4 Cannabis for Chronic Pain

REVIEW ARTICLE

Systematic Review and Meta-analysis of Cannabis Treatment forChronic Painpme_703 1353..1368

Eva Martín-Sánchez, MSc,* Toshiaki A. Furukawa, MD,§ Julian Taylor, PhD,† andJose Luis R. Martin, PhD*‡

*Department of Clinical Research, Castile-La Mancha Health Research Foundation (FISCAM), †Department ofExperimental Neurology and ‡Department Applied Research, National Hospital for Paraplegics, Toledo, Spain;§Department of Psychiatry, Nagoya City University, Medical School, Nagoya, Japan

A B S T R A C T

Setting. Cannabis preparations have been used as a remedy for thousands of years in traditionalmedicine. Clinical use of cannabinoid substances is restricted, due to legal and ethical reasons, aswell as limited evidence showing benefits.

Objective. To assess the efficacy and harms of cannabis preparations in the treatment of chronic pain.

Design. Systematic review and meta-analysis of double-blind randomized controlled trials thatcompared any cannabis preparation to placebo among subjects with chronic pain. An electronicsearch was made in Medline/Pubmed, Embase, and The Cochrane Controlled Trials Register(TRIALS CENTRAL) of all literature published until February 2008, as well as specific web pagesdevoted to cannabis. Studies were cross-checked, selected, and assessed.

Results. Eighteen trials were included. The efficacy analysis (visual analog scales) displayed a dif-ference in standardized means in favor of the cannabis arm of -0.61 (-0.84 to -0.37), with statisticalhomogeneity (I2 = 0.0%; P = 0.50). For the analysis of harms, the following Odds Ratios (OR) andnumber needed to harm (NNH) were obtained: for events linked to alterations to perception, OR:4.51 (3.05–6.66), NNH: 7 (6–9); for events affecting motor function, 3.93 (2.83–5.47), NNH:5 (4–6); for events that altered cognitive function, 4.46 (2.37–8.37), NNH: 8 (6–12).

Conclusions. Currently available evidence suggests that cannabis treatment is moderately efficaciousfor treatment of chronic pain, but beneficial effects may be partially (or completely) offset bypotentially serious harms. More evidence from larger, well-designed trials is needed to clarify thetrue balance of benefits to harms.

Key Words. Cannabis; Chronic Pain; Systematic Review; Meta-Analysis

Introduction

Cannabis preparations (Cannabis sativa) havebeen used as a remedy for thousands of years

[1]. The use of this plant in traditional medicine has

been documented in a range of countries, extend-ing from China to the rest of the world, for thetreatment, among other things, of strainedmuscles, convulsions, asthma, depression, pain [2],nausea, and vomiting [3,4] or as an appetite stimu-lant [5,6]. At present, the possible medical applica-tions of the plant or its natural or syntheticpharmacologically active agents are tightlyrestricted, both for ethical and legal reasons, andfor lack of solid scientific evidence to show that

Reprint requests to: José Luis R. Martin, Castile-La ManchaHealth Research Foundation (FISCAM), Edificio Bulevar,C/ Berna 2, Local 0-2, 45003 – Toledo, Castilla-LaMancha, Spain. Tel: +34-925281144; Fax: +34-925281149;E-mail: [email protected].

PAIN MEDICINEVolume 10 • Number 8 • 2009

© American Academy of Pain Medicine 1526-2375/09/$15.00/1353 1353–1368 doi:10.1111/j.1526-4637.2009.00703.x

their use can be efficacious in most of the treat-ments proposed [7]. Furthermore, evaluations ofclinical utility require evaluations of benefits as wellas harms, given potential negative effects of thesesubstances on neurotransmitters and neuromodu-lators [8].

Pain is a disagreeable sensorial and emotionalexperience that subjects associate with tissuedamage, real or potential [9]. Where the damage,and thus the attendant sensorial experience, is pro-longed to the point of being unlimited, and inmany cases, is accompanied by a marked psycho-logical component, it becomes chronic pain[9]. Many chronic-pain patients are dependentupon powerful analgesics and tend to relapseinto a cyclical situation of pain, inactivity, anddepression.

The existence of a solid biochemical basis fora link between central cannabinoid receptors(CB1&2), the principal psychoactive cannabinoidTHC—a natural isomer of delta-9-tetra-hydrocannabinol—and pain pathways, has madeclinical exploration in search of a potential analge-sic use plausible [10]. Consequently, initial clinicalstudies based on extrapolation of results of animalresearch [11] have been conducted on the use ofcannabinoids for pain situations. To date, however,no solid, conclusive data have emerged that wouldjustify the use of cannabis as an alternative to thecurrently marketed and accepted therapeutic anal-gesic arsenal [12,13].

In the light of the present dearth of solid evi-dence on cannabis for treatment of chronic painand the considerable controversy and media pres-sure surrounding the positive effects of this sub-stance, we decided to undertake this systematicreview and meta-analysis based on randomizedcontrolled studies on the topic, with efficacy indi-cators interpretable from the standpoint of dailyclinical practice.

