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Cannabidiol as a Treatment for Chronic Pain: A Survey of Patients’ Perspectives and Attitudes

Correspondence: Jan M Schilling; Tobias Moeller-Bertram Clinical Research, Vitamed Research, LLC, 44630 Monterey Ave, Suite 100, Palm Desert, CA, 92260, USA, Email [email protected]; [email protected]

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Abstract

Introduction

Cannabis products have become easily available and accessible after decriminalization of cannabis for recreational and medicinal use in many states. Cannabidiol (CBD) has been of increasing interest to patients and is being used to self-medicate a variety of ailments. However, very limited information is available to patients and providers to form an educated opinion regarding its indicated use to treat the many conditions this substance has been implied to be helpful for. The aim of this survey was to learn about participants’ attitudes and views towards cannabis-based medicine (CBM) with a focus on perception of “CBD” and its potential role for pain management.

Materials and Methods

We recruited survey participants from seven pain management clinics in Southern California to learn about their knowledge, beliefs, and personal experience with CBD products. After Institutional Review Board (IRB) review, an internet survey platform was utilized to administer the survey online.

Results

A total of 253 participants answered the survey. Participants were 45.4 ± 13.8 (Mean ± SD) years of age, the majority identified as white (56.1%), had an annual household income of less than $20,000, and were primarily insured by Medicare (22.5%) or Medicaid (43.9%). Among participants, 62.0% reported trying a CBD product [including products containing delta-9-tetrahydrocannabinol (THC)]. The majority responded that these products have helped their pain (59.0%) and allowed them to reduce their pain medications (67.6%), including opioids (53.7%). They reported believing that CBD was a good treatment option (71.1%), not harmful (74.9%), and not addictive (65.3%). About half of participants (51.9%) report that they would be more comfortable with their physician prescribing CBD products. The overall attitude and experience of participants regarding CBD is reported as positive, while 91.9% of people expressed a desire to learn more about it.

Summary

In summary, most participants expressed a positive attitude about CBD products as a treatment option, reported positive outcomes when used for multiple different conditions, and would prefer to obtain information about and prescription for CBD from their physicians.

Introduction

Public demand for the legalization of cannabis resulted in legalization of medical cannabis in the United States first in California in 1996. 1 As of December 2020, thirty-six states and 4 territories have legalized the use of marijuana for medical purposes, creating a new treatment option for patients seeking alternative therapies. Perceived health benefits have been reported in mainstream and social media like eg, pinterest. 2 Unfortunately, this growing body of information around cannabis-based medications, specifically CBD and related health benefit claims, is not based on sound scientific research in the vast majority of cases. To further complicate the picture, cannabis-based medications including CBD products are poorly regulated in terms of their production and testing, vary in purity and consistency, and are often mislabeled. 3 As a result, the consumer of cannabis-based medications including CBD often cannot be sure about the actual quality and content of the products they consume.

Fortunately, the scientific interest in cannabinoid research has increased in recent years. 4 In particular, there has been a focus on the phytocannabinoid cannabidiol (CBD). 5 , 6 However, the evidence available is inconclusive at best, and this emphasizes the need for scientifically valid information about this compound. 7

A PubMed search revealed that the number of published research studies investigating the effects of CBD has more than doubled since the year 2016. CBD has been investigated as a treatment for childhood epilepsy, 8 , 9 reviewed as a potential treatment for chronic pain, 10–13 and some studies suggest usefulness to treat anxiety disorders. 14–16 There is ongoing research about whether the legalization of cannabis products affects opioid use and abuse. Recent studies have discovered a negative correlation between opioid use and cannabis laws 17 and have suggested that cannabis products might decrease use of opioid medications and the associated risks. 17–22

Taken together, the consumer of CBD products faces a landscape in which there is budding scientific evidence of beneficial effects for several conditions against a background of unproven claims and questionable products on the market. This currently ambiguous situation and somewhat unclear messaging around cannabis-based medications to the public poses the important questions around the current knowledge and believes about these products. Surveyed populations to date include a primary care setting, 23 young adults 24 and social media posts. 2

Given that one leading cause mentioned for CBD consumption is pain, the aim of this study was to assess the knowledge base, beliefs, and personal experience with CBM and CBD products by surveying patients seen at a series of pain management clinics. These results can help to address the gap of patients believes and supported scientific findings around CBD and aid health care providers in navigating conversations with their patients around these compounds.

Materials and Methods

Material and Methods are reported according to the checklist for reporting Results of Internet E-surveys (CHERRIES). 25

Design

Participants were recruited voluntarily (convenience sample, no incentive) from seven pain clinics in Southern California. Surveys were administered between December 4th 2018 and February 4th 2019.

IRB (Institutional Review Board) Approval and Informed Consent

The research protocol was reviewed by the Western Institutional Review Board (WIRB) and was determined to be exempt from the requirement of IRB approval meeting the criteria under 45 CFR §46.101(b)(2), including waiver of informed consent. In the specific case of our data collection, the exemption was granted since our research was a voluntary survey, no direct identifiers were collected, and the results will not be submitted to the Food and Drug Administration (FDA) for marketing approval.

Development and Pre-Testing

The survey ( Supplemental Material 1 ) was designed (JMS, TMB, CGH) and underwent multiple rounds of internal review and editing by VitaMed Research, LLC. study staff. Our demographic questions were written similar to those being asked in the Census. For our questions about CBD we utilized Yes/No answers, answers on the Likert scale (3-point, 5-point), and some questions with guided answer choices including an “other” option. Following this we entered, reviewed, and tested the questions in the SurveyMonkey environment with several test-runs to eliminate spelling and formatting errors. After this a QR code was created in the software and posters and index cards were distributed in the clinics. This survey is a new survey and has not been utilized prior. The goal of this survey was to collect broad attitudes towards and perception of CBD products to help and guide the generation of new hypothesis.

Recruitment Process and Description of the Sample Having Access to the Questionnaire

The survey information/link was posted openly in the form of posters, flyers, and business cards containing QR-codes at seven pain clinic locations in Southern California including the University of California, San Diego, Department of Anesthesia Division of Pain Management. Three were locations of Desert Clinic Pain Institute in Riverside County. Three were locations of Summit Institute, two in Riverside County and one in San Bernardino County. Both Desert Clinic Pain Institute and Summit Institute are complex pain management clinics who primarily serve Medicare and Medicaid populations. The survey was open to be answered by all patients and staff within our clinics. Additionally, Clinic patients were recruited by clinic staff by direct invitation or by providing business cards during their appointment ( Supplemental Materials 2 and 3 ).

Survey Administration

The survey was accessed using a QR code linked to the electronic format. The survey consisted of 32 questions that are presented including their answer choices in Tables 1 and ​ and2 2 and Supplemental Tables 1 and 2 . The survey included questions about the participants demographics ( Supplemental Table 1 ; 12 questions; zip-code data not shown), awareness and efficacy ( Table 2 ; 6 questions), personal experience ( Table 3 ; 7 questions; open-ended item responses were reported verbatim in Supplemental Table 3 ), and knowledge and beliefs about CBD ( Table 3 ; 7 questions). All questions required an answer before proceeding to the next question, but each question had the option of a neutral answer or “Decline to answer”. Since flyers and index cards were publicly available in the clinics, it cannot be excluded that in addition to patients, their family members, friends, or clinic staff participated in the survey. Additionally, theoretically the possibility exists that a responder could have answered the survey more than once. This is prevented by a function of the survey platform that does not allow multiple answers of the survey from the same IP address. However, IP addresses were not collected by us to avoid registering any sort of identifiers. Because of these limitations we cautiously describe our cohort as participants in a pain clinic environment and not as patients.

