Dihydroetorphine for the provision of pain relief and anaesthesia

Abstract

The present invention provides a method of providing pain relief in a human subject in need thereof comprising administering (R)-dihydroetorphine to said subject, wherein said (R)-dihydroetorphine is administered in a dose of at least 0.01 g/kg, preferably at least 0.05 g/kg, and the level of respiratory depression in said subject is 65 or less % relative to the baseline level pre-administration of (R)-dihydroetorphine.

Claims

1. A method of providing pain relief in a human subject in need thereof comprising administering (R)-dihydroetorphine to said subject, wherein said (R)-dihydroetorphine is administered intravenously in a dose of 0.075 to 0.15 g/kg, wherein said dose provides a level of respiratory depression in said subject of 65% or less relative to a baseline level pre-administration of (R)-dihydroetorphine.

2. The method as claimed in claim 1, wherein the level of respiratory depression in said subject provided by said dose is between 20 and 65% relative to the baseline level pre-administration of (R)-dihydroetorphine.

3. The method as claimed in claim 1, wherein said respiratory depression is the average respiratory depression measured under iso-hypercapnic conditions for 1 hour following administration of said dose of (R)-dihydroetorphine intravenously over 10 minutes.

4. The method as claimed in claim 1, wherein said method increases a pain threshold level in said subject relative to a baseline level pre-administration of (R)-dihydroetorphine by at least 1.2 times.

5. The method as claimed in claim 1, wherein the pain is nociceptive pain.

6. A method of providing pain relief in a human subject in need thereof comprising administering (R)-dihydroetorphine to said subject, wherein said (R)-dihydroetorphine is administered intravenously in a dose of 0.075 to 0.15 g/kg, wherein said dose provides a peak respiratory depression in said subject of 20 to 80% relative to a baseline level pre-administration of (R)-dihydroetorphine.

7. The method as claimed in claim 6, wherein the peak respiratory depression in said subject provided by said dose is 30 to 40% relative to the baseline level prior to administration of (R)-dihydroetorphine.

8. The method as claimed in claim 6, wherein the peak respiratory depression is measured under iso-hypercapnic conditions for 1 hour following administration of said dose of (R)-dihydroetorphine intravenously over 10 minutes.

9. The method as claimed in claim 6, wherein said method increases a pain threshold level in said subject relative to a baseline level pre-administration of (R)-dihydroetorphine by at least 1.2 times.

10. The method as claimed in claim 6, wherein the pain is nociceptive pain.

11. A method of providing pain relief in a human subject in need thereof comprising administering (R)-dihydroetorphine to said subject, wherein said (R)-dihydroetorphine is administered intravenously in a dose of 0.075 to 0.15 g/kg, wherein said dose provides a ventilation ratio in said subject of at least 0.3.

12. The method as claimed in claim 11, wherein the ventilation ratio in said subject is between 0.3 and 0.6.

13. The method as claimed in claim 11, wherein the ventilation ratio in said subject is 0.3 to 0.5.

14. The method as claimed in claim 11, wherein the ventilation ratio is determined by measuring respiration pre-administration of (R)-dihydroetorphine and measuring respiration for 1 hour under iso-hypercapnic conditions post-administration of said dose of (R)-dihydroetorphine, wherein the (R)-dihydroetorphine is administered intravenously over 10 minutes.

15. The method as claimed in claim 11, wherein said method increases a pain threshold level in said subject relative to a baseline level pre-administration of (R)-dihydroetorphine by at least 1.2 times.

16. The method as claimed in claim 11, wherein the pain is nociceptive pain.

17. A method of providing pain relief in a human subject in need thereof whilst minimising risk of apnoea comprising administering (R)-dihydroetorphine to said subject, wherein a dose of (R)-dihydroetorphine that provides dose dependent pain relief and dose-independent respiratory depression is administered, wherein said (R)-dihydroetorphine is administered intravenously in a dose of 0.075 to 0.15 g/kg.

18. The method as claimed in claim 17, wherein a level of respiratory depression in said subject provided by said dose is between 40 and 65% relative to a baseline level pre-administration of (R)-dihydroetorphine.

19. The method as claimed in claim 17, wherein the level of respiratory depression in said subject provided by said dose is between 30 and 50% relative to the baseline level pre-administration of (R)-dihydroetorphine.

20. The method as claimed in claim 17, wherein said respiratory depression is the average respiratory depression measured under iso-hypercapnic conditions for 1 hour following administration of said dose of (R)-dihydroetorphine intravenously over 10 minutes.

