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British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 2016 Dec 16;83(4):751–763. doi: 10.1111/bcp.13176

Pharmacokinetics and pharmacodynamics of intrathecally administered Xen2174, a synthetic conopeptide with norepinephrine reuptake inhibitor and analgesic properties

Pieter Okkerse 1,, Justin L Hay 1, Elske Sitsen 2, Albert Dahan 2, Erica Klaassen 1, William Houghton 3,, Geert Jan Groeneveld 1,
PMCID: PMC5346871  PMID: 27987228

Abstract

Aim

Xen2174 is a synthetic 13‐amino acid peptide that binds specifically to the norepinephrine transporter, which results in inhibition of norepinephrine uptake. It is being developed as a possible treatment for moderate to severe pain and is delivered intrathecally. The current study was performed to assess the pharmacodynamics (PD) and the cerebrospinal fluid (CSF) pharmacokinetics (PK) of Xen2174 in healthy subjects.

Methods

This was a randomized, blinded, placebo‐controlled study in healthy subjects. The study was divided into three treatment arms. Each group consisted of eight subjects on active treatment and two or three subjects on placebo. The CSF was sampled for 32 h using an intrathecal catheter. PD assessments were performed using a battery of nociceptive tasks (electrical pain, pressure pain and cold pressor tasks).

Results

Twenty‐five subjects were administered Xen2174. CSF PK analysis showed a higher area under the CSF concentration–time curve of Xen2174 in the highest dose group than allowed by the predefined safety margin based on nonclinical data. The most common adverse event was post‐lumbar puncture syndrome, with no difference in incidence between treatment groups. Although no statistically significant differences were observed in the PD assessments between the different dosages of Xen2174 and placebo, pain tolerability in the highest dose group was higher than in the placebo group [contrast least squares mean pressure pain tolerance threshold of Xen2174 2.5 mg–placebo (95% confidence interval), 22.2% (−5.0%, 57.1%); P = 0.1131].

Conclusions

At the Xen2174 dose level of 2.5 mg, CSF concentrations exceeded the prespecified exposure limit based on the nonclinical safety margin. No statistically significant effects on evoked pain tests were observed.

Keywords: evoked pain, intrathecal, norepinephrine reuptake inhibitor, pharmacodynamics, pharmacokinetics

What is Already Known about this Subject

  • The venom of marine cone snails may provide a rich source of pharmacologically active compounds.

  • Xen2174 provides long‐lasting antinociception in nonclinical models.

What this Study Adds

  • Intrathecal drug administration in combination with performing a battery of evoked pain tasks in humans is feasible, even with concurrent cerebral spinal fluid sampling.

  • Owing to its pharmacokinetic and pharmacodynamic profile, it is unlikely that Xen2174 will be developed for the treatment of acute pain.

Tables of Links

TARGETS
G protein‐coupled receptors 2
α2‐adrenoceptors
Transporters 3
Norepinephrine transporter

These Tables list key protein targets and ligands in this article that are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 1, and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 2, 3.

Introduction

The majority of patients undergoing surgery experience moderate to severe pain in the postoperative period 4. Treatment consists of multiple pain relief agents and strategies. Significant side effects may occur with the use of opioids 5. Nonsteroidal anti‐inflammatory drugs (NSAIDs) and paracetamol are not sufficiently effective against moderate to severe postoperative pain and should be administered in combination with opioids 6, 7. Thus, there remains a clinical need for the development of new efficacious therapies with a beneficial side‐effect profile.

The venom of the marine cone snail genus Conus provides a rich source of pharmacologically active compounds 8. The peptide Mr1A, identified in the venom of Conus marmoreus, causes inhibition of norepinephrine (NE) uptake by the NE transporter (NET) in a selective, noncompetitive manner 9, 10. Mr1A showed an antinociceptive effect after intrathecal administration in mice 11, 12. This peptide has a relatively poor chemical stability in solution. To overcome this, Xen2174, modelled on Mr1A, was developed. Xen2174 is a synthetic 13‐amino acid peptide that does not cross the blood–brain barrier and is being developed for the intrathecal treatment of moderate to severe pain. In vitro pharmacology studies have demonstrated that Xen2174 binds specifically to the NET, but not to other central nervous system molecular targets, resulting in selective inhibition of NE uptake by NET in a noncompetitive manner 13. Tricyclic antidepressants are also potent NE reuptake inhibitors (NRIs), but their poor specificity relative to other monoamine transporters and various G protein‐coupled receptors results in dose‐limiting side effects in clinical use 12, 14. In vivo pharmacology studies in rat models of neuropathic pain have demonstrated that intrathecal administration of Xen2174 produces rapid and long‐lasting anti‐allodynic effects, which were found to be greater in magnitude and duration than those of intrathecal morphine 12. Additional pharmacology studies have demonstrated that Xen2174 also provides long‐lasting antinociception in a rat model of postsurgical pain 15. In an inflammatory pain model in rats (inflammation induced by injecting Freund's Complete Adjuvant), Xen2174 did not relieve pain after thermal latency or paw pressure tests (Investigator's brochure Xen2174. Xenome Ltd., unpublished). Toxicology studies have shown that Xen2174 causes convulsions and seizures when administered at high doses in rats and dogs. In a beagle dog study in which Xen2174 was administered intrathecally at doses of 0, 1, 2, 4 and 8 mg (5 animals/gender/dose), seizures were observed in three dogs; one in the 1 mg and two in the 2 mg dose group. In follow‐up dog study in which 24 animals were treated, no seizures or changes on EEG were observed after administration of 1, 2, 4 and 8 mg/animal. The no‐observed‐adverse‐effect level (NOAEL) in dogs was 1.0 mg/animal (Investigator's brochure Xen2174. Xenome Ltd., unpublished).

Xen2174 has previously been administered to humans in four clinical studies. However, only limited data have been available on the pharmacokinetic (PK) profile of Xen2174 in cerebrospinal fluid (CSF) and no conclusive data have been available on its analgesic properties in humans (Table 1). The aim of the current study was to assess the PK profile of Xen2174 in the plasma and CSF when administered intrathecally to healthy subjects, and to assess which modalities of pain were affected by treatment with Xen2174, using evoked pain tasks.

Table 1.

