Preclinical Science and Clinical Studies - Research Article

Med Cannabis Cannabinoids 2022;5:20–31 Received: November 22, 2021

Accepted: December 10, 2021
DOI: 10.1159/000521492 Published online: February 9, 2022

Medicinal Cannabis for the Treatment of Chronic

Refractory Pain: An Investigation of the Adverse
Event Profile and Health-Related Quality of Life
Impact of an Oral Formulation
Sarah Abelev a Leon N. Warne b, c, d Melissa Benson a Mark Hardy e
Sunny Nayee f John Barlow a
aApplied Cannabis Research, Sydney, NSW, Australia; bLittle Green Pharma, Perth, WA, Australia; cCollege of Science,

Health, Engineering and Education, Murdoch University, Perth, WA, Australia; dSchool of Pharmacy and Biomedical
Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia; eCA Clinics, Sydney, NSW,
Australia; fPain Management Department, Charing Cross Hospital, Imperial College Healthcare Trust, London, UK

Keywords important differences to determine meaningful change in

Adverse events · Cannabinoids · Improved pain intensity · HRQoL over time. Results: More than half (n = 91/151, 60.3%)
Improved pain impact · Medicinal cannabis of the participants experienced at least one AE during the
observation period (mean 133 ± 116 days). No serious AEs
were reported. Patient-reported pain impact scores were
Abstract significantly reduced across the cohort (p = 0.034), and pain
Introduction: Medicinal cannabis is prescribed in Australia intensity scores verged on significance (p = 0.053). The ma-
for patients with chronic refractory pain conditions. Howev- jority of patients saw meaningful improvements in sleep
er, measures of safety and effectiveness of different canna- (49.3%) and fatigue (35.6%). Conclusion: This analysis pres-
binoids are lacking. We designed an observational study to ents real-world data collected as part of standard of care.
capture effectiveness, adverse events (AEs), and health-re- More than one-third of patients benefited from oral medici-
lated quality of life (HRQoL) measures in patients prescribed nal cannabis, which is impactful given the refractory nature
an oral medicinal cannabis formulation at Cannabis Access of their pain. Amelioration of the impact of pain confirms
Clinics through the Cannabis Access Clinics Observational continued prescribing of this formulation and validates our
study (CACOS). Objectives: We aimed to evaluate effective- observational methodology as a tool to determine the ther-
ness, reported AEs, and change in patient-reported out- apeutic potency of medicinal cannabinoids.
comes in individuals prescribed a cannabinoid oil formula- © 2022 The Author(s)
tion for management of chronic pain. Methods: A cross-sec- Published by S. Karger AG, Basel

tional analysis was conducted on patients prescribed an oil

formulation of Δ9-tetrahydrocannabinol and cannabidiol for Introduction
pain symptoms of at least 3-month duration. Clinician-re-
ported AEs were organized by system, organ, class, and fre- Chronic pain is defined as pain enduring longer than
quency. Analysis of patient-reported responses to a ques- 3 months involving a spectrum of physical pain, disabil-
tionnaire was conducted using published minimal clinically ity, emotional disturbance, and social withdrawal [1].

karger@karger.com © 2022 The Author(s) Correspondence to:

www.karger.com/mca Published by S. Karger AG, Basel Leon N. Warne, l.warne @ lgp.global
This is an Open Access article licensed under the Creative Commons
Attribution-NonCommercial-4.0 International License (CC BY-NC)
(http://www.karger.com/Services/OpenAccessLicense), applicable to
the online version of the article only. Usage and distribution for com-
mercial purposes requires written permission.
Chronic pain affects between 15% and 30% of the adult Since November 2016, Australian clinicians have been
population worldwide [2], including 20% of Australians permitted to prescribe cannabis-based products to pa-
over the age of 45 [3], and imposes a significant socioeco- tients under the Special Access and Authorized Pre-
nomic burden on the community [4]. This burden is re- scribed Schemes. Anecdotally, prescribers benefit from
flected in a $139.3 billion (2018) cost to the Australian disease-specific prescription guidelines, emerging pro-
economy, most of which is attributed to reduced quality fessional development programs, and ongoing feedback
of life (QoL) [5]. The annual global cost of poorly man- from their patients.
aged chronic pain has historically exceeded heart disease, As the prescribing of pharmaceutical-grade medicinal
cancer, or diabetes by 2-fold [6]. cannabis products manufactured under Good Manufac-
While the mainstay of chronic pain management is turing Practice (GMP) continues to increase [18], studies
pharmacological therapy involving multimodal analge- assessing the effectiveness of these quality-controlled
sics (nonsteroidal anti-inflammatory drugs [NSAIDs] products in a real-world setting will become increasingly
and opioids) and adjuvant agents (anxiolytics and muscle relevant for Australian prescribers and patients. Accord-
relaxants) [7], this approach is rarely sustainable [1]. Opi- ingly, the study presented here investigates the safety and
oids are often poorly tolerated, ineffective in the long effectiveness of an orally administered oil formulation of
term [8], and have high potential for abuse [9]. A diverse medicinal cannabis containing equal parts of THC and
range of agents are prescribed to address the multidimen- CBD (10 mg/mL THC; 10 mg/mL CBD) prescribed for
sional nature of chronic pain and mitigate the known the treatment of symptoms associated with chronic pain
abuse potential. Despite these well-established approach- as part of the Cannabis Access Clinics Observational
es to treatment, many patients remain dissatisfied and re- Study (CACOS).
fractory, seeking alternative options to manage their pain The primary aim of this analysis was to evaluate the
and its impact on their day-to-day functioning [10]. effectiveness and characterize adverse events (AEs) and
The endocannabinoid system is known to control pain serious adverse events (SAEs) experienced by patients
at spinal and peripheral levels which has led to the explo- prescribed this oral formulation. The secondary aim was
ration of medicinal cannabis as a treatment option for the to assess the self-reported health-related quality of life
management of chronic pain. The cannabis plant con- (HRQoL) impact of this therapeutic intervention on a
tains over 60 cannabinoids with potential to interact with subset of participants using a validated quality of life in-
the endocannabinoid system, the two best studied being strument [19]. The cross-sectional analysis format pro-
Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). vides an opportunity to reflect on aspects of study design
These compounds are thought to work in concert to al- including sample size and clinical data management.
leviate pain through activation and modulation of can-
nabinoid, opioid, serotonergic, and transient receptor
potential pathways [7]. A cross-sectional survey of Aus- Methods
tralian medicinal cannabis patients repeatedly cited
chronic pain as the most common reason for use [11, 12]. Setting and Informed Consent
Several long-term prospective open-label studies support This study was a multi-centre, prospective, open-label, obser-
the use of medicinal cannabis for this indication [13–16]. vational study conducted within CA Clinics, a network of general
practice clinics throughout Australia that specialize in prescribing
These findings informed the Australian medicines regu- cannabinoid formulations. Participants gave informed consent to
lator, the Therapeutic Goods Administration (TGA) allow analysis of observational data collected as part of their rou-
guidelines, that found “moderate” evidence to support tine clinical care. This study (CACOS study) was approved by the
medicinal cannabis as a treatment for chronic non-cancer Bellberry Human Research Ethics Committee (Applied Cannabis
pain [17]. However, these studies are limited in their Research, ref: 2019-04-338).
translatability to the Australian context. Inhalational Study Population
(smoked or vaporized) administration of medicinal can- Patients were prescribed an orally administered oil formulation
nabis has limited applicability when demographic and containing equal parts of THC and CBD (10 mg/mL THC; 10 mg/
practical considerations favour oral administration. Fur- mL CBD; LGP Classic 10:10; Little Green Pharma, Perth, WA, Aus-
thermore, there is minimal information available to per- tralia) for the treatment of pain as a symptom of a chronic pain con-
dition as determined by the treating clinician at CA Clinics (Table 1).
mit product identity, assessment of consistency, and This formulation mimics other mixtures of CBD and THC except
measures of efficacy due to the diverse range of products that it is administered as an oil-based liquid formulation rather than
accessed in these studies. a spray [7]. For the purposes of this study, we used the definition of

