with various complex abnormalities in the gray and white matter of the brain that encompass emotional, autonomic and pain perception regions (including regions outside the normal pain matrix), all playing some role in the global clinical picture of CRPS.^25,26 An eﬀect of ketamine at any of these sites is also not excluded.

Drug high persisted somewhat between the 5-min ketamine infusions but dissipated within 60 min after termination of the infusion. Most participants severely disliked the psychomimetic side effects. The finding that drug high disappears upon the termination of ketamine infusion is reassuring for the chronic pain patient treated with ketamine, as its beneficial effect outlasts the ketamine infusion period significantly. However, in clinical practice we propose to add a benzodiazepine to the ketamine treatment to dampen these effects.

Ketamine is a chiral compound with two enantiomers: S(+)- and R(-)-ketamine.^27,28 We studied the S(+) variant for the reasons that it is currently the available compound in the Netherlands and is considered to have a two-fold greater analgesic potency than racemic ketamine or the R(-) variant.²⁹ S(+)-norketamine, S(+)-ketamine’s major and active metabolite, is rapidly produced in the liver, primarily via the CYP3A4 isoform of the microsomal cytochrome P450 system.³⁰Its analgesic potency is unknown in humans but animal data indicate that it is a factor of 2 to 3 less potent than ketamine and contributes 20 to 30% to ketamine’s analgesic eﬀect.^31–33 Like ketamine, norketamine inhibits the NMDA receptor at the ketamine speciﬁc site within the receptor.³¹ The consequence of our infusion schedule is that S(+)-norketamine concentrations remained below 120 ng/ml. Assuming that the animal data may be extrapolated to humans it follows that in the current study norketamine did not contribute to the observed analgesia/antinociception. The results of our study therefore point towards a ’pure’

S(+)-ketamine eﬀect on chronic pain modulation.

We refrained form inclusion of a placebo treatment in our study. The study was designed to compare S(+)-ketamine effect on experimental versus CRPS-1 pain in the same subject, and not to study the efficacy of S(+)-ketamine on pain relief. Possi- bly, the greater effect of S(+)-ketamine on CRPS-1 pain than experimental pain could partly be explained by a placebo-related effect. Previous studies from our laboratory intended to study the effect of S(+)-ketamine on pain relief in CRPS-1 patients indeed showed a significant albeit small placebo effect which averaged to about 15% of S(+)-ketamine’s analgesic effect (unpublished observation). However, in contrast to S(+)-ketamine in our current study, the effect of placebo disappeared rapidly upon the termination of infusion. Previous placebo studies on experimental heat pain revealed little or no systematic effect during and following placebo infusion.¹⁵ We therefore believe that the lack of a placebo group had only a minor effect on our study out- come. We would like to stress, however, that the use of a placebo arm in a study on S(+)-ketamine should be considered with care, especially when it is done to blind the researcher and patient. Blinding is not possible due to ketamine’s psychomimetic side effects and doctors/researchers (as well as the patients) are promptly aware of a difference in treatment. Also adding an active placebo and/or adding a benzodiazepine

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Chapter 5

to the ketamine treatment is of limited help as complete blinding is difficult due to the specific nature and coloring of the psychomimetic effects. Furthermore, when studying pain mechanisms, combining drugs with different modes of action will possibly interfere with interpretation of the data. Finally, our patient population was exclusively female, which reflects the high incidence of CRPS-1 in women rather than men (sex ratio = 4-5:1). Sex differences in analgesic treatment have been observed for opioids, but not for ketamine.^34,35 We, however, remain careful with blindly extrapolation of our results to the male patient population.

In conclusion, S(+)-ketamine aﬀects acute and chronic pain via distinct pathways.

Ketamine’s effect on acute pain is plasma concentration driven, displaying an on-off effect and involves inhibition of NMDAR and possibly activation of other (e.g., opioid) receptor systems involved in the processing of acute pain. Ketamine’s effect on chronic CRPS-1 pain is best described as pain dechronification, probably arising via long- term desensitization of upregulated NMDAR or via restoration/activation of top-down inhibitory control of pain sensory systems.

References

1. A. B. Petrenko, T. Yamakura, H. Baba, and K. Shimoji. The role of n-methyl-d- aspartate (nmda) receptors in pain: a review.

Anesth.Analg., 97(4):1108–1116, 2003.

2. B. A. Chizh. Low dose ketamine: a therapeutic and research tool to explore n-methyl-d- aspartate (nmda) receptor-mediated plastic- ity in pain pathways 1. J.Psychopharmacol., 21(3):259–271, 2007.

