Primary• To evaluate the analgesic effects of morphine, pregabalin and the two drugs as combination using PainCartSecondary• To evaluate the drug-sensitive central nervous system (CNS) functioning of morphine, pregabalin and the two drugs as…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Chronic Pain
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Pressure Pain: Pain Detection Threshold (PDT), Pain Tolerance Threshold
(PTT), Area Under the Curve (AUC), post-test Visual Analogue Scale (VAS)
• • Heat pain (pre-cold pressor: unexposed/normal and UVB-exposed skin, the
latter only for subjects with MED lower than 355 mJ/cm2 at screening): PDT, and
post-test VAS
• Cold Pressor: PDT, PTT, Area Above the Curve (AAC), post-test VAS
• Electrical Stair test: PDT, PTT, AUC, post-test VAS
• Electrical burst test: PDT, PTT, AUC, post-test VAS
• Conditioned Pain Modulation (CPM) Response (change from heat pain pre- and
post-cold pressor): PDT
• Short Form McGill Pain Questionnaire (SFMPQ) for pressure pain, heat
pain, cold pressor, electrical stair test and electrical burst test.
Secondary outcome
• Body sway:
o antero-posterior sway (mm);
• Visual Analog Scales (VAS) according to Bond and Lader to assess:
o mood (mm),
o alertness (mm), and
o calmness (mm).
• Visual Analog Scales (VAS) according to Bowdle to assess:
o Feeling high (mm)
o Internal perception (mm)
o External perception (mm)
• N-back
o Average reaction time (ms) (zero-, one-, two-back)
o Number of correct targets (zero-, one-, two-back)
o Number of incorrect targets (zero-, one-, two-back)
•o Number of faulty non-target responses (zero-, one-, two-back)
• Adaptive Tracking
o Average performance (%);
• Visual Verbal Learning Test (VVLT) memory testing
o Immediate recall trial 3 (number correct)
o Delayed recall (number correct)
o Delayed recognition (number correct)
o Delayed recognition (reaction time correct) (msec)
• Electroencephalography
o Frequency ranges for spectral analysis, Delta, Theta, Alpha, Beta, Gamma
• Simple Reaction Time Task (SRT)
o Reaction time (ms)
Questionnaires:
• State-Trait Anxiety Inventory (STAI)
o State anxiety score
• Brief Symptom Inventory (BSI)
o General somatic symptoms
o Cognitive symptoms
o Interpersonal sensitivity
o Depressed mood
o Anxiety
o Hostility
o Phobic anxiety
o Paranoid thoughts
o Psychoticism
o Global severity index
• PK parameters of morphine (and metabolite: morphine-6-glucuronide),
pregabalin by noncompartmental analysis of the plasma concentration-time data:
• AUCinf, AUClast, CL(/F), Cmax, t1/2, tlag, tmax, Vz(/F)
• Treatment-emergent (serious) adverse events ((S)AEs) throughout the study at
every study visit
• Concomitant medication throughout the study at every study visit
• Vital signs (Pulse Rate (bpm), Systolic blood pressure (mmHg), Oxygen
saturation, Diastolic blood pressure (mmHg)) as per assessment schedule
• Clinical laboratory tests (Hematology, blood chemistry, glucose, and
urinalysis) as per assessment schedule
• ECG parameters (Heart Rate (HR) (bpm), PR, QRS, QT, QTcF) as per assessment
schedule
Background summary
Chronic pain is one of the most prevalent and complex medical conditions in the
Western world. In general, around 20% of the population in Europe experiences
chronic pain, resulting in a large socio-economic burden, including the effect
on the patient*s environment and the health care system. Current pain drug
treatment options include opioids, anti-depressants, antiepileptics,
benzodiazepines and nonsteroidal anti-inflammatory drugs (NSAIDs).
60% of patients treated for chronic pain responds poorly to the above-mentioned
therapies. Prescription of opioids, currently the most effective class of
analgesics for moderate to severe chronic pain, has furthermore led to
complications related to their adverse effects, including sedation, cognitive
side-effects, and drug abuse liability. A solution for this may be by adding a
non-opioid analgesic to treatment with an opioid, which may lead to an
opioid-sparing effect . For example, therapies with combinations of morphine
and anti-epileptics (e.g., pregabalin) or anti-depressants(e.g.,
amitriptyline), may lead to an improved balance of therapeutic benefit and
adverse effects, tailored to the needs of individuals and stratified patient
groups.