Summary of previous clinical studies with Xen2174

Study Number (n) of subjects Dose Outcomes Serious adverse events a
Phase I study of Xen2174 administered intravenously in healthy male subjects n = 16 treated with Xen2174; n = 4 placebo 10–200 μg kg−1 No effects on nociceptive testing None
Phase I–II open‐label study of Xen2174 administered intrathecally in oncology patients with chronic pain n = 36 treated with Xen2174 0.025–40 mg No definitive conclusions regarding clinical benefit due to small number of patients per dose group and variation in type of pain. Each cohort contained at least one patient with >90% reduction in pain scores Confusion and dysphasia (0.25 mg), apnoea, unresponsiveness, grand mal seizure (40 mg), aseptic drug‐induced meningitis (40 mg)
Phase II study of Xen2174 administered intrathecally in adults prior to bunionectomy surgery (partially completed) n = 13 treated with Xen2174; n = 3 placebo 1.0 mg No final conclusion regarding clinical efficacy None
Phase I EEG safety study of Xen2174 administered in healthy male and female subjects n = 28 treated with Xen2174; n = 7 placebo 0.1–2.5 mg No apparent effects on EEG None

EEG, electroencephalogram

a

Considered to be related to the study drug

Materials and methods

The study was approved by the Medical Ethics Committee of the BEBO Foundation (Assen, the Netherlands). The study was conducted according to the Dutch Act on Medical Research Involving Human Subjects (WMO) and in compliance with Good Clinical Practice (ICH‐GCP) and the Declaration of Helsinki.

Subjects

Healthy male and female subjects between 18 and 45 years, with a body mass index (BMI) of 18–30 kg m−2 were enrolled. All subjects gave written informed consent. The subjects underwent a full medical screening to assess eligibility. Subjects with an abnormal electroencephalogram (EEG) at screening, a (family) history of epilepsy, a history of seizures, complaints of low back pain, regular user of any illicit drugs or history of drug abuse, a positive drug screen or other clinical significant abnormalities were excluded. Use of xanthine‐containing products and alcohol was not allowed from 1 day prior to admission to the clinical research unit and during the stay at the research unit. Subjects were not allowed to use any medications from 2 weeks prior to the start of the study days.

Experimental design

This was a randomized, double‐blind, placebo‐controlled, serial‐cohort, single ascending dose study of Xen2174 or placebo, administered intrathecally to healthy volunteers. At each dose stage, subjects were randomized to Xen2174 or placebo. Cohorts 1 and 2 consisted of eight subjects administered Xen2174 and three subjects receiving placebo. Cohort 3 consisted of eight subjects administered Xen2174 and two administered placebo. The three ascending doses of Xen2174 were 0.5 mg (cohort 1), 1.0 mg (cohort 2) and 2.5 mg (cohort 3). The maximum dose of 2.5 mg was chosen in order to have a threefold safety margin in the dose per kg body weight compared with the NOAEL in dogs. The lower dose of 0.5 mg was chosen based on the human equivalent dose of the median effective dose (ED50) in rats exposed to the Brennan model of postsurgical pain.

Subjects arrived at the clinical research unit on the day before dosing and remained in‐house for at least 56 h after study drug administration. The study drug was administered via a spinal needle at the L3–L4 or L4–L5 interspace, using a median approach. After administration, an intrathecal sampling catheter was left in place for the following 32 h. Subjects were asked to stay in bed in either a recumbent or supine position as much as possible during the period that the spinal catheter was in place, and up to 12 h after the spinal catheter had been removed.

Safety assessments were performed at specified time points and the occurrence of general symptoms was monitored continuously. The computer‐generated randomization list was prepared by the statistician prior to the start of the study. Doses were prepared by a pharmacist/technician not involved in any of the study procedures.

Study drug

Xen2174 in glucose 5% was given intrathecally as bolus injection of 3 ml. Glucose 5% was used as placebo. Before drug administration, the skin on the lower back was anaesthetized locally with 1–2 ml lidocaine. All intrathecal injections of the study drug were carried out by an experienced anaesthetist under aseptic conditions using a spinal catheter set. Owing to difficulties with CSF sampling, different spinal catheter sets were used during the course of the study: a Sprotte Special 21G needle with a 25G catheter, Pajunk, Geisingen, Germany (cohort 1), a 19G needle with a 23G catheter (five subjects in cohort 2) (Pajunk, Geisingen, Germany) and a Spinocath 22G catheter (six subjects in cohort 2, and 10 in cohort 3) (B Braun, Melsungen, Germany). With the Sprotte Special cannula catheter set, the study drug was administered using the Sprotte needle (epidural introducer with an atraumatic modified pencil point), after which the sampling catheter was left in place. The Sprotte needle had a directional bevel, which was directed cranially. The study drug was administered directly through the epidural introducer. The catheter was placed after drug administration at the same level via the introducer. For the Spinocath set, first an introducer was inserted into the epidural space. After that, the study drug was administered into the intrathecal space using a 25G/27G pencil point needle. Thereafter, the sampling catheter was inserted into the intrathecal space through the epidural introducer. With both catheter sets, the sampling catheter was inserted 2–5 cm into the intrathecal space and left in place for the following 32 h. The Pajunk catheter had three lateral orifices at the distal end of the catheter. The Spinocath catheter had a central and lateral opening on the catheter tip. The intrathecal needle was placed with the subject in the sitting position. After insertion of the spinal catheter, the catheter was secured and subjects were placed directly in supine position afterwards. They were asked to stay in the supine or recumbent position while the catheter was in place.

Study assessments

The primary objectives of the study were to evaluate the effects of Xen2174 on evoked pain tasks and to assess the PK profile of Xen2174 in the plasma and CSF. Nociceptive (pain) detection and tolerance thresholds were measured using a battery of evoked pain tasks. The battery takes approximately 25 min to complete. The evoked pain tasks (electrical pain, pressure pain and cold pressor tasks) were performed predose (twice) and 2, 4, 6, 8, 10, 48, 72 and 96 h after study drug administration. A training session was included as part of the screening examination, to reduce learning effects during the study. All tests had previously been shown to be sensitive to the effects of analgesics in healthy adults.

Pain intensity was measured continuously for each nociceptive task, using an electronic visual analogue scale (eVAS) scale ranging from 0 (no pain) to 100 (most intense pain tolerable). The equipment was programmed to cease giving stimuli if pain intensity reached the maximum possible score. For each task, the pain detection threshold (PDT), pain tolerance threshold (PTT) and area under the pain intensity–stimulation (−time for cold pressor) curve (AUC) were calculated.