Table 1

Have you tried a CBD product?, N (%), N = 247
Yes 152 (62.0)
No 87 (35.5)
Do you believe the CBD product has helped your condition?, N (%), N = 151
Not at all 1 (0.7)
Not really 13 (8.6)
A little bit 48 (31.8)
A lot 59 (39.1)
Completely 30 (19.9)
If a CBD product has helped your condition, what type of condition did it help? Check all that apply. N (%), N = 150
Back pain 101 (67.3)
Neck pain 67 (44.7)
Limb pain 35 (23.3)
Nerve pain 70 (46.7)
Fibromyalgia 31 (20.7)
Migraines 50 (33.3)
Other (please specify) 58 (38.7)
What types of products have you tried? Check all that apply. N (%), N = 151
Oral tincture 79 (52.3)
Edible 82 (54.3)
Capsule/Pills 34 (22.5
Spray 26 (17.2)
Cream 75 (49.7)
Ointment/oil 75 (49.7)
Inhaled/smoked 95 (62.9)
Other (please specify) 11 (7.3)
Did any of the CBD products you used contain THC (the chemical that gets you “high”)?, N (%), N = 151
Yes 85 (56.3)
No 51 (33.8)
I do not know 13 (8.6)
Decline to answer 2 (1.3)
Please choose the answer that best applies to this statement: I was able to reduce the amount of pain medication I take by using CBD products. N (%), N = 151
Strongly disagree 6 (4.0)
Disagree 7 (4.6)
Neither agree nor disagree 36 (23.8)
Agree 56 (37.1)
Strongly agree 46 (30.5)
Please choose the answer that best applies to this statement: I was able to reduce the amount of opioid medication I take by using CBD products. (eg, Percocet, Norco, Morphine, Oxycodone), N (%), N = 151
Strongly disagree 9 (6.0)
Disagree 6 (4.0)
Neither agree nor disagree 55 (36.4)
Agree 40 (26.5)
Strongly agree 41 (27.2)

Notes: A majority of participants has tried a CBD product in several different formulations and for several different conditions and believe it has helped. Most participants additionally have used CBD products containing THC. More than 50% of participants believe they were able to reduce their pain medication (including opioids) by using CBD products. Descriptive data are presented as N and percent replies per question (%).

Table 2

Comparison Between Products Containing CBD and CBD/THC

Did any product you used contain THC?
Yes No
Total N = 136 N = 85 N = 51
N % within ‘contain THC’ % within ‘reduce med’ N % within ‘contain THC’ % within ‘reduce med’ Χ 2
Able to reduce pain medication? 0.31
Strongly disagree 1 1.2 20.0 4 7.8 80.0
Disagree 3 3.5 50.0 3 5.9 50.0
Neither agree nor disagree 21 24.7 61.8 13 25.5 38.2
Agree 33 38.8 67.3 16 31.4 32.7
Strongly agree 27 31.8 64.3 15 29.4 35.7
Able to reduce opioid medication? 0.56
Strongly disagree 4 4.7 44.4 5 9.8 55.6
Disagree 3 3.5 60.0 2 3.9 40.0
Neither agree nor disagree 28 32.9 57.1 21 41.2 42.9
Agree 24 28.2 68.6 11 21.6 31.4
Strongly agree 26 30.6 68.4 12 23.5 31.6

Notes: Explorative analysis was performed to compare perceived medication reduction between products containing CBD and CBD/THC. No significant difference was found for either pain medication or opioid medication reduction between groups. “Yes” and “No” answers were analyzed by Pearson’s Chi-Square test. Descriptive data are presented as N and percent replies per question (%) either as % within “contain THC” or % within “reduce med”.

Table 3

Knowledge, Opinions, and Interest

Do you know if there is a difference between medical marijuana and CBD?, N (%), N = 241
No, there is no difference 6 (2.5)
I do not know 82 (34.0)
Yes, there is a difference 153 (63.5)
If you have used CBD products in the past, are you familiar with how much CBD is in the product you have used?, N (%), N = 241
Extremely familiar 34 (14.1)
Very familiar 42 (17.4)
Somewhat familiar 43 (17.8)
Not so familiar 33 (13.7)
Not at all familiar 15 (6.2)
I have not used CBD products 74 (30.7)
I believe CBD is a good treatment option. N (%), N = 239
Strongly disagree 8 (3.3)
Disagree 3 (1.3)
Neither agree nor disagree 58 (24.3)
Agree 50 (20.9)
Strongly agree 120 (50.2)
I believe CBD is harmful. N (%), N = 239
Strongly disagree 131 (54.8)
Disagree 48 (20.1)
Neither agree nor disagree 51 (21.3)
Agree 4 (1.7)
Strongly agree 5 (2.1)
I believe CBD can be addicting. N (%), N = 239
Strongly disagree 115 (48.1)
Disagree 41 (17.2)
Neither agree nor disagree 76 (31.8)
Agree 3 (1.3)
Strongly agree 4 (1.7)
If I were to consider using CBD, I would feel more comfortable if it was prescribed by a doctor. N (%), N = 237
Strongly disagree 25 (10.5)
Disagree 13 (5.5)
Neither agree nor disagree 76 (32.1)
Agree 60 (25.3)
Strongly agree 63 (26.6)
I would prefer to buy CBD products from my doctor over other sources (smoke shops, dispensaries, internet). N (%), N = 237
Strongly disagree 23 (9.7)
Disagree 20 (8.4)
Neither agree nor disagree 79 (33.3)
Agree 65 (27.4)
Strongly agree 50 (21.1)

Notes: About a third of Participants do not know if there is a difference between medical marijuana and CBD and a wide variety of responses exists regarding familiarity with CBD. At the same time, participants believed that CBD was a good treatment option, not harmful, and not addictive. About half of participants report that they would be more comfortable with their physician prescribing CBD products. Descriptive data are presented as N and percent replies per question (%).

Data Analysis

Data was analyzed utilizing IBM SPSS Statistics Subscription software (Build 1.0.0.1298 64-bit edition, IBM, Armonk, NY). Demographics and the results to our questions are presented as descriptive statistics. Pearson’s Chi-Square test was utilized for exploratory data analysis in Table 3 . The total N and missing answers are shown in each table and the percentage of total (%) was calculated as percentage of answered questions, unless “Missing” was specified as an answer result. In the Results section, we present the results as the “majority” of answers. The majority was defined as the sum of percent answer choices in one direction excluding the neutral answer choice on the Likert scale. For guided answer choices that included “other”, we presented some examples of the most frequently chosen answers. For Yes/No answer choices we presented the answer choice with the most frequent replies. The complete answer choices are listed in the data tables ( Tables 1 and ​ and2, 2 , Supplemental Tables 1 – 3 ).