Methods

Search StrategyAn electronic search was made in Medline/Pubmed, Embase, and The Cochrane ControlledTrials Register (TRIALS CENTRAL) of all litera-ture published until February 2008, using the fol-lowing search terms: “cannabis,” “cannabinoids,”“marijuana,” “THC,” “tetrahydrocannabinol,”“pain,” and “chronic pain.” This was followed by ageneral Internet search, covering medical websitesas well as specific pages devoted to the substance

under review. The websites reviewed includedthose of the International Association for Can-nabis as Medicine, Medical Marijuana InformationResource Centre, Center for Medicinal CannabisResearch (University of California) AmericanSociety of Clinical Oncology, Allied and Comple-mentary Medicine Database, and GW Pharma-ceutical. The search covered all languages, and wascompleted by cross-checking the references citedin the papers located, and consulting the registersof ongoing clinical trials: The Current ControlledTrials Register and ClinicalTrials.gov. In caseswhere additional information was required,authors were contacted directly for the purpose.

Study SelectionThe studies selected were double-blind, random-ized controlled trials having a crossover or paralleldesign. In the intervention group, subjects wererequired to have received any cannabis prepara-tion, which at minimum contained the canna-binoid, delta-9-tetrahydrocannabinol (THC),applied by any route of administration. Studieswere included that used the extract of the completeplant or the active agent—isolated and purified—whether alone or combined with other cannab-inoids such as cannabidiol. Synthetic derivates ofTHC, such as dronabinol, nabilone, or benzopyra-noperidine, a synthetic nitrogen analog of THC,were likewise included. In the control group, sub-jects were required to have received a placebo treat-ment. Subjects undergoing such interventionsmust have presented with chronic pain of a patho-logical or traumatic origin, defined as constant orintermittent pain, for a minimum of 6 months [9].

Quality AssessmentStudy quality was assessed independently by twoauthors of this review. Although studies were notrequired to have a quality threshold level otherthan the pre-established inclusion criteria, theirvalidity was analyzed by the Jadad scale [14]—Oxford quality scoring system—and particularlyby reference to the principal biases that affectclinical trials involving health interventions,namely, selection bias, performance bias, and attri-tion bias. According to the study design and themethodological quality of individual study, weassessed the supporting evidence of each studyusing the system of determining levels of evidenceand grades of recommendation for evidence basedclinical guidelines of The Scottish IntercollegiateGuidelines Network [15].

Martín-Sánchez et al.1354

Outcome MeasuresThe measure of efficacy chosen was the variable,“intensity of pain,” as scored by numeric analogscales.

Harms were assessed by analyzing the numberof adverse events experienced in each group. Theadverse events were classified with respect tothe specific anatomical or physiological systemaffected, and grouped by categories of events alter-ing the same function.

Statistical AnalysisTo study efficacy, we compiled each interventiongroup’s initial and final means and standard devia-tions (SD), measured on pain scales and quantifiedin the same direction; based on these, we thencalculated the change from baseline, and the differ-ences between final measures for the groupsstudied. The included studies used different scalesof pain intensity; therefore the effect of treatmentwas quantified as the standardized mean difference(SMD) between intervention and control groups,adding a final estimator of the overall effect size forall studies. Weighting was done by reference to thedegree of study precision, using the method of theinverse of the variance [16]. For the study of harms,the effect of the treatment was quantified by meansof the odds ratio (OR), thereby furnishing a finaljoint measure that, as with the continuous variables,indicated the size of the observed effect. All theanalyses were performed by fitting both fixed- andrandom-effects models. Heterogeneity betweenstudies was statistically studied using the c2 test andI2 statistic [17]. Possible publication bias was ascer-tained by means of funnel plots.

In the various analyses, studies having a paralleland crossover design were jointly meta-analyzed,entailing the use of a specific method that wouldtake account of existing within-patient correlationin the crossover design. In the continuous measuresanalysis, none of the studies supplied informationon the value of this correlation coefficient, whichwas calculated using extreme values—the furthestvs the closest possible to a parallel design—for allthe crossover studies. Binary measures were ana-lyzed using the Becker Balagtas method [18], whichuses ORs and their related standard error (SE)logarithmically, applying the corresponding cor-rection to the within-patient correlation. For thesemeasures, the same approach was used as for con-tinuous measures [18], with the same analyses beingrepeated for a correlation range of 0.1 to 0.5.

All analyses were performed using the RevMan4.2 (The Cochrane Collaboration, Oxford, UK)

[19] and STATA/SE 8.0 User for Meta-analysis(StataCorp, College Station, TX) [20] statisticsprograms.

