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Cannabinoid effects on responses to quantitative sensory testing among individuals with and without clinical pain: a systematic review

Chung Jung Mun1,┼, Janelle E. Letzen1,┼, Erica N. Peters2, Claudia M. Campbell1, Ryan Vandrey1, Julia Gajewski-Nemes1, Dana DiRenzo1, Christine Caufield-Noll3, Patrick H. Finan1,*

1Johns Hopkins University School of Medicine

2Canopy Growth Corporation

3Johns Hopkins Bayview Medical Center

1. Introduction

Despite its extensive history as a folk treatment for numerous health conditions [28],

controlled clinical studies on the efficacy of cannabis have only recently begun to

accumulate. The past half-century has witnessed several notable achievements in the science

of cannabis, including the extraction and identification of delta-9-tetrahydrocannabinol

(THC) as the primary psychoactive constituent of the cannabis plant [20] and the

identification of an endocannabinoid system in the mammalian brain [26,51,71]. Further,

interest in the utility of cannabinoids as potential analgesics has greatly increased over the

past decade.

Strong and consistent preclinical evidence from rodent models has suggested that

cannabinoids might be a promising class of analgesics [1,9,35,43,67]. However, efficacy

data from human clinical trials in patients with chronic non-cancer pain (CNCP) outcomes

are equivocal. Previous systematic reviews have generally found modest evidence for the

efficacy of cannabinoids on self-reported clinical pain outcomes across CNCP disorders,

with iatrogenic effects outpacing clinical gains [3,6,8,17,19,25,44,48,69].

Although reasons for this modest clinical translation are unclear, previous reviews have

concluded that there is a lack of high-quality evidence and have called for more rigorous

clinical trials. Quantitative sensory testing (QST) might be a valuable tool to improve study

*Address Correspondence to: Patrick H. Finan, Ph.D., Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 5510 Nathan Shock Dr., Suite 100, Baltimore, MD 21224, [email protected]. ┼Authors contributed equally

Conflict of Interest Authors CJM, JEL, CMC, JGN, DD, CCN, and PHF do not have a conflict of interest. ENP is currently employed by Canopy Growth Corporation, a cannabis company. However, Canopy Growth Corporation had no role on this manuscript besides supporting ENP’s time. Furthermore, Canopy Growth Corporation did not supply product for any of the studies included in the review. RV has received consulting fees or honoraria from Zynerba Pharmaceuticals, Canopy Health Innovations, Battelle Memorial Institute, and Brain Solutions Inc.

HHS Public Access Author manuscript Pain. Author manuscript; available in PMC 2021 February 01.

Published in final edited form as: Pain. 2020 February ; 161(2): 244–260. doi:10.1097/j.pain.0000000000001720.

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rigor and bolster mechanistic understanding of cannabinoid effects on clinical pain. QST

broadly refers to psychophysical methods for systematically quantifying somatosensory

function in individuals with and without chronic pain [73]. Previous work suggests that QST

can help identify changes in pain-related neural processing, making it an important tool for

analgesic development [7]. Because QST uses calibrated noxious stimuli to evaluate acute

pain responses in a controlled setting, key sources of variability are minimized by

standardizing sensory input parameters. Though QST responses are subject to substantial

inter- and intraindividual variability [21], increased pain sensitivity on measures of QST

predicts worse clinical pain outcomes in numerous clinical trials [24,66,85,86].

Recently, Lotsch, Weyer-Menkhoff, and Tegeder [43] conducted a review of six studies that

examined cannabinoid-based analgesia in human experimental settings. They found mixed

outcomes across studies for responses to QST stimuli following cannabinoid administration.

De Vita and colleagues [74] expanded on this work and conducted the first systematic

review and meta-analysis on cannabinoid administration during QST in healthy adults. In

total, they synthesized findings from 18 placebo-controlled studies and concluded that

cannabinoids exerted small effects on pain thresholds, but not overall pain intensity, during

QST. Further, they suggested that cannabinoid-related analgesia might occur via indirect

influences (i.e., changes in affective processes). Although this review provided valuable

information about cannabinoid-related analgesia on measures of pain threshold, tolerance,

and primary hyperalgesia in healthy individuals, it did not include studies assessing

cannabinoid analgesia to QST in chronic pain populations. Given that chronic pain patients

tend to show increased pain sensitivity compared to healthy controls [46], it is of interest to

understand the effects of cannabinoids on experimentally-induced pain in controlled settings

among chronic pain patients.

In the present review, we systematically synthesize the evidence for cannabinoid analgesic

effects in both healthy adults and patients with CNCP focusing on QST outcomes.

Specifically, we examine the existing evidence by grouping results based on study sample,

cannabinoid compounds, and sensory domain.

2. Methods

A protocol for this systematic review was established and pre-registered on PROSPERO

(CRD42018117367) on 12/19/2018. Data were extracted between 09/24/2018 and

01/08/2019 and the review was conducted in four stages: (1) compiling of a potential

abstract pool based on search terms, (2) abstract review, (3) full-text review of eligible

abstracts, and (4) data extraction from included full-texts.

2.1. Search Procedure

Reviewers used the Covidence web-based platform (Covidence systematic review software,

Veritas Health Innovation, Melbourne, Australia; www.covidence.org) for systematic

reviews to organize compiled abstracts. Searched databases included PsycINFO, Cochrane,

Google Scholar, Embase, and Pubmed. Search terms were: (“cannabi*” OR “marijuana” OR

“marihuana” OR “hashish” OR “THC”) AND [(“pain”) AND (“quantitative sensory testing”

OR “pain testing” OR “calibrated noxious stimuli” OR “threshold” OR “tolerance” OR

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“cold pressor” OR “cold water bath” OR “cold” OR “mechanical” OR “pressure” OR

“thermal” OR “heat” OR “electrical” OR “capsaicin” OR “hyperalgesia” OR “allodynia”

OR “temporal summation” OR “windup” OR “diffuse noxious inhibitory control” OR

“conditioned pain modulation” OR “nociceptive flexion reflex”)].

2. 2. Eligibility Criteria

2.2.a. Abstract Criteria for Full-Text Review—Peer-reviewed publications were

eligible for full-text review contingent on the following criteria: (1) relevant search terms

appeared in the abstract, (2) the publication was written in the English language, (3) the

study included human subjects only, (4) at least one cannabinoid agent (i.e., plant-based or

synthetic) was used, (5) at least one QST measure was used, (6) the manuscript was

accepted for publication prior to August 2018, and (7) the full text was available. Four

reviewers were involved in this stage (CJM, JEL, ENP, and PHF). Each was randomly

assigned as a reviewer for half of the available abstracts, so that each abstract was reviewed

independently by two individuals. Abstracts were considered for full-text review if both

reviewing authors marked the abstract for inclusion. Any conflicts were resolved by PHF or

ENP.

2.2.b. Full-text Criteria for Data Extraction—Full-texts associated with eligible

abstracts were further reviewed using the following criteria: (1) the study included a placebo

control, and (2) individuals were randomized to drug conditions. Two authors reviewed all

full-texts (CJM and JEL). Full-texts were included in the systematic review if both reviewing

authors marked the full-text for inclusion, and we decided a priori that PHF would resolve

any conflicts. However, there were no conflicts between CJM and JEL in this process (i.e.,

perfect inter-rater reliability).

2.2.c. Additional Manual Literature Search—Reference sections and search engines

were manually searched in addition to the procedure described above. Articles resulting

from this manual search were compared to articles resulting from the above-described

systematic search, yielding 5 new articles. Abstracts from these studies were added to

Covidence manually. CJM and JEL reviewed these 5 abstracts to determine their eligibility

for full-text review, and PHF resolved any conflicts.

2.3. Definitions of Predictor and Outcome Variables

We examined the overall effects reported in eligible full-texts using a Population,

Intervention, Comparison, Outcome (PICO) framework. First, we broadly grouped studies

based on population. Studies were further sub-grouped based on cannabinoid compound.

Finally, studies were further sub-grouped by QST sensory modality. For each subgrouping,

we summarize findings, examine potential dose-response effects, describe the consistency of

effects across studies, and offer brief conclusions.

2.3.a. Population—Although no study has provided direct evidence to determine

whether individuals with chronic pain have altered endocannabinoid system function,

previous work robustly shows differences in pain responses across quantitative sensory tests

between individuals with and without chronic pain. For this reason, studies were first

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broadly grouped based on population in order to identify meaningful patterns of results.

Studies within the “Healthy Adult Samples Only” category included samples of healthy,

pain-free adults aged 18 and older. Studies within the “Patient Samples Included” category

included either a sample of patients with CNCP only or a sample composed of individuals

both with and without CNCP.

2.3.b. Cannabinoid Compounds—Because the term cannabinoid includes a broad

array of compounds with distinct structures and mechanisms, it is important to narrowly

interpret study results to the specific compound of study rather than the class of cannabinoid

compounds. Further confounding factors of results could include routes of administration

(e.g., inhaled, oral), duration of use, concentration, food effects, and cannabinoid

combinations. Furthermore, previous work suggests that cannabinoid compounds can have

drastically different psychobehavioral effects. For instance, although THC is associated with

dose-dependent intoxication, cannabidiol (CBD) has no such dose-dependent effect and does

not have intoxicating effects [61,63]. Other studies have suggested that CBD may mitigate

some of the negative effects of THC, either enzymatically or through negative allosteric

modulation of CB1 receptors [68]. No set of studies has definitively determined whether one

cannabinoid compound, form (synthetic cannabinoid or phytocannabinoid), or route of

administration is preferable to pain patients [39,60]. For these reasons, we sub-grouped

studies based on cannabinoid compound and form to draw more meaningful conclusions

about the extant literature. Studies were classified as “Inhaled Cannabis” if the cannabis was

smoked or vaporized cannabis flower. Studies were classified as “Synthetic Cannabinoids” if

the study used either dronabinol or nabilone, both single-molecule synthetic pharmaceutical

products. Studies were classified as “Combined THC and CBD Formulations” if the drug

product tested contained both THC and CBD (e.g., the plant derived pharmaceutical Sativex,

which contains THC and CBD in roughly equal concentrations). Finally, studies were

classified as “Other Endocannabinoid Modulator” if the cannabinoid agent did not fit the

previously described categories (e.g., novel compounds).