Medicinal Cannabis for the Treatment of Med Cannabis Cannabinoids 2022;5:20–31 21

Chronic Refractory Pain DOI: 10.1159/000521492
 Table 1. Cohort demographics for AE and PROMIS analyses

AE analysis (n = 151) PROMIS analysis (n = 71) p value#

Age, mean (SD) 54.6 (15.9) 55.3 (15.4) 0.75

Sex, n (%)
Female 84 (55.6) 39 (54.9)
>0.9
Male 67 (44.4) 32 (45.1)
Pain indication, n (%)
Arthritis 42 (27.8) 17 (23.9)
Chronic pain unspecified 33 (21.9) 12 (16.9)
Neuropathic pain 34 (22.5) 19 (26.8)
Other musculoskeletal pain 25 (16.6) 18 (25.4)
Fibromyalgia 18 (11.9) 13 (18.3)
Cancer pain 11 (7.3) 2 (2.8) 0.65
Migraine 7 (4.6) 5 (7.0)
Endometriosis 6 (4.0) 6 (8.5)
Trigeminal neuralgia 3 (2.0) 2 (2.8)
CRPS 2 (1.3) 1 (1.4)
Postherpetic neuralgia 1 (0.7) 1 (1.4)
Observation period, mean (SD), days^ 133.3 (115.6) 139.2 (116.4) 0.72
Average dose, mean (SD), mg/day
THC 22.4 (13.0) 22.4 (13.0) >0.9
CBD 22.4 (13.0) 22.4 (13.0) >0.9

Other musculoskeletal pain covered presentations such as neck pain, back pain, and pain following injury. ^ Pe-
riod between reporting of AEs by the clinician or period elapsed between first and last PROMIS-29 completion. The
period is directly relevant to the period of data collection being analysed for each cohort. # p value calculated using
unpaired Student’s t test or Fisher’s exact test for sex and Kruskal-Wallis test for pain indication group comparisons.