Results

The manual and electronic search yielded 229studies that had used cannabis on pain sufferersfrom 1975 to February 2008. Perusal of theabstracts led to 128 of these studies being directlydiscarded. Of the remaining 101, nine wereongoing at the date of analysis and had no dataavailable for our study. As a result, a total of 93complete papers were reviewed, with only 18[21–37] of these fulfilling the criteria for inclu-sion in this review. Unpublished data were ana-lyzed in three of the studies included in thisreview, in two cases through direct contact withthe authors [28,34], and in the third through astudy presented in poster format [35]. Theremaining 74 were excluded for a number ofreasons: 25 failed to meet the requirement ofrandomized clinical trial methodology; 3 dis-played repeated data; 15 were conducted onhealthy volunteers and 4 on subjects with acutepain; 10 had an open design; 13 used outcomemeasures that lay outside the stated objectives ofthis review; and 3 were rejected, either becausenot all of the initially randomized subjects pre-sented with chronic pain or because initial painlevels in the different intervention groups werenot comparable. Two further studies wereexcluded: one [38] because the different interven-tion groups did not register similar baseline painintensity levels, something that could have been asource of bias in the results; and another becauseit assessed the effect of smoked cannabis [39], asit was felt that this form of administration didnot meet the ethical criteria for therapeutic use(Figure 1).

Of the 18 studies included, only eighthad relied on two intervention arms or groups(active agent vs placebo) [22,28,30,32–34,36,37],while the remainder had used a placebo controlgroup and various intervention arms, using dif-ferent cannabis preparations or increasing dosesof the same preparation. In addition, four of thestudies had included an intervention group withan analgesic drug (codeine or secobarbital)[23,26,29] excluded from the analyses of thisreview.

Study subjects registered differences in terms oftype and aetiology of pain, but aside from thesevariables, all presented with chronic pain of a con-

Cannabis for Chronic Pain: Meta-analysis 1355

tinuous or intermittent nature and of comparablebaseline intensity among the different interven-tion groups.

All studies but two [24,34] furnished informa-tion on the analgesic treatments permitted duringthe intervention period, and only seven reportedon study subjects’ history of prior consumption ofcannabis (Table 1).

Study QualityA summary of the methodological quality andlevel of evidence for each study is shown inTable 1. The studies displayed flaws with respectto control of selection bias. In most cases no infor-mation was provided regarding the concealmentallocation process or the method of randomization[21–27,29,30,34–37]. This phenomenon, which isusual in small trials, increases the risk of possibleselection bias [40].

All the studies were conducted on a double- ortriple-blind basis. However, adequacy of blindingwas not tested in any trial. Being a substance sur-rounded by considerable controversy in the media

and in society, cannabis has a marked placeboeffect, so that inadequate blinding would consti-tute an important source of bias in this type ofstudy. Yet, the characteristic side effects caused bythese substances render perfect masking extremelydifficult.

Another important flaw in terms of study qualitylay in the control of attrition bias. In 13 of thestudies there were losses and withdrawals of sub-jects [21–23,25,27–29,31–36], and only five speci-fied that they had been analyzed on an intention-to-treat basis [21,22,28,33,35]. These, moreover,were not conducted in accordance with the correctdefinition of intention-to-treat analysis, forexample, instead of including all randomized sub-jects for whom baseline measures had beenobtained in the analysis, subjects to be includedwere purposefully-defined as those who hadremained in the trial a minimum of 3 days [21].

Some trials [25,28,31] used a run-in period.This could limit generalizability as patients whoexperienced early intolerable adverse events or didnot respond to treatment were excluded.

Figure 1 Flow of studies throughselection process.+ Three studies with unpublisheddata.* Only placebo arms were used forcomparison.

SEARCH STRATEGY

MANUAL SEARCH:

67

ELECTRONICSEARCH:

162

229 REFERENCES IDENTIFIED

128 EXCLUDED

by ABSTRACT

EXCLUDED STUDIES:

74

INCLUDED STUDIES:

18

CANNABIS vs. PLACEBO: 14+

ON GOING STUDIES:

9

101 STUDIES POTENCIALLY ELEGIBLE FOR

INCLUSION

CANNABIS vs. PLACEBO

vs. ANALGESIC: 4*


Tab

le1

Cha

ract

eris

tics

ofin

clud

edst

udie

s

Stu

dyD

esig

n(D

urat

ion)

N (Dro

pout

s)P

atho

logy

Type

Inte

rven

tion

Bas

elin

eC

hara

cter

istic

s

Cur

rent

Trea

tmen

ts

Qua

liyA

sses

smen

t†

(Lev

elof

Evi

denc

e‡ )A

ge*

(yea

rs)

Fem

ale

(%)

Inte

nsity

ofP

ain*

(Sca

le)

Can

abis

Pre

viou

sU

se

Ber

man

etal

.,20

04[2

1]

Cro

ss-o

ver

(2w

+2w

+2w

;no

was

hout

perio

d)

48(3

)B

rach

ialp

lexu

sav

ulsi

onO

rom

ucos

alsp

ray

GW

-100

0-02

(2.7

mg

TH

C/2

.5m

gC

BD

)vs

GW

-200

0-02

(2.7

mg

TH

C)

vspl

aceb

o

3995

.8%

7.5

(Ele

ven

poin

tB

oxS

cale

)

45.8

%M

edic

inal

use

60.4

%R

ecre

atio

nal

use

No

anal

gesi

csw

ere

proh

ibite

d.C

oncu

rren

tm

edic

atio

nst

able

durin

gth

est

udy

and

prev

ious

4m

3(1

-)

Bla

keet

al.,

2006

[22]