To obtain a better understanding of combination pain therapies a consortium was
established through a Horizon 2020 European Union grant: QSPainRelief
(H2020-SC1-BHC-2018-2020). The consortium will investigate alternative novel
drug combinations with improved analgesic-, and reduced adverse effects in the
context of a full translational program: from in-silico modelling via in-vitro
models to two healthy volunteer studies and eventually in studies with pain
patients. All studies are performed by consortium members (www.qspainrelief.eu).
So far, in-silico, in-vitro, and preclinical research has been performed by the
QSPainRelief consortium to investigate which combination therapy may provide
the optimal analgesic-adverse effect profile. [Data not yet published] Data
have been gathered in the QSPainRelief model. Initial discussion and results
indicate that for this healthy volunteer study morphine (a potent µ-opioid
receptor) in combination with pregabalin (a α2-δ subunit specific,
voltage-dependent calcium channel ligand) may yield improved clinical utility
over either drug used as monotherapy.
PainCart and NeuroCart are two comprehensive and validated test batteries
commonly used in early-phase drug studies to profile pharmacodynamic effects of
(novel) drugs. PainCart consists of an evoked pain test battery that was used
previously to amongst others profile pregabalin and the opioid fentanyl.
NeuroCart is a Central Nervous System (CNS) test battery that is used to assess
drug-induced changes in CNS functioning. The batteries have previously been
used together to evaluate possible synergistic effects of two analgesics, and
to determine the CNS and analgesic profile of a novel investigational drug.
The aim of this first human experimental pain study, the QSPainRelief-novel A
trial, is to investigate the analgesic effects and effects on CNS functioning
of morphine and pregabalin as an analgesic combination in healthy subjects,
compared to each of the two analgesics alone and to placebo. A second,
similarly designed study is to follow in a year after this trial, to evaluate a
different combination of an opioid and a non-opioid analgesic that is proposed
by the QSPainRelief model.
Study objective
Primary
• To evaluate the analgesic effects of morphine, pregabalin and the two drugs
as combination using PainCart
Secondary
• To evaluate the drug-sensitive central nervous system (CNS) functioning of
morphine, pregabalin and the two drugs as combination by biomarker profiling
and the NeuroCart
• To evaluate the blood pharmacokinetic parameters of morphine, pregabalin and
the two drugs as combination
• To evaluate the safety and tolerability of morphine, pregabalin and the two
drugs as combination
Study design
This is a single centre, double blind, placebo-controlled, study to investigate
the effect of morphine and pregabalin on pain thresholds and cognitive
functioning.
Intervention
Investigational drug
Pregabalin
Pregabalin (Teva), 300 mg will be orally administered.
Morphine
Morphine hydrochloride (HCl) 3 mg and 7 mg will be administered intravenously.
Comparative drug
Matching placebo
Study burden and risks
No medical benefit is expected for study participants; however, this study will
provide more insight in a combination treatment for patients suffering from
chronic pain. Morphine and pregabalin are registered drugs which are widely
used in the clinic, amongst other analgesics. The safety profiles of these
compounds are well known. Both analgesic and adverse effects are likely to
occur. Symptoms such as, sedation, somnolence, dizziness, fatigue, reduced
vigilance, are to be expected following administration for both compounds, but
will be closely monitored by medically trained staff as part of the study
objectives. Subjecten will experience pain when the pain tests are performed.
These tests are validated rigorously and have a safety cut-off to prevent too
much pain and/or harm.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
1. Healthy subjects, 18 to 65 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. 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.
3. Able to participate and willing to give written informed consent and to
comply with the study restrictions.
Exclusion criteria
1. Evidence of any active or chronic disease or condition that could interfere
with, or for which the treatment of might interfere with, the conduct of the
study, or that would pose an unacceptable risk to the subject in the opinion of
the investigator (following a detailed medical history, physical examination,
vital signs (systolic and diastolic blood pressure, pulse rate, body
temperature) and 12-lead electrocardiogram (ECG)). Minor deviations from the
normal range may be accepted, if judged by the Investigator to have no clinical
relevance.