Results

A total of 253 participants started the survey and we received between 237 and 253 responses per question with the overall number of responses decreasing towards the end of the survey. Of the 152 participants that answered “yes” to having tried a CBD product, 151 answered the follow-up questions.

Analysis of demographic data ( Supplemental Table 1 , N = 253) shows that participants were 45.4±13.8 (Mean±SD) years old, the majority identified as white (56.1%), non-Hispanic (51.8%), had an annual household income of less/equal than $20,000 (56.1%), and received healthcare coverage through Medicare (22.5%) or Medicaid (43.9%). Additionally, 36.4% were unable to work due to disability and 5.1% of the cohort reported to have served on active duty in the United States armed forces.

Next, we asked the participants questions regarding awareness of CBD ( Supplemental Table 2 , N = 247). The majority reported knowing someone (family, friend, neighbor) who has used a CBD product (80.6%). Additionally, 80.6% report that somebody they know has previously suggested them to use a CBD product for their pain, while 29.6% report that their treating providers suggested use of a CBD product for their pain condition. When asked about the perceived efficacy of CBD products, 78.1% responded that they know somebody who has benefited from using a CBD product for their condition and 7.3% of participants report that someone they know developed side effects while using a CBD product. When asked if they were interested in learning more about the use of CBD to treat medical conditions, 91.9% replied with “yes”.

When asked if they have tried a CBD product, ( Table 1 , N = 151–247), 152 (62.0%) participants replied that they have tried a CBD product, and 56.3% report that the CBD product they have used contained tetrahydrocannabinol (THC). When asked if the CBD product helped their condition, participants responded “A lot” (39.1%), or “Completely” (19.9%). When asked about what conditions the CBD products have helped with the most frequently reported conditions were back pain (67.3%), nerve pain (46.7%), and neck pain (44.7%). When asked what type of products they have used, the most frequent responses were inhaled/smoked (62.9%), edibles (54.3%), and oral tinctures (52.3%). All other conditions and products reported can be viewed in detail in Table 1 and verbatim responses are listed in Supplemental Table 3 . When asked if using a CBD product was able to reduce the amount of pain medication in general, the majority agreed (37.1%) or strongly agreed (30.5%). Additionally, participants reported that the CBD product helped to reduce the amount of opioid medication specifically [“Agree” (26.5%), “Strongly Agree” (27.2%)]. When this data was analyzed by Pearson’s Chi-Square test ( Table 2 ) for perceived differences in pain and more specific opioid medication reduction between products containing either CBD or CBD/THC, we found no difference between groups [Χ 2 = 0.31 for “Able to reduce pain medication”; Χ 2 = 0.56 for “Able to reduce opioid medication”].

To gain further insights regarding knowledge, opinions, and interest we next asked a set of questions to all participants focusing on these topics ( Table 3 , N = 237–241). We were interested to know whether participants distinguish between medical marijuana and CBD with 63.5% answering “Yes, there is a difference”. We then asked the participants about their knowledge of CBD quantity in the product that they have used. Very similar percentages across possible answers were received pointing towards an overall unfamiliarity regarding knowledge of CBD content in used products. Overall, participants report that CBD is a good treatment option [“Agree” (20.9%), “Strongly Agree” (50.2%)], and disagree that CBD is harmful [“Disagree” (20.1%), “Strongly disagree” (54.8%)], or can be addicting [“Disagree” (17.2%), “Strongly disagree” (48.1%)]. Additionally, participants report being more comfortable if CBD products would be prescribed and or dispensed by a doctor [prescribed: “Strongly Agree“ (26.6%), “Agree” (25.3%), “Neither agree nor disagree“ (32.1%), “Disagree“ (5.5%), “Strongly disagree“ (10.5%)] [dispensed: “Strongly Agree” (21.1%), “Agree“ (27.4%), “Neither agree nor disagree“ (33.3%), “Disagree“ (8.4%), “Strongly disagree“ (9.7%)].

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Discussion

Discussion of Data

Taken together, participants report some perceived beneficial effects using CBM and CBD products including the reduction of pain medication. While the familiarity with dosing was mixed and participants used a wide variety of products including products containing THC, they report that these products have helped them with many different pain-involving and neurological conditions. This finding is in alignment with similar reports describing CBD effects ranging from placebo-equivalent to highly effective. 13 The effects of CBM and CBD on painful conditions seem to be context specific, with no effect on pain shown in patients with Crohn’s disease, 26 and pain-relieving effects reported for pain associated with Multiple Sclerosis, spinal cord injury, brachial plexus injury, limp amputation, 27 peripheral neuropathy 28 and fibromyalgia. 29 This cohort also reported that products both with and without THC have helped them to reduce overall pain medication and more specifically opioid medication. The ability of CBD to significantly reduce opioid use and improve chronic pain has also been reported in an 8-week prospective cohort study in chronic pain patients published by Capano et al. 30 In general, participants report a preference for obtaining products prescribed or recommended by their physician and to have the ability to access them in the doctor’s office rather than from other sources.

Overall, our study describes the attitudes and experiences of the participants with CBM and CBD-containing products (medical cannabis) in a pain management clinic environment with a large Medicare and Medicaid patient population. The majority of participants are residents of Riverside County, with a smaller amount from neighboring San Bernardino and San Diego Counties. The demographic representation of our cohort is in alignment with an anonymous survey distributed via social media that reported their sample of CBD users to be primarily white with a yearly household income of less than $25,000. 24 The data asking about participants awareness of CBD as a treatment option and efficacy ( Supplemental Table 2 ) show that the majority of participants have had interactions with their peers, and to a lesser degree their providers talking about CBD. A similar response was observed in a survey among primary care patients, where only 18% describes their medical providers as being a good source for information regarding cannabis derived medications. 31 When asked about their personal experience, 35.5% of participants have never tried a CBD product while those who have report trying several different products for multiple conditions. A majority described some positive effects of CBD products on their conditions and reduction of pain medication. It is important to mention that 36.5% of participants did not know or think that there is no difference between medical marijuana and CBD, further manifesting the criticism that we cannot say for certain which types of products were consumed. The survey question regarding the knowledge of CBD dosing showed that almost all answer choices were represented as similar percentages, suggesting that there is a high variability of familiarity with CBD content in CBD products. In a publication looking at the CBD concentration in a variety of products, one study shows inaccurate labeling of products in the majority of cases. 3 The combination of variable familiarity and CBD concentration in available products puts patients in a difficult position when they are in search for a standardized CBD product to try as a therapeutic option. In addition, it is unknown if there was any THC present in the consumed products. Here, requirements for quality control and labeling for all hemp-based products being marketed would take the guesswork out of exact dosing and allow for better understanding of the products that patients may be accessing. This is particularly needed as there are no quality studies evaluating CBD dosing ranges for pain. Additionally, there is a need to evaluate differences between efficacy of CBD isolate products and whole plant extracts (limited to