Par

alle

l(5w

+1w

follo

wup

)58

(4)

Rhe

umat

oid

arth

ritis

Oro

muc

osal

spra

yG

W-1

000-

02(2

.7m

gT

HC

/2.5

mg

CB

D)

vspl

aceb

o

62.8

(9.8

)79

%A

ctiv

egr

oup:

48.0

*P

lace

bogr

oup:

50.0

*(S

hort

-For

mM

cGill

Pai

nQ

uest

ionn

aire

)

2%M

edic

inal

use

3%R

ecre

atio

nal

use

Cur

rent

med

icat

ion

stab

lebe

fore

and

durin

gth

est

udy:

NS

AID

san

dpr

edni

solo

ne(1

m);

DM

AR

Ds

(3m

)

3(1

-)

Joch

inse

met

al.,

1978

[23]

Cro

ss-o

ver

(1d

+1d

+1d

+1d

+1d

;no

was

hout

perio

d)

37(2

)C

ance

r(m

alig

nanc

ies)

Cap

sule

s(o

ral

adm

inis

trat

ion)

BP

P2

mg

vsB

PP

4m

gvs

code

ine

sulp

hate

60m

gvs

code

ine

sulp

hate

120

mg

vspl

aceb

o

5782

.8%

No

info

rmat

ion

(0–1

00V

AS

ofP

ain)

No

info

rmat

ion

Ana

lges

icdr

ugs

wer

epr

ohib

ited

2(1

-)

John

son

and

Pot

ts,

2005

[35]

Par

alle

l(2w

)17

7C

ance

rO

rom

ucos

alsp

ray

GW

-100

0-02

(2.7

mg

TH

C/2

.5m

gC

BD

)vs

GW

-200

0(2

.7m

gT

HC

)vs

plac

ebo

60.2

(12.

3)46

%N

oin

form

atio

n(0

–10

Num

eric

alR

atin

gS

cale

)

2%M

edic

inal

use

10%

Rec

reat

iona

lus

e

Reg

ular

stro

ngop

ioid

anal

gesi

cm

aint

enan

cem

edic

atio

n

2(1

-)

Kill

este

inet

al.,

2002

[24]

Cro

ss-o

ver

(4w

+4w

+4w

;4w

ofw

asho

utpe

riod

afte

rev

ery

trea

tmen

tpe

riod)

16(0

)M

ultip

lesc

lero

sis

Cap

sule

s(o

ral

adm

inis

trat

ion)

Dro

nabi

nol(

TH

C)

(2.5

mg)

vspl

ant

extr

act

(2.5

mg

TH

C,

CB

Dan

dot

her

cann

abin

oids

)vs

plac

ebo

46(7

.9)

No

info

rmat

ion

No

info

rmat

ion

(0–1

00V

AS

ofP

ain)

37.5

%N

oin

form

atio

n3

(1-)

Not

cutt

etal

.,20

04[2

5]

Cro

ss-o

ver

34(1

2)S

ever

alpa

thol

ogie

sO

rom

ucos

alsp

ray

2.5

mg

TH

Cvs

2.5

mg

CB

Dvs

2.5

mg

TH

C/

2.5

mg

CB

Dvs

plac

ebo

46.7

0(1

0.08

)67

.6%

No

info

rmat

ion

(0–1

0V

AS

ofP

ain)

64.7

%M

edic

inal

use

0% Rec

reat

iona

lus

e

Cur

rent

med

icat

ion

stab

ledu

ring

the

stud

yan

dpr

evio

us4w

3(1

-)


Tab

le1

Con

tinue

d

Stu

dyD

esig

n(D

urat

ion)

N (Dro

pout

s)P

atho

logy

Type

Inte

rven

tion

Bas

elin

eC

hara

cter

istic

s

Cur

rent

Trea

tmen

ts

Qua

liyA

sses

smen

t†

(Lev

elof

Evi

denc

e‡ )A

ge*

(yea

rs)

Fem

ale

(%)

Inte

nsity

ofP

ain*

(Sca

le)

Can

abis

Pre

viou

sU

se

Noy

eset

al.,

1975

a[2

6]

Cro

ss-o

ver

(1d

+1d

+1d

+1d

+1d

;no

was

hout

perio

d)

10(0

)C

ance

rC

apsu

les

(ora

lad

min

istr

atio

n)5

mg

TH

Cvs

10m

gT

HC

vs15

mg

TH

Cvs

20m

gT

HC

vspl

aceb

o

51N

oin

form

atio

nN

oin

form

atio

n(0

–3H

ourly

Rat

ings

ofth

ese

verit

yof

Pai

n)

No

info

rmat

ion

Ana

lges

icdr

ugs

wer

epr

ohib

ited

2(1

-)

Noy

eset

al.,

1975

b[2

6]

Cro

ss-o

ver

(1d

+1d

+1d

+1d

+1d

;no

was

hout

perio

d)

36(2

)C

ance

rC

apsu

les

(ora

lad

min

istr

atio

n)10

mg

TH

Cvs

20m

gT

HC

vs60

mg

code

ine

vs12

0m

gco

dein

evs

plac

ebo

5172

.2%

No

info

rmat

ion

(0–3

Hou

rlyR

atin

gsof

the

seve

rity

ofP

ain)