2.3.c. Sensory Domains—Eligible full-texts were further sub-grouped based on the

QST sensory domain tested, which included heat, cold, mechanical, electrical, visceral, and

chemical modalities. The “heat” domain refers to noxious stimuli delivered through a

thermal stimulator. The “cold” domain refers to studies using tests involving exposure to

noxious cold stimuli (e.g., cold pressor test). The “mechanical” domain refers to noxious

stimuli delivered via pressure algometry or punctate probes. The “electrical” domain refers

to noxious stimuli administered by an electrodermal stimulator. The “visceral” domain refers

to noxious stimuli delivered via esophageal or rectal balloon distension. Finally, the

“chemical” domain refers to stimuli delivered via topical or injectable irritants. Given that

some studies interrogated pain processing via multiple modalities, we present results

separately by domain. For this reason, some studies are reported in more than one sensory

domain.

2.3.d. Outcome Measures—Within each sub-group, we describe outcomes based on

pain threshold, pain tolerance, evoked allodynia, and secondary hyperalgesia. Pain threshold

refers to the lowest stimulus intensity reported as painful. Pain tolerance refers to the

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maximum stimulus intensity or duration reported as bearable. Evoked allodynia is a reported

painful sensation to a non-noxious stimulus. Finally, secondary hyperalgesia is a reported

increase in pain sensitivity to a noxious stimulus applied over a region that surrounds, but

does not include, the primary affected area.

2.4. Extraction of Study Information

Two authors (CJM and JEL) divided the final set of full-text articles to extract relevant study

information, including study agents, dosing information, experimental design, sample

characteristics, evoked-pain methods, and outcomes. For studies including non-cannabinoid

agents, only contrasts related to cannabinoid vs. placebo outcomes were considered. All

extractions were cross-checked for accuracy.

2.5. Risk of Bias Assessment

In reviewing included studies, two authors (CJM and JEL) blindly completed independent

risk of bias assessments. Criteria and scoring were adapted from two prior systematic

reviews involving QST measures as primary outcomes [41,54].

The following domains were assessed: 1) blinding of participant to drug assignment; 2)

blinding of experimenter to drug assignment; 3) appropriateness and clarity of inclusion

criteria and recruitment approach; 4) age and sex matching of cases and controls; 5) control

for, or exclusion of, established confounders (e.g., medication and caffeine use prior to

testing; clinical pain level; menstrual phase; medical comorbidity or other individual

difference factors known to affect QST response; reported time frame in which QST was

administered).

Risk was coded on a 0–2 scale, with “low risk” assigned 0, “moderate risk” assigned 1, and

“high risk” assigned 2. Scores were then summed across categories to yield a total risk score

that ranged from 0 to 10, with higher scores indicating higher risk of bias. Specific guidance

for scoring within each category and risk level were adapted from Lewis et al. [41] and

shown in Table 1. All discordant scores within each domain were reviewed by a third author

(PHF) and discussed as a group (JEL, CJM, PHF) until consensus was reached.

3. Results

Figure 1 provides a flowchart of the number of studies included at each stage of the above-

described procedures. A total of 1217 abstracts were screened. Among these abstracts, 291

were duplicates, and 864 abstracts were excluded based on search criteria. A total of 62

abstracts underwent full-text review, and 23 of them were excluded because some additional

duplicates were uncovered and some studies had incorrect designs, conference abstracts,

incorrect intervention, and incorrect study outcomes. A total of 39 articles were reviewed for

the qualitative synthesis of our study. Characteristics of these included studies are

summarized in Table 2.

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3.1. Healthy Control Samples Only

3.1.a. Inhaled cannabis—Eight studies examined inhaled cannabis effects on QST

outcomes in healthy controls. Five of the 8 studies [11,12,14,22,76] used samples of

experienced cannabis users, and one study [27] did not report participants’ cannabis use

status. Two studies used both experienced cannabis users and cannabis-naïve samples

[49,50]. Sample sizes ranged from 13–64. All effects are in comparison to placebo (cannabis

that contained 0% THC). THC concentration ranged from 0 to 8% and reported THC doses

ranged from 0 to 31 mg. Detailed information on THC concentration, dose, and cannabis use

history is presented in Table 2.

3.1.a.1. Heat: Three studies probed inhaled cannabis-related analgesia via heat stimuli

[22,50,76]. One study found an analgesic effect on heat pain threshold [22]. The other

studies showed null effects on heat pain threshold and heat hyperalgesia induced through

intradermal capsaicin [50,76].

3.1.a.2. Cold: Four studies examined inhaled cannabis effects on cold pain responses

[11,12,14,76]. Two of these studies reported analgesic effects on cold pain threshold and

tolerance [12,14]. The remaining studies reported null results on cold pain threshold [11,76]

and tolerance [11].

3.1.a.3. Mechanical: Three studies conducted QST under inhaled cannabis using

mechanical stimuli [49,50,76]. Two studies reported analgesic effects on at least one

mechanical pain stimulus [49,76]. The other study reported null effects on pressure pain

threshold [50].

3.1.a.4. Electrical: Only one study examined the effects of inhaled cannabis on responses

to electrical stimuli. Hill [27] reported hyperalgesic effects on tests of electrical pain

threshold and tolerance.

3.1.a.5. Dose-Response: Three of the 8 studies evaluated dose-response effects of inhaled

cannabis and found significant dose-response relationships [12,22,76]. Cooper et al [12]

found analgesic effects on cold pain tolerance, but not threshold, comparing a low dose

(1.98% THC; 3–7 puffs; 11 mg) to placebo. Greenwald and Stitzer [22] found an analgesic

effect only at the high dose (3.55% THC; 9 puffs). Wallace et al. [76] found a null effect at a

low dose (2% THC by weight; 4 puffs), analgesic effect at an intermediate dose (4% THC

by weight; 4 puffs), and hyperalgesic effect at a high dose (8% THC by weight; 4 puffs).

3.1.a.6. Conclusion: Five out of 8 (62.5%) studies demonstrated an analgesic benefit of

inhaled cannabis on at least one QST outcome measure. These positive findings should be

interpreted against the backdrop of several null results and inconsistencies – both within and

across studies – in the type of QST response affected and the dose at which analgesia was

observed. Hyperalgesia was observed in two studies, and in one study this was observed at a

high dose, when lower doses in the same study produced null and analgesic effects. This

suggests an inverted-U dose-response relation between inhaled cannabis and QST outcomes.

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Also, the majority of studies were based upon experienced cannabis users. No study

examined the analgesic effects of inhaled cannabis on chemical or visceral stimuli.

3.1.b. Synthetic Cannabinoids—A total of 15 studies examined the effects of

synthetic cannabinoid pharmaceuticals (dronabinol; nabilone, a synthetic cannabinoid

analog with greater potency and bioavailability than dronabinol), vaporized synthetic

cannabinoids, or intravenous synthetic cannabinoids on QST responses in healthy adults.

Among 15 studies, three used samples of experienced cannabis users [12,23,42], four used

cannabis-naïve samples [33,40,52,53], three did not allow for recent use of cannabis

[4,31,58], and five did not report participants’ cannabis use status [18,34,57,79,87]. Sample

sizes ranged from 8–78. Of the 15 studies, one study administered the synthetic

cannabinoids through aerosol inhalation, three studies used intravenous administration, and

the rest of the studies used oral administration. In terms of dose, the range of dronabinol

dose was 5 to 20mg, and the range of nabilone dose was 0.5 to 3mg. The dose range for

intravenous administration was .022mg/kg body weight to .044mg/kg bodyweight, and

dosing for aerosol administration was .052mg/kg body weight.

3.1.b.1. Heat: Five studies examined the effects of synthetic cannabinoids on responses to

heat stimuli [4,31,33,52,58]. All five studies reported null results on all heat QST outcomes.

One study [87] did not report statistical tests.

3.1.b.2. Cold: Six studies examined synthetic cannabinoid effects on responses to cold

stimuli [4,12,31,34,52,53]. Only one study reported an analgesic effect [12]. Four studies

reported null effects [4,31,34,52], and one study reported a hyperalgesic effect [53].

3.1.b.3. Mechanical: Seven studies examined synthetic cannabinoid effects on response to

mechanical stimuli [4,23,33,40,42,52,57]. van Amerongen et al. [4] reported hyperalgesic

effect and the rest of the studies reported null effects across outcome measures.

3.1.b.4. Electrical: Five studies examined responses to electrical stimuli under synthetic

cannabinoids [4,23,52,57,79]. Two reported null effects [23,57], and three reported

hyperalgesic effects [4,52,79].

3.1.b.5. Chemical: One study chemically induced trigeminal excitation and found a null

effect on pain outcomes [78].

3.1.b.6. Visceral: One study used colonic distension following synthetic cannabinoids

administration [18] and found no effect on visceral pain threshold, but a hyperalgesic

response to increasing distention pressure was observed.

3.1.b.7. Dose-Response: Five out of the 15 (33.3%) studies assessed dose-response effects

of synthetic cannabinoids [12,23,31,33,34]. Only one study reported a positive effect of

high-dose dronabinol (20mg) on cold pain threshold, and positive effects of high and low

(10mg) doses on cold pain tolerance [12].