21. The method as claimed in claim 17, wherein said method increases a pain threshold level in said subject relative to a baseline level pre-administration of (R)-dihydroetorphine by at least 1.2 times.

22. The method as claimed in claim 17, wherein the pain is nociceptive pain.

23. A method of providing pain relief in a human subject in need thereof comprising administering (R)-dihydroetorphine to said subject intravenously in a dose of 0.075 to 0.15 g/kg, wherein said dose provides reduction in at least one opioid-related side effect when compared to the effect of a treatment with an equianalgesic dose of fentanyl.

24. The method as claimed in claim 23, wherein said opioid-related side effect is selected from the group consisting of respiratory depression, dizziness, euphoria, nausea, sedation and dysphoria.

25. The method as claimed in claim 24, wherein said opioid-related side effect provided by said dose is respiratory depression and said respiratory depression is 0 to 65%.

26. The method as claimed in claim 24, wherein said opioid-related side effect provided by said dose is respiratory depression and said respiratory depression is an average respiratory depression measured under iso-hypercapnic conditions for 1 hour following administration of said dose of (R)-dihydroetorphine intravenously over 10 minutes.

27. The method as claimed in claim 23, wherein said method increases a pain threshold level in said subject relative to a baseline level pre-administration of (R)-dihydroetorphine by at least 1.2 times.

28. The method as claimed in claim 23, wherein the pain is nociceptive pain.

29. A method of providing pain relief in a human subject in need thereof comprising administering (R)-dihydroetorphine to said subject intravenously in a dose of 0.075 to 0.15 g/kg, wherein said dose provides opioid-related respiratory depression of 65% or less relative to a baseline level pre-administration of (R)-dihydroetorphine and at least one of the following criteria is satisfied in 7.5 hours post administration of (R)-dihydroetorphine: average NAS score for dizziness of 0 to 50, average NAS score for euphoria of 0 to 60, average NAS score for nausea of 0 to 40, average NAS score for sedation of 0 to 60, or average NAS score for dysphoria of 0 to 40.

30. The method as claimed in claim 29, wherein the level of respiratory depression in said subject provided by said dose is between 20 and 65% relative to the baseline level pre-administration of (R)-dihydroetorphine.

31. The method as claimed in claim 29, wherein said method increases a pain threshold level in said subject relative to a baseline level pre-administration of (R)-dihydroetorphine by at least 1.2 times.

32. The method as claimed in claim 29, wherein the pain is nociceptive pain.

Description

(1) The present invention will now be described with reference to the following non-limiting example wherein:

(2) FIG. 1 illustrates calculation of average respiratory drug effect;

(3) FIG. 2a shows the plots of ventilation (L/min) versus time in the pilot study for placebo and eight R-DHE dosages;

(4) FIG. 2b shows a plot of ventilation ratio versus R-DHE dose in the pilot study (The data in panel B are meanSD);

(5) FIG. 2c shows a plot of % respiratory depression versus R-DHE dose in the pilot study (The data in panel C are meanSD);

(6) FIG. 3a shows the plots of ventilation (L/min) versus time in the main phase of the study for placebo and four R-DHE dosages;

(7) FIG. 3b shows a plot of ventilation ratio versus R-DHE dose in the main phase of the study (The data in panel B is meanSD);

(8) FIG. 3c shows a plot of % respiratory depression versus R-DHE dose in the main phase of the study (The data in panel C is meanSD);

(9) FIG. 4a shows the plots of ventilation (L/min) versus time in the main phase of the study for placebo and four fentanyl dosages;

(10) FIG. 4b shows a plot of ventilation ratio versus fentanyl dose in the main phase of the study (The data in panel B is meanSD);

(11) FIG. 4c shows a plot of % respiratory depression versus fentanyl dose in the main phase of the study;

(12) FIG. 5 shows model fits of ventilation ratio versus dose for R-DHE (A) and fentanyl (B);

(13) FIG. 6a shows the effect of R-DHE and fentanyl on peak analgesia, defined as the highest value of pain threshold in mA;

(14) FIG. 6b shows the effect of R-DHE and fentanyl on average analgesic effect, defined as the area under the pain threshold curve (AUC) from t=0 to t=8 h normalised by the baseline area.