chronic pain as described by the International Association for the doctor and pharmacist were consulted to retrospectively apply these
Study of Pain [20]. Candidates for this study were included if they categories to each relevant AE. SAEs and AEs were categorized using
met the following criteria: (1) adult aged 18 years or over, (2) report- the Medical Dictionary for Regulatory Activities (MedDRA, version
ing pain symptoms of at least 3-month duration, (3) previously tried 2019AB), a dictionary designed for use in the registration, documen-
and failed other analgesics, (4) sufficient cognitive function and En- tation, and safety monitoring of medicinal products using a System
glish language skills to complete questionnaires, and (5) seeking me- Organ Classes (SOC) hierarchy and Common Terminology Criteria
dicinal cannabis therapy within the CA Clinics network. Candidates for Adverse Event (CTCAE, version 5.0) definitions. CTCAE is a
were excluded from the study if they (1) had any severe cognitive, web-based application to assist in locating appropriate AE terms.
medical, or psychiatric condition that impaired their ability to pro- In addition to AE monitoring during clinical visits, patients
vide informed consent and complete questionnaires, (2) were wom- completed an online questionnaire during their treatment that in-
en who were pregnant or breastfeeding, or (3) were administering a cluded the question “Have you been experiencing any side effects
medicinal cannabis formulation other than the LGP Classic 10:10. from your medicinal cannabis prescribed by CA Clinics”? They were
Data were collected between December 2018 and May 2020 then given the option to choose from a list of possible side effects
from 151 participants. Clinical consult data were extracted from or choose “Other” or “None.” Patients did not report the severity
electronic medical records, and patient-reported outcome mea- of these side effects. This questionnaire was sent to participants
sures were captured and stored using Research Electronic Data once per week (online suppl. Fig. 1; for all online suppl. material,
Capture (REDCap). Details of the analysis cohort selection criteria see www.karger.com/doi/10.1159/000521492).
are shown in Figure 1. Patients who self-reported an AE in this questionnaire were
contacted by their CA Clinics clinician to assess the type of AE,
AE Reporting relatedness to study treatment, and severity. These clinician-veri-
Clinician-reported AEs and SAEs were collected at regular pa- fied patient data are reported here, as well as AEs reported during
tient monitoring visits conducted as part of routine standard of care. clinical visits.
The participant information consent form advised patients on the
study to visit their clinician once monthly for the first 3 months of Patient-Reported Outcomes Measurement Information System
treatment and once per 3-month period thereafter. Clinicians report- Analysis
ed the severity (mild/moderate/severe) and relatedness (unlikely/ The PROMIS-29 (v2.0) is a validated, generic (disease non-spe-
possibly/probably) of AEs within the clinical notes. In the event these cific) health-related quality of life (HRQoL) tool consisting of pa-
details were missing in consult notes for some AE cases, a medical tient-reported outcome measures across seven domains used to

22 Med Cannabis Cannabinoids 2022;5:20–31 Abelev/Warne/Benson/Hardy/Nayee/

DOI: 10.1159/000521492 Barlow
 Color version available online
Participants enrolled in CACOS prescribed LGP Classic 10:10
product (n=204)

Excluded (n=38)
♦ Indications other than chronic pain

Analysis inclusion Participants with chronic pain indication (n=166)

Excluded (n=0)
♦ No clinician-reported AE monitoring available

Clinician-reported AE analysis completed

(n=166)
AE reporting

Excluded (n=15)
♦ Administered non-LGP 10:10 products

Included in AE analysis (n=151)

Excluded (n=81)
♦ Did not complete ≥2 PROMIS-29
questionnaires during observational period
(n=79)
♦ <7 days between PROMIS-29 (n=2)

PROMIS-29 analysis

Included in PROMIS-29 analysis

(n=71)

Fig. 1. Cohort inclusion for AE and PROMIS analysis from CACOS participants that were prescribed the LGP
Classic 10:10 product. Two analysis cohorts were identified: the AE cohort (n = 166) and the PROMIS subgroup
(n = 85).

Medicinal Cannabis for the Treatment of Med Cannabis Cannabinoids 2022;5:20–31 23

Chronic Refractory Pain DOI: 10.1159/000521492
 How much did pain interfere with your day to day activities?
How much did pain interfere with work around the home?
How much did pain interfere with your ability to participate in social activities?
Fig. 2. PROMIS-29 questionnaire items as-
sessing “pain impact.” How much did pain interfere with your household chores?

evaluate physical, mental, and social health and wellbeing in peo- (n = 42; 27.8%), neuropathic pain (n = 34; 22.5%), and
ple with chronic illnesses [21]. It has been used as a primary way other musculoskeletal pain (n = 25; 16.6%). The mean
to measure change in HRQoL [22]. Figure 1 provides an outline of observation period was 133.3 (±114.5, range: 9–392) days
analysis inclusion. Figure 2 shows the survey items..
Patient data were included in the analysis if they had complet- (Table 1). The mean daily dose of cannabinoids for the
ed a minimum of two PROMIS-29 questionnaires during the ob- AE analysis cohort was 22.4 ± 13.0 mg THC and 22.4 ±
servational period, at the time of cross-sectional sampling. PRO- 13.0 mg CBD administered as a ∼2.25 mL volume of oral
MIS-29 data were excluded from participants who failed to com- oil.
plete two or more questionnaires. This questionnaire was sent to A majority of subjects in this analysis group presented
participants once per week (online suppl. Fig. 1).
The observational period for each patient was defined as the with a single chronic pain condition (n = 134/151, 88.7%),
time between first and last data points collected. The minimum while the remainder presented with two or more chronic
observation period for inclusion in the analysis was defined as ≥7 pain conditions. The mean age of the PROMIS-29 analy-
days given the PROMIS-29 is validated to a 7-day period. Analyses sis cohort was 55.3 (±15.4) years, with a slightly higher
of PROMIS-29 domains were conducted using T-score reference proportion of females (54.9%) than males. The most
tables from the PROMIS-29 v2.0 conversion tables [21]. Pain im-
pact scores were calculated based on NIH Task Force recommen- common chronic pain conditions included neuropathic
dations [23]. pain (n = 19, 26.8%), other musculoskeletal pain (n = 18,
25.4%), and arthritis (n = 17, 23.9%). The mean observa-
Statistical Analysis tion period was 139.2 (±116.4, range: 9–392) days (Ta-
Data were analysed using SPSS Statistics 1.0.0.1327 (IBM, ble 1). The mean daily dose of cannabinoids for the PRO-
Armonk, NY, USA) and GraphPad Prism v8 (GraphPad, San
Diego, CA, USA) for descriptive statistics. Effectiveness of treat- MIS analysis cohort was 22.4 ± 13.0 mg for THC and 22.4
ment was explored through the PROMIS-29 survey consisting ± 13.0 mg CBD, administered as a ∼2.25 mL volume of
of 8 pain domains, 7 of which use 5-point Likert scales and 1 of oral oil.
which uses a 10-point Likert scale. Raw scores were converted to A majority of subjects in this analysis group presented
standardized T scores using the PROMIS-29 scoring manual
with a single chronic pain condition (n = 45/71, 63.4%),
(v2.1). Means and standard deviations were calculated for con-
tinuous variables, and frequency as a proportion of the group while the remainder presented with two or more chronic
was calculated for categorical variables. Paired Student’s t test pain conditions. The mean cannabinoid dose was signifi-
was used for comparison of PROMIS T-score means over the cantly lower at the first time point compared with the last
observation period. Unpaired Student’s t test was used to com- time point collected (THC, 25.1 ± 27.5 mg, and CBD, 25.1
pare continuous variable means. The χ2 test (or Fisher’s exact
± 27.5 mg, for the first time point compared with THC,
test when n < 20) was used to compare categorical variables. A p
value below 0.05 was used to indicate statistical significance in 29.4 ± 24.0 mg, and CBD, 29.4 ± 24.0 mg, for the last time
all analyses. point; per day; two-way ANOVA; time point p < 0.0001;
cannabinoid p > 0.05). No significant differences between
analysis cohort demographics were found (p > 0.05) (Ta-
ble 1).
Results
Mild Adverse Events Associated with Medicinal
Demographics Cannabis Were Observed within the Study Cohort
One hundred and fifty-one participants contributed to Over half (n = 91/151; 60.3%) of the total AE analysis
the AE analysis, and a subset (71 participants) contrib- cohort (n = 151) experienced at least one AE during the
uted to the PROMIS-29 analysis. The mean age of the AE observational period, as reported by their clinician,
analysis cohort was 54.6 (±15.9) years, with a slightly while 39.7% (n = 60/151) of patients had no AEs. A to-
higher proportion of females (55.6%) than males. The tal of 196 AEs were attributed to 91 subjects, highlight-
most common chronic pain conditions included arthritis ing that some patients experienced multiple AEs. The

