T.R. Deer et al. (eds.), Comprehensive Treatment of Chronic Pain by Medical, Interventional, and Integrative Approaches,
DOI 10.1007/978-1-4614-1560-2_18, © American Academy of Pain Medicine 2013
Plants and Pain
It is a curious fact that we owe a great deal of our insight into
pharmacological treatment of pain to the plant world [ 1 ] .
Willow bark from Salix spp. led to development of aspirin and
eventual elucidation of the analgesic effects of prostaglandins
and their role in in ﬂ ammation. The opium poppy ( Papaver som-
niferum ) provided the prototypic narcotic analgesic morphine,
the ﬁ rst alkaloid discovered, and stimulated the much later
discovery of the endorphin and enkephalin systems. Similarly,
the pharmacological properties of cannabis ( Cannabis sativa )
prompted the isolation of D 9 -tetrahydrocannabinol (THC),
the major psychoactive ingredient in cannabis, in 1964 [ 2 ] .
It is this breakthrough that subsequently prompted the more
recent discovery of the body’s own cannabis-like system, the
endocannabinoid system (ECS), which modulates pain under
physiological conditions. Pro-nociceptive mechanisms of the
endovanilloid system were similarly revealed by phytochem-
istry of capsaicin, the pungent ingredient in hot chile peppers
( Capsicum annuum etc.), which activates transient recep-
tor potential vanilloid receptor-1 (TRPV1). Additional plant
products such as the mints and mustards activate other TRP
channels to produce their physiological effects.
The Endocannabinoid System
There are three recognized types of cannabinoids: (1) the
phytocannabinoids [ 3 ] derived from the cannabis plant, (2)
synthetic cannabinoids (e.g., ajulemic acid, nabilone,
CP55940, WIN55, 212-2) based upon the chemical structure
of THC or other ligands which bind cannabinoid receptors,
and (3) the endogenous cannabinoids or endocannabinoids.
Endocannabinoids are natural chemicals such as anandamide
(AEA) and 2-arachidonoylglycerol (2-AG) found in animals
whose basic functions are “relax, eat, sleep, forget, and
protect” [ 4 ] . The endocannabinoid system encompasses the
endocannabinoids themselves, their biosynthetic and cata-
bolic enzymes, and their corresponding receptors [ 5 ] . AEA
is hydrolyzed by the enzyme fatty-acid amide hydrolase
(FAAH) into breakdown products arachidonic acid and etha-
nolamine [ 6 ] . By contrast, 2-AG is hydrolyzed primarily by
the enzyme monoacylglycerol lipase (MGL) into breakdown
products arachidonic acid and glycerol [
7 ] and to a lesser
extent by the enzymes ABHD6 and ABHD12. FAAH, a
Role of Cannabinoids in Pain
Ethan B. Russo and Andrea G. Hohmann
E. B. Russo , M.D. (*)
GW Pharmaceuticals ,
20402 81st Avenue SW , Vashon , WA 98070 , USA
Pharmaceutical Sciences , University of Montana ,
Missoula , MT , USA
A. G. Hohmann , Ph.D.
Department of Psychological and Brain Sciences , Indiana University ,
101 East 10th Street , Bloomington , IN 47405 , USA
Cannabinoids are pharmacological agents of endog-•
enous (endocannabinoids), botanical (phytocan-
nabinoids), or synthetic origin.
Cannabinoids alleviate pain through a variety of •
receptor and non-receptor mechanisms including
direct analgesic and anti-in ﬂ ammatory effects,
modulatory actions on neurotransmitters, and inter-
actions with endogenous and administered opioids.
Cannabinoid agents are currently available in various •
countries for pain treatment, and even cannabinoids of
botanical origin may be approvable by FDA, although
this is distinctly unlikely for smoked cannabis.
An impressive body of literature supports cannabinoid •
analgesia, and recently, this has been supplemented
by an increasing number of phase I–III clinical trials.