Electrical stimulation task

For cutaneous electrical pain, Ag‐AgCl electrodes (3M Red‐Dot™, 3M Europe, Diegem, Belgium) were placed on the skin, 10 cm distal from the patella overlying the tibia. The electrical stimulus was delivered as two different paradigms by a computer‐controlled constant current stimulator (DS5, Digitimer, Cambridge, UK). For the single stimulus, adapted from methods described previously 16, 17 (10 Hz tetanic pulse with a duration of 0.2 ms), current intensity increased from 0 mA in steps of 0.5 mA·s−1 (cutoff 50 mA). For the repeated stimulus, adapted from methods described previously 18, each single stimulus (train of five, 1 ms square wave pulses repeated at 200 Hz) was repeated five times, with a frequency of 2 Hz at the same current intensity, with a random interval of 3–8 s between the repetitions. Current intensity increased from 0 mA in steps of 0.5 mA (cutoff 50 mA). The pain detection threshold was taken as the value (mA) when a subject indicated either that all five stimuli were painful or that the train of five stimuli, having started as feeling nonpainful became painful (VAS > 0). The pain intensity for each stimulation was measured using the eVAS slider, until the PTT was reached or a maximum of 50 mA was reached.

Pressure stimulation task

The method for inducing mechanical pressure pain was based on methods described previously, and was shown primarily to assess nociception generated from the muscle, with minimal contribution by cutaneous nociceptors 19, 20. Briefly, an 11 cm‐wide tourniquet cuff (VBM Medizintechnik GmbH, Sulz, Germany) was placed over the gastrocnemius muscle with a constant pressure rate increase of 0.5 kPa·s−1. The pneumatic pressure was increased until the subject indicated maximum pain tolerance using the eVAS slider, or a maximum pressure of 100 kPa was achieved, at which point the device released pressure to the cuff.

Cold pressor task

The method of cold pressor pain was based on the methods described previously 21, 22 and is the most commonly used test to induce inhibitory conditioned pain modulation (iCPM, also known as ‘diffuse noxious inhibitory control’) 23. Subjects placed their nondominant hand into a water bath (minimal depth 200 mm) at 35 ± 0.5°C for 2 min. At 1 min 45 s, a blood pressure cuff on the upper arm was inflated to 20 mmHg below resting diastolic pressure. At 2 min, the subject moved that hand from the warm water bath, directly into a similar sized bath at 1.0 ± 0.5°C. The subjects were instructed to indicate when the pain detection threshold was reached as well as the pain intensity, by moving the eVAS slider. When pain tolerance or a time limit (120 s) was reached, subjects were instructed to remove their hand from the water.

Conditioned pain modulation

Conditioned pain modulation is the activation of the pain‐modulatory mechanism, as part of the descending endogenous analgesia system 23. The degree of iCPM was assessed by comparing the electrical pain thresholds for the single stimulus paradigm before and within 5 min after the cold pressor task.

Measurements of drug concentrations in plasma and CSF

Samples for the determination of Xen2174 in the plasma were obtained at baseline, and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 32, 48 and 72 h postdose. CSF samples were obtained using the intrathecal catheter at baseline, and at 0.5, 1, 2, 4, 8, 12, 24 and 32 h postdose. The potential for Xen2174 to adhere to components of the sampling material was tested prior to study execution. Acceptable recovery was obtained. First, 0.2 ml CSF, representing the catheter dead‐space, was sampled and discarded. Subsequently, 0.3 ml was sampled with a new syringe, divided into two cryotubes and frozen at −70°C within 30 min of collection. Plasma was separated within 20 min of blood collection by centrifugation at 2000 g for 10 min. Samples were stored at −70°C until analysis. Plasma and CSF concentrations of Xen2174 were measured via high‐performance liquid chromatography with tandem mass spectrometry detection. The lower limits of quantification were 1.0 ng ml−1 and 10 ng ml−1 for the concentrations of Xen2174 in the plasma and CSF, respectively. Sample analysis was performed by Pharmaceutical Product Development, Inc., Richmond, VA, USA.

EEG

All subjects received a standard 21‐lead clinical EEG at the screening visit. The 1‐h EEG recording was performed to detect subjects with abnormal EEG activity or with preseizure activity when stressed, through hyperventilation (for at least 3 min) and photic stimulation. Study EEG recording was initiated 1 h predose and continued until 24 h postdose. Any change from the baseline EEG observed after dosing, and interpreted in a blinded fashion by the clinical neurophysiologist as clinically significant, was reported as an adverse event (AE).

Statistics

No formal power analysis was performed. However, a previous study in which the electrical stimulation task was performed and where analgesia could be measured in healthy subjects used similar group sizes 16. The statistical analysis plan was part of the study protocol. For Xen2174, all PK parameters were analysed by noncompartmental methods. Summary statistics for each PK parameter were calculated for each dose group. The individual and median concentrations were plotted vs. time, both on a linear and a logarithmic scale. Dose proportionality was assessed from dose‐normalised AUC.

Residual Q‐Q plots were produced, to check the assumption of normality of the error term in the mixed‐effects models. This was done by visual inspection, the Shapiro–Wilk test statistic and the P‐value for the test of normality. All PDT and PTT variables followed a log‐normal distribution and were therefore log‐transformed before analysis. Transformed parameters were back‐transformed after analysis.

To assess the interaction effect of Xen2174 on nociceptive variables, the (transformed) variables were analysed with a mixed‐model analysis of variance, with treatment, time and treatment by time as fixed factor, subject as random factor and the (average) predose value as covariate. The contrasts calculated within the model were between the placebo and active treatments. Contrasts within the overall treatment effect and the time effect were estimated and reported, along with 95% confidence intervals. Subjects assigned to placebo within each cohort were treated as a single group. All calculations were performed using SAS for windows V9.1.3 (SAS Institute, Inc., Cary, NC, USA).

Results

A total of 33 healthy subjects (four females) participated in the study (Figure 1); subjects were aged 18–43 years (mean age 25.6 years) and had a BMI of 19–30 kg m−2 (mean 24.4 kg m−2). The clinical phase of the study started on 28 December 2011, and the last study visit was on 18 June 2012. One subject in cohort 3, in whom CSF sampling was not possible, was replaced. The replacement subject was dosed in an unblinded fashion. Only PK assessments were performed in this subject.

Figure 1.

Figure 1

Flow chart of study design

Owing to sampling problems with the spinal catheter, the study was amended. During the cohort 1 treatment, the diameter of the spinal catheter was increased, and during the cohort 2 treatment the type of spinal catheter was changed. Owing to a high incidence of postlumbar puncture syndrome in cohort 1, only male subjects with a BMI above 23 kg m−2 were recruited in cohorts 2 and 3.

A large number of AEs was observed in this study (Table 2). There was no clear difference in the severity or duration of AEs between the different dosing groups and placebo. The most commonly reported AE was postlumbar puncture syndrome (25 out of 33 subjects). This AE was reported in all dose groups. In the majority of the subjects, complaints of headache as the presentation of postlumbar puncture syndrome started after removal of the spinal sampling catheter. In two subjects, the severity of these complaints was mild, in 16 subjects moderate and in seven subjects severe. Subjects experiencing these complaints were treated with paracetamol and caffeine. Because of inadequate treatment response, 11 subjects were treated with an epidural blood patch; one subject was treated with two epidural blood patches. Evoked pain tasks were not performed subsequent to analgesic dosing for postlumbar puncture syndrome.