24 Med Cannabis Cannabinoids 2022;5:20–31 Abelev/Warne/Benson/Hardy/Nayee/

DOI: 10.1159/000521492 Barlow
Table 2. Clinician-reported adverse events for LGP Classic 10:10 product during the observational period

MedDRA system organ class AEs, (n) Patients MedDRA system organ class AEs, (n) Patients
reporting reporting
AE, (n) AE, (n)

Psychiatric disorders, n (%) Metabolism and nutritional disorders, n (%)

Total 66 (34) 57 (63) Total 7 (4) 6 (7)
Somnolence 25 (38) 23 (40) Increased appetite 4 (57) 3 (50)
Anxiety 9 (14) 7 (12) Decreased appetite 3 (43) 3 (50)
Insomnia 8 (12) 7 (12) Eye disorders, n (%)
Confusional state 3 (5) 2 (4) Total 7 (4) 4 (4)
Disorientation 4 (6) 3 (5) Ocular discomfort 3 (43) 1 (25)
Euphoria 4 (6) 4 (7) Dry eyes 2 (29) 1 (25)
Paranoia 4 (6) 3 (5) Flushing in eyes 1 (14) 1 (25)
Dissociation 3 (5) 3 (5) Eye swelling 1 (14) 1 (25)
Depression 3 (5) 3 (5) Cardiac disorders, n (%)
Hypervigilance 2 (3) 1 (2) Total 6 (3) 5 (5)
Tachyphrenia 1 (2) 1 (2) Increased blood pressure 5 (83) 4 (75)
Gastrointestinal disorders, n (%) Palpitations 1 (17) 1 (25)
Total 43 (22) 34 (37) Skin and subcutaneous tissue disorders, n (%)
Dry mouth/throat 18 (42) 14 (41) Total 2 (1) 2 (2)
Nausea 13 (30) 10 (29) Skin irritation 1 (50) 1 (50)
Diarrhoea 6 (14) 5 (15) Skin burning sensation 1 (50) 1 (50)
Abdominal discomfort 3 (7) 3 (9) Musculoskeletal and connective tissue disorders, n (%)
Nausea and vomiting 1 (2) 1 (3) Total 2 (1) 2 (2)
Constipation 2 (5) 1 (3) Muscle tightness 1 (50) 1 (50)
Nervous system disorders, n (%) Muscle twitching 1 (50) 1 (50)
Total 38 (19) 31 (34) Social circumstances, n (%)
Dizziness 10 (26) 10 (32) Total 2 (1) 1 (1)
Paraesthesia 5 (13) 3 (10) Rumination 1 (50) 1 (100)
Memory impairment 4 (11 3 (10) Social withdrawal 1 (50) 1 (100)
Vertigo 4 (11) 2 (6) Vascular disorders, n (%)
Sedation 3 (8) 3 (10) Total 1 (0.5) 1 (1)
Restlessness 3 (8) 2 (6) Orthostatic hypotension 1 (100) 1 (100)
Seizure 2 (5) 2 (6) Blood and lymphatic system disorders, n (%)
Dysgeusia 2 (5) 2 (6) Total 1 (0.5) 1 (1)
Agitation 2 (5) 1 (3) Anaemia 1 (100) 1 (100)
Tremor 1 (3) 1 (3) Ear and labyrinth disorders, n (%)
Gait disturbance 1 (3) 1 (3) Total 1 (0.5) 1 (1)
Headache 1 (3) 1 (3) Tinnitus 1 (100) 1 (100)
General disorders and administration site conditions, n (%)
Total# 196 91
Total 28 (12) 21 (22)
Fatigue 6 (39) 6 (48) #Patients could experience a single AE on multiple occasions,
Lethargy 11 (39) 7 (33)
and hence the number of patients often exceeding the total num-
Balance problems 0 (11) 0 (14)
Pain 2 (7) 2 (10) ber of AEs.
Irritability 1 (4) 1 (5)

