1. Introduction
Since the synthesis of fentanyl by Paul Janssen in 1960, it has become possible to administer very high doses of opioids.22 12,19,62 41,71 1,20,24,32 11 21 24 61 12,19,66
After decades of low research activity,46 30,40 4,40 3 68 65 16,42,55 15,18,36,40 76
A recent systematic review and meta-analysis of cannabinoids supports the hypothesis of cannabinoid-induced analgesia,63 9
Rodriguez-Munoz et al.55 56 55 2,12 56
The pain model applied in this study is able to produce and quantify OIH in healthy volunteers.2,34,35,44
In this randomized, placebo-controlled, double-blinded, crossover study, we examined the effect of 1600-mg orally administered CBD on OIH (in square millimeters) in healthy volunteers in a well-established pain model.34 remifentanil infusion used to induce hyperalgesia. In a previous study of our group, placebo application without deception reduced the area of hyperalgesia about 20%.57
2. Material and methods
2.1. General study design
The local ethics committee (ID 2019-01217; Ethikkommission Nordwest-und Zentralschweiz, Basel, Switzerland) and the medical approval agency Swissmedic (ID 2020DR2016) approved this study (registered at clinicaltrials.gov
This study is a prospective, randomized, placebo-controlled, double-blinded, crossover study examining the effect of CBD on OIH, allodynia, and pain. Each volunteer underwent 2 interventions of electrically induced acute pain (Fig. 1 ). Between the first and second intervention, a minimum washout period of 2 weeks was required to avoid habituation effects and to ensure complete CBD clearance. In both interventions, participants received a remifentanil infusion for 30 minutes, 100 minutes after ingestion of the CBD or placebo to induce OIH. The participants received either 1600 mg of oral CBD or placebo after 6 hours of fasting. A syringe pump (Injectomat Agilia, Fresenius Kabi, Bad Homburg, Germany) was used to intravenously administer 0.1 μg/kg/min remifentanil . During the interventions, participants were continuously monitored by pulse oximetry (IntelliVue X2, Philips, Best, the Netherlands) and regularly asked about their well-being to screen for possible side effects. All reported side effects were protocoled at the case report form. Randomization of the study medication order was conducted by random number generator. The pharmacy of the University Hospital of Basel provided the study medication for each participant with a medication ID for the first and second interventions. To prevent accidental interchange, study medication was only provided per experiment of one single participant by the pharmacy. Because of the medication ID, the member of the study team responsible for assessing pain, hyperalgesia, and allodynia and the participant were blinded to the order of the study medication. The experiments were conducted twice a day, starting 08.30 am respective 1 pm in a separate room in the hospital with access restricted to participants and the study staff only. External interference and noise were kept to a minimal. Participants were positioned in a comfortable lying position with the arm used for measurements abducted at 45°. During sensory testing, the participants were instructed to keep their eyes shut, settings of current generator were not visible for participants. All measurements were performed by the same study investigator to minimize differences in interpersonal evaluation.
Figure 1.: Participant randomization scheme CBD, cannabidiol.
Pain, hyperalgesia, and allodynia were assessed every 10 minutes for 100 minutes (Fig. 2 ). A NRS (0, no pain and 10, worst pain imaginable) was used to assess the level of pain. Hyperalgesia was determined using a 256 mN von Frey filament and allodynia using a dry cotton swab to assess the affected area.
Figure 2.: Schematic illustration of experimental setup. CBD, cannabidiol;NRS, numeric rating scale.
2.2 Subjects
Volunteers were recruited through an advertisement on the homepage of the University of Basel, and inclusion occurred on a “first come, first served” basis with a balanced sex distribution (50% male and 50% female volunteers). Inclusion criteria were healthy (American Society of Anesthesiologists Physical Status I-II) adults (18 years and older) with a body mass index of 18.5 to 25 kg/m2 (Fig. 1 ). Exclusion criteria were frequent consumption of cannabinoids or other intoxicants, and regular intake of medications potentially interfering with pain sensation (analgesics, antihistamines, calcium and potassium channel blockers, antidepressants, corticosteroids). Neuropathy, chronic pain, neuromuscular disease, psychiatric disease, known or suspected kidney or liver disease, pregnancy/lactation, or a known allergy/hypersensitivity to CBD or remifentanil also leads to exclusion. Female participants in childbearing age were tested for pregnancy prior each intervention and received information concerning contraception in the participant information.