Discussion of Current Literature

Current Evidence for CBD and Pain

When looking at the current literature, it is evident, that well-controlled studies investigating the effects of CBD on pain are currently not available. 7 However, some literature is starting to investigate its effects. For example, a well-controlled study of purified CBD has demonstrated that CBD has low abuse potential, even within sensitive populations. 32 In a preclinical study, CBD use has also been attributed to reducing drug-seeking behavior in mice. 33 These positive results have brought up discussions about the role of CBD in combating the world’s opioid epidemic. While studies have investigated the combined use of fentanyl with CBD, the results were inconclusive and currently the impact of CBD on opioids is not known. 7 , 34 Another recent study was investigating the role that CBD plays on craving behavior in abstinent individuals with heroin use disorder. 35 This study shows that CBD doses (Epidiolex) of 400 mg and 800 mg were able reduce craving and anxiety induced by heroin’s cues compared to placebo. However, while the CBD doses of 400 mg and 800 mg are relevant from a pharmacologic and therapeutic perspective, these doses vastly exceed the regularly commercially available hemp-CBD products which may present cost challenges as Epidiolex therapy is around $16,000/year. 34 Several manuscripts review the current state of knowledge and point out important questions. Specifically, could CBD have a role in addressing the national opioid crisis? 10 , 11 Conversely, the data supporting THC as an analgesic and for opioid-sparing effects is more robust, specifically for neuropathic pain. 36–39 The known benefit of THC for pain raises the question of whether the small THC component in some products was responsible for perceived analgesic effects and reduction of pain medications in our cohort, further highlighting the uncertainty of product content/potency consumed by respondents.

Patients Perceptions

Multiple surveys focusing on patients perspectives have been published. 18 , 19 , 40–42 In the patient-focused surveys by Boehnke et al, improved quality of life, better side effect profile, improved pain and health, and decreased opioid use were reported among medical cannabis users. 19 , 41 , 42 Both the reported improved pain and decreased opioid use show similarities with our reported findings for “CBD products”, but these results need to be interpreted in the context of uncertainty regarding the CBD/THC content of the products consumed by respondents of this survey. Additionally, participants in this cohort reported being able to reduce overall use of pain medication. A different survey reported that consumers are using CBD as a specific therapy for multiple different conditions including pain, anxiety, depression, and sleep disorders. 40 In general, survey data emphasizes the need for controlled research investigating the potential use of CBD for a variety of conditions.

Study Limitations

This study has several limitations that need to be discussed. Regarding the demographics, the survey participants in this cohort are predominantly insured by Medicare or Medicaid and a limitation could be that this is not reflective of the general pain patient population and general population that is exposed to available CBD preparations. Additionally, terms like “CBD product”, “Hemp”, “Cannabis”, “Medical Cannabis”, “Medical Marijuana” that have been added to this manuscript and explained in the glossary were not well defined for the survey participants. One question in Table 1 (“Did any of the CBD products you used contain THC (the chemical that gets you “high”?”) additionally needs clarification. With this question, we intended to ask participants if they distinguish between products that are sold as “CBD only” products and products that contain THC in higher percentages than 0.3%. Since the verbiage does not clearly state this intent, the results of this question therefore need to be interpreted with caution. This survey was distributed in a pain clinic environment and was not limited to patients. We cannot exclude that family members or clinic staff participated in the survey. Also, the relatively small sample size (n=253) is associated with bias (eg, a voluntary response bias) and may not be generalizable, particularly since only 70% have used a product. There are general limitations in a survey design, including non-sampling biases. 43 Additionally, there is the potential for recall bias, the representativeness of the sample, and the inherent uncertainty about what constitutes a “CBD product”. Medical cannabis and cannabinoid products have been associated with a prominent placebo effect particularly important to keep in mind with self-reported benefits. 44 Given these limitations, this is a well-described cohort demographically, and the data can be interpreted in this particular context. Voluntary surveys such as this one can help to identify areas for future more controlled research.

Conclusion

Taken together, the opinions, beliefs, and experiences about and with CBM and CBD were predominantly positive in this cohort. Participants reported to be able to reduce overall pain and specifically opioid medication and would be more comfortable receiving CBD through prescription or purchase from their healthcare provider. It is now our responsibility as medical and scientific communities, working with the FDA, to produce well-designed studies that can either support or disprove the anecdotes about cannabis and hemp by providing a stronger evidence-base for effectiveness in treating pain and other conditions, and continue to press for quality control of any product being consumed by patients.

Acknowledgments

We would like to thank our clinic personnel in the Center of Excellence clinics of Desert Clinic Pain Institute and Summit Institute for their help and efforts in completing this study.

Glossary

Cannabidiol (CBD) product – Any product that has a high CBD, and “low or no” (< 0.3%) THC content. This nomenclature was used in our survey.

Cannabinoid Any substance that acts on the cannabinoid receptor system, both plant-derived and synthetic

Cannabis – A genus of plants with several species

CBD – Cannabidiol, a naturally occurring compound found in the Cannabis plant

CBM – Cannabis-based medicine

Hemp – The CBD-rich cannabis species containing less than 0.3% THC

Medical Cannabis/Marijuana – herbal drug derived from plants of the genus Cannabis containing >0.3% of THC

Disclosure

Vitamed Research, LLC. was supported by an unrestricted grant from Verséa™ Pharmaceuticals.

Dr Moeller-Bertram is Co-Founder and Chief Medical Officer for Verséa™ Pharmaceuticals. He also was supported by grants from Versea Holdings, LLC, during the conduct of the study.

Dr Backonja is a medical advisor as Medical Director for Verséa™ Pharmaceuticals.

Dr Wallace is a medical advisor for Verséa™ Pharmaceuticals.

Dr Michelle Sexton is a medical advisor for Verséa™ Pharmaceuticals and reports personal fees from Verséa™ Pharmaceuticals, outside the submitted work.

Dr Jan M Schilling reports grants from Verséa™ Pharmaceuticals, during the conduct of the study.

The authors report no other conflicts of interest in this work.

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An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia

* Corresponding author. Address: Anesthesia and Pain Research Unit, Department of Anesthesiology, Leiden University Medical Center, H5-022, 2300 RC Leiden, the Netherlands. Tel: +31 71 526 9111. E-mail address: [email protected] (A. Dahan).

Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Abstract

Keywords: Cannabis, Chronic pain, Fibromyalgia, Pharmacokinetics, THC, CBD, Placebo cannabis, Pain models

1. Introduction

In the current opioid epidemic, there is the need for pharmaceutical alternatives to opioid treatment in patients with chronic pain. An alternative may be found in the chemicals of the cannabis plant (Cannabis sativa L.), which contains over 500 chemical components, with more than 100 of them being cannabinoids. 8 Cannabinoids, or more specifically phytocannabinoids, are the main active chemical components of the cannabis plant. They exhibit most of their pharmacological effects via cannabinoid type 1 (CB1) and type 2 (CB2) G-protein-coupled receptors. CB1 receptors are located mainly in the central nervous system, whereas CB2 receptors are mostly found on immune cells. 21 These receptors form part of the endocannabinoid system, a modulatory biological system that influences the activity of different neurotransmitters with their own ligands, the endocannabinoids, such as anandamide and 2-arachidonoylglycerol. 22 As for cannabis, its major cannabinoid is ∆ 9 -tetrahydrocannabinol (THC), a partial CB1-receptor agonist, that produces a variety of effects including altered cognition and motor function, analgesia, and psychotropic effects (eg, drug high). 3 Another key component of cannabis is cannabidiol (CBD) that, while nonintoxicating, does affect mood and cognition. 16 It is a CB2 receptor antagonist and additionally has agonist activity at the 5HT-receptor and stimulates the vanilloid receptor type 1 with similar efficacy as capsaicin. 2,7,11,29