mean AEs reported (by clinicians) per participant were defined by the TGA and CTCAE reporting requirements.
2.2. Table 2 describes the AEs reported for the analysis No grade 4 or 5 events were reported.
cohort within the defined observational period (n = The relatedness of the AEs to medicinal cannabis treat-
151). ment was reported. Most AEs were probably related (n =
The severity analysis revealed the majority of AEs re- 150/196, 76.5%) or possibly related (n = 76/196, 38.8%) as
ported (n = 168/196; 85.7%) were mild (grade 1), as op- opposed to unlikely related (n = 6/196, 3.1%) to treatment
posed to moderate (n = 54/196; 27.6%; grade 2) or severe with LGP Classic 10:10 oil. No SAEs were reported with-
(n = 10/196; 5.1%; grade 3) in intensity, per the grading in the observational period for this cohort of patients.

Medicinal Cannabis for the Treatment of Med Cannabis Cannabinoids 2022;5:20–31 25

Chronic Refractory Pain DOI: 10.1159/000521492
Table 3. Change to PROMIS domains over the observational period with medicinal cannabis treatment [23–26]

Measure (range) First (n = 71) Last (n = 71) p value Improved Not changed Worsened MCID
mean (SD) mean (SD) n (%) n (%) n (%)

PROMIS-29 domains
Pain intensity (0–10) 6.3 (2.1) 5.7 (2.3) 0.053 24 (32.9) 33 (45.2) 16 (21.9) 2.0 [23]
Domains as T-scores (population mean 50, SD 10)
Pain interference 64.7 (7.9) 63.5 (8.4) 0.16 27 (37) (34.1) 26 (35.6) 20 (27.4) 2.0 [23]
Fatigue 54.9 (10.6) 55.5 (10.3) 0.62 26 (35.6) 25 (34.2) 22 (30.1) 2.5 [24]
Sleep disturbance 53.6 (10.0) 51.4 (9.5) 0.13 36 (49.3) 11 (15.1) 13 26 (35.6) 2.0^
Anxiety 52.7 (8.6) 53.2 (10.2) 0.61 17 (23.3) 37 (50.7) 19 (26.0) 2.3 [25]
Depression 53.2 (8.8) 52.8 (9.1) 0.67 17 (23.3) 37 (50.7) 19 (26.0) 3.0 [25]
Satisfaction with social role 40.5 (9.5) 40.4 (8.3) 0.93 23 (31.5) 34 (46.6) 16 (21.9) 2.0^
Physical function 35.8 (8.3) 36.2 (7.7) 0.58 26 (35.6) 30 (41.1) 17 (23.3) 1.9 [23, 26]
Impact score (raw score, 8–50) 33.5 (10.2) 31.1 (10.0) 0.034* 35 (47.9) 21 (28.8) 17 (23.3) 3.0 [23]
Impact shift – – – 17 (23.6) 43 (58.3) 13 (18.1) –

Bold values indicate the placement of the cohort majority. Impact shift is defined as change from mild impact (8–27) to moderate impact
(28–34) to severe impact (≥35) based on impact score cutoffs. A positive impact shift shows patients changed in a positive direction from
a detrimental impact level to a lesser one (i.e., severe → moderate/moderate → mild). MCID, minimal clinically important difference. ^ MCID
= 2.0 as default given there is no published MCID value in the literature to reference. * p < 0.05 compared to first (paired Student’s t test).

Psychiatric and Gastrointestinal-Related AEs was a 3.2 ± 1.9-point reduction (p < 0.0001) compared to
Accounted for the Majority Reported a 2.6 ± 0.6-point increase in those that had worsened pain
The majority of the cohort experienced at least one AE intensity (n = 16; p < 0.0001).
(n = 91/151; 60.3%). AEs were classified by the MedDRA Impact score was also calculated based on responses to
SOC and reported based on frequency and the number of targeted pain impact items (Fig. 2). A significant decrease
patients experiencing each AE (Table 2). The majority of in pain impact score was found overall, with the mean
AEs experienced fell under psychiatric disorders (n = impact score reduced by 2.3 ± 9.4 points (p = 0.034). Of
66/196; 33.7%), followed by gastrointestinal disorders (n those with a meaningful improvement (based on minimal
= 43/196; 21.9%) and nervous system disorders (n = clinically important difference [MCID] = 3.0; n = 35), a
38/196; 19.4%). The two former categories accounted for mean 9.6 ± 7.9-point decrease was observed (p < 0.0001).
∼55% of all reported AEs. Somnolence (n = 23/196; Most subjects experienced an improvement in pain im-
11.7%) and dry mouth/throat (n = 14/196, 7.1%) were the pact (47.9%) suggesting that the reduction in pain inten-
most common AEs experienced. sity was having an effect on patients’ quality of life that
was not reflected in the pain intensity measurements.
Improvements in Pain Intensity and Pain Impact Conversely, a mean 8.7 ± 4.5-point increase was seen in
Scores Were Observed those with worsened pain impact outcomes (p < 0.0001,
Within the PROMIS-29 analysis subset (n = 71), we n = 17).
found a significant improvement in the impact of pain
and an improvement verging on significance for pain in- Sleep Disturbance and Fatigue Significantly Improved
tensity when comparing first and last completed ques- in the Majority of Patients
tionnaires within the observational period for each sub- There were no statistically significant improvements
ject (Table 3). Analysis showed a reduction in overall pain across the other PROMIS-29 domains when comparing
intensity scores (−0.6 ± 2.5-point reduction; ∼9% de- mean T-scores across the observation period (Table 3).
crease; p = 0.053) approaching significance. When pain However, the majority of subjects who reported changes
intensity changes were assessed using the published min- to fatigue and sleep disturbance domains noted improve-
imal clinically important differences (MCID) value [23] ments (sleep disturbance 49.3% improved; fatigue 35.6%
(2.0 change), 32.9% of the cohort was improved com- improved) (Table 3). Evaluation of only those that were
pared with 45.2% unchanged and 21.9% worsened. The improved (based on MCID cutoffs) showed a significant
average intensity change in those that improved (n = 24) improvement in sleep disturbance T-scores (−12.5 ± 6.5