The experimental setup, including the assessment of pain (NRS), hyperalgesia, and allodynia, was explained to the volunteers prior to the first intervention, and financial compensation for participation in the study was paid.
2.3 Study medication
The study medications, manufactured by the pharmacy of the University Hospital of Basel, were provided in single-dose brown-glass bottles (8 mL volume) labelled in a blinded manner (for each participant and intervention, 2 bottles with a medication ID for the first and second intervention).
The investigational medical product (IMP) contained 800 mg CBD in 8 mL oily solution per bottle for per os administration. The placebo solution only contained 8 mL oily solution and was matched to the IMP so that it could not be distinguished by either the participant or the assessor. To achieve a dosage of 1600-mg CBD for each intervention, 2 bottles of the IMP or placebo solution were administered.
2.4 Remifentanil
Intravenous remifentanil infusions with a dose of 0.1 μg/kg/min for 30 minutes were used in previous studies investigating the OIH in the same acute pain model.2,33,35
According to Koppert et al.35
2.5 Experimental pain model and assessment
Every volunteer passed through 2 interventions with intradermal electrically induced pain by directly activating C fibers primarily and A-delta fibers to smaller degree.34 74 69 33,35,44
Two microdialysis catheters with internal stainless steel wires were inserted in parallel into the intradermal, volar surface of the right forearm for a length of approximately 10 mm and separated by 5 mm from each other. The catheters were filled with 0.9% saline, and a continuous flow of 0.2 μL/min was ensured by a syringe pump (CMA 402, CMA Microdialysis AB, Kista, Sweden) to facilitate conduction. The stainless steel wires were attached to a constant current stimulator (Digitimer S7; Digitimer Ltd, Hertfordshire, United Kingdom), and monophasic rectangular electrical pulses of 0.5-millisecond duration were applied with alternating polarity at 2 Hz. The current was titrated to target a pain rating of 6 of 10 on an NRS (0 = no pain, 10 = worst pain imaginable).
To compensate for early pain habituation, adjustments were made during 15 minutes after installation to reach a stable 6 out 10 on the NRS for each intervention. For 100 minutes, volunteers were asked to rate the NRS at every 10-minute interval. Hyperalgesia and allodynia areas were assessed by the investigator accordingly. The volunteer was blinded to the applied milliampere (mA) values. One-hundred minutes after IMP administration, an infusion of 0.1 μg/kg/min remifentanil for 30 minutes was administered to cause OIH. Previous studies showed that shortly after the remifentanil infusion was terminated, hyperalgesia increased and the hyperalgesic area remained significantly enlarged compared with baseline values.35
2.6 End points
The primary end point was the area of hyperalgesia measured from minute 140 to minute 200 after oral application of CBD. This equalized 10 minutes after the termination of a 30-minute remifentanil infusion (Fig. 2 ). Secondary end points were the effect of CBD vs placebo on the NRS and area of allodynia measured during the same period. In addition, whole-blood CBD levels at baseline and at 130 minutes and 200 minutes after oral administration were measured. We also analyzed the effect of remifentanil on pre- and postinfusion assessments.