182 E.B. Russo and A.G. Hohmann
postsynaptic enzyme, may control anandamide levels near
sites of synthesis, whereas MGL, a presynaptic enzyme [ 8 ] ,
may terminate 2-AG signaling following CB
1 receptor acti-
vation. These enzymes also represent therapeutic targets
because inhibition of endocannabinoid deactivation will
increase levels of endocannabinoids at sites with ongoing
synthesis and release [ 9 ] . The pathways controlling forma-
tion of AEA remain poorly understood. However, 2-AG is
believed to be formed from membrane phospholipid precur-
sors through the sequential activation of two distinct enzymes,
phospholipase C and diacylglycerol lipase- a . First, PLC
catalyzes formation of the 2-AG precursor diacylglycerol
(DAG) from membrane phosphoinositides. Then, DAG is
hydrolyzed by the enzyme diacylglycerol lipase- a (DGL- a )
to generate 2-AG [
199 ] .
There are currently two well-de ﬁ ned cannabinoid recep-
tors, although additional candidate cannabinoid receptors
have also been postulated. CB
1 , a seven transmembrane
spanning G-protein-coupled receptor inhibiting cyclic AMP
release, was identi ﬁ ed in 1988 [ 10 ] . CB 1 is the primary neu-
romodulatory receptor accounting for psychopharmacologi-
cal effects of THC and most of its analgesic effects [ 11 ] .
Endocannabinoids are produced on demand in postsynaptic
cells and engage presynaptic CB
1 receptors through a retro-
grade mechanism [ 12 ] . Activation of presynaptic CB
tors then acts as a synaptic circuit breaker to inhibit
neurotransmitter release (either excitatory or inhibitory)
from the presynaptic neuron ( vide infra ) (Fig. 18.1 ). CB 2 was
identi ﬁ ed in 1992, and while thought of primarily as a periph-
eral immunomodulatory receptor, it also has important
Fig. 18.1 Putative mechanism of endocannabinoid-mediated
retrograde signaling in the nervous system. Activation of metabotropic
glutamate receptors ( mGluR ) by glutamate triggers the activation of the
phospholipase C ( PLC )-diacylglycerol lipase ( DGL ) pathway to gen-
erate the endocannabinoid 2-arachidonoylglycerol ( 2-AG ). First, the
2-AG precursor diacylglycerol ( DAG ) is formed from PLC-mediated
hydrolysis of membrane phospholipid precursors ( PIPx ). DAG is
then hydrolyzed by the enzyme DGL- a to generate 2-AG. 2-AG is
released from the postsynaptic neuron and acts as a retrograde signal-
ing molecule. Endocannabinoids activate presynaptic CB
which reside on terminals of glutamatergic and GABAergic neurons.
Activation of CB
1 by 2-AG, anandamide, or exogenous cannabinoids
(e.g., tetrahydrocannabinol, THC ) inhibits calcium in ﬂ ux in the presyn-
aptic terminal, thereby inhibiting release of the primary neurotransmitter
(i.e., glutamate or GABA) from the synaptic vesicle. Endocannabinoids
are then rapidly deactivated by transport into cells (via a putative endo-
cannabinoid transporter) followed by intracellular hydrolysis. 2-AG is
metabolized by the enzyme monoacylglycerol lipase ( MGL ), whereas
anandamide is metabolized by a distinct enzyme, fatty-acid amide
hydrolase ( FAAH ). Note that MGL co-localizes with CB
1 in the pre-
synaptic terminal, whereas FAAH is localized to postsynaptic sites.