In this experimental trial, we explored the effect of pharmaceutical-grade cannabis in patients with chronic pain caused by the fibromyalgia (FM) syndrome. Fibromyalgia is characterized by chronic widespread pain, often accompanied by secondary symptoms including sleep disturbance, tiredness, and cognitive symptoms such as memory deficits. 10 This condition predominantly affects women, with a worldwide prevalence of 2% to 8% and conventional pharmacologic treatment is considered only mildly effective. 5,8,17

We explored the analgesic effects of inhaled pharmaceutical-grade cannabis using the cannabis plant with all its natural components. We tested 4 different varieties with exact knowledge on their THC and CBD content. The varieties used were Bedrocan with a high THC/low CBD content, Bedrolite with a high CBD/low THC content, Bediol with a combined high THC/high CBD content, and a placebo variety without any THC or CBD content. This approach enabled exploration of cannabis effects on pain relief relative to placebo cannabis that was similar in smell, appearance, and handling compared with the other varieties. We assessed relief of experimental pressure pain, electrical pain, and spontaneous pain (primary endpoints), as well as the subjective and psychotropic effects. We hypothesized that compared with placebo treatment, all THC-containing treatments would cause greater analgesic responses for both spontaneous pain and evoked pain models.

2. Methods

2.1. Ethics and trial registration

This single-center, double-blind, placebo-controlled, 4-way crossover study, with acronym Spirocan, was performed at the Anesthesia and Pain Research Unit of the Department of Anesthesiology at LUMC. The protocol was approved by the local institutional review board and the Central Committee on Research Involving Human Subjects in The Hague. The study was registered at trialregister.nl under identifier NTR6091 and in the European Union Drug Regulating Authorities Clinical Trials (EUDRACT) database under identifier 2015‐003811‐39. Before enrollment, all patients gave written informed consent.

2.2. Patients: inclusion and exclusion criteria

Female patients diagnosed with FM were approached to participate in the study through announcements in local newspapers and the web site of the association of patients with FM. When patients indicated interest in the study and were diagnosed with FM by a rheumatologist, they were queried for inclusion and exclusion criteria. Inclusion criteria were: a pain score ≥5 for most of the day (on a verbal pain scale from 0 = no pain to 10 = most pain imaginable) and positive diagnostic criteria of the 2010 American College of Rheumatology. 28 These criteria include a widespread pain index (WPI) ≥7 (on a scale from 0 to 19) and a symptom severity (SyS) score ≥5 (on a scale from 0 to 12) or a WPI of 3 to 6 and a SyS score ≥9. The WPI defines the number of body areas in which a patient experienced pain during the past week; the SyS score indicates the level of other main symptoms of FM such as fatigue, nonrefreshing sleep, and cognitive symptoms. The presence of autonomic complaints such as diarrhea or obstipation, dizziness, dry mouth/eyes, etc. was not a reason for exclusion, as we consider these symptoms consistent with the FM syndrome. Exclusion criteria included age

2.3. Study design: drugs, inhalation, and blood sampling

Patients visited the research unit on 5 occasions. On their first visit, the patients were screened (medical history, physical examination, and urinalysis) and familiarized with the experimental setup (they were, for example, trained in the inhalation process). On each of their next visits, the patients received 1 of 4 possible cannabis treatments (in random order) with at least 2 weeks between visits.

The active cannabis substances were composed of the dried, milled, and homogenized flowers of the plant Cannabis sativa L., which were cultivated under standardized conditions in line with the requirements of good manufacturing practices (GMP). We used 4 distinct pharmaceutical-grade cannabis varieties, all obtained from Bedrocan International BV (Veendam, the Netherlands) and all prepared by Proxy Laboratories BV (Leiden, the Netherlands) under GMP conditions:

(1) Bedrocan: The Bedrocan cannabis variety contains 22% THC (220 mg per gram) and less than 1% CBD. It was developed in the Netherlands out of a requirement by the Dutch Health Ministry to have a “high THC” variety available to patients. We used 100 mg that contained 22.4-mg THC and less than 1-mg CBD.

(2) Bediol: The Bediol cannabis variety is characterized by the combination of 6.3% THC (63 mg per gram) and 8% CBD (80 mg per gram). We used 200 mg that contained 13.4-mg THC and 17.8-mg CBD.

(3) Bedrolite: This variety is composed of 9% CBD (90 mg per gram) and less than 1% THC. We used 200 mg that contained 18.4-mg CBD and less than 1-mg THC.

(4) Placebo: The placebo was derived from the Bedrocan cannabis variety after selective removal of the cannabinoids by solvent extraction by Proxy Laboratories BV under GMP conditions. After removal of the cannabinoids, the specific terpene profile (responsible for smell and taste) was restored in a subsequent manufacturing step. Consequently, the placebo had a moisture content and terpenoid profile matching the active drug (Bedrocan).

Study medication was analyzed for cannabinoid content, terpene profile, and water content by an independent quality control laboratory. In addition, tests were performed to ensure that unwanted elements were absent such as adulterants, microbes, heavy metals, and pesticides. The pharmacy and ethics committee reviewed and approved the products’ quality certificates before dispensing the cannabis to the research team. During the study, all varieties were refrigerated at 2 to 8 °C in triple-layer laminated foil pouches.

Patients were dosed with cannabis vapor. All cannabinoids are mostly present in the plant in their acid form. Application of heat is needed for decarboxylation of the cannabinoid acids into their active forms (eg, THC acid into THC). 9 All 4 cannabis varieties were vaporized using the Volcano Medic vaporizer (Storz & Bickel GmbH & Co, Tuttlingen, Germany)—a safe and reliable method of intrapulmonary administration of cannabinoids. 13,30 The Volcano heated the homogenized plant material to 210 °C to allow for conversion of the THC acid and CBD acid into THC and CBD vapor for inhalation. The vapor was collected in an 8-L plastic balloon that, after inflation, was detached from the vaporizer and subsequently equipped with a mouthpiece for inhalation. For the purpose of blinding, the balloon was covered with an opaque plastic bag so that no variation in density of the vapor was visible between visits. The evaporation process was performed by a member of the research team not involved in the study proceedings. Before and after each evaporation, the device was cleaned with alcohol. The complete content of the balloon was inhaled through the mouth within 3 to 7 minutes, and each breath was held for 5 seconds after each inhalation.

On each occasion, an arterial line was placed in the left or right radial artery for blood sampling. Five milliliter of blood was obtained at t = 0 (control sample, before inhalation), 5, 10, 20, 30, 40, 50, 60, 90, 120, and 180 minutes after the start of inhalation. Blood was collected in EDTA tubes (covered with an aluminum foil), centrifuged at 2000g at 4°C; separated plasma was stored at −80°C until analysis. The samples were analyzed by Analytical Biochemical Laboratory BV, Assen, the Netherlands. All handling of the samples was done in a darkened room to prevent the cannabis molecules from disintegrating. Determination of the CBD, THC, and its active metabolite 11‐hydroxy‐THC (11-OH-THC) plasma concentrations was performed using liquid chromatography with tandem mass spectrometer detection (LC‐MS/MS). In Supplemental Materials 1 to 3, the analysis specifications including chromatograms of the 3 cannabis varieties are given for 2 (low and high) concentrations (available at http://links.lww.com/PAIN/A705).