No

info

rmat

ion

Ana

lges

icdr

ugs

wer

epr

ohib

ited

2(1

-)

Nur

mik

koet

al.,

2007

[33]

Par

alle

l(4w

)12

5(2

0)P

erip

hera

lne

rve

lesi

onO

rom

ucos

alsp

ray

GW

-100

0-02

(2.7

mg

TH

C/2

.5m

gC

BD

)vs

plac

ebo

Act

ive

grou

p:52

.4(1

5.8)

Pla

cebo

grou

p:54

.3(1

5.2)

Act

ive

grou

p:55

.6%

Pla

cebo

grou

p:62

.9%

Act

ive

grou

p:7.

3(1

.4)

Pla

cebo

grou

p:7.

2(1

.5)

(0–1

0N

umer

ical

Rat

ing

Sca

le)

20%

Cur

rent

stab

lean

alge

sic

med

icat

ion

5(1

++)

Pin

sger

etal

.,20

06[3

7]

Cro

ss-o

ver

(4w

+5w

was

hou

t+4w

)

30P

atho

logi

cst

atus

ofth

esk

elet

alan

dlo

com

otor

syst

em

Cap

sule

s(o

ral

adm

inis

trat

ion)

Nab

ilone

(TH

C)

(1–4

mg

/day

)vs

plac

ebo

55(5

0–63

)§77

%7.

8(6

.0–8

.5)§

(0–1

0V

AS

ofP

ain)

No

info

rmat

ion

No

info

rmat

ion

3(1

-)

Rog

etal

.,20

05[2

8]P

aral

ell(

5w)

66(2

)M

ultip

lesc

lero

sis

Oro

muc

osal

spra

yG

W-1

000-

02(2

.7m

gT

HC

/2.

5m

gC

BD

)vs

plac

ebo

49.2

(8.3

)78

.8%

6.5

(1.6

)(N

umer

ical

Rat

ing

Sca

le-1

1P

ain

Sco

re)

47%

Med

icin

alus

e16

.7%

recr

eatio

nal

use

Neu

roph

atic

pain

med

icat

ion

stab

ledu

ring

the

stud

yan

dpr

evio

us4w

5(1

++)

Ska

rabe

ket

al.,

2008

[36]

Par

alle

l(4w

+4w

follo

w-u

p)40

(7)

Fib

rom

yalg

iaC

apsu

les

(ora

lad

min

istr

atio

n)N

abilo

ne(T

HC

)(0

.5–1

.0m

g)vs

plac

ebo

Act

ive

grou

p:47

.6(9

.13)

Pla

cebo

grou

p:50

.11

(5.9

6)

No

info

rmat

ion

Act

ive

grou

p:6.

86(2

.14)

Pla

cebo

grou

p:6.

2(1

.46)

(0–1

0V

AS

ofP

ain)

No

prev

ious

use

for

pain

man

agem

ent

Cur

rent

trea

tmen

tsfo

rfib

rom

yalg

ia.

Not

tobe

gin

any

new

ther

apie

s

3(1

-)

Sta

quet

etal

.,19

78a

[29]

Cro

ss-o

ver

(1d

+1d

+1d

;no

was

hout

perio

d)

30(4

)C

ance

rC

apsu

les

(ora

lad

min

istr

atio

n)4

mg

NIB

vs50

mg

code

ine

vspl

aceb

oN

oin

form

atio

nN

oin

form

atio

nN

oin

form

atio

n(0

–3S

ubje

ctiv

eas

sess

men

tsof

pain

inte

nsity

)

No

info

rmat

ion

Ana

lges

icdr

ugs

wer

epr

ohib

ited

2(1

-)


Sta

quet

etal

.,19

78b

[29]

Cro

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Lastly, studies varied considerably in how out-comes were assessed and reported. Specifically,several studies expressed data as median values[22,25,30,37], without standard deviations[21,32,33,35], or as nonquantitative data [23,24].With regard to harms, several studies failed toreport independent data for patients with pain astheir primary symptom [31,32], or failed to discussthe adverse effects of treatment [23]. This hetero-geneity in the trials meant that some studiesincluded in this review could not be analyzedquantitatively.

Quantitative AnalysisEfficacyMeasured in terms of the change from the baselineintensity of pain, registered an SMD for a fixed-effects model of -0.61 (-0.84 to -0.37), using anintra-subject correlation coefficient of r = 0.3 inthe crossover studies. All the studies yielded resultsin the same direction, and no statistical hetero-geneity was in evidence (I2 = 0.0%; P = 0.50)(Figure 2). The analyses were repeated using acorrelation range of 0.1–0.5, without registeringstatistically significant changes. Sufficient datawere not obtained for conducting a final measuresanalysis—without baseline data being taken intoaccount—among the different treatment armsunder study. Funnel plot showed no sign of asym-metry, so examination of possible publication biasfailed to yield positive results.

Of the 18 studies included, only one analyzedthe intensity of pain as a dichotomous variable,defining response as a reduction of 50% or morein the score compared with baseline, so it was notpossible to carry out this analysis.