3. C. N. Sang. Nmda-receptor antagonists in neuropathic pain: experimental methods to clinical trials. J.Pain Symptom.Manage., 19(1 Suppl):S21–S25, 2000.

4. R. J. Schwartzman, J. Grothusen, T. R.

Kiefer, and P. Rohr. Neuropathic central pain: epidemiology, etiology, and treatment options. Arch.Neurol., 58(10):1547–

1550, 2001.

5. Q. Q. Zhou, H. Imbe, S. Zou, R. Dubner, and K. Ren. Selective upregulation of the flip-flop splice variants of ampa receptor subunits in the rat spinal cord after hindpaw inflamma- tion. Brain Res.Mol.Brain Res., 88(1-2):186–

193, 2001.

6. J. Sorensen, A. Bengtsson, J. Ahlner, K. G.

Henriksson, L. Ekselius, and M. Bengts- son. Fibromyalgia–are there diﬀerent mechanisms in the processing of pain? a double

blind crossover comparison of analgesic drugs.

J.Rheumatol., 24(8):1615–1621, 1997.

7. S. Mercadante, E. Arcuri, W. Tirelli, and A. Casuccio. Analgesic eﬀect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study. J.Pain Symp- tom.Manage., 20(4):246–252, 2000.

8. R. Bell, C. Eccleston, and E. Kalso. Ketamine as an adjuvant to opioids for cancer pain.

Cochrane.Database.Syst.Rev., (1):CD003351, 2003.

9. G. E. Correll, J. Maleki, E. J. Gracely, J. J.

Muir, and R. E. Harbut. Subanesthetic ketamine infusion therapy: a retrospective analysis of a novel therapeutic approach to complex regional pain syndrome. Pain Med., 5(3):263–275, 2004.

10. R. T. Kiefer, P. Rohr, A. Ploppa, K. H. Al- temeyer, and R. J. Schwartzman. Complete recovery from intractable complex regional pain syndrome, crps-type i, following anesthetic ketamine and midazolam. Pain Pract., 7(2):147–150, 2007.

11. N. Nesher, I. Serovian, N. Marouani, S. Chazan, and A. A. Weinbroum. Ketamine spares morphine consumption after transtho- racic lung and heart surgery without ad- verse hemodynamic eﬀects. Pharmacol.Res., 58(1):38–44, 2008.

86

(16)

12. J. Zakine, D. Samarcq, E. Lorne, M. Moubarak, P. Montravers, S. Beloucif, and H. Dupont. Postoperative ketamine admin- istration decreases morphine consumption in major abdominal surgery: a prospective, randomized, double-blind, controlled study.

Anesth.Analg., 106(6):1856–1861, 2008.

13. H. Merskey and Bogduk K. Classification of chronic pain: definitions of chronic pain syn- dromes and definition of pain terms. Seattle, IASP, 1994.

14. S. Bruehl, R. N. Harden, B. S. Galer, S. Saltz, M. Bertram, M. Backonja, R. Gayles, N. Rudin, M. K. Bhugra, and M. Stanton- Hicks. External validation of iasp diagnostic criteria for complex regional pain syndrome and proposed research diagnostic criteria. international association for the study of pain.

Pain, 81(1-2):147–154, 1999.

15. E. Olofsen, R. Romberg, H. Bijl, R. Mooren, F. Engbers, B. Kest, and A. Dahan. Alfen- tanil and placebo analgesia: no sex diﬀer- ences detected in models of experimental pain. Anesthesiology, 103(1):130–139, 2005.

16. J. Schuttler, D. R. Stanski, P. F. White, A. J. Trevor, Y. Horai, D. Verotta, and L. B. Sheiner. Pharmacodynamic modeling of the eeg eﬀects of ketamine and its enantiomers in man. J.Pharmacokinet.Biopharm., 15(3):241–253, 1987.

17. D. W. Herd, B. J. Anderson, N. A. Keene, and N. H. Holford. Investigating the pharma- codynamics of ketamine in children. Paedi- atr.Anaesth., 18(1):36–42, 2008.

18. E. Sarton, L. J. Teppema, C. Olievier, D. Nieuwenhuijs, H. W. Matthes, B. L. Ki- eﬀer, and A. Dahan. The involvement of the mu-opioid receptor in ketamine-induced respiratory depression and antinociception.

Anesth.Analg., 93(6):1495–500, table, 2001.