(15) FIG. 7a shows the maximum and mean NAS scores for nausea during pain relief treatment with each of a dose of 0.15 g/kg (R)-dihydroetorphine, 3 g/kg fentanyl and placebo;

(16) FIG. 7b shows the maximum and mean NAS scores for sedation during pain relief treatment with each of a dose of 0.15 g/kg (R)-dihydroetorphine, 3 g/kg fentanyl and placebo;

(17) FIG. 7c shows the maximum and mean NAS scores for dizziness during pain relief treatment with each of a dose of 0.15 g/kg (R)-dihydroetorphine, 3 g/kg fentanyl and placebo;

(18) FIG. 7d shows the maximum and mean NAS scores for euphoria during pain relief treatment with each of a dose of 0.15 g/kg (R)-dihydroetorphine, 3 g/kg fentanyl and placebo;

(19) FIG. 7e shows the maximum and mean NAS scores for dysphoria during pain relief treatment with each of a dose of 0.15 g/kg (R)-dihydroetorphine, 3 g/kg fentanyl and placebo;

(20) FIG. 8 shows the R-DHE dose response in the cold pressor test model for nociceptive pain

(21) FIG. 9 shows a questionnaire for completing by patients in assessing other opioid-related side effects associated with treatment of each of 0.15 g/kg (R)-dihydroetorphine and 3 g/kg fentanyl at intervals for 7.5 hours, starting 1 hour after administration of drug was ceased, wherein the scale 0-100 for each side effect is a NAS score.

EXAMPLES

Example 1a

(22) In the examples R-DHE was compared to fentanyl, which is a selective and high affinity MOR agonist that produces dose-dependent respiratory depression and apnoea at high dose (2-3 g/kg and greater). Fentanyl is currently the opioid of choice for the treatment of many types of moderate to severe pain.

(23) Methods

(24) The phase 1 study had two parts. Initially a dose-ascending, cohort group, single-blinded pilot study (part 1) was performed for dose-finding. After the pilot study was completed, the R-DHE doses were selected for the main study (part 2), a randomised, double-blind, placebo- and active comparator (fentanyl)-controlled study was performed. Parallel group study was performed.

(25) Subjects

(26) One hundred and two male healthy volunteers (10 in the pilot study and 92 in the main study) participated in the study after approval of the protocol was obtained from the Leiden University Medical Center (LUMC) Human Ethics Committee and the Central Committee on Research Involving Human Subjects (CCMO, The Hague). Written and oral informed consent was obtained prior to enrolment of the volunteers into the study. All volunteers provided a medical history and a physical examination, 12-lead ECG and blood screening was conducted before enrolment. The eligible volunteers were between the ages of 18 and 45 years, weighed between 65 and 100 kg, had a body mass index between 18 and 30 kg/m.sup.2 and a forced expired lung volume in 1 s of >85% of predicted. Study subjects were healthy with no history of major medical disease, alcohol abuse, illicit drug use or heavy smoking. Volunteers had not used medication (including vitamins, herbal and/or mineral supplements) in the seven days preceding dosing, or during the course of the study, or opioids or opioid antagonists in the 90 days prior to dosing. Finally, participants had to fast for at least 6 hours prior to the administration of study medication.

(27) Study Design

(28) Pilot studyThe respiratory effects of 3 escalating doses of R-DHE and 1 infusion of placebo were tested on 4 separate days with at least 1 week for wash out between test sessions. Three subjects received 0.025, 0.05 and 0.1 g/kg R-DHE and placebo (cohort 1), three others 0.0125, 0.075 and 0.1 g/kg R-DHE and placebo (cohort 2) and the last three subjects 0.05, 0.125 and 0.15 g/kg R-DHE and placebo (cohort 3). From the results of this study the doses of the main study were determined. After infusion of the drug was completed ventilation was continuously measured breath to breath for 1 hour under iso-hypercapnic conditions (see below).

(29) Main studyIn this double-blind randomized study 92 volunteers participated. None of them had been part of the pilot study and all were dosed only once. 46 subjects participated in the respiratory part of the study and the 46 other subjects in the analgesia part. In both parts, placebo (n=6), 0.0125 g/kg R-DHE (n=4), 0.075 g/kg R-DHE (n=6), 0.125 g/kg R-DHE (n=6), 0.15 g/kg R-DHE (n=4), 0.5 g/kg fentanyl (n=4), 1 g/kg fentanyl (n=6), 2 g/kg fentanyl (n=6) and 3 g/kg fentanyl (n=4) was administered by intravenous infusion over 10 minutes. The randomization list was prepared by the sponsor of the study and sent to the local pharmacy where blinded syringes were prepared based on the weight of the subject. Each syringe was identical in size, drug volume and color and was unmarked. The randomization list was available to the sponsor, the pharmacy and an independent data safety monitoring committee.