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3.1.b.8. Conclusion: Only one out of 15 studies (6.7%) supported an analgesic benefit of

synthetic cannabinoids on QST outcomes, which was a dose-dependent response [12].

Importantly, all participants in this one positive study were daily cannabis smokers, a

methodological feature that distinguishes the study from most other studies reviewed.

Although five other studies failed to show an analgesic response to synthetic cannabinoids

using the cold pressor task, none included daily cannabis users. From these data, then, we

can conclude that synthetic cannabinoids, in general, are unlikely to alter acute pain

sensitivity to QST in healthy adults who are not frequent cannabis users. Because most of

the studies showing hyperalgesic effects did not report cannabis use status, it is unclear how

use at the time of study participation contributed to results. Overall, however, the bulk of the

evidence (60%; 9 out of 15) for synthetic cannabinoid formulations suggests an absence of

any effect on QST outcomes and a considerable proportion of studies (33.3%; 5 out of 15)

showed a hyperalgesic effect, especially in response to an electrical stimulus.

3.1.c. Combined THC and CBD formulations—Only one study used a combined

THC/CBD agent to examine QST outcomes in 18 healthy adults [37]. This study reported on

QST outcomes across several sensory domains. The sample was based upon 18 cannabis-

naïve participants. In this study, the unspecified 20mg pharmaceutical quality cannabis plant

extract that contained THC and CBD in the ratio of 2:1 was administered orally.

3.1.c.1. Heat: Kraft and colleagues [37] reported null effects on heat pain threshold and

tolerance following THC/CBD formulation administration.

3.1.c.2. Mechanical: Kraft et al. [37] also reported null effects on pin prick and brush-

induced pain in both non-sensitized and sensitized skin.

3.1.c.3. Electrical: Finally, Kraft et al. [37] found mixed effects on electrical stimuli;

whereas there were null effects on electrical pain threshold and tolerance on both non-

sensitized skin and the skin area with secondary hyperalgesia, there was a hyperalgesic

effect on sensitized skin stimulated at 250 Hz.

3.1.c.4. Dose-Response: Kraft and colleagues [37] did not examine dose-response effects.

3.1.c.5. Conclusion: It is difficult to provide a meaningful conclusion for this domain, as

only one study was available. The pattern of responses was not consistent across sensory

domains tested in the study. No study examined the analgesic effects of combined

THC/CBD formulations on a cold, chemical, or visceral stimulus.

3.1.d. Other Endocannabinoid Modulators—Two studies examined the effects of

other endocannabinoid modulators on QST outcomes in healthy adults [32,59]. Neither

study reported participants’ cannabis use history. Sample sizes ranged from 20–43.

Kalliomaki and colleagues [32] used 400 and 800μg of oral solution of AZD1940– a novel

peripherally restricted cannabinoid CB1/CB2 receptor agonist. Rukwied and colleagues [59]

administered four 12 mm (in diameter) skin patches soaked with 50μl cannabinoid receptor

ligand HU210.

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3.1.d.1. Heat: Rukwied and colleagues [59] reported analgesic effects of HU210 (i.e., a

cannabinoid CB1/CB2 receptor agonist) on responses to painful heat stimulation after

capsaicin injection. Kalliomaki and colleagues [32], on the other hand, reported a null effect

on heat pain threshold following administration of AZD1940–a novel peripherally restricted

cannabinoid CB1/CB2 receptor agonist.

3.1.d.2. Mechanical: On tests of brush allodynia after intradermal capsaicin injection, the

HU210 produced an analgesic effect on brush allodynia [59], whereas the AZD1940 was

associated with null effects [32].

3.1.d.3. Dose-Response: Neither study examined dose-response relationships.

3.1.d.4. Conclusion: The two reviewed studies found mixed effects of other

endocannabinoid modulators on QST outcomes, which is likely partly attributable to vast

differences in mechanisms of action between the HU210 agent (i.e., a CB1 receptor agonist)

and AZD1940 formulation (i.e., a peripherally acting CB1/CB2 receptor agonist). Notably,

positive outcomes reported by Rukwied and colleagues [59] were only obtained at certain

assessment time points in a repeated measures design with a small sample (N=20). The

analgesic evidence of non-THC/CBD endocannabinoid modulators is unclear with these

current data.

3.2. Patient Samples Included

3.2.a. Inhaled cannabis—Five studies used inhaled cannabis to measure changes in

calibrated pain responses among patients with primary neuropathic pain [80,81] and

neuropathy secondary to diabetes [77], HIV [16], and spinal cord injury or disease [82].

Inclusion criteria in these studies allowed for both cannabis-naïve participants and those

with positive cannabis use history; however, all stipulated that participants needed to refrain

from use at least 7–30 days before enrollment. Sample sizes ranged from 16–50. All effects

are compared to placebo (0% THC). THC concentrations ranged from 0 to 7% for total THC

doses of 0 to 34mg.

3.2.a.1. Heat: Four studies used painful heat stimulation in patients with neuropathic pain

[16,80–82]. All studies reported null effects.

3.2.a.2. Mechanical: Five studies used painful mechanical stimulation in patients with

neuropathic pain [16,77,80–82]. Only one of these studies reported a positive effect (i.e.,

brush and von Frey hair evoked pain; [77]), with null effects across remaining studies.

3.2.a.3. Dose-Response: Four out of the 5 studies (80%) evaluated dose-response effects

of inhaled cannabis [77,80–82]. Only one study reported a significant dose-response effect

of cannabis [77]. Specifically, the high dose (7% THC; 3 puffs; 28mg) showed the greatest

reduction in brush and von Frey hair evoked pain, followed by the medium dose (4% THC; 3

puffs; 16mg), low dose (1% THC; 3 puffs; 4mg), and placebo (0% THC; 3 puffs; 0mg;

[77]).

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3.2.a.4. Conclusion: The bulk of the evidence (80%; 4 out of 5 studies) suggests null

effects of inhaled cannabis on QST outcomes among patients with neuropathic pain. History

of cannabis use was mixed among these samples. The lone analgesic finding from Wallace

and colleagues [77] was qualified by a small sample (N=16) and dose-dependent effects that

deviated from prior literature. Whereas a previous study had shown hyperalgesia at a high

dose of inhaled cannabis in healthy subjects [76], Wallace et al. [77] found analgesia

exclusively at the high dose. No study examined the analgesic effects of inhaled cannabis on

cold, electrical, chemical, or visceral pain stimuli. Hyperalgesic effects were not reported

among these studies.

3.2.b. Synthetic Cannabinoids—Four studies examined QST outcomes among

patients with clinical pain after synthetic cannabinoid (i.e., dronabinol, nabilone)

administration. Clinical conditions studied under these conditions include Multiple Sclerosis

(MS; [72]), fibromyalgia [65], Irritable Bowel Syndrome (IBS; [36]), and functional chest

pain disorders [47]. Participants in these studies were generally asked to abstain from

cannabis use 7–60 days prior to study participation. Sample sizes ranged from 13–40

participants. The dose range for dronabinol was 2.5mg daily for one week to 10mg daily for

four weeks, and the lone nabilone study used a 2mg daily dose for 7 days [65].

3.2.b.1. Heat: Only one study examined the effects of synthetic cannabinoids on heat pain

and found null results in patients with MS and central pain [72].

3.2.b.2. Cold: Svendsen and colleagues [72] also found null effects using noxious cold

stimuli in their MS sample.

3.2.b.3. Mechanical: Of the two studies that examined mechanical pain outcomes under

synthetic cannabinoids [65,72], only one showed an analgesic effect [72]. Specifically,

patients with MS and central pain had higher pressure pain thresholds after cannabinoid use;

however, there were no differences in punctate temporal summation and brush allodynia.

There were also null effects on the number of tender points and pressure pain threshold in

fibromyalgia patients following synthetic cannabinoids administration [65].

3.2.b.4. Visceral: Two studies used visceral stimuli to examine calibrated pain responses

[36,47]. Both studies found null results among patients with IBS or functional chest pain.

3.2.b.5. Dose-Response: Two out of the 4 studies assessed dose-response effects of

synthetic cannabinoids [36,65]. None showed dose-response effects.

3.1.b.6. Conclusion: Only one out of four studies (25%) supported synthetic cannabinoid-

related analgesia during systematized, painful stimulation. No study examined the effects of

synthetic cannabinoids on electrical or chemical pain stimuli. Notably, the study providing

evidence for synthetic cannabinoid-related analgesia reported one significant finding (i.e.,

increased pressure pain threshold in MS patients) across seven QST measures tested, and the

authors did not correct for multiple testing. Furthermore, the QST assessment was conducted

before and after an extended treatment period (approximately 3 weeks) rather than in an

acute administration design. Hyperalgesic effects were not reported among these studies.

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While most studies in this category required individuals to abstain from cannabis use for a

period of time before participation, previous cannabis use history was not well-documented.

3.2.c. Combined THC and CBD formulations—Three studies used a combined

THC:CBD agent (i.e., Sativex) to examine QST responses in patients with clinical pain,

including neuropathic pain [64] or MS [10]. One study used cannabis-naïve participants

[10], and two studies required that participants refrained from cannabis use 7 days [55] or

one year [64] prior to study participation. Sample sizes ranged from 17 to 246 participants.

The range of Sativex doses was 2.7mg to 129.6mg THC and 2.5mg to 120mg CBD.

3.2.c.1. Mechanical: Two studies in patients with neuropathic pain examined responses

during delivery of mechanical stimuli [55,64]. One study found analgesic effects on brush

and punctate allodynia [55], but null effects were observed on these outcomes in the other

study [64].