19. T. Sprenger, M. Valet, R. Woltmann, C. Zim- mer, R. Freynhagen, E. F. Kochs, T. R.

Tolle, and K. J. Wagner. Imaging pain modulation by subanesthetic s-(+)-ketamine.

Anesth.Analg., 103(3):729–737, 2006.

20. M. E. Goldberg, R. Domsky, D. Scaringe, R. Hirsh, J. Dotson, I. Sharaf, M. C. Torjman,

and R. J. Schwartzman. Multi-day low dose ketamine infusion for the treatment of complex regional pain syndrome. Pain Physician, 8:175–179, 2005.

21. R. T. Kiefer, P. Rohr, A. Ploppa, H. J. Di- eterich, J. Grothusen, S. Koﬄer, K. H. Al- temeyer, K. Unertl, and R. J. Schwartzman.

Eﬃcacy of ketamine in anesthetic dosage for the treatment of refractory complex regional pain syndrome: an open-label phase ii study.

Pain Med., 9(8):1173–1201, 2008.

22. D. Pud, Y. Granovsky, and D. Yarnitsky. The methodology of experimentally induced dif- fuse noxious inhibitory control (dnic)-like effect in humans. Pain, 2009.

23. S. Lautenbacher and G. B. Rollman. Possible deﬁciencies of pain modulation in ﬁbromyal- gia. Clin.J.Pain, 13(3):189–196, 1997.

24. C. D. King, F. Wong, T. Currie, A. P. Maud- erli, R. B. Fillingim, and III Riley, J. L.

Deﬁciency in endogenous modulation of prolonged heat pain in patients with irritable bowel syndrome and temporomandibular disorder. Pain, 143(3):172–178, 2009.

25. P. Y. Geha, M. N. Baliki, R. N. Harden, W. R.

Bauer, T. B. Parrish, and A. V. Apkarian.

The brain in chronic crps pain: abnormal gray-white matter interactions in emotional and autonomic regions. Neuron, 60(4):570–

581, 2008.

26. F. Seifert and C. Maihofner. Central mechanisms of experimental and chronic neuropathic pain: ﬁndings from functional imaging studies. Cell Mol.Life Sci., 66(3):375–390, 2009.

27. K. Hirota and D. G. Lambert. Ketamine: its mechanism(s) of action and unusual clinical uses. Br.J.Anaesth., 77(4):441–444, 1996.

28. R. Kohrs and M. E. Durieux. Ke- tamine: teaching an old drug new tricks.

Anesth.Analg., 87(5):1186–1193, 1998.

29. M. W. Hollmann, M. H. van der Vegt, A. Da- han, and J. Vrancken. Perioperative use of ketamine: from k to better. Ned Tijdsch Anes- thesiol, 20:6–12, 2008.

87

(17)

Chapter 5

30. Y. Hijazi and R. Boulieu. Contribution of cyp3a4, cyp2b6, and cyp2c9 isoforms to n- demethylation of ketamine in human liver mi- crosomes. Drug Metab Dispos., 30(7):853–

858, 2002.

31. B. Ebert, S. Mikkelsen, C. Thorkildsen, and F. M. Borgbjerg. Norketamine, the main metabolite of ketamine, is a non-competitive nmda receptor antagonist in the rat cortex and spinal cord. Eur.J.Pharmacol., 333(1):99–104, 1997.

32. M. Shimoyama, N. Shimoyama, A. L. Gor- man, K. J. Elliott, and C. E. Inturrisi. Oral ketamine is antinociceptive in the rat forma- lin test: role of the metabolite, norketamine.

Pain, 81(1-2):85–93, 1999.

33. Jr. Holtman, J. R., P. A. Crooks, J. K.

Johnson-Hardy, M. Hojomat, M. Kleven, and E. P. Wala. Eﬀects of norketamine enantiomers in rodent models of persistent pain. Pharmacol.Biochem.Behav., 90(4):676–

685, 2008.

34. E. Sarton, E. Olofsen, R. Romberg, Hartigh J.

den, B. Kest, D. Nieuwenhuijs, A. Burm, L. Teppema, and A. Dahan. Sex diﬀer- ences in morphine analgesia: an experimental study in healthy volunteers. Anesthesiology, 93(5):1245–1254, 2000.

35. M. J. Sigtermans, E Olofsen, E. Y. Sarton, J. W. Kleef van, and A. Dahan. Pk/pd modeling of the analgesic and side eﬀects of low-dose s(+)-ketamine in healthy volunteers. Anesthesiology, ASA Annual meeting, abstract A1584, 2008.

88