To investigate the analgesic profile of different classical and non-classical analgesic compounds using a battery of pain tests (PainCart) in healthy subjects compared to a negative control.Secondary:- Investigate the association between subjective…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Pain
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pharmacodynamic endpoints
- Thermal Pain (Normal Skin): Pain Detection Threshold (PDT).
-Thermal Pain (UVB Skin): Pain Detection Threshold (PDT).
- Electrical Stair (pre-cold pressor): Pain Tolerance Threshold (PTT).
- Pressure Pain: Pain Tolerance Threshold (PTT).
- Cold Pressor: Pain Tolerance Threshold (PTT).
- VAS Feeling high
Secondary outcome
Pharmacodynamic endpoints
- Electrical Stair (pre-cold pressor): Pain Detection Threshold (PDT), Area
Under the Visual Analogue Scale (VAS) pain Curve (AUC), and post-test VAS.
- Electrical Stair (post-cold pressor): PDT, PTT, AUC, and post-test VAS.
- Conditioned Pain Modulation Response (change from electrical stair pre- and
post cold pressor): PDT, PTT, AUC.
- Evoked potentials: somatosensory evoked potentials (SEP) using the electrical
stimulus measuring peak-to-peak (PtP) somatosensory evoked potentials (SEP)
amplitude in vertex EEG, or other exploratory endpoints.
- Pressure Pain: PDT, AUC, and post-test VAS.
- Cold Pressor: PDT, AUC, and post-test VAS.
- VAS Bond & Lader (Alertness, mood, calmness)
- VAS Bowdle (internal perception, external perception, *feeling high*)
- Pharmaco-EEG: power (resting eyes closed, open and during pressure pain and
cold pressor).
- Adverse events, laboratory safety, blood pressure, pulse rate and ECG
parameters
Pharmacokinetic analysis will only be performed if relevant pharmacodynamic
effect is observed.
The following endpoints will be determined for Δ9-THC and its active
metabolites 11-OH-THC and THC-COOH; promethazine and paracetamol. They will be
derived by non-compartmental analysis of the plasma concentration-time data:
- The area under the plasma concentration-time curve from zero to
infinity(AUC0-inf);
- The maximum plasma concentration (Cmax);
- The area under the plasma concentration-time curve from zero to t of the last
measured concentration above the limit of quantification (AUC0-last);
- The time to reach maximum plasma concentration (tmax);
- The terminal disposition rate constant (*z) with the respective half-life
(t*).
- Other parameters, including Vz/F, CL/F, and other parameters as appropriate,
as well as dose adjusted parameters, may be determined.
Background summary
The complex clinical reality of pain medicine demands novel analgesic
therapeutics. Different cannabinoids have been shown to be effective in various
pain conditions, including neuropathic pain related to multiple sclerosis or
and pain related to oncological disease. The PainCart could be a useful tool to
investigate the analgesic properties of novel active pharmaceutical ingredients
including cannabinoid formulations, but needs to be pharmacologically validated
for this specific class of compounds. In addition, potential sedative effects
rather than analgesic effects of psychoactive compounds need to be investigated
as part of the pharmacological validation of the PainCart.
The current study aims to investigate the analgesic effects of a compound
targeting the cannabinoid system: Δ9-THC (Namisol®, ECP002A, oral formulation
developed by Echo Pharmaceuticals), and, the still not completely understood
mechanism of action most widely used analgesic, paracetamol (acetaminophen,
generic oral formulation) using a validated pain test battery. In addition,
promethazine will be included to investigate the effects of sedation on the
PainCart outcome measures.
Study objective
To investigate the analgesic profile of different classical and non-classical
analgesic compounds using a battery of pain tests (PainCart) in healthy
subjects compared to a negative control.
Secondary:
- Investigate the association between subjective psychotropic effects (*Feeling
high* and changes in internal and/or external perception) and cannabinoid
analgesia.
- Investigate the association between subjective sedative effects (Changes in
alertness, mood and calmness) and cannabinoid analgesia.
- Investigate the feasibility, applicability, safety, tolerability, and
reproducibility of the pain test battery in healthy subjects.
- Investigate the similarity between the analgesic profile of paracetamol and
Δ9-THC using the PainCart test battery.
- Investigate the similarity between the subjective sedative effects (changes
in alertness, mood and calmness) of Δ9-THC and promethazine.
Study design
This will be a randomized double-blind, double dummy, placebo-controlled, four
way cross-over single dose study.