3.2.c.2. Electrical: Only one study used painful, electrical stimuli to examine pain

outcomes in patients with MS. Specifically, the flexion reflex – which assesses spinal and

supraspinal pain pathways involved in pain control – was used as an electrical QST

outcome. The authors found positive effects on RIII threshold (i.e., pain threshold) and

reflex area (i.e., level of pain perception; [10]).

3.2.c.3. Dose-Response: None of these studies examined dose-response effects.

3.2.c.4. Conclusion: Two out of three studies (66.7%) supported analgesic benefits of

combined THC/CBD formulations during QST among individuals with clinical pain.

However, these positive findings should be interpreted with caution because (1) only three

studies were available for two different QST modalities; and (2) none of the studies tested

dose-response relationships. Hyperalgesic effects were not reported among these studies.

Prior experience with cannabis use and sample sizes greatly varied across studies.

3.2.d. Other Endocannabinoid Modulators—One study examined the effects of a

non-THC/CBD endocannabinoid modulator in patients with neuropathic pain who did not

report cannabis use at the time of the study.

3.2.d.1. Mechanical: Salim and colleagues [62] reported null effects on pain responses to

mechanical stimuli (i.e., von Frey hair-evoked pain) following ajulemic acid administration

among patients with neuropathic pain.

3.2.d.2. Dose-Response: This study did not examine dose-response relationships.

3.2.d.3. Conclusion: It is difficult to provide a meaningful conclusion for this domain

based on one study that tested effects on 21 participants.

4. Discussion

Our systematic review of 39 placebo-controlled studies found a lack of consistent evidence

for beneficial cannabinoid effects on QST responses in comparison to placebo among

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samples with and without CNCP. This finding is commensurate with results from a recent

systematic review and meta-analysis of studies in healthy volunteers [74] and expands this

work by examining studies with a broader battery of QST measures and those including

CNCP samples. Further, our findings from studies of experimentally induced pain are

consistent with conclusions of numerous systematic reviews of the clinical efficacy of

cannabinoids for CNCP, which have generally shown weak and inconsistent effects of

cannabinoids on measures of clinical pain [3,6,8,17,19,25,44,45,48,69].

As highlighted in previous reviews, many studies examining cannabinoid-related analgesia

have had relatively small sample sizes and have weak to moderate methodological rigor

[25,69]. These concerns make it difficult to conclude whether potential analgesic effects

from cannabinoids have been masked by study limitations, only occur under specific

circumstances for individuals with specific characteristics, or truly do not outperform

placebo responses. The studies reviewed here generally were deemed to have low-to-

moderate risk of bias. However, heterogeneity in research design and methods across studies

has substantially limited the potential to establish a reliably reproducible cannabinoid

analgesic effect using QST. Prospective studies should select key study design elements

(e.g., see Table 3) that promote rigor and reproducibility. A unique contribution of the

present review is its inclusive focus on multiple cannabinoids and routes of administration,

dose-response effects, a wide range of QST stimuli, and a differentiation of results obtained

from healthy participants versus patients with CNCP. We structured our review to identify

patterns in the extant literature that may inform the development of future studies.

Recommendations based on our observations are described below and summarized in Table

3.

4.1 Differences in Healthy Subjects versus CNCP

The overall pattern of findings did not substantively vary between healthy subjects and

patients with CNCP. Examination of the literature based on sample type revealed two main

observations. First, CNCP studies—particularly those involving patients with neuropathic

pain—more frequently employed mechanical tests of allodynia relative to studies in healthy

controls. Cannabinoid administration, though, did not consistently produce analgesia for

allodynia tests, and positive findings were observed under unique experimental contexts that

have not yet been reproduced. In fact, the evidence is so variable that we can only conclude

that any observable experimental effect of cannabinoid analgesia involving QST stimuli is

likely to be nuanced and not broadly generalizable. Second, most studies testing

cannabinoid-related analgesia via QST in clinical samples used patients with neuropathic

pain or patients with MS and central pain. Evidence for efficacy of inhaled cannabis,

synthetic cannabinoids (dronabinol), and other endocannabinoid modulators (HU210 and

AZD1940) was limited for patients with neuropathic pain or MS; however, there was modest

evidence for efficacy of combined THC/CBD formulations in a limited number of studies.

Recommendations: The evidence gathered to date does not suggest that basic tests of

cannabinoid analgesia to QST stimuli are stronger, more consistent, or more informative

when conducted among healthy subjects compared to patients. In addition to dose-escalating

studies in healthy volunteers, future research efforts may focus on rigorous, reproducible

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study designs in well-characterized clinical samples that help answer specific clinical

research questions. Future research should also determine whether there are differences in

the endogenous function of the endocannabinoid system or processing of exogenous

cannabinoids as a function of chronic pain status.

4.2. Differences across Cannabinoid Compounds

The term “cannabis” is commonly used as an umbrella term that refers to a broad range of

compounds from the cannabis plant and its synthetic derivatives. These compounds have

different routes of administration and vary substantially in pharmacokinetic and

pharmacodynamic properties [13,29,30,75]. Studies inconsistently controlled for factors

(e.g., calorie intake, caffeine consumption) that might affect the pharmacodynamic

properties of cannabinoids. Our literature search revealed studies that could be categorized

across four broad classes of cannabinoids: cannabis plant (smoked or vaporized), synthetic

cannabinoid formulations, combined THC/CBD formulations, and other endocannabinoid

modulators.

For inhaled, whole plant, cannabis, the majority of studies with healthy adults observed

significant analgesia on QST outcomes. However, only one of five studies in CNCP

participants demonstrated analgesia. Dose-response evaluation in these studies suggest an

inverted U-shape response to dose, but dose calculations for inhaled botanical cannabis

products can be challenging and were not able to be calculated in all studies. Additional

research, particularly using methods in which dose delivery can be more carefully

controlled, is needed to reconcile the differences in outcomes between healthy and CNCP

populations and to identify target doses most likely to be effective for analgesia.

The bulk of the evidence suggests that synthetic cannabinoids products, including

dronabinol and nabilone, do not provide analgesia to QST stimuli in either healthy subjects

or patients with CNCP. The two studies (out of a total of 19) that did reveal an analgesic

effect of synthetic cannabinoids were rigorously conducted, but each was a small study (Ns

≤ 30) and had notable methodological or analytic caveats that will require direct replication,

including use of a daily cannabis smoking sample [12] and an extended treatment design in

MS patients [72].

THC/CBD hybrid compounds and other endocannabinoid modulators were sparsely studied

among healthy subjects and revealed mixed findings. Kraft et al. [37] conducted the most

comprehensive study of THC/CBD in healthy subjects and reported null findings across

QST responses to heat, mechanical, and electrical stimuli. The absence of analgesic effects

across these tests, however, is qualified by the fact that the study was potentially

underpowered to detect an effect (N=18). Alternatively, there was somewhat consistent,

positive evidence in support of THC/CBD’s analgesic effect on QST measures in CNCP

patients (two of three studies), but inter-study heterogeneity precludes firm conclusions

about the potential reproducibility of observed effects.

Recommendations: Taken together, the available evidence does not support a consistent

trend for QST-examined analgesic responses to synthetic cannabinoids in either healthy

subjects or patients with chronic pain. Future studies are encouraged to (1) compare effects

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among cannabis-naïve and daily cannabis users, given the imbalance of studies reporting

positive evidence for analgesia among daily users and adverse effects for individuals who

were naïve to cannabis; (2) examine agents that combine THC and CBD, given that there

was a trend for analgesia in two out of three studies among CNCP patient populations; (3)

establish dose-response relationship and improve dose measurement for inhaled cannabis

studies; and (4) use extended dosing paradigms as a comparison to acute dosing paradigms.

It is possible that cannabinoid effects on the peripheral and/or central processing of noxious

stimuli differ as a function of dose quantity and/or frequency. Further, future research should

potentially prioritize THC/CBD formulations to examine cannabinoid-induced changes in

pain processing among neuropathic pain patients, but it is unclear whether similar

mechanisms are affected across other clinical pain conditions.

4.3. Differences across QST Measures

QST approaches used in the reviewed literature varied widely. Between and within studies,

there were generally inconsistent outcomes across QST approaches, and many studies did

not control for multiple comparisons. Only two notable patterns emerged. First, although

most studies did not show synthetic cannabinoid-related analgesia, most positive findings

were observed in tests of cold pain sensitivity. Second, several studies, primarily in healthy

controls, reported hyperalgesic responses to electrical stimulation.

It is unclear why these two sensory domains showed these trends. Regarding observed

hyperalgesia, QST responses are generally known to be influenced by a wide range of

individual difference factors, such as ethnicity and affective disposition [15]. It is possible

that such factors could have contributed to the hyperalgesic response to cannabis, but most

studies were underpowered to explore these possibilities through moderation analysis.

Additional factors, such as cannabis use history and participants’ sex, may have also played

a role in promoting hyperalgesia; indeed, three of the hyperalgesic effects were observed in

cannabis naïve samples [4,37,53], and one study examining sex differences found that men

exhibited greater cannabis-induced analgesia than women [14]. Another mechanistic

possibility might be binding of exogenous cannabinoid ligands to CB1 and CB2 receptors,

especially in frontolimbic regions. Specifically, CB1 receptors are pervasively expressed

along limbic, nociceptive, descending pain modulatory pathways [2]. Exogenous

cannabinoids can impart both excitatory and inhibitory responses, resulting in complex

biochemical reactions that yield pro- or anti-nociceptive outcomes [56,83].