(30) Study Medications

(31) Placebo was normal saline (0.9% NaCl).

(32) Fentanyl was obtained from Hameln Pharmaceuticals (Hameln Germany).

(33) R-DHE was manufactured by SCM Pharma Limited on behalf of Mundipharma Research Limited (Cambridge, UK).

(34) Solutions of each of R-DHE and fentanyl were prepared by conventional techniques.

(35) All drugs were infused intravenously (through an intravenous line in the arm or hand) using a syringe pump (Beckton Dickinson, St. Etienne, France).

(36) Respiratory Measurements

(37) Following infusion, ventilation was continuously measured on a breath-to-breath basis for 1 hour under iso-hypercapnic conditions. End-tidal gas forcing and data acquisition were performed using the dynamic end-tidal forcing technique. This technique is well established and is described in, inter alia, Journal of Physiology (1990), 428, 485-499, PLoS Medicine (2007), 4, e239, 1195-1203 and British Journal of Anaesthesia (2005), 94(6), 825-834, the entire contents of which are hereby incorporated by reference. The advantages of the end-tidal forcing technique are that respiratory response of the test drug is (1) independent of the confounding effects of changes in arterial CO.sub.2 and (2) independent of the speed of administration of the drug. The technique therefore allows reliable comparison of drug effect on the ventilatory control system, i.e. differences induced by R-DHE and fentanyl in dose-response relationships are due to CO.sub.2-independent differences in pharmacokinetics and dynamics.

(38) The dynamic end-tidal forcing technique enables the investigator to force end-tidal PCO.sub.2 and end tidal PO.sub.2 to follow a specific pattern over time. In the current study the end-tidal oxygen (O.sub.2) level was clamped to a value of 110 mmHg, while the end-tidal carbon dioxide (CO.sub.2) concentration was slowly increased to a value that caused ventilation levels of 202 L/min. This end-tidal CO.sub.2 value was maintained throughout the study. On average this was achieved by increasing end-tidal PCO.sub.2 to 6.65 kPa (50 mmHg).

(39) The volunteers were comfortably positioned in a hospital bed and breathed through a face mask positioned over their nose and mouth which was connected to a pneumotachograph and differential pressure transducer (#4813, Hans Rudolph, Myandotta, Mich.). The pneumotachograph received fresh gas from a gas-mixing system consisting of three mass flow controllers (Bronkhorst High Tech, Veenendaal, The Netherlands) for oxygen, carbon dioxide and nitrogen. A personal computer running ACQ software (Erik Kruyt, Leiden University Medical Center, Leiden, The Netherlands) provided control signals to the mass flow controllers, allowing adjustment of the inspired gas concentrations to steer the end-tidal O.sub.2 and CO.sub.2 concentrations according to a pre-set pattern over time. The inspired and expired oxygen and carbon dioxide concentrations and the arterial hemoglobin-oxygen saturation were measured with a Datex Multicap gas monitor (near the mouth) and Datex Satellite Plus pulse oximeter, respectively (Datex-Engstrom, Helsinki, Finland). End-tidal concentrations of oxygen and carbon dioxide, inspired minute ventilation (Vi), and oxygen saturation were collected for further analysis. Ventilation levels and end-tidal concentrations were observed in real time on a breath-to-breath basis on a computer screen.

(40) Respiratory measurements started when the inspired minute ventilation had reached a steady state; 4-5 min later drug infusion was started. Respiratory measurements ended 65 min after the end of drug infusion (t=70 min).

(41) Pain Measurements

(42) Pain was induced using a transcutaneous electrical stimulus to the skin over the left tibial bone (10 cm above the ankle). A 20 Hz (pulse duration 0.1 ms) stimulus train was delivered to the subject causing activation of cutaneous nociceptors. The stimulus train started at 0 mA and was increased at a rate of 0.5 mA per 2 s (with a cut-off value of 128 mA). The delivery of the current was controlled by a computer via a current stimulator which was connected to a control box with two buttons. The subject was instructed to press the first button when pain was felt (i.e. pain threshold) and the second button when the subject wanted the stimulus train to stop (i.e. pain tolerance). These respective currents were collected on disc for further analysis. The subject was familiarized with the system prior to the study to obtain reliable baseline values. In this study, the pain threshold values were used in the analysis. Four pain threshold values (i.e. predrug values) were obtained in the 30 minutes prior to drug infusion. These values were averaged and served as a baseline estimate. Following drug infusion, pain measurements were obtained at the following time points (t=0 is the start of drug infusion): 10 (end of infusion), 15, 30, 45, 65, 75, 90, 105, 120, 150, 180, 210, 240, 300, 365, 420 and 480 min.