2.7 Assessment of hyperalgesia and allodynia
The area of pinprick hyperalgesia was determined using a 256 mN von Frey filament, and subsequently, the area of allodynia was determined using a dry cotton swab. Measurements were conducted from a more distant to a more central site along 4 orthogonal lines (distal, proximal, lateral, and medial) drawn onto the skin with tick marks indicating each centimeter. Distal and proximal measurements were begun 12 cm from the site of electrical stimulation, whereas lateral and medial measurements were begun a maximum of 6 cm from the site, depending on the size of the forearm. In both cases, the instrument was moved toward the site of stimulation in 1-cm increments until the subject reported either increased pain sensations from the von Frey filament (hyperalgesia) or an unpleasant, “rougher” sensation from the cotton swab gently stroked on the skin (allodynia). Each direction was at least measured twice per time point to ensure consistent data. To create an area from these linear measurements, we assumed the field to be elliptic. The area was calculated using the formula: π D・d (where D is the vertical diameter and d the horizontal diameter). To not overestimate the impact of the wide axis measurements, a minimum of 1-cm radius was defined.
2.8 Measurement of cannabidiol whole-blood levels
To determine CBD levels in whole blood, blood was drawn from a peripheral catheter placed in the cubital vein of the arm not used for electrical stimulation. Three blood samples (SARSTEDT Monovette 9 mL, custom made potassium fluoride 45 mg/9 mL, reference number: 17,265, Hôpital du Valais, Switzerland) were drawn immediately before, at 130 minutes, and at 200 minutes after CBD intake. The initial blood sample served to ensure participant compliance (prior to first intervention) and medication washout prior to the second intervention in case participants received CBD during the first intervention. After collection, blood samples were immediately cooled at 4°C and kept cool until evaluation by the Institute of Forensic Medicine of the University of Basel within 7 days during the routine measurements performed by the institute.
Whole-blood samples were prepared using automated online solid-phase extraction and were analyzed by gas chromatography tandem mass spectrometry using a method adapted from previous analyses.47,58 51,53
2.9 Statistical analyses
Participant characteristics are shown as numbers (proportions), medians with interquartile ranges, and means ± SDs as appropriate (Table 1 ). The mean currents used are also presented as medians with interquartile ranges.
Table 1 -
Baseline characteristics.
Baseline characteristics
No. of participants
24
Age
25 ± 7
Male
11 (45.8%)
Female
13 (54.1%)
BMI [kg/m2 ]
22.0 ± 1.9
Ethnicity
White European
22 (91.6%)
Asian
1 (4.2%)
Mixed African European
1 (4.2%)
Data shown as median with interquartile range (age) and mean with SD (BMI).
BMI, body mass index.
We quantified NRS, the area of hyperalgesia, and the area of allodynia using the mean ± SD over all measured time points. Mean differences in the area of hyperalgesia, area of allodynia and pain for CBD vs placebo were assessed by 2-sample, paired t tests. No adjustments for P values were made.
Differences in current at the first and second sessions were examined using a Wilcoxon signed-rank test, and differences in sex for area of hyperalgesia, area of allodynia, and NRS were examined using Wilcoxon–Mann–Whitney tests.
CBD concentrations measured at 200 minutes were plotted against the area of hyperalgesia, area of allodynia, and the NRS (from minute 140 to minute 200). The line of best fit from a least-squares linear regression, the P value for the CBD coefficient, and Pearson r were also reported. In addition, CBD concentrations measured at 200 minutes (presented as median [Q1, Q3]) against the area of hyperalgesia, the area of allodynia, and the NRS at 200 minutes were plotted.
Sample size was estimated to show a 20% decrease in hyperalgesia for CBD vs placebo in a paired t test using an α of 5% and a power of 90%. Our rationale was as follows: A recent study of our group revealed that a placebo application without deception is able to reduce the area of hyperalgesia about 20%.57 Fig. 1 ).
3. Results
3.1. Baseline characteristics
Participants were recruited from May 2020 through September 2020. All participants (n = 24) were white European except for 1 Asian and 1 of mixed African and European ancestry, had a balanced male and female ratio, and were aged 18 to 54 years (mean age, 25 ± 7 years). Mean body mass index was 22.0 ± 1.9 kg/m2 (Table 1 ).