Recommendations: Researchers are encouraged to select QST approaches that are

especially relevant to the clinical population in question (e.g., brush/von Frey tests in

patients with neuropathic pain, rectal balloon distension in patients with IBS, pressure pain

in patients with fibromyalgia) or focus on dynamic QST measures thought to measure

central sensitization. Multiple comparisons corrections should be considered when

administering a larger QST battery. Finally, future studies should critically evaluate the roles

of sex, ethnicity, and affective-motivational processes to aid in interpretation of results. None

of the studies with clinical samples reported analyses that linked QST changes with changes

in clinical pain ratings. Future research should examine whether any specific QST

approaches have specific clinical relevance for capturing cannabinoid-related analgesia.

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4.4. Dose-Response Findings

Nearly half of the studies (44%) evaluated dose-response effects and findings varied both in

magnitude and direction, with some studies showing the strongest analgesic effects at the

highest dose [22] and others showing the stronger effects at lower doses [12,76]. More than

half of the studies (53%) that tested dose-response effects failed to find any response

variation across doses [31–34,36,57,65,81,82], and patterns of findings were not

substantively different between cannabinoid compounds or QST modalities. Notably, to

date, no study using THC/CBD formulations has examined dose-response effects.

Interpretation of these findings is challenged by several factors that can be addressed in

future research. Importantly, dose has not been clearly and consistently operationalized

across studies to permit reproducible research. For example, “low,” “moderate,” and “high”

dose designations have typically been used to reference THC content, but these designations

may not be comparable across compounds, or even within studies using the same compound

due to methodological challenges in consistent/complete dose delivery (e.g. using a paced

puffing procedure for inhaled cannabis is subject to titration via puff topography), as well as

potential individual differences in drug absorption and metabolism [29]. Additionally, with

respect to inhaled cannabis, the true “dose” of cannabis flower likely involves a complex

interaction of a variety of constituent compounds with THC, and the pharmacodynamics and

kinetic profile of these interactions is not well understood. Thus, although the extant

literature provides a signal that analgesic responses to cannabinoid administration may be

dose dependent, the strength of that evidence across studies is weak and limited by poor

dose operationalization and experimental control.

Recommendations: Future studies should critically examine dose-response relationships

and match doses to previous work to reduce heterogeneity. It should be also noted that

concentration and the pharmacodynamics and pharmacokinetic properties of drugs largely

depends on metabolism, which substantially varies across individuals [70,84]. To better

understand dose-response, studies should also consider examining individual differences in

metabolism of cannabinoids, and how they are associated with the level of analgesic effects.

4.5. Strengths and Limitations

One strength of this review is its thorough assessment of the evidence for cannabinoid-

related analgesia to systematized pain stimuli [38,73]. Another strength is the inclusion of

studies that used clinical pain samples, thus providing a clinically-relevant expansion on De

Vita and colleagues’ review. Despite these strengths, there were several notable limitations.

First, the data gathered did not permit a meta-analysis. De Vita and colleagues [74]

previously conducted a meta-analysis using studies on experimental pain in the context of

cannabis in healthy adults. However, because our research questions were broad and

inclusive of a wide range of studies, there was substantial heterogeneity of study designs,

populations, cannabinoid compounds, and QST outcomes that precluded a valid meta-

analysis. Second, we determined analgesic, null, or hyperalgesic evidence using a p-value

cutoff because this was the most consistently available metric across studies. However, this

may not accurately reflect actual clinical effects in an underpowered or methodologically

flawed study [5]. Third, Covidence, a web-based systematic review platform that we used in

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the present study, does not retain information on voting history of abstract screening. Hence,

we were not able to calculate inter-rater reliability (i.e., Cohen’s Kappa coefficient) for the

agreement for abstract inclusion. However, we note that any conflicts were resolved by

another author (either PHF or ENP) as a tie-breaking vote, and then discussed as a group to

form consensus. Finally, we could not provide insights on dynamic QST measures, given

limited evidence.

4.6. Conclusion

Consistent with previous reviews, the present systematic review found poor consistency of

findings for the efficacy of cannabinoids as an analgesic agent. Limitations in reviewed

studies hinder conclusions about the efficacy of cannabinoids as analgesic agents. Future

work should focus on clinical populations, examine dose-response relationships, and better

characterize mediating and moderating factors.

Acknowledgement

Funding for this research was supported by the NINDS T32 NS070201 (for CJM’s postdoctoral training), NIDA F32DA049393 (awarded to CJM), NIDA K23DA035915 (awarded to PHF), NHLBI F32HL143941 (awarded to JEL), and NIDA R01DA043075 (awarded RV). We would like to acknowledge Mr. Hunter Land for his insightful comments on portions of this manuscript.

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Figure 1: PRISMA Flow Chart

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Table 1.

Criteria used in the risk of bias assessment

Category Low Risk Moderate Risk High Risk

Participant Blind Explicitly stated and described Stated or implied, but not described Not blinded or not stated

Experimenter Blind Explicitly stated and described Stated or implied, but not described Not blinded or not stated

Inclusion Criteria Adequately described and justified inclusion criteria and recruitment

strategy

One of the following: ICa) inadequate inclusion criteria justification or ICb)

inadequate recruitment strategy and/or description

Both (ICa) and (ICb)

Age and Sex Matching

Both of the following: ASMa) ≤10% difference between groups in mean age; ASMb) ≤10% difference between groups

in sex distribution

>10% difference on either (ASMa) or (ASMb)

>10% difference on both (ASMa) and (ASMb)

Confounder Control Explicitly stated control of at least 4 confounders listed above

Explicitly stated control of 3 confounders listed above

<3 confounders controlled or not explicitly stated

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Ta b

le 2

.

C ha

ra ct

er is

tic s

of in

cl ud

ed s

tu di

es

A ut

ho rs

( C

ou nt

ry )

Sa m

pl e

(N )

A ge

O th

er s

am pl

e ch

ar ac

te ri

st ic

s C

an na

bi no

id I

nf o

Q ST

S en

so ry

D

om ai

n

R is

k of

B

ia s

E ff

ec t

St ud

ie s

In cl

ud in

g H

ea lt

hy A

du lt

s O

nl y

C oo

pe r

et a

l., 2

01 3

(U SA

) H

ea lth

y A

du lts

(3

0) 27

( M

ea n)

M al

e: 5

0% E

th ni

ci ty

: B

la ck

( 67

% ),

W hi

te (

20 %

),

O th

er (

13 %

) C

an na

bi s

U se

H is

to ry

: C

ur re

nt u

se

T yp

e: 1.

I nh

al ed

C an

na bi

s 2.

S yn

th et

ic C

an na

bi no

id (

D ro

na bi

no l,

ca ps

ul e)

A ct

iv e

D os

e: 1.

1 .9

8% , 3

.5 6%

T H

C in

8 00

m g

ci ga

re tte

s; 3

–7 p

uf fs

2. 1

0m g,

2 0m

g D

os e-

R es

po ns

e: Y

C ol

d 4

M ix

ed (

nu ll

an d

po si

tiv e)

C oo

pe r

et a

l., 2

01 6

(U SA

) H

ea lth

y A

du lts

(4

2) 28

( M

ea n)

M al

e: 5

0% E

th ni

ci ty

: B

la ck

( 62

% ),

W hi

te (

26 %

),

O th

er (

12 %

) C

an na

bi s

U se

H is

to ry

: C

ur re

nt u

se o

f >

3 ci

ga re

tte s,

> 4

tim es

w ee

kl y

fo r

> 4

w ee

ks p

ri or

to s

cr ee

ni ng

T yp

e: I

nh al

ed C

an na

bi s

A ct

iv e

D os

e: 3

.5 6%

, 5 .6

% T

H C

; p uf

fe d

w ith

4 0-

s in

te rv

al s

un til

c ig

ar et

te 7

0%

py ro

liz ed

D os

e- R

es po

ns e:

Y

C ol

d 4

M ix

ed (

nu ll

an d

po si

tiv e)

C oo

pe r

et a

l., 2

01 8

(U SA

) H

ea lth

y A

du lts

(1

8) 29

.9 (

M ea

n) M

al e:

6 7%

E th

ni ci

ty :

B la

ck (

55 %

), W

hi te

( 28

% ),

O

th er

( 17

% )

C an

na bi

s U

se H

is to

ry :

C ur

re nt

u se

r of

> 3

ci ga

re tte

s, >

4 tim

es w

ee kl

y fo

r >

4 w

ee ks

p ri

or to

s cr

ee ni

ng

T yp

e: I

nh al

ed C

an na

bi s

A ct

iv e

D os

e: 5

.6 %

T H

C ; p

uf fe

d un

til

80 0m

g ci

ga re

tte w

as 7

0% p

yr ol

iz ed

D os

e- R

es po

ns e:

N

C ol

d 5

N o

co m

pa ri

so n

of c

an na

bi s

v.

pl ac

eb o;

c an

na bi

s +

o pi

oi d

on ly

E sf

an dy

ar i e

t a l.,

20

07 (

U SA

) H

ea lth

y A

du lts

(5

2) 35

.5 (

M ea

n) M

al e:

4 2%

E th

ni ci

ty :

N R

C an

na bi

s U

se H

is to

ry :

N R

T yp

e: S

yn th

et ic

C an

na bi

no id

(D

ro na

bi no

l, ca

ps ul

e) A

ct iv

e D

os e:

7 .5

m g

D os

e- R

es po

ns e:

N

V is

ce ra

l 2

M ix

ed (

nu ll

an d

po si

tiv e)

G re

en w

al d

& S

tit ze

r, 20

00 (

U SA

) H

ea lth

y A

du lts

(1

3) 18

–4 5

(R an

ge )

M al

e: 6

9% E

th ni

ci ty

: W

hi te

( 80

% ),

O th

er (

20 %

) C

an na

bi s

U se

H is

to ry

: C

ur re

nt u

se

be tw

ee n

3– 20

c ig

ar et

te s

pe r

w ee

k in

th

e m

on th

p ri

or to

s cr

ee ni

ng

T yp

e: I

nh al

ed C

an na

bi s

A ct

iv e

D os

e: 3

.5 5%

T H

C ; 1

8 pu

ff s

of

ci ga

re tte

w ei

gh in

g 75

0– 99

0m g

D os

e- R

es po

ns e:

Y

H ea

t 3

M ix

ed (

nu ll

an d

po si

tiv e)

G re

gg e

t a l.,

1 97

6 (U

SA )

H ea

lth y

A du

lts

(1 5)

24 .5

( M

ea n)

M al

e: 1

00 %

E th

ni ci

ty :

W hi

te (

10 0%

) C

an na

bi s

U se

H is

to ry

: Pr

ev io

us u

se ,

bu t n

ot o

ve r

m od

er at

e us

e

T yp

e: S

yn th

et ic

C an

na bi

no id

( IV

) A

ct iv

e D

os e:

.0 22

m g/

kg , .