(43) Sample Size and Statistical Analysis

(44) The pilot study was designed to determine which doses of R-DHE to be tested in the main study. Four doses were chosen for the main study, 0.0125 g/kg, 0.125 g/kg, 0.075 g/kg and 0.15 g/kg.

(45) For the main study, sample size selection was achieved by performing a power analysis in NONMEM (Beal, B. L., Sheiner, L. B., Boeckman, A. J., Bauer, R. J., User's Guide, Icon Development Solutions, Ellicott City, Md., 1989-2011) using estimated data on the effect of opioids on respiratory depression (pilot study and Clin. Pharmacol. Ther. 2007, 81: 50-58). An inter-subject variability in effect of 50% (.sup.2=0.25) and a 10% residual error for effect (.sup.2=0.01) and aimed to detect a value of <0.5 or >2 (where C.sub.50A(R-DHE)/C.sub.50R(R-DHE)=C.sub.50A(FENTANYL)/C.sub.50R(FENTANYL) and C.sub.50A and C.sub.50R are the concentrations causing 50% analgesia and respiratory depression for drugs R-DHE (R-DHE) and fentanyl (FENTANYL), respectively) with <0.05 and =0.8. In the analysis we assumed that C.sub.50A(R-DHE)=C.sub.50A(FENTANYL) (i.e. concentrations are equianalgesic). Values of <0.5 indicated that fentanyl produces respiratory depression at concentrations at least twice as low as R-DHE and vice versa for >2. It was assumed that the logarithm of the C.sub.50 ratio has a normal distribution with variance=1. The sample size selection was then verified by simulations in NONMEM with 1,000 simulated data sets. The analysis resulted in a sample size of 34, which was rounded upwards to 40 (20 subjects per opioid treatment). Six additional subjects were added to receive placebo. The subject number chosen for the analgesia part of the study was identical to that calculated for the respiratory part of the study.

(46) Average Respiratory Drug Effect

(47) The breath-to-breath data were averaged over 1-min episodes. In order to get an impression of the average drug effect on respiration, we calculated the area below the respiration curve (AUC) from t=0 to t=70. Referring to FIG. 1, first the area-under-the curve (AUC) was calculated for the respiration curve (blue line from A to A). This AUC (grey field) was subtracted from the area obtained by taking baseline ventilation (A) forward (the arrow from point A to B; the baseline area AUC is the box depicted by the red broken lines ABCD). Next the data were normalized by the baseline area giving an average % of respiratory depression (average drug effect=[baseline area AUCAUC]/baseline area AUC An average drug effect of 40 indicates an average of 40% respiratory depression over the measured time period (0-70 min). The average drug effect and time to peak effect were analyzed using a one-way analysis of variance (factor dose). The R-DHE and fentanyl data were analyzed separately in Sigmaplot v12.3 (Systat Software GmbH, Ekrath, Germany). P-values <0.05 were considered significant. Values given are meanSD.

(48) Peak Respiratory Depression

(49) For each subject peak respiratory depression was calculated as the nadir in ventilation and presented as ratio relative to baseline (e.g. a value of 0.5 indicates a nadir in ventilation in magnitude 50% of baseline ventilation). Using the statistical package R (version 8.2; www.r-project.org), a sigmoid E function was fitted through the R-DHE and fentanyl dose-effect data (effect=peak respiratory depression) using a model of the form:
Peak effect(dose)=100+[E.sub.MIN100][dose.sup.+ED.sub.50.sup.]eqn. (1)
where ED.sub.50 is the dose causing a 50% effect (ventilation in the middle of baseline ventilation and E.sub.MIN), E.sub.MIN the asymptotic minimum in ventilation, and a shape parameter. P-values <0.01 were considered significant. The data analysis was performed on the complete data set (fentanyl data and R-DHE data from pilot and main studies). The data are presented as meanSD.
Analgesic Effect

(50) Two measures of analgesic effect were calculated in each experiment: peak analgesia (defined as the highest value of pain threshold in mA) and average analgesic effect (as defined as the area under the pain threshold curve from t=0 to t=8 h normalised by the baseline area, see above). Peak and average analgesic effects were analyzed using a one-way analysis of variance (factor dose). The R-DHE and fentanyl data were analyzed separately using SigmaPlot v 12.3. P-values <0.05 were considered significant. Values given are meanSD.