2.4. Study design: pain tests, questionnaires, and safety

All subjects rated their FM pain on an 11-point visual analogue scale (from 0 = no pain to 10 = most severe pain imaginable) at baseline (before cannabis inhalation) and at 1, 2, and 3 hours after inhalation.

Two experimental pain tests were performed:

(1) Pressure pain test 18 : A pressure algometer (FDN 100; Wagner Instruments Inc, Greenwich, CT) was used to deliver pressure pain on a skin area of 1 cm 2 between the thumb and index finger; the affected area overlays the adductor pollicis muscle. The algometer has a force capacity (±accuracy) of 100 ± 2 N (10 ± 0.2 kgf) and graduation of 1 N (100 gf), respectively. A gradually increasing pressure was manually applied, and the subjects were asked to indicate when the procedure became painful (pressure pain threshold). All measurements were obtained in triplicate at t = 0 (baseline), 12, 22, 32, 42, 62, 92, 122, 152, and 182 minutes after the start of inhalation. The 3 measurements were averaged for further analysis.

(2) Electrical pain test 20 : Electrical pain was induced using a locally designed computer interfaced electrical currents stimulator (CICS, Leiden University Medical Center, Leiden, the Netherlands). The stimulator was connected to 2 electrodes (surface area 0.8 cm 2 ) placed on the tibial surface of the right leg, approximately 10 cm above the medial malleolus. The stimulator produced a stimulus train (stimulus duration 0.2 ms at 10 Hz) that increased from 0 mA at 0.5 mA/second (cutoff 128 mA). The subjects were instructed to press a control button when pain was first felt (pain threshold) and when the pain became unbearable (pain tolerance; this ended the stimulus train). Measurements were obtained at t = 0, 10, 20, 30, 40, 60, 90, 120, 150, and 180 minutes after the start of cannabis inhalation.

Two questionnaires were taken to assess the effect of drug treatment on mental and psychoactive cannabis effects:

(1) Bowdle questionnaire 4,30 : This questionnaire evaluates 3 psychedelic effects (drug high, alterations in internal perception, and alterations in external perception) from 13 questions scored on a 100-mm visual analogue scale (from 0, no effect, to 100, maximum effect). Internal perception reflects inner feelings that do not correspond with the reality and is derived from questions regarding the hearing of unrealistic voices or sounds and having unrealistic thoughts and paranoid or anxious feelings. The external perception indicates a misperception of an external stimulus or change in the awareness of the subject’s surroundings and is derived from questions regarding the perceptual change of body parts, the change of surroundings, the altered passing of time, the difficulty of controlling thoughts, and the change in color and sound intensity.

(2) Bond and Lader questionnaire 3,30 : The Bond and Lader scales are calculated from sixteen 100-mm visual analogue scales. The endpoints are set at antonymous word pairs such as “alert–drowsy,” “well coordinated–clumsy,” “mentally slow–quick witted,” and “incompetent–proficient.” The study participant’s task is to make a mark on each scale at the point that best describes how they currently feel considering that the 2 anchors reflect the greatest extent they experience each state. Responses from these 16 scales are then scored to yield 3 main factors of alertness (alert, strong, clear‐headed, coordinated, energetic, quick‐witted, attentive, proficient, and interested), contentment (contented, happy, amicable, gregarious, and tranquil), and calmness (calm and relaxed). A high score indicates impairment.

The subjects were queried before drug inhalation and at 30-min intervals after the start of inhalation. Adverse events and serious adverse events were collected in the case record form. In case of a serious adverse event, the event was treated, and no further measurements were obtained. In case of an adverse event (eg, nausea, vomiting, headache, and dizziness), no further action was taken apart from supportive care.

2.5. Randomization, allocation, and blinding

Randomization was performed by the pharmacy using a computer-generated randomization list. A distinct randomization sequence was created for each subject; randomization sequence was controlled with just 2 subjects with an identical treatment sequence. On the day before the experiment, the subject was allocated to treatment by the pharmacy after receiving a fax message from the investigators with the participant’s identifier code and study visit number. Treatment was prepared on the day of the study and collected by a technician from the pharmacy in a closed opaque canister labeled with the patient’s identifier code and study visit number; the contents of the canister were emptied in the vaporizer. The study team was next presented with the filled opaque balloon just before the actual cannabis inhalation. The investigators (and patients) remained blinded until data analysis was complete (June 2018). The study was independently monitored ensuring that all good clinical practice requirements were met.

2.6. Statistical analysis: sample size and assessment of treatment effects

Considering the data from Wallace et al., 25 we calculated the need for 20 subjects to allow for a significant separation between treatments with a power >0.9 and alpha = 0.05. In case of dropout after one visit, the data were discarded, and a new subject was recruited. Before the data analyses, all variables were screened for missing data, homoscedasticity, distribution abnormalities, and outliers. For both primary and secondary endpoints, the effect of active treatment (Bedrocan, Bedrolite, or Bediol) on the change in effect was compared between treatments using a mixed model. Treatment was set as a fixed effect, a random effect for the subject was added to account for repeated measurements over time, and treatment order was added as a covariate. For spontaneous pain, the responder rate was determined for each treatment and compared with placebo responder rates using a χ 2 test. A responder was defined as having a reduction in spontaneous pain score of at least 30% or 50% at one or more measurements. In addition, the change in spontaneous pain score relative to baseline was related to the drug high score by Spearman’s ρ. The number of adverse events between the 3 active treatments and placebo was analyzed using a χ 2 test. SPSS (IBM Corp Released 2017; IBM SPSS Statistics for Windows, Version 25.0, Armonk, NY: IBM Corp) was used for all analyses with P values

3. Results

Twenty-five patients were recruited for participation. Five patients ended their participation after their first study visit for unknown reasons (n = 1), side effects such as dizziness and nausea (n = 3), and fear of needles (n = 1) (Fig. ​ (Fig.1). 1 ). All were replaced by another patient according to the protocol. The 20 patients who completed the trial were on average 39 ± 13 years with an average weight of 82 ± 20 kg and height of 169 ± 7 cm (body mass index 29 ± 7 kg/m 2 ). At screening, patients reported an average verbal pain score of 7.20 ± 1.24 units and were all diagnosed with FM with a WPI of 13.9 ± 2.6, SyS of 9.2 ± 1.3, and 14.9 ± 2.9 of positive tender points.

Consort flow diagram. FM, fibromyalgia.