04 4m

g/ kg

D os

e- R

es po

ns e:

Y

M ec

ha ni

ca l,

E le

ct ri

ca l

3 H

yp er

al ge

si a

H ill

e t a

l., 1

97 4

(U SA

) H

ea lth

y A

du lts

(3

1) 21

–3 0

(R an

ge )

M al

e: 1

00 %

E th

ni ci

ty : N

R C

an na

bi s

U se

H is

to ry

: N

R

T yp

e: I

nh al

ed C

an na

bi s

A ct

iv e

D os

e: 1

.4 %

T H

C , ~

12 m

g D

os e-

R es

po ns

e: N

E le

ct ri

ca l

8 H

yp er

al ge

si a

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A ut

ho rs

( C

ou nt

ry )

Sa m

pl e

(N )

A ge

O th

er s

am pl

e ch

ar ac

te ri

st ic

s C

an na

bi no

id I

nf o

Q ST

S en

so ry

D

om ai

n

R is

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ec t

K al

lio m

äk i e

t a l.,

20

12 (

Sw ed

en )

H ea

lth y

A du

lts

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29 .3

( M

ea n)

M al

e: 1

00 %

E th

ni ci

ty :

N R

C an

na bi

s U

se H

is to

ry :

N aï

ve

T yp

e: S

yn th

et ic

C an

na bi

no id

( N

ab ilo

ne ,

ca ps

ul e)

A ct

iv e

D os

e: 1

, 2 , o

r 3m

g D

os e-

R es

po ns

e: Y

H ea

t, M

ec ha

ni ca

l t o

C ap

sa ic

in

4 C

om pl

et el

y nu

ll

K al

lio m

äk i,

et a

l.,

20 13

( Sw

ed en

) H

ea lth

y A

du lts

(4

3) 28

.1 y

ea rs

(M

ea n)

M al

e: 1

00 %

E th

ni ci

ty :

N R

C an

na bi

s U

se H

is to

ry :

N R

T yp

e: O

th er

( A

Z D

19 40

, o ra

l) A

ct iv

e D

os e:

4 00

μg , 8

00 μg

D os

e- R

es po

ns e:

Y

H ea

t, M

ec ha

ni ca

l t o

C ap

sa ic

in

4 C

om pl

et el

y nu

ll

K ar

ni ol

e t a

l., 1

97 5

(B ra

zi l)

Pr es

um ab

ly

H ea

lth y

A du

lts (

5) 25

–2 9

(R an

ge )

M al

e: 1

00 %

E th

ni ci

ty :

N R

C an

na bi

s U

se H

is to

ry :

N R

T yp

e: T

H C

:C B

N (

C an

na bi

no l,

liq ui

d) A

ct iv

e D

os e:

2 5m

g T

H C

, 5 0m

g C

B N

, 25

m g

T H

C +

12 .5

m g

C B

N , 2

5m g

T H

C +

25 m

g C

N B

, a nd

2 5m

g T

H C

+ 50

m g

C B

N D

os e-

R es

po ns

e: Y

C ol

d 6

C om

pl et

el y

nu ll

K ra

ft e

t a l.,

2 00

8 (G

er m

an y)

H ea

lth y

A du

lts

(1 8)

23 .5

( M

ea n)

M al

e: 0

% E

th ni

ci ty

: N

R C

an na

bi s

U se

H is

to ry

: N

aï ve

T yp

e: T

H C

:C B

D (

2: 1,

o ra

l) A

ct iv

e D

os e:

2 0m

g to

ta l

D os

e- R

es po

ns e:

N

H ea

t, E

le ct

ri ca

l t o

C ap

sa ic

in

2 M

ix ed

( nu

ll an

d hy

pe ra

lg es

ia )

L ee

e t a

l., 2

01 3

(U K

) H

ea lth

y A

du lts

(1

2) 24

–3 4

(R an

ge )

M al

e: 1

00 %

E th

ni ci

ty :

N R

C an

na bi

s U

se H

is to

ry :

N aï

ve

T yp

e: S

yn th

et ic

C an

na bi

no id

( N

R ,

ca ps

ul e)

A ct

iv e

D os

e: 1

5m g

D os

e- R

es po

ns e:

N

M ec

ha ni

ca l t

o C

ap sa

ic in

4 M

ix ed

( nu

ll an

d po

si tiv

e)

L ib

m an

& S

te rn

, 19

85 (

C an

ad a)

H ea

lth y

A du

lts

(7 8)

21 (

M ea

n) M

al e:

0 %

E th

ni ci

ty :

W hi

te (

10 0%

) C

an na

bi s

U se

H is

to ry

: 50

% tw

ic e

m on

th ly

u se

f or

> 2

ye ar

s, 5

0% d

id n

ot

ex ce

ed li

fe tim

e us

e of

2 4

tim es

T yp

e: S

yn th

et ic

C an

na bi

no id

( N

R ,

ca ps

ul e)

A ct

iv e

D os

e: 1

0m g,

2 0m

g D

os e-

R es

po ns

e: Y

M ec

ha ni

ca l

2 M

ix ed

( nu

ll an

d po

si tiv

e)

M ils

te in

e t a

l., 1

97 4

(C an

ad a)

H ea

lth y

A du

lts

(6 4)

38 .3

( M

ea n)

M al

e: 5

0% E

th ni

ci ty

: N

R C

an na

bi s

U se

H is

to ry

: 50

% w

ith

re gu

la r

us e

in th

e pa

st y

ea r,

50 %

w ith

no

u se

in th

e pa

st y

ea r

T yp

e: I

nh al

ed C

an na

bi s

A ct

iv e

D os

e: 1

.5 %

T H

C ; 6

00 m

g to

ta l

D os

e- R

es po

ns e:

N

H ea

t, M

ec ha

ni ca

l 3

N ul

l

M ils

te in

e t a

l., 1

97 5

(C an

ad a)

H ea

lth y

A du

lts

(3 1)

32 .8

( M

ea n)

M al

e: 5

2% E

th ni

ci ty

: N

R C

an na

bi s

U se

H is

to ry

: 50

% u

se 2

– 36

5 tim

es in

th e

pa st

y ea

r, 50

% N

aï ve

T yp

e: I

nh al

ed C

an na

bi s

A ct

iv e

D os

e: 1

.5 %

T H

C ; 6

00 m

g to

ta l

D os

e- R

es po

ns e:

N

M ec

ha ni

ca l

4 Po

si tiv

e

N ae

f et

a l.,

2 00

3 (S

w itz

le rl

an d)

H ea

lth y

A du

lts

(1 2)

26 (

M ea

n) M

al e:

5 0%

E th

ni ci

ty : N

R C

an na

bi s

U se

H is

to ry

: N aï

ve

T yp

e: S

yn th

et ic

C an

na bi

no id

(D

ro na

bi no

l, ca

ps ul

e) A

ct iv

e D

os e:

2 0m

g D

os e-

R es

po ns

e: N

M ec

ha ni

ca l,

H ea

t, E

le ct

ri ca

l

3 C

om pl

et el

y nu

ll

N ae

f et

a l.,

2 00

4 (S

w itz

le rl

an d)

H ea

lth y

A du

lts (

8) 26

–5 0

(R an

ge )

M al

e: 5

0% E

th ni

ci ty

: N R

C an

na bi

s U

se H

is to

ry : N

aï ve

T yp

e: S

yn th

et ic

C an

na bi

no id

(D

ro na

bi no

l, ae

ro so

l i nh

al at

io n

an d

IV )

A ct

iv e

D os

e: 0

.0 53

m g/

kg D

os e-

R es

po ns

e: N

C ol

d 4

H yp

er al

ge si

a

R af

t e t a

l., 1

97 7

(U SA

) H

ea lth

y A

du lts

(1

0) 18

–2 8

(R an

ge )

M al

e: 1

00 %

E th

ni ci

ty : N

R T

yp e:

S yn

th et

ic C

an na

bi no

id (

N R

, I V

) M

ec ha

ni ca

l, E

le ct

ri c

6 C

om pl

et el

y nu

ll

Pain. Author manuscript; available in PMC 2021 February 01.

A uthor M

anuscript A

uthor M anuscript

A uthor M

anuscript A

uthor M anuscript

Mun et al. Page 26

A ut

ho rs

( C

ou nt

ry )

Sa m

pl e

(N )

A ge

O th

er s

am pl

e ch

ar ac

te ri

st ic

s C

an na

bi no

id I

nf o

Q ST

S en

so ry

D

om ai

n

R is

k of

B

ia s

E ff

ec t

C an

na bi

s U

se H

is to

ry : N

R A

ct iv

e D

os e:

0 .0

22 m

g/ kg

, a nd

0.

