Primary objectives- To evaluate the effects of buprenorphine on fentanyl induced analgesia using the PainCart test battery in OT patients, when compared to placebo.Secondary objectives- To evaluate the effects of buprenorphine on fentanyl induced…
ID
Source
Brief title
Condition
- Neurological disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Thermal pain: PDT (°C)
• Pressure Pain: PDT (kPa), PTT (kPa), area-under-the-curve (AUC) (kPa*mm) and
post-test VAS (mm)
• Electrical Burst: PDT (mA), PTT (mA), AUC (mA*mm) and post-test VAS (mm)
• Electrical Stair: PDT (mA), PTT (mA), AUC (mA*mm) and post-test VAS (mm)
• Cold Pressor: pain detection threshold (PDT) (s), area-above-the-curve (AAC)
(s*mm) and post-test visual analogue scale (VAS) (mm)
Secondary outcome
• Saccadic eye movement
o saccadic reaction time (s),
o saccadic peak velocity (°/s), and
o saccadic inaccuracy (%);
• Smooth pursuit eye movements:
o percentage of time the eyes of the subjects are in smooth pursuit of the
target (%);
• Body sway:
o antero-posterior sway (mm);
• Adaptive tracking:
o average performance (%);
• Pupillometry (mm)
• VAS Bond & Lader (Alertness, mood, calmness) (mm)
• VAS Bowdle (internal perception, external perception, *feeling high*) (mm)
• ARCI-49
Exploratory
• Treatment-emergent (serious) adverse events ((S)AEs)
• Concomitant medication throughout the study at every study visit
• Pharmacokinetic parameters such as Cmax and AUC
Background summary
Buprenorphine is a partial agonist at the µ-opioid receptor (MOR) and is used
for the medication assisted treatment of opioid use disorder (OUD). In recent
years the use of opioids has increased in the U.S.A. and Europe, and an
increase in the use of buprenorphine has been recorded. Buprenorphine has high
affinity for the MOR and therapeutic plasma concentrations achieve >= 70%
receptor occupancy. As a partial agonist, buprenorphine has a ceiling effect on
respiratory depression such that it does not cause apnoea when administered
alone and minute ventilation is not suppressed beyond 50 to 60%. This is in
contrast with the effects of the full MOR agonist fentanyl, which does elicit
complete respiratory depression when administered at high doses. Literature is
inconclusive on whether buprenorphine has a ceiling effect on analgesia, in
part due to insufficient investigation into the analgesic effect of high doses
of buprenorphine, which can only be achieved in opioid-tolerant (OT) patients
due to side effects of opioid treatment in healthy volunteers.
A previous study that was conducted by CHDR in collaboration with the LUMC
anaesthesiology department (CHDR1754, of which the results are yet
unpublished), has shown that sustained high therapeutic levels of buprenorphine
can inhibit the respiratory depressive effects of IV bolus fentanyl in OT
patients. Buprenorphine formulations are being developed as a treatment for
OUD, to prevent fentanyl-induced deaths. Worldwide, many patients are
administered buprenorphine for various conditions, and it is expected that this
number will increase in the coming years due to an increasing number of
patients who are on medication assisted treatment of opioid use disorder. If
buprenorphine is used by an increasing number of patients with OUD, the
previous findings warrant additional research to be performed on the effects of
buprenorphine on IV fentanyl induced analgesia and other CNS functions. In
clinical practice, fentanyl is often used as an analgesic drug in the emergency
and operating room. Patients with OUD who are being treated with buprenorphine
will have sustained high plasma concentrations of buprenorphine, which might
limit the analgesic properties of fentanyl when this drug is administered in a
medical environment such as the ER. Hence, it is of great importance that
knowledge is gained regarding the pharmacodynamic interaction of the two study
drugs regarding the effects on pain.
The aim of this study is to evaluate the effects of buprenorphine on fentanyl
induced analgesia and CNS effects in OT patients, when compared to placebo.
Study objective
Primary objectives
- To evaluate the effects of buprenorphine on fentanyl induced analgesia using
the PainCart test battery in OT patients, when compared to placebo.
Secondary objectives
- To evaluate the effects of buprenorphine on fentanyl induced CNS effects
using the NeuroCart test battery in OT patients, when compared to placebo.
Exploratory Objectives
- To develop a mathematical model describing the pharmacokinetic
(PK)/pharmacodynamic (PD) interaction between buprenorphine and fentanyl
concentrations and their effect on analgesia and CNS functions in OT patients.
Study design
This will be a randomised, double-blind, placebo-controlled, cross-over study
to evaluate effects of buprenorphine on fentanyl induced analgesia and CNS
effect in OT patients.
Buprenorphine/ placebo:
subjects are randomised to treatment group 1 or 2
treatment group 1: an initial bolus of 0.25 mg 70 kg-1 followed by continuous
infusion of 0.1 mg 70 kg-1 h-1 / placebo
treatment group 2: an initial bolus of 1.25 mg 70 kg-1 followed by continuous
infusion of 0.5 mg 70 kg-1 h-1 / placebo
Fentanyl:
each treatment group will receive up to four boluses of 0.1 - 0.4 mg 70 kg*1
Intervention
Buprenorphine/placebo will be administered for 6 hours. Fentanyl boluses will
be given by dose escalation +2HR,
+3HR, +4HR and +5HR after starting administration of buprenorphine/placebo to
investigate the pharmacodynamic
interaction between buprenorhine and fentanyl.