Two participants were excluded from the study because of CBD in the basal blood sample, and one due to emotional distress during the intervention. These participants were replaced by newly recruited volunteers. Data of excluded participants were not analyzed. Complete data sets were available for 21 participants. Apart from 1 report of moderate nausea and a slight temporary decrease in oxygen saturation, no other relevant side effects occurred.
The median current used during the first and second interventions did not differ significantly (14.1 mA [Q1-Q3 = 9.3-17.4] vs 14.8 mA [Q1-Q3 = 10.3–18.5], P = 0.794, Wilcoxon signed-rank test).
3.2. Pain, hyperalgesia, and allodynia response
We compared NRS, area of hyperalgesia, and allodynia during the remifentanil infusion between 100 and 130 minutes for the period 140 to 200 minutes after infusion stopped (Fig. 3 ). There were significant increases in NRS (2.2 [1.4-3.3] vs 5.1 [4.4-5.7], P < 0.001), area of hyperalgesia (12.3 cm [4.5-25.4] vs 25.3 cm [15.1-39.6], P < 0.001), and area of allodynia (4.8 cm [1.7-9.1] vs 11.0 cm [5.2-23.8], P = 0.003). Furthermore, the area of hyperalgesia from 140 to 200 minutes significantly increased compared with baseline measurements (17.0 cm [8.1-28.7] vs 25.3 cm [15.1-39.6], P = 0.013). There was no significant difference between CBD or placebo on hyperalgesia, allodynia, or pain at any time point (Fig. 3 ).
Figure 3.: Outcome variable of intradermal electrical stimulation over time. All values are represented as box-plots (whiskers display minimum and maximum values). CBD, cannabidiol; NRS, numeric rating scale.
Pain (NRS), area of hyperalgesia, and area of allodynia did not differ significantly between sexes: male (n = 11) vs female (n = 12) participants NRS 5.4 vs 4.7 (P = 0.073), area of hyperalgesia 25.5 vs 23.0 cm2 (P = 0.432), and area of allodynia 16.1 vs 9.7 cm2 (P = 0.375).
3.3. cannabidiol whole blood levels
The mean whole-blood concentration of CBD at 130 minutes was 4.1 ± 3.0 µg/L (mean ± SD), and at 200 minutes, it was 8.2 μg/L ± 6.9 µg/L (mean ± SD). Using Pearson r no significant correlation between CBD levels and hyperalgesia, allodynia or mean pain from minute 140 to minute 200 could be shown. The slight correlation was isolated to time point 200 minutes, but significance was not reached (Fig. 4 ).
Figure 4.: The left panel shows the relationship between the measured CBD concentration at the time point 200 minutes with the average pain score (NRS), area of hyperalgesia, and allodynia over time . The right panel shows the relationship between the measured CBD concentration at the time point 200 minutes with the pain score (NRS), area of hyperalgesia, and area of allodynia at the same time point (200 min). CBD, cannabidiol; conc, concentration; NRS, numeric rating scale; r , Pearson correlation coefficient.
Two participants were excluded and replaced due to CBD contamination in baseline blood sample. Apart from CBD, no other analyte (CBN, THC, THC-OH, and THC-COOH) was detected above their respective limits of detections in any of the whole-blood samples.
4. Discussion
In this prospective, randomized, double-blinded, placebo-controlled, crossover trial investigating healthy adults, the oral application of 1600-mg CBD in fasted state induced no effect on OIH, pain, and allodynia.