04 4m

g/ kg

D os

e- R

es po

ns e:

Y

R ed

m on

d et

a l.,

2 00

8 (C

an ad

a) H

ea lth

y A

du lts

(1

7) 22

.9 (

M ea

n) M

al e:

4 1%

E th

ni ci

ty : N

R C

an na

bi s

U se

H is

to ry

: N o

us e

> 3

m on

th s

pr io

r to

s cr

ee ni

ng

T yp

e: S

yn th

et ic

C an

na bi

no id

( N

ab ilo

ne ,

or al

) A

ct iv

e D

os e:

.5 m

g, 1

m g

D os

e- R

es po

ns e:

Y

H ea

t 3

C om

pl et

el y

nu ll

R ob

er ts

e t a

l., 2

00 6

(U SA

) H

ea lth

y A

du lts

(1

3) 18

–4 9

(R an

ge )

M al

e: 5

4% E

th ni

ci ty

: N R

C an

na bi

s U

se H

is to

ry : N

o re

ce nt

u se

T yp

e: S

yn th

et ic

C an

na bi

no id

(D

ro na

bi no

l, ca

ps ul

e) A

ct iv

e D

os e:

5 m

g D

os e-

R es

po ns

e: N

H ea

t 3

C om

pl et

el y

nu ll

R uk

w ie

d et

a l.,

2 00

3 (U

K )

H ea

lth y

A du

lts

(2 0)

29 (

M ea

n) M

al e:

5 0%

E th

ni ci

ty : N

R C

an na

bi s

U se

H is

to ry

: N R

T yp

e: O

th er

( H

U 21

0, s

ki n

pa tc

h) A

ct iv

e D

os e:

5 0μ

l H U

21 0

so lu

tio n

co ve

ri ng

4 cm

2 of

s ki

n fo

r 24

h rs

D os

e- R

es po

ns e:

N

H ea

t, M

ec ha

ni ca

l 8

M ix

ed (

nu ll

an d

po si

tiv e)

va n

A m

er on

ge n

et a

l.,

20 18

( N

et he

rl an

ds )

H ea

lth y

A du

lts

(2 4)

24 (

M ea

n) M

al e:

5 2%

E th

ni ci

ty : W

hi te

( 96

% ),

O th

er s

(4 %

) C

an na

bi s

U se

H is

to ry

: N o

hi st

or y

of

ill ic

it dr

ug u

se o

r po

si tiv

e dr

ug s

cr ee

n

T yp

e: S

yn th

et ic

C an

na bi

no id

( N

am is

ol ,

ca ps

ul e)

A ct

iv e

D os

e: 1

0m g

D os

e- R

es po

ns e:

N

H ea

t, E

le ct

ri ca

l, M

ec ha

ni ca

l

2 M

ix ed

( nu

ll an

d hy

pe ra

lg es

ia )

W al

la ce

e t a

l., 2

00 7

(U SA

) H

ea lth

y A

du lts

(1

9) 28

.9 (

M ea

n) M

al e:

5 8%

E th

ni ci

ty : W

hi te

( 37

% ),

O th

er s

(6 3%

) C

an na

bi s

U se

H is

to ry

: S om

e us

e in

th

e pa

st 6

m on

th s,

b ut

a bs

ta in

ed 1

m

on th

p ri

or to

s cr

ee ni

ng

T yp

e: I

nh al

ed T

H C

A ct

iv e

D os

e: 2

% , 4

% , a

nd 8

% T

H C

b y

bo dy

w ei

gh t,

4 pu

ff s

D os

e- R

es po

ns e:

Y

C ol

d, H

ea t,

M ec

ha ni

ca l

1 M

ix ed

( nu

ll an

d hy

pe ra

lg es

ia )

W al

te r

et a

l., 2

01 5

(G er

m an

y) H

ea lth

y A

du lts

(3

0) 27

.4 (

M ea

n) M

al e:

5 0%

E th

ni ci

ty : N

R C

an na

bi s

U se

H is

to ry

: N R

T yp

e: S

yn th

et ic

C an

na bi

no id

( N

R ,

ca ps

ul e)

A ct

iv e

D os

e: 2

0m g

D os

e- R

es po

ns e:

N

E le

ct ri

ca l

8 H

yp er

al ge

si a

W al

te r

et a

l., 2

01 6

(G er

m an

y) H

ea lth

y A

du lts

(1

5) 26

.5 (

M ea

n) M

al e:

5 3%

E th

ni ci

ty : N

R C

an na

bi s

U se

H is

to ry

: N R

T yp

e: S

yn th

et ic

C an

na bi

no id

( N

R ,

ca ps

ul e)

A ct

iv e

D os

e: 2

0m g

D os

e- R

es po

ns e:

N

C he

m ic

al 6

C om

pl et

el y

nu ll

Z ei

de nb

er g

et a

l.,

19 73

( U

SA )

H ea

lth y

A du

lts (

4) 25

–2 9

(R an

ge )

M al

e: 1

00 %

E th

ni ci

ty : N

R C

an na

bi s

U se

H is

to ry

: N R

T yp

e: S

yn th

et ic

C an

na bi

no id

( N

R ,

ca ps

ul e)

A ct

iv e

D os

e: 1

5m g

D os

e- R

es po

ns e:

N

H ea

t 3

Si gn

if ic

an ce

te

st in

g re

su lts

N R

St ud

ie s

In cl

ud in

g P

at ie

nt S

am pl

es

A br

am s

et a

l., 2

00 7

(U SA

) A

du lts

w ith

sy

m pt

om at

ic H

IV -

as so

ci at

ed s

en so

ry

ne ur

op at

hy (

50 )

48 .5

( M

ea n)

M al

e: 8

7% R

ac e:

W hi

te (

45 %

), B

la ck

( 38

% ),

H

is pa

ni c

(1 5%

), O

th er

s (2

% )

C an

na bi

s U

se H

is to

ry :

> 5

tim es

pr

ev io

us u

se

T yp

e: I

nh al

ed C

an na

bi s

A ct

iv e

D os

e: 3

.5 6%

T H

C ; ~

5 pu

ff s

of

0. 9g

c ig

ar et

te D

os e-

R es

po ns

e: N

H ea

t t o

C ap

sa ic

in ,

M ec

ha ni

ca l

3 M

ix ed

( nu

ll an

d po

si tiv

e)

Pain. Author manuscript; available in PMC 2021 February 01.

A uthor M

anuscript A

uthor M anuscript

A uthor M

anuscript A

uthor M anuscript

Mun et al. Page 27

A ut

ho rs

( C

ou nt

ry )

Sa m

pl e

(N )

A ge

O th

er s

am pl

e ch

ar ac

te ri

st ic

s C

an na

bi no

id I

nf o

Q ST

S en

so ry

D

om ai

n

R is

k of

B

ia s

E ff

ec t

C on

te e

t a l.,

2 00

9 (I

ta ly

) A

du lts

w ith

se

co nd

ar y

pr og

re ss

iv e

M S

(1 7)

51 .1

( M

ea n)

M al

e: 2

9% E

th ni

ci ty

: N

R C

an na

bi s

U se

H is

to ry

: N

aï ve

T yp

e: T

H C

:C B

D (

Sa tiv

ex , o

ro m

uc os

al

sp ra

y) A

ct iv

e D

os e:

E ac

h sp

ra y

ha d

2. 7m

g T

H C

an

d 2.

5m g

C B

D ; M

ax d

os e

w as

48 s

pr ay

s ov

er 2

4h rs

D os

e- R

es po

ns e:

N

E le

ct ri

ca l

4 M

ix ed

( nu

ll an

d po

si tiv

e)

K lo

ok er

e t a

l., 2

01 1

(N et

he rl

an ds

) A

du lts

w ith

ir

ri ta

bl e

bo w

el

sy nd

ro m

e (2

2)

32 .5

( M

ea n)

M al

e: 3

2% E

th ni

ci ty

: N

R C

an na

bi s

U se

H is

to ry

: Fr

ee f

ro m

u se

>

2 m

on th

s pr

io r

to s

cr ee

ni ng

T yp

e: S

yn th

et ic

C an

na bi

no id

(D

ro na

bi no

l, ca

ps ul

e) A

ct iv

e D

os e:

5 m

g, 1

0m g

D os

e- R

es po

ns e:

Y

V is

ce ra

l 6

C om

pl et

el y

nu ll

M al

ik e

t a l.,

2 01

7 (U

SA )

A du

lts w

ith

un ex

pl ai

ne d

no n-

ca rd

ia c

ch es

t p ai

n (1

3)

40 .8

( M

ea n)

M al

e: 1

5% E

th ni

ci ty

: N

R C

an na

bi s

U se

H is

to ry

: N

R

T yp

e: S

yn th

et ic

C an

na bi

no id

(D

ro na

bi no

l, ca

ps ul

e) A

ct iv

e D

os e:

1 0m

g da

ily f

or 4

w ee

ks D

os e-

R es

po ns

e: N

V is

ce ra

l 4

M ix

ed (

nu ll

an d

po si

tiv e)

N ur

m ik

ko e

t a l.,

2 00

4 (U

K &

B el

gi um

) A

du lts

w ith

un

ila te

ra l

pe ri

ph er

al

ne ur

op at

hi c

pa in

an

d al

lo dy

ni a

(1 25

)

53 .4

( M

ea n)

M al

e: 4

4% E

th ni

ci ty

: W hi

te (

97 %

), O

th er

s (3

% )

C an

na bi

s U

se H

is to

ry : N

o us

e 7

da ys

pr

io r

to r

an do

m iz

at io

n

T yp

e: T

H C

:C B

D (

Sa tiv

ex , s

ub lin

gu al

sp

ra y)

A ct

iv e

D os

e: E

ac h

sp ra

y ha

d 2.