Table 2.

Summary of treatment‐emergent adverse events (AEs) by frequency [n(%)]. AEs occurring more than once within one treatment are reported

Treatment Placebo (n = 8) Xen2174 0.5 mg (n = 8) Xen2174 1.0 mg (n = 8) Xen2174 2.5 mg (n = 9)
Subjects with ≥ 1 AE 8 (100) 8 (100) 8 (100) 9 (100)
Number of different AEs 16 15 13 17
Postlumbar puncture syndrome 5 (62.5) 5 (62.5) 7 (87.5) 8 (88.9)
Catheter site‐related reaction 7 (87.5) 3 (37.5) 4 (50.0) 6 (66.7)
Back pain 3 (37.5) 2 (25.0) 4 (50.0) 5 (55.6)
Headache 5 (62.5) 3 (37.5) 4 (50.0) 2 (22.2)
Paraesthesia 3 (37.5) 1 (12.5) 1 (12.5) 1 (11.1)
Dizziness 3 (37.5) 1 (11.1)
Fatigue 1 (12.5) 1 (12.5) 2 (22.2)
Musculoskeletal stiffness 3 (33.3)
Presyncope 2 (25.0) 1 (12.5)
Somnolence 1 (12.5) 2 (22.2)

Other commonly reported AEs were catheter site‐related reaction and back pain. This included a bruised feeling on the back, irritation, pain and stiffness. Paraesthesia was experienced by six subjects – in two during administration, and in four during the period when the catheter was in place. All these complaints were mild, and resolved shortly after spinal catheter removal.

One subject experienced a serious AE during the study. This subject continued to have headache complaints after treatment with the epidural blood patch. He was evaluated at the emergency room of the local university hospital to exclude severe pathology. No abnormalities were found on a computed tomography scan of the head, and the subject was discharged from the hospital the next morning. The headache complaints resolved without sequelae.

One subject reported persistent tinnitus after participation in the study, which persisted beyond the end of the clinical phase of the study. This subject was referred to an otolaryngologist for follow up.

No consistent clinically relevant abnormalities in vital signs, chemistry and haematology blood results, urinalysis, electrocardiograms or 24‐h EEG registrations were observed.

Evoked pain tasks

The mean changes in the least squares means from baseline over 96 h following Xen2174/placebo administration for the different evoked pain task variables (AUC, PDT, PTT) were evaluated. The summary statistics of the PTT are provided in Table 3. The time course for the mean change in the PTT from baseline in the first 48 h following Xen214/placebo administration for the different evoked pain tasks is shown in Figure 2.

Table 3.

Least squares means for the pain tolerance thresholds and estimates of difference, 95% confidence intervals and P‐values for main contrasts

Parameter LS means Contrast
Placebo Xen2174 0.5 mg Xen2174 1.0 mg Xen2174 2.5 mg Treatment P‐value Xen2174 0.5 mg ‐ Placebo Xen2174 1.0 mg ‐ Placebo Xen2174 2.5 mg ‐ Placebo
Cold PTT (s) 39.94 33.18 34.84 38.58 0.5419 –16.9% (−38.1%, 11.5%) P = 0.2072 –12.8% (−35.1%, 17.2%) P = 0.3502 –3.4% (−27.8%, 29.2%) P = 0.8091
Electrical repeated PTT (mA) 11.01 10.06 10.39 14.19 0.0713 –8.7% (−33.4%, 25.2%) P = 0.5610 –5.7% (−30.3%, 27.8%) P = 0.6967 28.9% ( −3.3%, 71.7%) P = 0.0811
Electrical single PTT (mA) 25.54 22.85 22.52 29.92 0.1801 –10.5% (−33.2%, 19.8%) P = 0.4406 –11.8% (−34.0%, 17.8%) P = 0.3805 17.1% (−10.4%, 53.2%) P = 0.2372
iCPM: Delta electrical stair PTT (mA) –1.88 –1.05 –0.83 –1.20 0.7615 0.83 (−1.29, 2.96) P = 0.4294 1.05 (−1.06, 3.16) P = 0.3162 0.68 (−1.48, 2.84) P = 0.5253
Pressure PTT (kPa) 60.52 54.36 53.68 73.95 0.0328 –10.2% (−30.1%, 15.5%) P = 0.3888 –11.3% (−30.7%, 13.6%) P = 0.3285 22.2% ( −5.0%, 57.1%) P = 0.1131

iCPM, inhibitory conditioned pain modulation; kPa, kilopascal; LS, least squares; mA, milliampere; PTT, pain tolerance threshold; s, seconds

Figure 2.

Figure 2

Time course of the mean change from baseline profile in least squares means for the pain tolerance threshold (PTT) for electrical stimulation tasks (single [A] and repeated [B] stimulus), the cold pressor task [C] and the pressure stimulation task [D] after administration of single doses of Xen2174 (0.5, 1.0 or 2.5 mg) or placebo. Vertical lines represent the 95% confidence intervals

Following treatment with Xen2174 2.50 mg, we observed an increase in the PTT over a prolonged period of time for the electrical stimulation tasks [single (overall treatment P‐value, contrast least squares mean of the PTT Xen2174 2.5 mg – placebo (95% confidence interval), contrast P‐value / P = 0.1801, 17.1% (−10.4%, 53.2%), P = 0.2372] and repeated stimulation [P = 0.0713, 28.9% ( −3.3%, 71.7%), P = 0.0811] and the pressure stimulation task [P = 0.0328, 22.2% ( −5.0%, 57.1%), P = 0.1131]. There were no clear differences in PTT between the different dose groups for iCPM [P = 0.7615, 0.68 (−1.48, 2.84), P = 0.5253] or the cold pressor task (P = 0.5419, −3.4% [−27.8%, 29.2%], P = 0.8091). AUCs and PDTs for the different pain tasks did not show any significant results. Seventeen subjects missed one or more nociceptive tests because of concurrent postlumbar puncture headache and treatments.

Drug concentrations in CSF and plasma

The mean PK concentration–time profiles and the corresponding PK variables of Xen2174 in the CSF are shown in Figure 3 and Table 4, respectively. The mean half‐life ranged between 4.27 h and 7.14 h in the CSF. The AUC (concentration–time) from time zero to infinity (AUC0–∞) values increased more than proportionally with dose in all dose groups.

Figure 3.

Figure 3

Mean cerebrospinal fluid (CSF) Xen2174 concentration–time profile by cohort. Vertical lines represent the standard deviation

Table 4.