(51) Results

(52) Pilot studyNine volunteers completed the study without unexpected side effects. One subject developed ECG changes that, although not clinically relevant, precluded proper assessment of the effect of the study medication on the ECG. As a precautionary measure, another subject replaced this subject after having completed a placebo and 0.05 g/kg R-DHE experiment.

(53) The clamped end-tidal PCO.sub.2 was 6.60.5 kPa (49.53.8 mmHg) and baseline (pre-drug) ventilation was 21.51.7 L/min. The mean respiratory responses to R-DHE are given in FIG. 2A. All dosages of R-DHE displayed a nadir in ventilation, which occurred at t=17.13.8 min following the start of drug infusion. The respiratory responses to R-DHE dosages of 0.075, 0.10, 0.125 and 0.15 g/kg overlap. The dose-response curves (peak respiratory depression and average drug effect) are given in FIGS. 2B and C showing that the dose-response levels off at dosages of 0.075 g/kg and greater (R-DHE 0.075, 0.125 and 0.15 g/kg: P>0.05). The peak respiratory depression occurred with doses of 0.075 g/kg and greater at a ventilation ratio of about 0.4. The average % respiratory depression reached a ceiling of about 40-45% with doses 0.075 g/kg and greater. With a 40-45% average respiratory depression, the average level of respiration achieved in the volunteer who received the drug was 55-60% relative to baseline.

(54) A small positive trend was observed in the ventilation data as was best observed in the placebo responses. The magnitude of the trend ranged from 30-60 ml.Math.min.sup.2 (about 1.5-3% of total ventilation) and corresponds with the presence of a slow component (time constant about 1 hr) in the ventilatory response to CO.sub.2.

(55) Main study: Respiration. All 46 subjects completed the study without unexpected side effects. In the R-DHE experiments, the end-tidal PCO.sub.2 was clamped at 6.80.2 kPa (51.01.5 mmHg) and baseline (pre-drug) ventilation was 19.31.4 L/min. The mean respiratory responses to R-DHE are given in FIG. 3A. No nadir in ventilation was observed in the placebo data and the lowest R-DHE dose tested. The time to peak effect was dose-independent and occurred at 17.35.5 min. The dose-response curves (for peak respiratory depression and average drug effect) are given in FIGS. 3B and C respectively showing that the dose-response levels off at a ventilation level of approximately 40% of baseline. Specifically the peak respiratory depression occurred with doses of 0.075 g/kg and greater and at a ventilation ratio of about 0.5. The average % respiratory depression reached a ceiling of about 30-40% with doses 0.075 g/kg and greater. With a 30-40% average respiratory depression, the level of respiration achieved in the volunteer who received the drug was 60-70% relative to baseline. None of the subjects that received R-DHE developed irregular breathing or apnoea.

(56) In the fentanyl experiments, the end-tidal PCO.sub.2 was clamped at 6.60.1 kPa (49.50.8 mmHg) and baseline (pre-drug) ventilation was 20.20.9 L/min. A nadir in respiratory response was observed for all doses tested (FIG. 4A). The time to peak effect was dose-independent and occurred on average at 12.82.1 min. The dose-response curves (for peak respiratory depression and average drug effect) are given in FIGS. 4B and C respectively. Dose-dependent respiratory depression was apparent in peak ventilation (P<0.001) and average drug effect (P<0.001). The maximum observed respiratory depression was observed at the highest fentanyl dose tested (3 g/kg; peak effect=19% of baseline). Two subjects developed irregular breathing after the highest dose of fentanyl, one of which developed apnoea (defined by the absence of breathing activity >20 s), just after ending the 10-min fentanyl infusion.

(57) The parameter estimates of the model analysis of peak respiratory depression are given in Table 1 below.

(58) TABLE-US-00002 TABLE 1 Parameter estimates of the model analysis of peak respiratory depression 2.5% 97.5% Parameter Mean SD percentile percentile ED.sub.50 R-DHE (g/kg) 0.04 0.009 0.026 0.06 ED.sub.50 Fentanyl (g/kg) 1.27 0.116 1.04 1.50 1.80 0.32 1.23 2.51 E.sub.MIN R-DHE (% of baseline) 32.8 0.06 16.7 42.6 E.sub.MIN Fentanyl 0 .sup.2 0.014 0.002 0.010 0.019 ED.sub.50 is the dose causing a 50% reduction in ventilation, E.sub.MIN the asymptotic minimum in ventilation, a shape parameter and .sup.2 is the variance of the residual error.