2. Clinically significant abnormalities, as judged by the investigator, in
laboratory test results (including hepatic and renal panels, complete blood
count, chemistry panel and urinalysis). In the case of uncertain or
questionable results, tests performed during screening may be repeated before
randomization to confirm eligibility or judged to be clinically irrelevant for
healthy subjects.
3. Positive Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab),
or human immunodeficiency virus antibody (HIV Ab) at screening.
4. Systolic blood pressure (SBP) greater than 140 or less than 90 mm Hg, and
diastolic blood pressure (DBP) greater than 90 or less than 50 mm Hg at
screening.
5. Abnormal findings in the resting ECG at screening defined as:
a. QTcF> 450 or < 300 msec for men and QTcF> 470 or < 300 msec for women
b. Notable resting bradycardia (HR < 45 bpm) or tachycardia (HR > 100 bpm)
c. Personal or family history of congenital long QT syndrome or sudden death;
d. ECG with QRS and/or T wave judged to be unfavourable for a consistently
accurate QT measurement (e.g., neuromuscular artefact that cannot be readily
eliminated, arrhythmias, indistinct QRS onset, low amplitude T wave, merged T-
and U-waves, prominent U waves);
e. Evidence of atrial fibrillation, atrial flutter, complete branch block,
Wolf-Parkinson-White Syndrome, or cardiac pacemaker
6. Use of any medications (prescription or over-the-counter [OTC]), within 14
days of study drug administration, or less than 5 half-lives (whichever is
longer). Exceptions are paracetamol (up to 4 g/day) and ibuprofen (up to
1g/day), which are allowed up to 2 days before screening and 2 days before each
study drug administration. Other exceptions will only be made if the rationale
is clearly documented by the investigator.
7. Use of any vitamin, mineral, herbal, and dietary supplements within 7 days
of study drug administration, or less than 5 half-lives (whichever is longer).
Exceptions will only be made if the rationale is clearly documented by the
investigator.
8. Participation in an investigational drug or device study (last dosing of
previous study was within 90 days prior to first dosing of this study).
9. History of abuse of addictive substances (alcohol, illegal substances) or
current use of more than 21 units (for males) or 14 units (for females) of
alcohol per week, drug abuse, or regular user of sedatives, hypnotics,
tranquillisers, or any other addictive agent
10. Positive test for drugs of abuse at screening or pre-dose.
11. Alcohol will not be allowed from at least 24 hours before screening or each
admission.
12. Current use of tobacco or nicotine products and unable to abstain from use
of these products within the previous 3 months before the first dose
administration.
13. Is demonstrating excess in caffeine consumption (more than eight cups of
coffee or equivalent per day).
14. Any confirmed significant allergic reactions (urticaria or anaphylaxis)
against any drug, or multiple drug allergies (non-active hay fever is
acceptable).
15. Loss or donation of blood over 500 mL within three months (males) or four
months (females) prior to screening or intention to donate blood or blood
products during the study.
16. If a woman, pregnant, or breast-feeding, or planning to become pregnant
during the study.
17. Not willing to practice effective contraception during the study and not
willing and able to continue contraception for at least 90 days after their
last dose of study treatment.
18. Any known factor, condition, or disease that might interfere with treatment
compliance, study conduct or interpretation of the results such as drug or
alcohol dependence or psychiatric disease.
19. Known hypersensitivity to the investigational drug or comparative drug or
drugs of the same class, or any of their excipients.
20. Fitzpatrick skin type IV, V and VI, wide-spread acne, tattoos or scarring
interfering with the area of interest (i.e. upper back).
21. Any current, clinically significant, known medical condition in particular
any existing conditions that could have affected sensitivity to cold (such as
atherosclerosis, Raynaud*s disease, urticaria, hypothyroidism) or pain
(paraesthesia, etc.).
22. Subjects who indicated nociceptive tests intolerable at screening or who
achieved tolerance at >80% of maximum input intensity for the cold pressor
or electrical pain tasks.
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 | EUCTR2021-005826-39-NL |
CCMO | NL79589.056.21 |