Intervention
During the course of the study, on every one of the study days, a subject will
get, in random order:
- Δ9-Tetrahydrocannabinol (Δ9-THC, Namisol®, ECP002A/5), provided by Echo
Pharmaceuticals, \ (2 tablets of 5 mg will be administered) and matching
placebo (ECP002A/5P, oral tablets)
- Paracetamol (1 g) and matching placebo, oral capsule
- Promethazine (50 mg) and matching placebo, oral capsules
Study burden and risks
The current formulation of Δ9-THC (Namisol ®) has been administered in multiple
studies including healthy volunteers and different patient populations. Δ9-THC
has potential side effects, but is generally considered safe, even in high
dosages. Possible side effects include confusion, hallucinations, delusions,
decreased coordination, dizziness, drowsiness, elevated or relaxed mood,
anxiety, headache, nausea, stomach pain, trouble concentrating, vomiting and
weakness. No specific antidotes are deemed necessary.
Paracetamol is a mild analgesic and antipyretic, and is recommended for the
treatment of most painful and febrile conditions, for example, headache
including migraine and tension headaches, toothache, neuralgia, backache,
rheumatic and muscle pains, dysmenorrhoea, sore throat, and for relieving the
fever, aches and pains of colds and flu. Also recommended for the symptomatic
relief of pain due to non-serious arthritis. Adverse effects of paracetamol are
rare but hypersensitivity including skin rash may occur. There have been
reports of blood dyscrasias including thrombocytopenia, neutropenia,
pancytopenia, leukopenia and agranulocytosis but these were not necessarily
causality related to paracetamol.
Promethazine is a classic H1-antihistamine with some anticholinergic effects.
Daily doses up to 150 mg are prescribed for the treatment of allergic rhinitis
and motion sickness. Singles doses up to 50 mg are prescribed to induce mild
sedation. Adverse effects are mostly observed in the realm of CNS depression.
In addition, its anticholinergic effects increase the risk of narrow-angle
glaucoma or prostatic hyperthrophy. Both of which are not relevant for the
population under investigation. Finally, drug-induced phototoxicity has been
reported for promethazine. However, UV-A radiation is considered to be the
driving force behind this, rather than the UV-B radiation used in the UVB
model.(13) In addition, the timing of UVB exposure 24 hours prior to a single
drug administration, minimise the risk for the subjects of developing a
phototoxic reaction.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
1. Healthy subjects, 18 to 45 years of age, inclusive. Healthy status is defined by absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead ECG, haematology, blood chemistry, and urinalysis;
2. Female subjects are required to have an intrauterine device, a contraceptive implant or are willing to continuously use oral contraceptives (i.e. skip their menstruation) during the study period;
3. Body mass index (BMI) between 18 and 30 kg/m2, inclusive, and with a minimum weight of 50 kg and a maximum weight of 100 kg;
4. Able to participate and willing to give written informed consent and to comply with the study restrictions.
Exclusion criteria
1. Legal incapacity or inability to understand or comply with the requirements of the study;
2. Clinically significant findings as determined by medical and psychiatric history taking, physical examination, ECG and vital signs;
3. Haemodynamic status at screening: systolic <100 and >160 mmHg, diastolic <50 and >95 mmHg, heart rate <45 and >100 bpm measured on the non-dominant (non-leading/non-writing hand) arm;
4. Any current, clinically significant, known medical condition in particular any existing conditions that would affect sensitivity to cold (such as atherosclerosis, Raynaud*s disease, urticaria, hypothyroidism) or pain (disease that causes pain, hypesthesia, hyperalgesia, allodynia, paraesthesia, neuropathy, etc.);
5. Subjects indicating pain tests intolerable at screening or achieving tolerance at >80% of maximum input intensity for any pain test for cold, pressure and electrical tests;
6. Have a urine drug screen detecting illicit drug of abuse (morphine, benzodiazepines, cocaine, amphetamine, THC, methamphetamines, MDMA) or a positive alcohol breath test at screening;
7. Consume, on average, >8 units/day of (methyl)xanthines (e.g. coffee, tea, cola, chocolate) and not able to refrain from use during each stay at the CHDR clinic;
8. History or clinical evidence of alcoholism or drug abuse;
9. Smoking of >5 cigarettes/day or equivalent and not able to abstain from smoking cigarettes during each stay at the CHDR clinic;
10. Use of prescription medication, over-the-counter medication, or herbal supplement within 7 days of nociceptive assessments;
11. Participation in a clinical trial within 90 days of screening or more than 4 times in the previous year;
12. Loss of blood >= 500 mL within 3 months (males) or 4 months (females) before screening;
13. Known hypersensitivity to the investigational drug or comparative drug or drugs of the same class, or any of their excipients;
14. Dark skin (Fitzpatrick skin type V or VI), wide-spread acne, tattoos or scarring on back; and/or
15. Subjects of childbearing potential who are unwilling or unable to use a highly effective barrier method of contraception for the duration of the study and for 3 months after the last dose of study treatment.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-003496-30-NL |
| CCMO | NL54643.056.15 |