26 Med Cannabis Cannabinoids 2022;5:20–31 Abelev/Warne/Benson/Hardy/Nayee/

DOI: 10.1159/000521492 Barlow
points; p < 0.0001; n = 36) and fatigue T-scores (−8.6 ± and consistency allowing direct dose comparability across
4.5 points; p < 0.0001, n = 26). These subjects received an patients. Coupled with clinician oversight and monitor-
average daily dose of 21.0 ± 10.1 mg THC + 21.0 ± 10.1 ing, the findings presented here allow for clinically rele-
mg CBD. vant insights to be gained that are lacking from anecdotal
Similarly, evaluation of only those that reported wors- reports of poorly defined cannabis use.
ening fatigue showed significantly increased T-scores We have focused our comparisons of the current anal-
(+11.85 ± 8.7 points; p < 0.0001, n = 22). The same was ysis with those of existing published studies of nabiximols
seen in subjects reporting increased sleep disturbance (Sativex®; GW Pharma Ltd., Salisbury, UK), as both
(+11.2 ± 7.2 points; p < 0.0001, n = 26). It is noted that products are administered orally and contain an equiva-
within the sleep domain, participants appeared either to lent ratio of THC to CBD (1:1 THC:CBD). There are
have improved or to have worsened sleep, unlike other comparative differences worth noting in that nabiximols
domains where the majority were categorized as “not is an oromucosal spray, whereas LGP Classic 10:10 is an
changed.” oil formulation. Despite this difference, nabiximols pro-
A dose analysis was completed for the sleep distur- vides a useful comparator as a GMP-manufactured phar-
bance domain with subjects stratified based on improve- maceutical-grade product that has been evaluated exten-
ment, no change, or worsening of sleep disturbance. The sively in regulator-approved trials and clinical studies for
average daily dose in subjects who improved was lower pain indications [28–33] in contrast to recent large cohort
(21.0 ± 10.1 mg THC + 21.0 ± 10.1 mg CBD) relative to studies examining inhaled formulations alone or in com-
the daily dose in subjects who reported no change (21.1 ± bination with oral formulations [2, 13–15, 34].
13.3 mg THC plus 31.1 ± 13.3 mg CBD) or worsening
(25.1 ± 16.1 mg THC plus 25.1 ± 16.1 mg CBD) in sleep Analgesic Effects Are Consistent with Existing Clinical
disturbance. Trials of Nabiximols
Pain impact scores were significantly reduced across
Anxiety and Depression Score Changes Were in Line the study population. The average daily dose reported in
with Other Domains this study (22.4 mg THC and 22.4 mg CBD) closely re-
The majority of the cohort reported no change in anx- sembled that of previously published clinical studies of
iety (50.7%) and depression (50.7%) domains based on nabiximols that reported consistent improvements in
MCID cutoff analysis (MCIDs 2.3 and 3.0, respectively) pain-related outcome measures [29–33, 35].
(Table 3). The relative division between improvement, no Johnson et al. [31] reported nabiximols (23 mg THC
change, and worsening in these two mental health do- and 22 mg CBD per day) was effective in management of
mains was consistent with other domains including phys- intractable cancer-related pain, with 43% of patients
ical functioning, pain interference, and social satisfaction. achieving ≥30% improvement in mean pain score, an ef-
fect not seen with THC alone and consistent with long-
term follow-up [32]. Furthermore, Ueberall et al. [33]
Discussion showed a lower nabiximols dose (19.2 mg THC and 17.8
mg CBD per day) leads to reductions in pain and im-
The present study analyses real-world evidence (RWE) provement in the subjective experience of pain in a mixed
collected as part of the standard of care to explore safety, chronic pain condition cohort (n = 800), which is consis-
tolerability, and self-reported effectiveness of a medically tent with the amelioration of pain intensity we found in
prescribed pharmaceutical-grade medicinal cannabis the current study.
product (LGP Classic 10:10). Within the cohort, the ma- Tolerance was not directly assessed in this study co-
jority of subjects experienced at least one AE during the hort; however, due to the up-titrating nature of medicinal
observation period, with no SAEs reported. Encourag- cannabis prescribing, an average higher cannabinoid
ingly, pain impact scores were significantly reduced dose was associated with the final time point compared to
across the cohort (Table 3). Additionally, most subjects the first. The up-titrating nature of medicinal cannabis
reported improvements in sleep disturbance and fatigue, prescribing may fully explain this phenomenon, or there
both known to be highly related to one’s ability to manage may be some level of tolerance developed. Additional
and cope with pain [27]. analyses exploring tolerance are needed in observational
The use of a standardized pharmaceutical-grade GMP- cohorts to address this question. Analyses of this kind
manufactured product within the cohort ensures quality may be possible in a complete analysis of the CACOS data

Medicinal Cannabis for the Treatment of Med Cannabis Cannabinoids 2022;5:20–31 27