4.1. Pain model
Besides its broad reflection of pain processing, the strength of the model applied is the simultaneous assessment of local pain and central sensitization.34 14,42
4.2. Clinical relevance
Despite growing awareness of OIH,1,20,24,32 19
Besides the sparse evidence of CBD as a therapeutic in treatment of pain and hyperalgesia,8,10 37 13
CBD interacts with several receptors and intracellular messengers that have been identified as possible targets for the modulation of pain. Preclinical studies could show several antinociceptive effects on mechanical allodynia via the modulation of 5-HT1A-receptors,18,29 14,54 73
Recent research on the ability of CBD to antagonize σ-1-receptor revealed a potential target for the treatment of neuropathic pain.55 56 28 52
4.3. Route of administration, dose, and pharmacokinetics
Cannabidiol (Epidiolex) is approved by the US Food and Drug Administration for treating certain forms of epilepsy in patients, so far for oral use only.28 remifentanil was, thus, not possible. We aimed for the highest recommended maintenance dosage of 20 mg/kg/d28 43
In a recent review, Millar et al.49 7,45 5
Previous preclinical data about the effectiveness of CBD on hyperalgesia and pain are inconsistent. Costa et al. used similar doses (20 mg/kg) to investigate antihyperalgesic properties of CBD in rats. While showing anti-inflammatory effects during repetitive dosing, single doses of 20 mg/kg had no effect on nociceptive thresholds in animal trials.16 54
Costa et al. measured the dose-dependent anti-inflammatory and antihyperalgesic effect of CBD after carrageenan infiltration of rat paws 1 hour after CBD administration. Lower doses of 5 to 7.5 mg/kg required repetitive dosing, but single doses of 10 to 40 mg/kg were sufficient to stop hyperalgesia.14 63 39
4.4. Cannabidiol whole-blood levels
Our blood samples were analyzed by the Institute for Forensic Medicine of the University of Basel. According to their standards (conditions of Swiss traffic law), all measurements are done using whole blood. The blood/plasma (b/p) ratio of CBD has not been thoroughly examined. However, b/p-ratios of the structurally related THC of 0.39 to 0.63 have been reported.23,60 68 26 59 64
Overall, there is a lack of dose-ranging studies.49 7,27,43,67 27 28,68 6,17,64,75 58 58 50 72 68
Two participants were excluded from our analyses due to CBD in the control blood sample. No anamnestic abnormalities were detected, and the laboratory did not find any contamination with THC metabolites. Acknowledging the high variability in half-life, we assume that these participants were slow metabolizers and had residual CBD from the first meeting.49,50 Fig. 4 ). We have no conclusive explanation for this outlier.
4.5. Strength and limitations
Our research approach was based on a well-established pain model, which produced stable OIH like already demonstrated in several studies.2,33,35,44,70
We were well aware of the poor bioavailability of orally administered CBD. Regarding the low whole-blood levels of CANAB I,58 27 17,38
Despite knowing the desired effect of serving food with CBD, we insisted on an empty stomach prior to and during the intervention to achieve equal conditions and even more to ensure maximal safety by minimizing the risk of aspiration due to remifentanil . We decided against repetitive dosing because this would not be transferable to the clinic of acute pain or premedication prior to anaesthesia. Preferred intravenous administration was not available at the time; Meyer et al. recently published an article on intravenous CBD application in human.48
Kathmann et al. showed that CBD is an allosteric modulator of mu- and delta-opioid receptors on rat cerebral cortex membrane homogenates, but very high concentrations were needed for this effect. They doubt that in vivo conditions such CBD levels could be achieved.31 55 7
5. Conclusion
CBD at a high single oral dose of 1600 mg is not effective in reducing OIH. Before neglecting the effect of CBD on OIH, research should focus on drug formulations that enable higher drug levels after single dosing (eg, intravenous application) or aim for indications where repetitive administration is suitable. Based on our results, a single oral dose in fasted state cannot be recommended as a therapeutic to prevent OIH in the perioperative setting.
Conflict of interest statement
The authors have no conflicts of interest to declare.
Acknowledgements
The authors thank Allison Dwileski (scientific assistant), Clinic for Anaesthesia, Intermediate Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital Basel, Basel, Switzerland for providing editorial assistance.
Support was provided solely from sources of Clinic for Anaesthesia, Intermediate Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital of Basel, Basel Switzerland.
The full protocol and raw data are available up on request at: [email protected]
This work should be attributed to the Clinic for Anaesthesia, Intermediate Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital of Basel, Basel Switzerland.
Clinical trial number: NCT04059978, URL: https://clinicaltrials.gov/ct2/show/NCT04059978
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