Cannabis inhalation was achieved in (minutes:seconds) 5:03 ± 2:54 (21 ± 11 inhalations; Bedrocan), 6:57 ± 4:05 (23 ± 11 inhalations; Bediol), 5:30 ± 2:37 (22 ± 10 inhalations; Bedrolite), and 2:48 ± 1:40 (14 ± 6 inhalations; Placebo). The complete content of the balloon was inhaled by all subjects. All 3 active treatments, but not placebo, were associated with several adverse effects (Table ​ (Table1), 1 ), with frequent effects related to the inhalation of cannabis (coughing during inhalation in 65%-70%, sore throat and bad taste during inhalation in 25%-35% of participants). Most adverse effects unrelated to the inhalation process were drug high in 40% to 80%, dizziness in 15% to 20%, and nausea in 5% to 30% of participants. Two patients reported feelings of drug high after placebo treatment. There were no differences in frequency of adverse effects between active treatments (P > 0.05). No serious adverse events occurred.

Table 1

Incidence of adverse events.

After inhalation of all 3 active treatments, THC, its metabolite 11-OH-THC, and CBD, were detectable with the following CMAX and TMAX values (Fig. ​ (Fig.2). 2 ). Bedrocan: THC 82 ± 20 ng/mL at t = 5 minutes, 11-OH-THC 5 ± 3 ng/mL at 10 minutes, and CBD 0.2 ± 0.3 ng/mL at 5 minutes; Bediol: THC 76 ± 35 ng/mL at t = 5 minutes, 11-OH-THC 5 ± 3 ng/mL at 10 minutes, and CBD 80 ± 029 ng/mL at 5 minutes; and Bedrolite: THC 13 ± 5 ng/mL at t = 5 minutes, 11-OH-THC 0.9 ± 0.5 ng/mL at 10 minutes, and CBD 155 ± 57 ng/mL at 5 minutes. No cannabinoids were detectable after placebo inhalations.

Plasma concentrations of ∆ 9 -tetrahydrocannabinol (THC), its metabolite 11-hydroxy-THC (11-OH-THC), and cannabidiol (CBD) after inhalation of 3 cannabis varieties, Bedrocan (A), Bediol (B), and Bedrolite (C). Data are mean ± 95% confidence interval.

None of the treatments had an effect greater than placebo on spontaneous pain scores or electrical pain responses (Fig. ​ (Fig.3 3 and Table ​ Table2). 2 ). By contrast, both Bedrocan and Bediol caused a significant increase in tolerance to the pressure applied to the skin over the adductor pollicis muscle for the duration of the study. The largest effect was observed for the cannabis variety that contained high doses of both THC and CBD (Bediol) with an increase in tolerated pressure of 9 to 11 kgf from t = 20 to 90 minutes (P < 0.001 vs placebo; t = 0 minutes is the start of cannabis inhalation). Over this same time range, Bedrocan increased the tolerated pressure by 7 to 9 kgf (P = 0.006 vs placebo). With respect to spontaneous pain scores and tolerance to pressure pain, Bediol had significantly greater effects than Bedrolite (P = 0.04 for both endpoints, Table ​ Table2 2 and Fig. ​ Fig.3 3 ).

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Effect of cannabis varieties Bedrocan, Bediol, Bedrolite, and placebo cannabis on spontaneous pain scores (A), pressure pain threshold (B), and drug high (C). Data are mean ± SEM and are relative to baseline. NRS, numerical rating score; VAS, visual analogue scale.

Table 2

Effect of treatment on experimental pain and spontaneous pain responses.

After placebo treatment, 11 and 6 patients had 30% and 50% reduction in pain scores on at least one measurement period, respectively. Comparing these responder rates to active treatment, significantly more patients responded to Bediol with a decrease in spontaneous pain by 30% (n = 18, P = 0.01; Fig. ​ Fig.4) 4 ) but not with a decrease by 50% (n = 9, P = 0.052). At both responder rates, all other treatments had response profiles not different from placebo (Fig. ​ (Fig.4). 4 ). Spontaneous pain scores were strongly correlated with the magnitude of drug high for Bedrocan (ρ = −0.5, P < 0.001) and for Bediol (ρ = −0.5, P < 0.001).

Cannabis responder rates: (A) Percentage responders with a decrease of at least 30% in spontaneous pain scores on at least one measurement. (B) Percentage responders with a decrease of at least 50% in spontaneous pain scores on at least one measurement.

Psychoactive effects of treatment, as measured by the Bowdle questionnaire, are given in Table ​ Table3. 3 . Bedrocan and Bediol caused moderate drug high responses, on average just below 50% of the maximum possible response (Fig. ​ (Fig.3B), 3 B), but significantly greater than placebo (P < 0.001). Bedrolite had less intense drug high responses compared with either Bedrocan (P = 0.003) or Bediol (P < 0.001). Small effects were seen for changes in internal perception (Bediol vs placebo, max. mean difference with placebo 7 mm, P = 0.009, Table ​ Table3) and 3 ) and external perception (Bedrocan and Bediol vs placebo, max. mean difference with placebo 17 mm, P < 0.001), indicative of limited psychosis-like effects after Bedrocan and Bediol treatment. Bedrolite caused smaller changes in internal perception than Bediol (P = 0.04) and smaller changes in external perception than both Bediol (P = 0.004) and Bedrocan (P = 0.01). The responses to the Bond and Lader questionnaire indicate mild deterioration in mood observed during Bediol treatment (max. mean difference with placebo 11 mm, P = 0.02, Table ​ Table3) 3 ) and mild deterioration in alertness during Bedrocan (max. mean difference with placebo 21 mm, P = 0.02). Some small differences in mood and alertness were observed among the 3 active treatments (Table ​ (Table3 3 ).

Table 3

Effect of treatment on subjective feelings derived from the Bowdle questionnaire and Bond and Lader questionnaire.

In Figure ​ Figure5A, 5 A, the plasma THC concentration vs Δpressure pain for the 3 active cannabis varieties is plotted showing loops with counterclockwise direction. Using a nonparametric collapsing approach, we closed the loops to give the relationship between the estimated THC effect-site (or steady-state) concentration and Δpressure pain (Fig. ​ (Fig.5 5 B) 19 (Using ke0obj, written and kindly provided by Dr. S.L. Shafer [Stanford University, Palo Alto, CA]). The effect of Bedrocan (blue dots) is derived from just THC (reference drug). The effect of Bediol (red dots) is lower than expected from its steady-state THC concentration range, indicative of an antagonist effect of CBD (when combined with THC) on the pressure pain response. By contrast, when CBD is administered without relevant THC content (Bedrolite, green dots), a small THC-independent analgesic effect is apparent.

(A) Plasma THC concentration (CP) vs the change in pressure pain threshold after treatment with Bedrocan (blue dots), Bediol (red dots), and Bedrolite (green dots). The arrows indicate the direction of effect, starting at the large yellow circle. (B) Estimated steady-state or effect-site (CE) concentration vs the change in pressure pain threshold for the 3 active cannabis varieties. THC, tetrahydrocannabinol.

4. Discussion

The main findings of this experimental study in chronic pain patients with FM are that:

(1) none of the treatments had an effect greater than placebo on spontaneous pain scores; (2) compared to placebo responder rates, significantly more patients responded to Bediol (containing high doses of THC and CBD) with a decrease in spontaneous pain by 30%; the 2 other active treatments had response profiles not different from placebo; (3) the reduction in spontaneous pain scores was correlated with the magnitude of drug high; (4) pressure pain threshold increased significantly in patients treated with Bedrocan and Bediol, 2 cannabis varieties with a high THC content; (5) Bedrolite, a cannabis variety with a high CBD content was devoid of analgesic activity in any of the spontaneous or evoked pain models; and (6) CBD increased plasma concentrations of THC but had an antagonistic effect on analgesia when combined with THC.