Cerebrospinal fluid (CSF) pharmacokinetic parameters for Xen2174

Dose Xen2174 (mg) Cmax (ng ml −1 ) Tmax (h) (h) AUC last (h*ng ml −1 ) AUC 0–∞ (h*ng ml −1 )
Xen2174 0.5 mg Mean 4080 0.50 7.14 6532 8081
SD 4090 0.00 4.69 5717 7930
Xen2174 1.0 mg Mean 5600 1.40 4.27 29 655 29 912
SD 3340 1.47 0.790 15 348 15 443
Xen2174 2.5 mg Mean 33 200 0.56 4.83 157 594 159 146
SD 16 600 0.18 0.843 63 810 64 089

AUC0–∞, The area under the curve from time zero to infinity; AUClast, The area under the curve from time zero to the last measurable concentration; Cmax, peak concentration; Tmax, time to reach Cmax; t½, half‐life

The PK concentration–time profiles and variables of Xen2174 in the plasma are shown in Table 5 and Figure 4. In general, concentrations were approximately 500‐ to 2000‐fold lower in the plasma than the CSF. Average plasma peak maximum concentration increased from 5.49 ng ml−1 at the 0.5 mg dose level to 9.75 ng ml−1 at 1 mg and 15.4 ng ml−1 at the 2.5 mg dose level. Cmax appeared to increase slightly less than proportionally with dose between 0.5 and 2.5 mg. The average time to reach the plasma Cmax (Tmax) was 1.94, 3.69 and 6.89 h, for the 0.5, 1, and 2.5 mg doses, respectively. AUC0–∞ increased proportionally to dose.

Table 5.

Plasma pharmacokinetic parameters for Xen2174

Dose Xen2174 (mg) C max (ng ml −1 ) T max (h) (h) AUC last (h*ng ml −1 ) AUC 0‐∞ (h*ng ml −1 )
Xen2174 0.5 mg Mean 5.49 1.94 5.79 34.2 45.3
SD 3.20 1.15 2.38 12.4 10.9
Xen2174 1.0 mg Mean 9.75 3.69 5.96 69.7 87.5
SD 3.49 2.89 3.28 15.9 14.5
Xen2174 2.5 mg Mean 15.4 6.89 8.62 200 221
SD 5.83 3.14 1.41 39.7 39.3

AUC0–∞, The area under the curve from time zero to infinity; AUClast, The area under the curve from time zero to the last measurable concentration; Cmax, peak concentration; SD, standard deviation; Tmax, time to reach Cmax; t½, half‐life

Figure 4.

Figure 4

Mean plasma Xen2174 concentration–time profile by cohort. Vertical lines represent the standard deviation

Discussion

The present study showed that the 2.5 mg dose of Xen2174 administered intrathecally was able to influence pain thresholds in several evoked pain tasks. The pain tasks showed an increase in PTTs for the electrical pain tasks and the pressure pain task in favour of the highest dose of Xen2174 tested, although statistical significance was not reached.

In nonclinical experiments, intrathecal administration of Xen2174 produced anti‐allodynic and antinociceptive effects in rats 12, 15. The chronic constriction injury (CCI) model and the L5/L6 ligation model used in the study by Nielsen et al. 12 are both models for neuropathic pain, while Obata and colleagues 15 used a model of postincisional pain. The models used in the present study were mainly for acute nociceptive pain. Owing to the differences in aetiology in these models, no direct translation can be made between the results in nonclinical results and the results in humans. Dosages in the present study were based on nonclinical data. The EC50 in a functional assay for the binding of Xen2174 to the NET, resulting in the inhibition of NE uptake by the transporter ,was 183 nM, which corresponds to a concentration of 0.26 mg l−1. The ED50 in the CSF for antinociception in the Brennan model for postoperative pain in rats was 0.86 μg intrathecally (hypothetical concentration in the CSF 3.2 mg l−1). The ED50 for anti‐allodynia in the CCI model in rats was 15.7 nmol (22.1 μg, leading to a hypothetical CSF concentration of 81.9 mg l−1) 12. It was expected that dosages in the range of 1.0–2.5 mg would lead to CSF concentrations above the observed EC50 and ED50, and thus induce nociceptive effects. The observed Cmax (after administration of 2.5 mg of Xen2174) in the CSF of 33.2 mg l−1 was above the ED50 for antinociception in the Brennan model but below the ED50 for anti‐allodynia in the CCI model.

The Xen2174 1.0 mg intrathecal dose in dogs was determined as the NOAEL in dogs in nonclinical studies. The ratio of the AUC0–∞ measured in the CSF in the Xen2174 2.5 mg dose group in humans compared with that in dogs after a 1 mg intrathecal injection was 1.43 (unpublished data). A preferred and expected safety margin for this AUC0–∞ ratio for single intrathecal doses of Xen2174 in dogs (expected ratio to be at least 10) was not reached, leading the sponsor to discontinue further development of this compound.

Xen2174 is one of a novel class of NRIs for the treatment of pain. It has been shown to exert its effects via spinal activation of α2‐adrenoceptors subsequent to NE reuptake inhibition 12. Other NRIs include tricyclic antidepressants and tapentadol. The tricyclic antidepressant imipramine increases the PTT for pressure pain and for electrical stimulation 24. Tapentadol combines opioidergic activity with noradrenergic activity, with both mechanisms accounting for the analgesic effects. It is efficacious in the treatment of moderate to severe acute pain compared with placebo 25. Furthermore, tapentadol caused activation of conditioned pain modulation in patients with diabetes in an experimental setting 26.

Several polymorphisms are known for the NET gene (SLC6A2). Patients carrying the homozygous SNP2 G/G variant of this gene reported a longer analgesic onset time after medication administration than heterozygous and A/A homozygous patients 27. Hypothetically, a larger overall analgesic effect could have been observed if SNP2 G/G subjects had been excluded from the study. An equipotent analgesic effect might have been achieved with lower CSF concentrations. Unfortunately, no genotyping for polymorphisms was performed in the present study.

In addition to local anaesthetics, which are used for spinal anaesthesia, there are several analgesic compounds that are intrathecally administered. Clonidine, an α2‐adrenergic receptor agonist, showed analgesic action after intrathecal and epidural administration 28, 29. Ziconotide, a synthetic equivalent of the venom of a marine snail, exerts its effect by binding and blocking voltage‐sensitive calcium channels 30. Opioids show postoperative analgesia when administered intrathecally 31. Intrathecal NSAIDs have been tested for their analgesic efficacy in patients but are not used in current clinical practice 32. Only two studies have reported the use of evoked pain models after intrathecal drug administration 29, 33. Intrathecal ketorolac, an NSAID, was tested in a study in healthy volunteers but did not show an effect on pain from acute heat stimuli 33. Clonidine caused an increase in heat pain tolerance after intrathecal administration 29. In the current study, we confirmed that intrathecal drug administration in combination with performing a battery of evoked pain tasks is feasible, even with concurrent CSF sampling.