7m g

T H

C a

nd 2

.5 m

g C

B D

; M ax

do

se w

as 4

8 sp

ra ys

in 2

4 ho

ur s

D os

e- R

es po

ns e:

N

M ec

ha ni

ca l

2 C

om pl

et el

y po

si tiv

e

Sa lim

e t a

l., 2

00 5

(G er

m an

y) A

du lts

w ith

ch

ro ni

c ne

ur op

at hi

c pa

in

(2 1)

50 .9

( M

ea n)

M al

e: 6

2% E

th ni

ci ty

: N R

C an

na bi

s U

se H

is to

ry : N

o cu

rr en

t us

e

T yp

e: O

th er

( A

ju le

m ic

a ci

d, o

ra l)

A ct

iv e

D os

e: 4

0m g

fi rs

t 4 d

ay s;

8 0m

g la

st 3

d ay

s; 1

4 da

ys to

ta l u

se D

os e-

R es

po ns

e: N

M ec

ha ni

ca l

3 C

om pl

et el

y nu

ll

Se rp

el l e

t a l.,

2 01

4 (U

K , C

ze ch

R ep

ub lic

, R

om an

ia , B

el gi

um ,

an d

C an

ad a)

A du

lts w

ith

pe ri

ph er

al

ne ur

op at

hi c

pa in

(2

46 )

57 .3

( M

ea n)

M al

e: 3

9% E

th ni

ci ty

: W hi

te (

99 %

), O

th er

s (1

% )

C an

na bi

s U

se H

is to

ry : N

on e

in th

e pa

st y

ea r

T yp

e: T

H C

:C B

D (

N R

, o ro

m uc

os al

sp

ra y)

A ct

iv e

D os

e: E

ac h

sp ra

y ha

d 2.

7m g

T H

C

an d

2. 5m

g C

B D

; M ax

d os

e w

as 4

8 sp

ra ys

in

2 4h

rs D

os e-

R es

po ns

e: N

M ec

ha ni

ca l

3 C

om pl

et el

y nu

ll

Sk ra

be k

et a

l,. 2

00 8

(C an

ad a)

A du

lts w

ith

fi br

om ya

lg ia

( 40

) 48

.9 (

M ea

n) M

al e:

8 %

R ac

e: N

R C

an na

bi s

U se

H is

to ry

: N o

us e

of

ca nn

ab is

f or

p ai

n m

an ag

em en

t

T yp

e: S

yn th

et ic

C an

na bi

no id

( N

ab ilo

ne ,

ca ps

ul e)

A ct

iv e

D os

e: 0

.5 m

g/ da

y 1s

t w ee

k,

1m g/

da y

2n d

w ee

k, 1

.5 m

g/ da

y 3r

d w

ee k,

2m

g/ da

y 4t

h w

ee k

D os

e- R

es po

ns e:

Y

M ec

ha ni

ca l

3 C

om pl

et el

y nu

ll

Sv en

ds en

e t a

l., 2

00 4

(D en

m ar

k) A

du lts

w ith

M S

an d

ce nt

ra l p

ai n

(2 4)

50 (

M ed

ia n)

M al

e: 4

2% E

th ni

ci ty

: N R

C an

na bi

s U

se H

is to

ry : N

o us

e w

ith in

3

m on

th s

of s

cr ee

ni ng

T yp

e: S

yn th

et ic

C an

na bi

no id

(D

ro na

bi no

l, ca

ps ul

e) A

ct iv

e D

os e:

2 .5

m g

da ily

a t s

ta rt

, in

cr ea

se d

by 2

.5 m

g ev

er y

ot he

r da

y; M

ax

do se

o f

5m g

B ID

( 10

m g

da ily

to ta

l) D

os e-

R es

po ns

e: N

C ol

d, H

ea t,

M ec

ha ni

ca l

2 M

ix ed

( nu

ll an

d po

si tiv

e)

W al

la ce

e t a

l 2 01

5 (U

SA )

A du

lts w

ith p

ai nf

ul

di ab

et ic

p er

ip he

ra l

ne ur

op at

hy (

16 )

56 .9

( M

ea n)

M al

e: 5

6% R

ac e:

W hi

te (

44 %

), B

la ck

( 50

% ),

H

is pa

ni c

(6 %

)

T yp

e: I

nh al

ed C

an na

bi s

M ec

ha ni

ca l

2 C

om pl

et el

y po

si tiv

e

Pain. Author manuscript; available in PMC 2021 February 01.

A uthor M

anuscript A

uthor M anuscript

A uthor M

anuscript A

uthor M anuscript

Mun et al. Page 28

A ut

ho rs

( C

ou nt

ry )

Sa m

pl e

(N )

A ge

O th

er s

am pl

e ch

ar ac

te ri

st ic

s C

an na

bi no

id I

nf o

Q ST

S en

so ry

D

om ai

n

R is

k of

B

ia s

E ff

ec t

C an

na bi

s U

se H

is to

ry : N

o us

e w

ith in

30

d ay

s of

s cr

ee ni

ng A

ct iv

e D

os e:

1 %

, 4 %

, 7 %

T H

C y

ie ld

in g

4m g,

1 6m

g, 2

8m g

T H

C p

er d

os in

g se

ss io

n, r

es pe

ct iv

el y

D os

e- R

es po

ns e:

Y

W ils

ey e

t a l.,

2 00

8 (U

SA )

A du

lts w

ith c

en tr

al

an d

pe ri

ph er

al

ne ur

op at

hi c

pa in

(3

8)

46 (

M ed

ia n)

M al

e: 5

3% E

th ni

ci ty

: W hi

te (

87 %

), B

la ck

( 3%

),

H is

pa ni

c (3

% ),

O th

er s

(7 %

) C

an na

bi s

U se

H is

to ry

: P re

vi ou

s us

e re

qu ir

ed , b

ut r

eq ui

re d

to a

bs ta

in f

ro m

us

e 30

d ay

s pr

io r

to p

ar tic

ip at

io n

T yp

e: I

nh al

ed C

an na

bi s

A ct

iv e

D os

e: 3

.5 %

, 7 %

T H

C ; 9

p uf

fs

to ta

l D

os e-

R es

po ns

e: Y

H ea

t, M

ec ha

ni ca

l 1

C om

pl et

el y

nu ll

W ils

ey e

t a l.,

2 01

3 (U

SA )

A du

lts w

ith c

en tr

al

an d

pe ri

ph er

al

ne ur

op at

hi c

pa in

(3

9)

50 (

M ea

n) M

al e:

7 2%

E th

ni ci

ty : W

hi te

( 72

% ),

B la

ck (

13 %

),

H is

pa ni

c (8

% ),

O th

er s

(8 %

) C

an na

bi s

U se

H is

to ry

: P re

vi ou

s us

e re

qu ir

ed , b

ut r

eq ui

re d

to a

bs ta

in f

ro m

us

e 30

d ay

s pr

io r

to p

ar tic

ip at

io n

T yp

e: I

nh al

ed C

an na

bi s

A ct

iv e

D os

e: 1

.2 9%

, 3 .5

3% T

H C

; 8 –1

2 pu

ff s

to ta

l D

os e-

R es

po ns

e: Y

H ea

t, M

ec ha

ni ca

l 1

M ix

ed (

nu ll

an d

po si

tiv e)

W ils

ey e

t a l.,

2 01

6 (U

SA )

A du

lts w

ith in

ju ry

an

d di

se as

e of

th e

sp in

al c

or d

(4 2)

46 .4

( M

ea n)

M al

e: 6

9% E

th ni

ci ty

: W hi

te (

62 %

), B

la ck

( 12

% ),

H

is pa

ni c

(1 7%

), O

th er

s 9%

) C

an na

bi s

U se

H is

to ry

: R eq

ui re

d to

re

fr ai

n 7

da ys

p ri

or to

p ar

tic ip

at io

n

T yp

e: I

nh al

ed C

an na

bi s

A ct

iv e

D os

e: 2

.9 %

, 6 .7

% T

H C

; 8 –1

2 pu

ff s

to ta

l D

os e-

R es

po ns

e: Y

H ea

t, M

ec ha

ni ca

l 0

C om

pl et

el y

nu ll

Pain. Author manuscript; available in PMC 2021 February 01.

A uthor M

anuscript A

uthor M anuscript

A uthor M

anuscript A

uthor M anuscript

Mun et al. Page 29

Table 3.

Consistent study limitations and recommendations for future work examining cannabinoid-related analgesia

Category Limitations Recommendations

Study Sample 1. Few studies in clinical populations 2. Poor characterization of psychosocial mediators/moderators

1. Focus on clinical pain conditions, rather than healthy controls 2. Characterize sex differences 3. Measure the impact of cannabis use history 4. Examine the influence of pain catastrophizing and negative affect

Cannabinoid Agents

1. Limited reports on dose-response relationships 2. Limited work on non-THC agents 3. Poor characterization of pharmacodynamic profiles

1. Examine dose-response relationships 2. Categorize “low”, “medium”, and “high” doses consistent with previous literature to avoid heterogeneity 3. Report constituent effects in plant-based cannabis or combined formulations

QST Approach 1. Wide heterogeneity in QST battery 2. Limited tests of central sensitization 3. Poor control for multiple tests and outcome measures

1. Conduct QST batteries restricted to empirically-selected and clinically- relevant tests and outcome measures 2. Include dynamic QST protocols (e.g., conditioned pain modulation, temporal summation) 3. Use multiple comparisons corrections 4. Complete QST in both an area of clinical pain and non-painful body site

Pain. Author manuscript; available in PMC 2021 February 01.