(59) The model fits are given in FIGS. 5A (R-DHE) and B (fentanyl). On the y-axis, ventilation is relative to pre-drug baseline ventilation. The continuous thick lines are the model fits and the thin lines are the 2.5% and 97.5% percentiles. The curves are extrapolated to 0.3 g/kg (R-DHE) and 6 g/kg (fentanyl). In panel A, the closed circles are data from the main study, the open circles are data from the pilot study. In panels A and B, the respective ED.sub.50 and E.sub.MIN values are depicted by the symbol and broken grey lines. For both drugs the ED.sub.50 is the dose half-way between baseline ventilation and E.sub.MIN; for fentanyl this is at 50% respiratory depression, for R-DHE at 33.6%

(60) Two parameters were significantly different between treatments (P<0.01): ED.sub.50 and E.sub.MIN. An apparent 30-fold difference in potency was observed with ED.sub.50 values of 0.04 g/kg for R-DHE and 1.27 g/kg for fentanyl. For fentanyl the value of E.sub.MIN or the asymptotic minimum ventilation was not different from zero, but greater than zero for R-DHE: 32.8% of baseline ventilation or 6.6 L/min (P<0.01). The shape parameter and residual error variance (.sup.2) did not differ between treatments.

(61) Main study: AnalgesiaAll 46 subjects completed the study without unexpected side effects. Baseline pain thresholds were 11.80.9 mA (R-DHE), 12.70.4 mA (fentanyl) and 11.00.6 mA (placebo). The effect of placebo was limited with an effect no greater than 10% of baseline. Both R-DHE and fentanyl produced dose-dependent effects in terms of peak analgesic effect and average drug effect (FIGS. 6A and B; drug-effect: P<0.01) with no indication of reaching a ceiling.

(62) In our study we observed that over the dose range tested, both fentanyl and R-DHE displayed a dose-dependent increase in peak pain response and average analgesic effect (FIGS. 6A and B). These data provide proof that for R-DHE, in contrast to respiration, pain relief does not display ceiling over the dose range tested. At the highest dose tested both drugs produced an increase in pain threshold of about 100% (R-DHE 0.15 g/kg response=1.95pre-drug response; Fentanyl 3.0 g/kg response=2.1pre-drug response). This indicates a R-DHE-fentanyl difference in potency of 18.5. This difference is smaller than the apparent potency difference observed for respiratory depression (factor=30). However, since the ED.sub.50 is an estimation of ventilation in the middle of baseline ventilation and E.sub.MIN, a better comparison than ED.sub.50 would be the dose causing 50% depression of ventilation (in absolute values). For fentanyl this is identical to ED.sub.50 (1.27 g/kg), and for R-DHE this is 0.075 g/kg. This then suggests a potency difference of 17 very similar to the value observed for antinociception.

(63) The mechanism responsible for achieving ceiling effect is not clear. On possibility is that concurrent activation of ORL1-receptors compromises the MOR-mediated antinociceptive effect. However although R-DHE has affinity for the ORL1 receptor, its Ki is several orders of magnitude higher than for the MOR. Whether such low affinity for the ORL1 receptor is sufficient to cause the profound ceiling observed is questionable. Another possible mechanism may be related to R-DHE's high affinity for the KOR, which is approximately 1 order of magnitude lower than for the MOR. It may be, for example, that at high doses the R-DHE-induced and MOR-mediated respiratory depression is antagonised by the effect of R-DHE at the KOR.

(64) A final proposed mechanism involves the intra neuronal regulatory protein -arrestin. Opioid receptors belong to the 7-transmembrane G-protein-coupled receptors that, upon activation, bind to intracellular G-proteins and -arrestin 1 and/or -arrestin 2 proteins. It has been shown that absence of -arrestin 2 protein causes the attenuation of morphine-induced respiratory depression with maintained antinociception. It was hypothesized that (G-protein independent) activation of -arrestin 2 is involved in MOR signal transduction of respiratory neurons but not in neurons involved in modulation of pain pathways. It may well be that extent of G protein and of -arrestin 2 activation is ligand specific. The findings in this study may be explained by a lesser ability of R-DHE to activate -arrestin 2.

(65) The mechanism of the differential R-DHE effect on respiration and analgesia is also not clear. It may be due to a difference in receptor density at brain sites involved in analgesia versus brain sites involved in respiratory depression. Another mechanism involved may be the lesser ability of R-DHE to engage the transduction protein -arrestin 2, as discussed above. This latter mechanism explains both the observed ceiling effect in R-DHE-mediated respiratory depression and the selectivity of the ceiling effect.