An increase of 28.9% in least square means (electrical repeat PTT) and 22.2% (pressure PTT) was observed after administration of Xen2174 compared with placebo. Similar effect sizes for electrical pain (42%) and pressure pain (22%) testing were observed after administration of an analgesic dose of alfentanil in previous research 34, suggesting that the difference we observed in pain tolerance was clinically relevant. The observed increase in PTTs lasts for a long period (Figure 2), whereas the CSF concentration steadily drops (Figure 3). The prolonged analgesic effect cannot be explained by the CSF concentrations but it should be noted that such a measure is a surrogate for tissue concentration and receptor binding, and therefore may reflect a similar distribution to the effect site (reflected by half‐life for equilibration, t1/2,ke0) to that observed with other analgesics and consequential clearance from the effect site 35. Although no mechanistic validation can be provided, the long duration of action has already been observed in nonclinical experiments, in which doses of intrathecal Xen2174 provided longer relief of tactile allodynia in CCI rats compared with morphine 12.

An increase in pain tolerance was observed in the electrical pain tasks and the pressure pain task, but no differences were observed in the cold pressor task. Earlier research with a centrally acting NRI, imipramine, also did not show an effect on the cold pressor task 24. The lack of effect on this task could suggest that administration of Xen2174 has only local effects, at and below the level of administration, but no effects at higher levels – for example, at the level of the brainstem. There was a difference in the level of administration of the study drug (L4–L5) and the dermatomes in which the cold pressor task was performed (C6–C8). In a study in which several amide local anaesthetics were compared, drug administration was performed at the second or third lumbar interspace, and the maximum level of sensory block to pinprick was level T2 in all dose groups 36. This might also be why no effects of Xen2174 on iCPM could be observed. The centrally acting NRI, tapentadol, has been shown to increase iCPM 26. Other explanations for the conflicting outcomes might include the fact that different methods were used to measure iCPM, or differences in patient populations.

Many studies employ evoked pain tasks to assess the analgesic effects of new drugs in healthy human subjects. Most of these studies test only one or two modalities of pain 37. The advantage of the method that was used in the current study was the combination of the different pain tasks in a standardized way. Earlier research has shown the advantages of multi‐modal pain testing 38. Different evoked pain tests have different sensitivities for different analgesics 37. Using only one pain task could lead to a negative trial, while using a broad set of pain tasks could give a better understanding of how the different mechanisms that play a role in evoked pain tests are influenced, and therefore of the different pharmacological properties of a new compound. The models used in the present study represent only acute nociceptive pain models. No spontaneous, chronic or neuropathic pain was investigated. Therefore, caution should be exercised when interpreting our results.

While it has been shown that many different analgesics that are known to be effective in clinical acute and chronic pain management can affect the different tests that were used in this pain battery 37, 39, 40, the acute responses tested in the current study are not necessarily good models of chronic pain. Given the mode of action of Xen2174 to enhance descending inhibition, these acute measures may not adequately assess efficacy in clinical settings of chronic pain.

The limitation of multi‐modal testing is the large number of different outcome variables. In the present study, five PD tests, yielding 15 different variables, were analysed without applying a correction for multiple testing. Only a weak signal for a dose–response relationship was observed in the study. Therefore, the multi‐modal battery of pain tasks should be considered as a first screening tool for studying the analgesic properties of pain compounds in development. When the analgesic effect of a new drug on a certain pain mechanism has been established, predefining a primary outcome measure would prevent the need to correct for multiple testing. Furthermore, the present study was not formally powered for analgesic efficacy on the evoked pain tasks.

CSF sampling was limited in cohorts 1 and 2 because of catheter sampling difficulties. The introduction of a different type of intrathecal catheter improved the sampling success rate in the second part of cohort 2 treatment and in cohort 3. The total volume of CSF in humans is approximately 170 ml 41. Administration of 2.5 mg Xen2174 intrathecally would theoretically lead to a Cmax of 14 705 ng ml−1. We found a Cmax of 33 200 ng ml−1 after administration of 2.5 mg of Xen2174. This may suggest that the study drug was not completely mixed throughout the CSF at Tmax. Alternatively, the CSF volume in which the drug can freely diffuse, even if proper mixing had occurred, was overestimated for yet unknown reasons. The PK in the CSF is different to that in the plasma. Drugs administered intravenously are rapidly distributed within the central distribution volume. The PK of drugs administered in less ‘well‐stirred’, oscillating fluid systems, like the CSF, is more difficult to predict 41, 42; as such, it is difficult to predict drug concentrations at a particular level in the spinal column or intracranially. However, describing the dose–response relationship is more feasible if the site of injection of a drug is directly at the target site 41, which was the case in the present study.

No PK or PK/PD modelling was performed on the data. As discussed previously, the site of administration was the same as that of sampling. As a consequence, the drug concentrations of the CSF samples may have been the sum of the concentration in the CSF and that of the drug solution that had not yet fully distributed throughout the CSF, for which we could not quantitatively correct. The development of a PK model on these CSF data would have resulted in high uncertainty in parameter estimates and large values for variability, also contributed by the limited number of subjects. As a result, the parameter estimates were not expected to have physiological meaning, but merely to describe the observations in the lower spine. Moreover, Xen2174 has a high molecular weight and is therefore not expected passively to cross the blood–brain barrier to a large extent, apart from leakage. Finally, using the PK models that describe the CSF concentrations in the lower spine as the driving force for the PD would also have resulted in parameter estimates with high levels of uncertainty and large between‐subject variability – in our view, parameter estimates that have limited physiological meaning. The purpose of measuring CSF and plasma samples was to provide quantitative evidence of CNS exposure and limited plasma exposure, which, in our view, is sufficiently supported by the noncompartmental analysis. Given the lack of real physiological meaning that PK parameter estimates would have had, it was decided not to develop a PK model; similarly, the development of a PKPD model would not have been logical.

Based on the literature, the incidence of postlumbar puncture syndrome was higher than expected. In a study in which the same intrathecal catheter was used, one out of eight subjects reported headaches 43. A possible explanation for this difference might be the age difference (63.3 years vs. 25.6 years in our study). Younger age is an established risk factor for the occurrence of postlumbar puncture headache. Other reported risk factors are a low BMI and female gender 44. Nonetheless, the exclusion of women and subjects with a BMI below 23 kg m−2 from cohorts 2 and 3 did not reduce the incidence or severity of this AE.