HarmsThe papers included in this review chiefly yieldeddata on adverse events affecting the centralnervous system (CNS) and gastro-intestinalsystem (GIS), so that two different meta-analyseswere performed, using intra-subject correlationcoefficient ranges of 0–0.5 as above, for all thecrossover studies. The results displayed no statis-tical change in response to a change in the coeffi-cient used. Overall between-studies heterogeneityonly appeared, for some outcomes, as from the useof a coefficient �0.5. This is probably due to theconsiderable rise in the precision of the intra-studymeasure. Data are shown with a within-patientcorrelation of 0.3.

CNS-related EventsFor events related to mood disturbances, weobserved an OR for cannabis-based interventiongroups of 4.11 (1.33–12.72), with a heterogeneitytest statistic of I2 = 0%; P = 0.79; NNH = 8 (5, 19)for euphoria and 2.56 (0.66–9.92); I2 = 0%;P = 0.49; NNH = 29 (16, 253) for dysphoria(Figure 3).

Events linked to alterations in perception(blurred vision, visual hallucinations, tinnitus, dis-

Figure 2 Meta-analysis of efficacy: intensity of pain by visual analog scale (VAS).* Parallel design.SD = standard deviation; r = within-patients coefficient; SMD = standardized mean differences; CI = confidence interval.


orientation, confusion, dissociation, acute psycho-sis) displayed a risk, for cannabis groups of 4.51(3.05–6.66), with I2 = 2.8%; P = 0.42; NNH: 7(6–9) (Figure 4).

For events affecting motor function (speech dis-orders, ataxia, muscle twitching, numbness), therisk for the intervention groups was 3.93 (2.83–5.47), with I2 = 0%; P = 0.68; NNH: 5 (4–6)(Figure 5).

For events that altered cognitive function(impaired memory, disturbance in attention, dis-connected thought) in these same interventiongroups, the respective figures were: 4.46 (2.37–8.37), with I2 = 0%; P = 0.99; NNH: 8 (6–12)(Figure 6).

Although a high level of homogeneity of theresults has been identified, a stratified subgroupanalysis of the following variables was performed:study quality (assessed as �3 vs >3 on the Jadadscale), study design (parallel vs cross-over),chronic pain type (cancer pain vs noncancer pain),and route of drug administration (capsules vs sub-lingual spray). In all the included studies theresults were essentially the same as those obtainedin the global analysis, with a very similar size ofeffect. Only in a few cases where the number of

included studies was reduced, and therefore with alimited global sample size, was the statistical sig-nificance lost. As such the analysis that was mostaffected were those made with respect to change inmood, where the process of stratification lead tothe majority of the meta-analysis being performedon a minimal number of two to three studies,whereas P values of 0.19 were obtained for studieswith a quality of �3 and 0.47 for studies with aparallel design for “euphoria” as the adverse event.For the event “dysphoria” a P = 0.98 was obtainedfor drugs administered as a sublingual spray,P = 0.55 in studies with patients with noncancerpain, P = 0.46 combined with cross-over studiesalone, P = 0.20 with parallel studies alone, P = 0.23with a study quality of �3, and P = 0.52 withstudies with a quality >3. For the rest of the events,the results did not vary following stratification ofthe variables, with the exception of statistical sig-nificance, where a P value of 0.08 was observed forevents related with alteration in perception, fol-lowing a meta-analysis of the six studies that useddrug administration in the form of a sublingualspray.

In the case of the GIS, a risk was in evidence forcannabis-based intervention groups in all catego-

Figure 3 Meta-analysis of events related to mood disturbances.* Parallel design.OR = odds ratio; SE = standard error; CI = confidence interval; r = within-patients coefficient; BB = Becker Balagtas method.


ries of events analysed, that is, nausea, vomiting,increased appetite, dry mouth, dysgeusia or badtaste, abdominal pain, dyspepsia, and diarrhea. Noquantitative results are shown as heterogeneitybetween studies was observed in the data analysis.

All the analysis were performed following botha fixed and random effect model. No differenceswere observed between the size of the effectbetween both models.

Lastly, meta-analyses were conducted to ascer-tain possible differences in the results, using ORsand relative risk, and assuming all the studies to beparallel. The results obtained, though obviouslyregistering slight differences on the measure ofassociation being changed, displayed no significantchange vis-à-vis the remaining analyses reported.The overall correlation obtained by using either

the 0.1 or 0.5 intra-subject correlation coefficientcriterion was greater than 0.8. This homogeneityacross the analyses is rendered perfectly evident,on referring to the figures shown and seeing thatthe variables analysed plot similar trends for allstudies.

Discussion

This systematic review found evidence of efficacyin the use of cannabis therapy for patients withchronic pain. Yet we also found a high number ofserious adverse events in the very short term, prin-cipally at the level of the central nervous system.