Chronic Refractory Pain DOI: 10.1159/000521492
at the study close, as opposed to within a cross-sectional Reported Adverse Events Are Consistent with Existing
analysis such as is presented here. Two published long- Published Studies
term follow-up studies [30, 32] showed no evidence of More than half of the participants (60.3%) experienced
tolerance to a 1:1 THC:CBD oral formulation being de- at least one AE during the observation period with no
veloped. SAEs experienced, as reported by their treating clinicians.
This proportion of AEs is consistent with existing studies
Changes to Sleep Disturbance Are Consistent with of medicinal cannabis products [36, 37] and analgesics
Existing Clinical Trials of Nabiximols including opioids [38].
Sleep disturbance decreased in the current study co- The most common AEs reported in the literature for
hort (49.3% reporting meaningful improvements based nabiximols are consistent with those in the present study.
on MCID) which is consistent with the outcomes of sev- These included psychiatric (somnolence), gastrointesti-
eral trials of nabiximols. Specifically, two studies [29, 30] nal (dry mouth and nausea), and nervous system-related
showed sleep disturbance was improved with nabiximols (dizziness), all of which presented with mild to moderate
over a 4-week period with a similar dosing schedule (26 severity in chronic pain trials of nabiximols within a dose
mg THC and 24 mg CBD per day), while a study in mul- range similar to the present study [29–32, 35]. At the time
tiple sclerosis patients (mean dose 19.7 mg THC and 18.3 of reporting, the World Health Organization adverse
mg CBD) showed significantly less sleep disruption after drug reaction database (VigiAccessTM) also aligns with
12 weeks of treatment compared to baseline [35]. Addi- our findings, with nervous system disorders (39%), gas-
tionally, Ueberall et al. [33] reported approximately half trointestinal disorders (33%), and psychiatric disorders
of the cohort had improvements in sleep quality with (23%) being the most commonly reported SOC classes for
nabiximols (at equivalent doses), which is consistent with nabiximols adverse drug reactions [39].
the proportion improved in the current analysis. While fewer well-controlled studies of medicinal can-
Interestingly, while Johnson et al. [31] found no effect nabis in chronic pain exist outside those involving nabix-
of nabiximols on sleep quality after 2 weeks, the follow-up imols, the findings of the present study reinforce the ob-
study of mean length 25 days (range: 2–579) saw reduced servation that THC at an intermediate-dose/or mixture is
sleep disruption, potentially suggesting a longer time pe- effective in alleviating chronic pain and improving
riod is required for sleep effects to be observed. Portenoy HRQoL, while unbridled THC exposure can cause unde-
et al. [28] also reported improved sleep and pain over a sirable side effects [13–16]. One such side effect is anxiety.
5-week period with low (2.7–10.8 mg THC and 2.5–10 mg Interestingly, we did not observe any significant changes
CBD daily) and moderate nabiximols doses (16.2–27 mg to anxiety or depression scores in the study cohort despite
THC and 15–25 mg CBD daily). However, a higher-dose some patients taking meaningful doses of THC. This is an
group (29.7–43.2 mg THC and 27.5–40 mg CBD daily) important finding given that THC has been shown to
did not show such an effect. This potentially suggests have dose-dependent effects on anxiety responses [40].
sleep improvements are somewhat dose dependent, with The majority of AEs reported in the literature are typ-
higher doses impeding sleep benefit, possibly due to in- ically associated with THC-containing medications as
creased AEs (such as anxiety, nausea, or insomnia). This opposed to CBD-only medications and may also be linked
observation is in line with what we have observed in this to the excipients (i.e., oral oil). The AEs most commonly
analysis, with the lowest average cannabinoid dose asso- reported in medications where the predominant active
ciated with sleep improvements compared to those re- pharmaceutical ingredient is CBD (notably studies using
porting unchanged or worsened sleep (with higher aver- EpidiolexTM, which lacks THC [41–43]) are mild to mod-
age cannabinoid doses). Finally, the average cohort ob- erate pyrexia, upper respiratory tract infection, and som-
servational period was 133.4 days (Table 1). The subset of nolence, as well as gastrointestinal upset [41–43]. How-
patients reporting improved sleep had a mean observa- ever, these studies involved an epilepsy cohort with fever
tional period of 147.2 days (minimum 22.3 days), sup- disorders. Furthermore, high doses of anticonvulsants
porting this longer (>2-week) time period hypothesis in were administered concomitantly with a relatively high
relation to self-reported sleep outcomes. Due to the cross- CBD dosing regimen (i.e., 10–20 mg/kg/day), a combina-
sectional study design, it is unclear whether the medicinal tion known to elevate the risk of AEs [44]. These clini-
cannabis lowered pain levels leading to better sleep, or if cally significant differences in the study population make
improvements in sleep disturbance and fatigue were di- comparisons with the findings of the current study chal-
rectly due to the benefits of treatment. lenging.