In the present study, there was a weak signal that Xen2174, at a dose of 2.5 mg, increased the PTT for pressure pain. However, at the highest dose level tested, CSF Xen2174 concentrations exceeded the required exposure limit based on the nonclinical safety margins, which makes it unlikely that the compound can be used in practice for the treatment of acute pain.

Competing Interests

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author). P.O., J.L.H., E.S., A.D., E.K. and G.J.G. declare no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work. W.H. is a former employee of Xenome Ltd.

This study was funded by Xenome Ltd.

Contributors

P.O., J.L.H., W.H. and G.J.G. designed the study and wrote the study protocol. P.O., E.S., A.D. and G.J.G. were involved in the clinical execution of the study. E.S., A.D., E.K. and W.H. provided substantial contributions to the study design and the analysis of the data. All authors discussed the results and commented on the manuscript. All authors approved the final paper.

Okkerse, P. , Hay, J. L. , Sitsen, E. , Dahan, A. , Klaassen, E. , Houghton, W. , and Groeneveld, G. J. (2017) Pharmacokinetics and pharmacodynamics of intrathecally administered Xen2174, a synthetic conopeptide with norepinephrine reuptake inhibitor and analgesic properties. Br J Clin Pharmacol, 83: 751–763. doi: 10.1111/bcp.13176.

Trial registration: The trial was registered in the trial register of the Committee on Research Involving Human Subjects (CCMO, https://www.toetsingonline.nl, NL38941.056.11).