The results recorded in this systematic reviewand meta-analysis clarify the existing controversyas to both the efficacy and harms associated with

n/N lnOR(BB, r=0.3) OR(BB) (fixed); Cannabis Placebo (SE) 95 % CI

Figure 4 Meta-analysis of events linked to alterations in perception.* Parallel design.OR = odds ratio; SE = standard error; CI = confidence interval; r = within-patients coefficient; BB = Becker Balagtas method.


the therapeutic use of cannabinoids, in the contextof one of the conditions on which most researchhas been done with such compounds [41]. In termsof efficacy, this substance displays a positive andmoderate short-term trend toward a reduction inthe intensity of pain in chronic patients, but thesame cannot be said for the harms. In this case, theresults call into question the possibility of thistherapy being efficacious over long periods of timein a medical condition as demanding of therapeu-tic intervention. This study, with trial interven-tions lasting a mean of 25 days, yielded an OR ofabove four for a number of these adverse events(cognitive function, motor function, and alter-ations in perception) and an OR of above three formood disturbances. For visual alterations, thenumber needed to harm could be close on three.

Methodological ConsiderationsMost of the studies included in this review had acrossover design. Yet this design may not be the

most appropriate for clinical assessment of can-nabinoid compounds if a correct wash-out periodis not taken into consideration [42], a period thatwas excessively short in an appreciable percentageof studies evaluated in this review. Furthermore,this lack of a correct washout period in the studiesmeans that the results of the meta-analyses shownmight be less extreme than they were in real life,due to the carry-over effect on the placebo inter-ventions, in terms both of efficacy and adverseevents, of the groups that began the trials in theactive agent intervention.

Mention should also be made of the highnumber of sources of variability among the studiesincluded in this review. While all the patientsincluded in the studies presented with chronicpain—with differences in aetiology and type—thesame was not true of the study designs, interven-tions and doses. This was why joint analysis ofstudies having parallel and crossover designs wasperformed on the basis of intra-subject adjust-

Figure 5 Meta-analysis of events affecting motor function.* Parallel design.OR = odds ratio; SE = standard error; CI = confidence interval; r = within-patients coefficient; BB = Becker Balagtas method.


ments in the latter to offset the effect of the samesubjects crossing over to different interventionarms [18]. There being no data published by thestudies, a correlation range of 0.1–0.5 was used onthe assumption that any higher level of correlation(>0.5) might even question the validity of the trialsper se at an individual level. Insofar as the interven-tions were concerned, we chose studies that usedthe cannabinoid THC (natural or synthetic) in thearm comparing the active agent to placebo; notonly is THC the plant’s most abundant activeagent, but it is also the one that is most widely usedin clinical practice and displays the greatest anal-gesic and psychoactive properties [43,44]. Lastly,with respect to dosage, different dose ranges werepooled to prevent the effect of the interventionbeing overestimated as a result of analyses alwaysbeing conducted by reference to the same placebogroups. Nevertheless, the results showed—statistically and graphically—great homogeneitybetween studies, rendering it unnecessary forcomparisons by subgroup to be performed for thisvariable. The high degree of homogeneity amongthe studies included could be due to the relativelyshort duration of the intervention. With longerduration interventions, a greater trend toward het-

erogeneity among analyzed variables would beexpected, possibly reflecting differences in the effi-cacious dose range, the principle active agent usedor individual patient’s characteristics. At present,no possible dose-response relationship can beestablished.

An exhaustive search was made to complete thisstudy, which included several diverse standarddatabases as well as grey literature, and unpub-lished data, although the small size of the majorityof the included studies made it impossible toexclude the possibility of a publication bias eventhough the specific result was not significantaccording to the funnel plot analysis. The diffi-culty of detecting publication bias when samplesizes are small constitutes a limitation in this study,particularly as the obtained results could varyslightly with respect to the real situation found inthe clinical practice.

The studies included in this review were mainlypilot trials seeking an initial trend or direction insupport of or against the efficacy of cannabis inchronic pain, rather than a therapeutic approxima-tion of efficacy. Consequently, these studies sufferfrom important methodological flaws in terms ofsubject assignment to the different intervention

Figure 6 Meta-analysis of events that altered cognitive function.* Parallel design.OR = odds ratio; SE = standard error; CI = confidence interval; r = within-patients coefficient; BB = Becker Balagtas method.


groups, follow-up procedure, and possibleoutcome reporting bias, as was mentioned abovewhen analyzing their quality. Accordingly, thesepoints will have to be taken into account duringthe design phase of future clinical trials that focuson the clinical efficacy of this substance.

Clinical ImplicationsCannabis and its derivates have displayed thera-peutic properties for a range of disorders. On theone hand, there is evidence of anti-emetic prop-erties for the treatment of the nausea and vomit-ing that ensue as side effects of chemotherapy.This evidence comes from meta-analysis of ran-domized clinical trials [3,4] that in the same wayof this study, show positive results for the efficacyof cannabinoid compounds compared withplacebo and habitual anti-emetic treatments, andwhich also report adverse events of differentseverity with results which are statistically signifi-cant against cannabinoid compounds. On theother hand, although no meta-analysis or quanti-tative studies have been published that providesolid conclusions regarding the efficacy and/orsafety of pharmacological interventions based oncannabinoid compounds for the treatment ofother pathologies, other published clinical studiesexist that have reported a hyperphagic effect inthe regulation of hunger and treatment ofanorexia-cachexia syndrome [5,6], a reduction inthe spasticity that accompanies diseases such asmultiple sclerosis [45], and a decrease in intraocu-lar pressure for treatment of patients with glau-coma [46].