Study burden and risks
Buprenorphine: adverse drug reactions commonly reported are sedation,
dizziness, sleep, miosis, hypoventilation, nausea, vomiting, hyperhidrosis and
headache. Hallucinations and other psychotomimetic effects can occur although
more rarely. Hypotension leading to syncope can occur. Buprenorphine may cause
significant respiratory depression when taken in combination with
benzodiazepines or other CNS depressants. The planned doses are within the
therapeutic range and have previously been safely administered to similar
patient populations both in trials and in clinical practice.
Care will be taken when treating patients with impaired respiratory function or
patients who are receiving drugs that can cause respiratory depression.
Experience has shown that naloxone is beneficial in reversing a reduced
respiratory rate. Respiratory stimulants such as doxapram are also effective.
The intensity and duration of action is affected in patients with impaired
liver failure, which will be assessed during screening.
All healthy subjects will receive ondansetron 4 mg IV prior to buprenorphine
infusion. A second dose of 4 mg can be administered as needed for management of
nausea and vomiting. Patients administered chronic opioids can receive no more
than two 4-mg IV doses of ondansetron as needed for management of nausea and
vomiting.
Fentanyl: the most commonly reported adverse drug reactions are nausea,
vomiting, muscle rigidity, hypotension or hypertension, bradycardia and
sedation. Other adverse reactions that have been reported are dizziness,
blurred vision, nausea, vomiting, hyperhidrosis, pruritus, urticaria,
laryngospasm and anaphylaxis.
The planned doses in this study are not expected to cause respiratory
insufficiency, based on a previous study performed at CHDR and LUMC (CHDR1754).
However, fentanyl will be given only in an environment where the airway can be
controlled and by personnel who will monitor the airway. Respiratory depression
is dose-related and can be reversed by an antagonist such as naloxone. Multiple
doses of naloxone may be necessary because the respiratory depression will last
longer than the duration of action of the opioid antagonist. Subjects will
remain under appropriate surveillance. Resuscitation equipment and opioid
antagonists will be readily available. Adequate spontaneous breathing must be
established and maintained before discharge from the Post-Anaesthesia Care Unit
(PACU).
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
1. Signed the ICF and able to comply with the requirements and restrictions
listed therein;
2. Male and female, age 18 to 55 years, inclusive;
3. Women of childbearing potential (defined as all women who are not surgically
sterile or postmenopausal for at least 1 year prior to informed consent) must
have a negative pregnancy test prior to enrolment and must agree to use a
medically acceptable means of contraception from screening through at least 3
months after the last dose of study drug.
4. BMI 18 to 32 kg/m2, inclusive;
5. Opioid-tolerant patients administered opioids at daily doses >= 60 mg oral
morphine equivalents (See Appendix A);
6. Stable as defined by the Investigator, based on a medical evaluation that
includes the patient*s medical and surgical history, physical examination,
vital signs, 12-lead ECG, haematology, blood chemistry, and urinalysis;
7. No current use of any CNS depressants, besides opioids, prescribed or
otherwise for 5 half-lives of the product before first study drug
administration unless assessed as safe by the principal investigator.
Exclusion criteria
1. Clinically significant risk factors of Torsades de Pointes (e.g., heart
failure, hypokalaemia, family history of Long QT Syndrome) or an ECG
demonstrating a Fridericia*s corrected QT interval (QTcF) > 450 msec in males
and QTcF > 470 msec in females at screening;
2. Currently meet the criteria for diagnosis of moderate or severe substance
use disorder according to the DSM-5 criteria on any substances other than
opioids, caffeine, or nicotine;
3. Any active medical condition, organ disease or concurrent medication or
treatment that may either compromise subject safety or interfere with study
endpoints (including sleep apnoea, other significant respiratory illness,
history or risk of difficult intubation, limited cervical spine mobility or
limited oral excursion);
4. Not able to abstain from smoking cigarettes during each dose administration
day;
5. Consume, on average, >27 units/week of alcohol in men and >20 units/week of
alcohol in women (1 unit = 1 glass (250 mL) beer, 125 mL glass of wine or 25 mL
of 40% spirit);
6. Use of buprenorphine 10 days prior to the first study drug administration;
7. Use of prescription or OTC medications that are clinically relevant CYP P450
3A4 or CYP P450 2D6 inducers or inhibitors from 14 days prior to study drug
administration;
8. History of suicidal ideation within 30 days prior to informed consent or
history of a suicide attempt in the 6 months prior to informed consent;
9. Measured systolic blood pressure greater than 160 or less than 95 mmHg or
diastolic pressure greater than 95 mmHg prior to Day 1;
10. History or presence of allergic response to buprenorphine or fentanyl;
11. Opioid-tolerant patients who have demonstrated allergic reactions (e.g.,
food, drug, atopic reactions or asthmatic episodes) which, in the opinion of
the Investigator and sponsor, interfere with their ability to participate in
the trial.
12. Estimated glomerular filtration rate <60 mL/min as estimated by the CKD-EPI
equation;
13. Clinical significant anaemia at screening or donation of > 250 mL of blood
or plasma within the last 3 months;
14. Positive serology tests for HIV, acute hepatitis B, or acute hepatitis C
(OT patients with asymptomatic hepatitis B or C infection may be enrolled);
15. AST or ALT levels >3.0 times the upper limit of normal at screening;
16. 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);
17. Treatment with another investigational drug within 3 months prior to dosing
or having participated in more than 4 investigational drug studies within 1
year prior to screening;
18. Site staff or subjects affiliated with, or a family member of, site staff
directly involved in the study.
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
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-000012-39-NL |
| CCMO | NL76423.056.21 |
| OMON | NL-OMON27786 |