References

  • 1. Southan C, Sharman JL, Benson HE, Faccenda E, Pawson AJ, Alexander SP, et al. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. Nucl Acids Res 2016; 44 (Database Issue): D1054–D1068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Alexander SPH, Davenport AP, Kelly E, Marrion N, Peters JA, Benson HE, et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein‐coupled receptors. Br J Pharmacol 2015; 172: 5744–5869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Alexander SPH, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, et al. The Concise Guide to PHARMACOLOGY 2015/16: Transporters. Br J Pharmacol 2015; 172: 6110–6202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg 2003; 97: 534–540. [DOI] [PubMed] [Google Scholar]
  • 5. Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G. Analgesic drugs In: Rang and Dale's Pharmacology, 7 edn, eds Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G. London, United Kingdom: Elsevier, 2012; 510–524. [Google Scholar]
  • 6. Maund E, McDaid C, Rice S, Wright K, Jenkins B, Woolacott N. Paracetamol and selective and non‐selective non‐steroidal anti‐inflammatory drugs for the reduction in morphine‐related side‐effects after major surgery: a systematic review. Br J Anaesth 2011; 106: 292–297. [DOI] [PubMed] [Google Scholar]
  • 7. Popping DM, Zahn PK, Van Aken HK, Dasch B, Boche R, Pogatzki‐Zahn EM. Effectiveness and safety of postoperative pain management: a survey of 18 925 consecutive patients between 1998 and 2006 (2nd revision): a database analysis of prospectively raised data. Br J Anaesth 2008; 101: 832–840. [DOI] [PubMed] [Google Scholar]
  • 8. Sharpe IA, Gehrmann J, Loughnan ML, Thomas L, Adams DA, Atkins A, et al. Two new classes of conopeptides inhibit the alpha1‐adrenoceptor and noradrenaline transporter. Nat Neurosci 2001; 4: 902–907. [DOI] [PubMed] [Google Scholar]
  • 9. Sharpe IA, Palant E, Schroeder CI, Kaye DM, Adams DJ, Alewood PF, et al. Inhibition of the norepinephrine transporter by the venom peptide chi‐MrIA. Site of action, Na + dependence, and structure–activity relationship. J Biol Chem 2003; 278: 40317–40323. [DOI] [PubMed] [Google Scholar]
  • 10. Bryan‐Lluka LJ, Bonisch H, Lewis RJ. chi‐Conopeptide MrIA partially overlaps desipramine and cocaine binding sites on the human norepinephrine transporter. J Biol Chem 2003; 278: 40324–40329. [DOI] [PubMed] [Google Scholar]
  • 11. McIntosh JM, Corpuz GO, Layer RT, Garrett JE, Wagstaff JD, Bulaj G, et al. Isolation and characterization of a novel conus peptide with apparent antinociceptive activity. J Biol Chem 2000; 275: 32391–32397. [DOI] [PubMed] [Google Scholar]
  • 12. Nielsen CK, Lewis RJ, Alewood D, Drinkwater R, Palant E, Patterson M, et al. Anti‐allodynic efficacy of the chi‐conopeptide, Xen2174, in rats with neuropathic pain. Pain 2005; 118: 112–124. [DOI] [PubMed] [Google Scholar]
  • 13. Brust A, Palant E, Croker DE, Colless B, Drinkwater R, Patterson B, et al. chi‐Conopeptide pharmacophore development: toward a novel class of norepinephrine transporter inhibitor (Xen2174) for pain. J Med Chem 2009; 52: 6991–7002. [DOI] [PubMed] [Google Scholar]
  • 14. Sindrup SH, Otto M, Finnerup NB, Jensen TS. Antidepressants in the treatment of neuropathic pain. Basic Clin Pharmacol Toxicol 2005; 96: 399–409. [DOI] [PubMed] [Google Scholar]
  • 15. Obata H, Conklin D, Eisenach JC. Spinal noradrenaline transporter inhibition by reboxetine and Xen2174 reduces tactile hypersensitivity after surgery in rats. Pain 2005; 113: 271–276. [DOI] [PubMed] [Google Scholar]
  • 16. Dahan A, Romberg R, Teppema L, Sarton E, Bijl H, Olofsen E. Simultaneous measurement and integrated analysis of analgesia and respiration after an intravenous morphine infusion. Anesthesiology 2004; 101: 1201–1209. [DOI] [PubMed] [Google Scholar]
  • 17. Olofsen E, Romberg R, Bijl H, Mooren R, Engbers F, Kest B, et al. Alfentanil and placebo analgesia: no sex differences detected in models of experimental pain. Anesthesiology 2005; 103: 130–139. [DOI] [PubMed] [Google Scholar]
  • 18. Arendt‐Nielsen L, Frokjaer JB, Staahl C, Graven‐Nielsen T, Huggins JP, Smart TS, et al. Effects of gabapentin on experimental somatic pain and temporal summation. Reg Anesth Pain Med 2007; 32: 382–388. [DOI] [PubMed] [Google Scholar]
  • 19. Polianskis R, Graven‐Nielsen T, Arendt‐Nielsen L. Computer‐controlled pneumatic pressure algometry – a new technique for quantitative sensory testing. Eur J Pain 2001; 5: 267–277. [DOI] [PubMed] [Google Scholar]
  • 20. Polianskis R, Graven‐Nielsen T, Arendt‐Nielsen L. Pressure‐pain function in desensitized and hypersensitized muscle and skin assessed by cuff algometry. J Pain 2002; 3: 28–37. [DOI] [PubMed] [Google Scholar]
  • 21. Eckhardt K, Li S, Ammon S, Schanzle G, Mikus G, Eichelbaum M. Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation. Pain 1998; 76: 27–33. [DOI] [PubMed] [Google Scholar]
  • 22. Jones SF, McQuay HJ, Moore RA, Hand CW. Morphine and ibuprofen compared using the cold pressor test. Pain 1988; 34: 117–122. [DOI] [PubMed] [Google Scholar]
  • 23. Pud D, Granovsky Y, Yarnitsky D. The methodology of experimentally induced diffuse noxious inhibitory control (DNIC)‐like effect in humans. Pain 2009; 144: 16–19. [DOI] [PubMed] [Google Scholar]
  • 24. Enggaard TP, Poulsen L, Arendt‐Nielsen L, Hansen SH, Bjornsdottir I, Gram LF, et al. The analgesic effect of codeine as compared to imipramine in different human experimental pain models. Pain 2001; 92: 277–282. [DOI] [PubMed] [Google Scholar]
  • 25. Frampton JE. Tapentadol immediate release: a review of its use in the treatment of moderate to severe acute pain. Drugs 2010; 70: 1719–1743. [DOI] [PubMed] [Google Scholar]
  • 26. Niesters M, Proto PL, Aarts L, Sarton EY, Drewes AM, Dahan A. Tapentadol potentiates descending pain inhibition in chronic pain patients with diabetic polyneuropathy. Br J Anaesth 2014; 113: 148–156. [DOI] [PubMed] [Google Scholar]
  • 27. Kim H, Lee H, Rowan J, Brahim J, Dionne RA. Genetic polymorphisms in monoamine neurotransmitter systems show only weak association with acute post‐surgical pain in humans. Mol Pain 2006; 2: 24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Eisenach JC, De KM, Klimscha W. alpha(2)‐adrenergic agonists for regional anesthesia. A clinical review of clonidine (1984–1995). Anesthesiology 1996; 85: 655–674. [DOI] [PubMed] [Google Scholar]
  • 29. Ginosar Y, Riley ET, Angst MS. Analgesic and sympatholytic effects of low‐dose intrathecal clonidine compared with bupivacaine: a dose–response study in female volunteers. Br J Anaesth 2013; 111: 256–263. [DOI] [PubMed] [Google Scholar]
  • 30. Webster LR, Fakata KL, Charapata S, Fisher R, MineHart M. Open‐label, multicenter study of combined intrathecal morphine and ziconotide: addition of morphine in patients receiving ziconotide for severe chronic pain. Pain Med 2008; 9: 282–290. [DOI] [PubMed] [Google Scholar]
  • 31. Fournier R, Weber A, Gamulin Z. Intrathecal sufentanil is more potent than intravenous for postoperative analgesia after total‐hip replacement. Reg Anesth Pain Med 2005; 30: 249–254. [DOI] [PubMed] [Google Scholar]
  • 32. Angst MS. Intrathecal cyclooxygenase inhibitors in humans: don't throw in the towel! Anesthesiology 2010; 112: 1082–1083. [DOI] [PubMed] [Google Scholar]
  • 33. Eisenach JC, Curry R, Tong C, Houle TT, Yaksh TL. Effects of intrathecal ketorolac on human experimental pain. Anesthesiology 2010; 112: 1216–1224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. Luginbuhl M, Schnider TW, Petersen‐Felix S, Arendt‐Nielsen L, Zbinden AM. Comparison of five experimental pain tests to measure analgesic effects of alfentanil. Anesthesiology 2001; 95: 22–29. [DOI] [PubMed] [Google Scholar]
  • 35. Lotsch J, Skarke C, Schmidt H, Grosch S, Geisslinger G. The transfer half‐life of morphine‐6‐glucuronide from plasma to effect site assessed by pupil size measurement in healthy volunteers. Anesthesiology 2001; 95: 1329–1338. [DOI] [PubMed] [Google Scholar]
  • 36. Luck JF, Fettes PD, Wildsmith JA. Spinal anaesthesia for elective surgery: a comparison of hyperbaric solutions of racemic bupivacaine, levobupivacaine, and ropivacaine. Br J Anaesth 2008; 101: 705–710. [DOI] [PubMed] [Google Scholar]
  • 37. Oertel BG, Lotsch J. Clinical pharmacology of analgesics assessed with human experimental pain models: bridging basic and clinical research. Br J Pharmacol 2013; 168: 534–553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38. Staahl C, Reddy H, Andersen SD, Arendt‐Nielsen L, Drewes AM. Multi‐modal and tissue‐differentiated experimental pain assessment: reproducibility of a new concept for assessment of analgesics. Basic Clin Pharmacol Toxicol 2006; 98: 201. [DOI] [PubMed] [Google Scholar]
  • 39. Olesen AE, Andresen T, Staahl C, Drewes AM. Human experimental pain models for assessing the therapeutic efficacy of analgesic drugs. Pharmacol Rev 2012; 64: 722–779. [DOI] [PubMed] [Google Scholar]
  • 40. Staahl C, Olesen AE, Andresen T, Arendt‐Nielsen L, Drewes AM. Assessing efficacy of non‐opioid analgesics in experimental pain models in healthy volunteers: an updated review. Br J Clin Pharmacol 2009; 68: 322–341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Kuttler A, Dimke T, Kern S, Helmlinger G, Stanski D, Finelli LA. Understanding pharmacokinetics using realistic computational models of fluid dynamics: biosimulation of drug distribution within the CSF space for intrathecal drugs. J Pharmacokinet Pharmacodyn 2010; 37: 629–644. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42. Shen DD, Artru AA, Adkison KK. Principles and applicability of CSF sampling for the assessment of CNS drug delivery and pharmacodynamics. Adv Drug Deliv Rev 2004; 56: 1825–1857. [DOI] [PubMed] [Google Scholar]
  • 43. den Daas I, Wemer J, Abou FK, Tamminga W, de BT , Spanjersberg R, et al. Serial CSF sampling over a period of 30 h via an indwelling spinal catheter in healthy volunteers: headache, back pain, tolerability and measured acetylcholine profile. Eur J Clin Pharmacol 2013; 69: 1083–1090. [DOI] [PubMed] [Google Scholar]
  • 44. Kuntz KM, Kokmen E, Stevens JC, Miller P, Offord KP, Ho MM. Post‐lumbar puncture headaches: experience in 501 consecutive procedures. Neurology 1992; 42: 1884–1887. [DOI] [PubMed] [Google Scholar]

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