(66) Other Opioid-Related Side Effects

(67) Other opioid-related side effects associated with treatment of each of 0.15 g/kg (R)-dihydroetorphine and 3 g/kg fentanyl were assessed at intervals for 7.5 hours, starting 1 hour after administration of drug was ceased, by asking the patients to complete the questionnaire shown in FIG. 9 wherein the scale 0-100 for each side effect is a NAS score.

(68) The average NAS score for each side effect was calculated.

Example 1b

(69) In a follow up study the effect of higher doses of R-DHE were investigated. The study was conducted on 19 healthy volunteers.

(70) The selection of subjects, formulation of R-DHE, administration (10 min i.v.), respiratory measurements (using the dynamic end-tidal forcing technique) and statistical analysis was identical to the main study described above, except that the doses of R-DHE tested were 0.2 g/kg (6 subjects), 0.25 g/kg (6 subjects), 0.3 g/kg (6 subjects) and 0.4 g/kg (6 subjects).

(71) The ventilation ratio determined for each drug dose is shown in the table below.

(72) TABLE-US-00003 Dose of R-DHE (g/kg) Ventilation Ratio 0.2 0.4 0.25 0.25 0.3 0.25 0.4 0.2

(73) These results show that the ceiling effect in respiratory depression extends to higher doses of R-DHE than are required to achieve clinically useful analgesic levels. At a dose of 0.2 g/kg of R-DHE the level of respiration in the volunteers was still about 40%. At higher doses (0.3 g/kg and 0.4 g/kg) an increase in peak mean respiratory depression was observed but this was stable at about 20 to 25%. Such levels are acceptable in controlled environments.

Example 2

Cold Pressor Test to Determine Analgesic Effect

(74) The cold pressor test is an established model for nociceptive pain assessment in healthy volunteers. The test was carried out according to conventional procedures.

(75) The R-DHE doses tested in the cold pressor model were 0.05 g/kg (8 subjects), 0.1 g/kg (8 subjects), 0.2 g/kg (8 subjects) or 0.3 g/kg (8 subjects) or placebo, all given as a 10 minute i.v. infusion.

(76) In the study, the healthy volunteers immersed their non-dominant hand in a stirred, thermostatically-controlled cold water bath having a temperature of 3 C. for 2 minutes. During the immersion the volunteer rated the pain he or she experienced continuously with 0 representing no pain and 100 representing the worst pain imaginable. The volunteer also rated the pain experienced at time points (pre-dose, 10 minutes, 30 min, 1, 2, 4, 8, 12 and 24 hours post-infusion. The cumulative area under the curve of the visual analogue scale-time profile from 0 to 120 seconds for each cold pain test was calculated. A graph of the AUC versus baseline was plotted for each time point.

(77) The % change from baseline was calculated as follows: 100(AUC at t (time) with drug-AUC at t (same time) baseline/AUC at t baseline) and the results are shown in FIG. 8. Thus, for example, if the AUC for baseline was 100 and the AUC at time 10 minutes for R-DHE was 20, then the % change from baseline is 100((20100)/100), i.e. 80%. This is plotted on FIG. 8 as 20%. Similarly if the AUC for baseline was 100 and the AUC at time 10 minutes for R-DHE was 80, then the % change from baseline is 100((80100)/100), i.e. 20% and this is plotted on FIG. 8 as 80%. Thus in FIG. 8, 100% shows that no pain relief versus baseline is achieved and 0% shows that complete pain relief is achieved.

(78) FIG. 8 shows that for a dose of R-DHE of 0.05 g/kg, 0.1 g/kg, 0.2 g/kg or 0.3 g/kg significant levels of analgesia are achieved. Significantly FIG. 8 shows that the level of analgesia achieved is dose dependent. In other words, FIG. 8 shows that, unlike for respiratory depression, no ceiling effect in analgesia is observed.

(79) The results for placebo shown in FIG. 8 are a change from the baseline of approximately 18%, which is in line with the expected value of about 20%. Notably the results for R-DHE are significantly greater than a 20% change from baseline and for the higher doses of R-DHE (0.2 g/kg or 0.3 g/kg) are greater than 50% of baseline, even 1 hour after administration. Even at 4 hours after administration, the higher doses of R-DHE (0.2 g/kg or 0.3 g/kg) show a change from baseline that is significantly greater than the placebo.