28 Med Cannabis Cannabinoids 2022;5:20–31 Abelev/Warne/Benson/Hardy/Nayee/

DOI: 10.1159/000521492 Barlow
 Psychosis-related AEs typically ascribed to chronic use for things such as pain syndromes or response rate. Par-
of THC [40, 45], including psychosis, euphoria, halluci- ticipants taking more than one medicinal cannabis prod-
nations, and paranoia, were reported at low frequency uct concurrently during the observation period (includ-
within the current study (Table 2). One potential expla- ing the test product) were excluded from analysis.
nation for this may be related to the drug formulation While data on AEs related to drug-drug interactions
(i.e., oral oil). Oral administration prevents rapid-onset were not explicitly collected as part of our study, it is a
high THC concentrations that are typical of inhaled prod- notable area to be explored in future studies given the
ucts [46–48], potentially reducing the incidence of THC- known interactions between cannabinoids and metabo-
related side effects. In comparison, pharmacokinetic lism of other prescribed drugs [49, 50]. It should be noted
studies of oral THC-containing products have shown a that all participants within the analysed cohort had previ-
delay in reaching peak plasma concentration (>2 h) com- ously tried and failed other analgesics prior to being pre-
pared with inhaled administration [47, 48]. scribed medicinal cannabis. A proportion of participants
were still taking concomitant medications for their pain
The Relevance of RWE in the Context of Medicinal or other conditions including opioids and/or NSAIDs.
Cannabis While we are able to identify those participants that were
In the absence of randomized controlled trials (RCTs), taking additional medications, an analysis of the influ-
our data show that analysis of RWE collected as part of ence of these substances is beyond the scope of this study.
patients’ routine care can yield useful information. RCTs The monitoring of expectancy effects associated with per-
are the gold standard required to determine drug efficacy; ceived effectiveness of the study intervention is also be-
however, there is a scarcity of this level of research activ- yond the scope of this study.
ity among the medicinal cannabis sector. Future studies need to include formal monitoring of
The research scarcity may in part be explained by the any changes to the administration of opioids or analgesic
inability to create and protect intellectual property be- medications for patients being prescribed medicinal can-
cause cannabinoids are naturally occurring compounds nabis products. This was absent from the current analysis,
that have been used medicinally, but without evidence for and therefore we cannot comment on how changes to
millennia. This experience precludes many traditional other medications may have affected the patient-reported
drivers of commercial drug development because of like- outcomes presented here. Polypharmacy for chronic pain
ly failure to recoup R&D costs through market exclusiv- patients is an important consideration. As such, amend-
ity of the end-registered product. Our observational ap- ments to our protocol need to be made to capture data on
proach and retrospective analyses of data collected as part changes to other concomitant medications, especially
of standard care must be prioritized to ensure prescribing opioids in the future.
of medicinal cannabis is evidence based. Tolerability would best be assessed through establish-
ing rates of AEs among study dropouts. This information
Limitations is gathered in clinical notes to be included in subsequent
There are some limitations to the interpretation of our CACOS study analyses. Subsequent analyses will also
data. Notably, the study was not controlled. It was obser- benefit from inclusion of severity and relatedness infor-
vational in nature and relied upon the accuracy of pa- mation by AE type.
tient-reported information. Patient observations were Finally, we recognize that the experience of pain is
not validated independently. The observation period var- complex – a merging of sensory and affective processes.
ied broadly across the study population given the cross- The affective component of pain is thought to be modu-
sectional nature of the analysis; some patients were re- lated by opioid and endocannabinoid neurotransmitter
cently enrolled while others were 12 months into their systems [51]. Despite administering a cannabinoid recep-
course of treatment. There has been no attempt to correct tor modulator and recognizing that participants were ad-
for observation period length for each individual partici- ministering additional pain medications, this study does
pant and relate this to their patient-reported outcomes, not explore an important affective feature of pain treat-
beyond ensuring a minimum of 7 days between survey ment: the expectation surrounding effectiveness of treat-
completion. The irregularity of patient reporting inter- ment also known as a placebo effect. This is an emergent
vals has also not been accounted for in the PROMIS-29 theme in cannabinoid research, and future work should
analysis. Furthermore, we did not sub-classify our pa- interrogate participants’ expectations as part of routine
tients or make other attempts to control for selection bias questionnaires.

Medicinal Cannabis for the Treatment of Med Cannabis Cannabinoids 2022;5:20–31 29

Chronic Refractory Pain DOI: 10.1159/000521492
 Conclusions Conflict of Interest Statement

L.N.W. reports personal fees from Little Green Pharma, out-

The results of this study demonstrated a significantly side the submitted work. All other authors have no conflicts of
positive effect of LGP Classic 10:10 oral medicinal can- interest to declare.
nabis oil on the impact of pain (as measured by using the
PROMIS-29 HRQoL tool). A reduction in pain intensity
scores verged on significance (p = 0.053). This is a clini- Funding Sources
cally relevant finding considering that this patient cohort
comprises refractory cases where relief has not been ob- This project was jointly funded by Little Green Pharma (LGP)
tained with existing medications, including opioids, and Applied Cannabis Research (ACR). Participants were pre-
scribed an LGP cannabinoid medication by clinicians from Can-
NSAIDs, and steroids. nabis Access Clinics (CAC). ACR analysed observational data
This analysis also highlights that medicinal cannabis is from consenting CAC patients.
not efficacious for all, a finding that is consistent with
most other drug classes. Successful treatment of one-
third of refractory patients has significant impacts on the Author Contributions
total refractory population size and greatly affects the
HRQoL of those who have found relief with medicinal S.A. and M.B. ran data analysis. S.A., M.B., L.N.W., and J.B.
cannabis. This study further highlights the need for con- wrote the body of the manuscript. S.A., L.N.W., and J.B. prepared
the manuscript for submission to the journal. M.H. advised on pa-
tinued research in this field, ideally comprising follow-on tient records. M.H. and S.N. provided specialist medical and tech-
RCTs that can more adequately address dose, responder nical advice.
characteristics, and potential effect size.

Acknowledgments Data Availability Statement

The authors wish to thank Ms. Belen Gomez and Dr. Natalie The data that support the findings of this study are not pub-
Beveridge for their assistance in establishing the data collection licly available. The data are contained within patient records that
facilities for this project. are securely stored for access by CAC staff and researchers only.
Further enquiries can be directed to the corresponding author.

Statement of Ethics

This study (CACOS study) was reviewed and approved by the

Bellberry Human Research Ethics Committee (Applied Cannabis
Research, Approval No. 2019-04-338). Written informed consent
was obtained from participants to participate in the study.

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Chronic Refractory Pain DOI: 10.1159/000521492