Major strengths of our study are the measurement of plasma concentrations of the inhaled cannabinoids enabling the correlation of plasma concentration rather than dose to effect, the use of a placebo cannabis variety exempt from THC and CBD but with the original terpene profile of the Bedrocan variety, and the testing of well-defined cannabis varieties in a group of patients with a well-defined chronic pain condition. Limitations of the study are the short treatment period and lack of validation of the experimental measures in FM.

Over the past years, cannabis has become increasingly popular for medical use. Currently, an increasing number of countries legalized or are planning to legalize cannabis for medicinal purposes. For instance, in the Netherlands, standardized cannabis has been available in pharmacies on prescription since 2003. However, cannabinoids typically have modest effects with small effect sizes and numbers needed to treat >20. 24 In addition, the effect of cannabinoids in relieving chronic pain seems to diminish over time. 24 Still, many patients report using cannabis for the treatment of chronic pain with promising results. 23 We performed a small experimental study to explore the acute analgesic effects on experimental measures of 3 cannabis varieties that ranged in THC and CBD content after a single inhalation.

Our experimental study was not designed to provide direct evidence for the clinical use of cannabis in FM but may be used to design future clinical trials. In addition, our approach allows to link the observed effect with THC and CBD plasma concentrations and to detect possible pharmacokinetic and/or pharmacodynamic interactions. Here, we discuss the performance and outcome of the study with focus on the use of placebo cannabis, pharmacokinetics, potential analgesic efficacy of THC and CBD, and adverse effects.

4.1. Placebo cannabis

We used a placebo cannabis variety (ie, a cannabis plant devoid of THC or CBD but with the full terpene profile) as a comparator to ensure blinding of treatment. Cannabis placebo varieties without cannabinoids have been used before. 27 Our placebo plant material had a similar smell and appearance as the other cannabis varieties. The importance of successful blinding in clinical trials on cannabis analgesia has recently been highlighted. 26 Although our approach theoretically allows for blinding of treatment during inhalation, we cannot exclude that lack of psychoactive symptoms from placebo inhalation during the course of the study had some influence on the outcome in some of the pain models. This is especially relevant given the study crossover design. Indeed, at the end of the study, 13/20 (65%) patients guessed correctly that they had received placebo treatment. On the other hand, the terpenes present in the placebo plant may have exerted some effects. Terpenes are assumed to interact with cannabinoids (entourage effect), improving their pharmacodynamic effects (eg, by increasing pulmonary uptake and change binding of cannabinoids to their receptors), but also have effects of their own, including anti-inflammatory, antidepressant, and analgesic effects. 12,22 This then suggests that the placebo cannabis variety used in our study is best considered an active placebo. Hence, the observation of an appreciable placebo effect in the relief of spontaneous pain is not surprising.

4.2. Pharmacokinetics

4.3. Outcome of the acute experimental pain tests

Two cannabis varieties, Bedrocan and Bediol, were analgesic in the pressure pain model but had no effect in the electrical pain model or on relief of spontaneous pain. The pressure pain test seems especially suited for exploring treatment effects in FM pain, as it elicits mechanical muscle stimulation through Aδ- and C-fiber activation and better reflects the symptoms of patients with FM than electrical pain, which produces direct sensory nerve stimulation. 19 We previously used electrical noxious stimulation as a model of acute pain and showed high sensitivity of opioids in alleviating transcutaneous electrical pain. 20 The current data suggest that cannabis may have limited use in acute pain treatment.

Interestingly, when CBD and THC were combined (in Bediol), CBD had antagonistic pharmacodynamic effects (Fig. ​ (Fig.5B), 5 B), possibly because of an antagonistic or negative modulatory action at the CB1 receptor. 6 Despite this pharmacodynamic antagonism, the analgesic responses exceeded those of Bedrocan, possibly because of the CBD-induced increase in THC concentrations. The opposed direction of the pharmacokinetic and pharmacodynamic CBD–THC interactions is an indication of the complex pharmacological behavior of cannabinoids in humans. When CBD is given without relevant THC content (ie, Bedrolite, containing predominantly CBD), just small analgesic effects not different from placebo became apparent. This is somewhat surprising, as it is our experience and that of others that patients with chronic pain report beneficial effects from CBD treatment. 23 Possibly, such effects are related to improvement of insomnia, anxiety, cognition, and/or mood. In addition, it may well be that a single CBD administration may be insufficient to elicit analgesic responses, or that the dose was too low.

4.4. Side effects

Some side effects of active treatment were observed. One-third of patients reported sore throat and bad taste, whereas two-thirds coughed during the 5- to 7-minute inhalation of the active treatments. In the course of the study, one-third of patients experienced nausea without vomiting. All symptoms were rated as mild. An important observation was that most patients disliked the feeling of drug high after inhalation, although the intensity was rated as moderate (Fig. ​ (Fig.3C). 3 C). Because this is a general observation in chronic pain patients treated with psychedelic medication, we recently studied the ability to temper the feeling of drug high induced by racemic ketamine. We observed that drug high intensity was reduced by 30% during administration of the nitric oxide donor sodium nitroprusside. 15 Because cannabis and ketamine produce their psychotropic effects through separate pathways (N-methyl- d -aspartate receptor antagonism vs CB1-receptor agonism), further studies are needed to discover viable options to reduce THC-related drug high without reducing analgesia. Still, it may be that this may have a negative effect on analgesic efficacy because we observed that relief of spontaneous pain was correlated with drug high scores. This suggests that some level of intoxication is required for an analgesic cannabis effect, or that the lack of complete blinding due to the occurrence of psychotropic side effects (or symptoms during inhalation) influenced pain scoring to some extent.

In conclusion, in this experimental and highly controlled study, we explored the pharmacokinetics and pharmacodynamics of 3 active cannabis varieties in chronic pain patients with FM. The most important observation is that when simultaneously inhaled, THC and CBD interact in complex fashions with synergistic pharmacokinetic but antagonistic pharmacodynamic interactions. The analgesic efficacy of active treatment was limited to varieties that contained THC and was observed exclusively in the evoked pressure pain model. None of the active treatments were effective in reducing spontaneous pain scores more than placebo. Further studies are needed to assess efficacy and safety (including addictive behavior) in clinical trials with prolonged treatment periods and explore the role of psychotropic effects in the development of analgesia.

Conflict of interest statement

This investigator-initiated trial was performed in collaboration with Bedrocan International BV (Veendam, the Netherlands). Bedrocan International BV was responsible for the production and delivery of the cannabis products and the Volcano device for cannabis inhalation. M.A. Kowal is an employee of Bedrocan International BV, the Netherlands. He commented on the protocol and final version of the paper. The other authors have no conflict of interest to declare.

Appendix A. Supplemental digital content

Supplemental digital content associated with this article can be found online at http://links.lww.com/PAIN/A705.

Footnotes

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.painjournalonline.com).

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