With respect to treatment of chronic pain withthese substances, existing knowledge has beendrawn from extrapolation of results yielded byanimal studies [11,47] or small clinical trials,which in some cases, have reported contradictoryfindings [31,32]. Insofar as a synthesis of results isconcerned, the nature of the systematic reviewspublished until now has been qualitative [7,12,13],or quantitative solely for neuropathic pain, withspecial attention paid to the compound’s efficacyrather than to its adverse events [48]. This newsystematic review has, however, been able to meta-analyze the studies included and report the effectsfound from a quantitative stance, with overall riskestimators that are easily interpretable in clinicalpractice. Special care is thus called for as regardsthe harms of this intervention. Added to the speedat which these events appear is the severity of someof them: in longer-term trials (4–5 weeks), forinstance, cases of acute psychosis were observed

[24,28,33,36], with percentages of naive subjectsranging from 36.3% to 80% in these studies.Although this variable failed to attain statisticalsignificance in our analysis, there is neverthelessevidence of a dangerous trend indicating that thelack of a significant result is only a question ofstatistical power. Indeed, this finding is especiallyremarkable, bearing in mind the fact that epide-miological studies have highlighted the relation-ship between recreational use of cannabis andpsychosis [49,50] and the association of long-termheavy cannabis use and harmful effects on braintissues [51]. Moreover, prior to randomization anumber of the studies reviewed had an open phase[25,28,31] in which all subjects took the activeagent: such a phase would thus screen out subjectswith low tolerance to the substance and reduce anyadverse events during the trial in the remainder.Hence, when it comes to extrapolating theirresults to daily clinical practice, such studies mightwell be overestimating the intervention’s efficacyand underestimating its adverse events.

None of the studies included reported informa-tion regarding the potential addictive effect ofthese substances on the studied patients. Thiseffect has probably not been studied in theincluded RCTs as the patients were not followedafter the study and that the study was performed ina duration (average: 25 days) insufficient for themanifestation of these signs. As a suggestion forfuture studies, it would be convenient to performan adequate follow up of patients, to study themedium to long term development of adverseevents with these substances, among them addic-tive effects, which represent one of the principleconcerns regarding the legalization and standard-ization of their use.

When analyzing their results, future trials willhave to make due allowance for previous use ofcannabis by study subjects, whether for therapeu-tic or recreational purposes. Due to their lipo-soluble nature, cannabis and its derivates tend toaccumulate in adipose tissue. This, in turn, acts asa reservoir that continuously releases them, possi-bly resulting in more potent effects in regularusers [41]. For other effects, however, cannabishas shown a certain degree of tolerance with thepassage of time, and larger doses would berequired to achieve the same intensity of effect asin nonconsumers [52]. Most of the studies did notpermit consumption during a period of 1–3months preceding the trial, but this period is pro-bably insufficient to eliminate the differencesamong regular, sporadic, and nonconsumers. Fur-


thermore, 11 of the studies furnished no infor-mation on prior consumption.

Most of the studies assessed were silent as toprognosis of pain [53] and subjects’ ranking on theWorld Health Organisation analgesic scale [54].This, coupled with the dearth of randomized clini-cal trials that compare the effect of cannabis and itsderivates against other analgesics enjoying scien-tifically proven efficacy and standard use in clinicalpractice, means that, even though it may displayefficacy, this systematic review cannot categorizecannabis as a future first-, second-, or third-linetreatment against pain. The undertaking of effi-cacy or equivalence studies using known analgesictreatments—gold standards—and pragmatic resultmeasures—time until the need for alternativetreatment—as comparisons would furnish infor-mation on the role that cannabis might play in thepresent therapeutic arsenal. Such studies under-taken in the medium and long term would, more-over, afford clarity as regards the pharmacologicalparameters that would ensure a better benefit-riskratio in the form of more beneficial preparations,doses, or administration routes for each type ofpatient.

In conclusion, currently available evidence indi-cates that treatment of chronic pain based on can-nabinoid compounds would entail more risk thanbenefit, including the risk of the appearance ofevents in which the pain—if it is of low intensity—might even come to pose a secondary problemin the subject. Nevertheless, the antinociceptiveeffects of this substance constitute an open avenuefor study and research aimed at developing afuture line of analgesics efficacious in certain typesof patients, based on and subject to specific dosesand administration routes.

Acknowledgement

We should like to thank José Manuel Estrada for his col-laboration in the bibliographic search, Teresa Seoane forher advice on the statistical analysis, Michael Benedictfor his assistance with the editing, and all the authors oftrials who so unstintingly shared their unpublished datawith us.

Funding

This study was partially funded by the Spain NationalDrug Plan. No type of funding was received from thepharmaceutical industry. None of the funding organiza-tions had any role in the study conduct, analysis, interpre-tation of the results or approval of the manuscript.

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4 Cannabis for Chronic Pain