The existence of an endocannabinoid transporter remains controver-
sial. Pharmacological inhibitors of either endocannabinoid deactivation
(e.g., FAAH and MGL inhibitors) or transport (i.e., uptake inhibitors)
have been developed to exploit the therapeutic potential of the endocan-
nabinoid signaling system in the treatment of pain (Figure by authors
with kind assistance of James Brodie, GW Pharmaceuticals)
18318 Rol e of Cannabi noids in Pain Management
effects on pain. The role of CB
2 in modulating persistent
in ﬂ ammatory and neuropathic pain [
13 ] has been recently
reviewed [ 14, 15 ] . Activation of CB 2 suppresses neuropathic
pain mechanisms through nonneuronal (i.e., microglia and
astrocytes) and neuronal mechanisms that may involve inter-
feron-gamma [ 16 ] . THC, the prototypical classical cannabi-
noid, is a weak partial agonist at both CB
1 and CB
Transgenic mice lacking cannabinoid receptors (CB
1 , CB 2 ,
GPR55), enzymes controlling endocannabinoid breakdown
(FAAH, MGL, ABHD6), and endocannabinoid synthesis
(DGL- a , DGL- b ) have been generated [ 17 ] . These knock-
outs have helped elucidate the role of the endocannabinoid
system in controlling nociceptive processing and facilitated
development of inhibitors of endocannabinoid breakdown
(FAAH, MGL) as novel classes of analgesics.
A Brief Scienti ﬁ c History of Cannabis and Pain
Centuries of Citations
Cannabis has been utilized in one form or another for treat-
ment of pain for longer than written history [ 18– 21 ] .
Although this documentation has been a major preoccupa-
tion of the lead author [ 22– 25 ] , and such information can
provide provocative direction to inform modern research on
treatment of pain and other conditions, it does not represent
evidence of form, content, or degree that is commonly
acceptable to governmental regulatory bodies with respect to
Anecdotes Versus Modern Proof of Concept
While thousands of compelling stories of ef ﬁ cacy of canna-
bis in pain treatment certainly underline the importance of
properly harnessing cannabinoid mechanisms therapeuti-
cally [ 26, 27 ] , prescription analgesics in the United States
necessitate Food and Drug Administration (FDA) approval.
This requires a rigorous development program proving con-
sistency, quality, ef ﬁ cacy, and safety as de ﬁ ned by basic
scienti ﬁ c studies and randomized controlled trials (RCT)
[ 28 ] and generally adhering to recent IMMPACT recommen-
dations [ 29 ] , provoking our next question.
Can a Botanical Agent Become a Prescription
Most modern physicians fail to recognize that pharmacog-
nosy (study of medicinal plants) has led directly or indirectly
to an estimated 25 % of modern pharmaceuticals [
30 ] . While
the plethora of available herbal agents yield an indecipherable
cacophony to most clinicians and consumers alike, it is cer-
tainly possible to standardize botanical agents and facilitate
their recommendation based on sound science [
31 ] . Botanical
medicines can even ful ﬁ ll the rigorous dictates of the FDA
and attain prescription drug status via a clear roadmap in the
form of a blueprint document [
32 ] , henceforth termed the
Botanical Guidance : http://www.fda.gov/downloads/Drugs/
ucm070491.pdf . To be successful and clinically valuable,
botanicals, including cannabis-based medicines, must dem-
onstrate the same quality, clinical analgesic bene ﬁ t, and
appropriately safe adverse event pro ﬁ le as available new
chemical entities (NCE) [ 28 ] .
The Biochemical and Neurophysiological Basis
of Pain Control by Cannabinoids
Thorough reviews of therapeutic effects of cannabinoids in
preclinical and clinical domains have recently been pub-
lished [ 33, 34 ] . In essence, the endocannabinoid system
(ECS) is active throughout the CNS and PNS in modulating
pain at spinal, supraspinal, and peripheral levels.
Endocannabinoids are produced on demand in the CNS to
dampen sensitivity to pain [ 35 ] . The endocannabinoid sys-
tem is operative in such key integrative pain centers as the
periaqueductal grey matter [ 36, 37 ] , the ventroposterolateral
nucleus of the thalamus [ 38 ] , and the spinal cord [ 39, 40 ] .
Endocannabinoids are endogenous mediators of stress-
induced analgesia and fear-conditioned analgesia and sup-
press pain-related phenomena such as windup [ 41 ] and
allodynia [ 42 ] . In the periphery and PNS [ 13 ] , the ECS has
key effects in suppressing both hyperalgesia and allodynia
1 [ 43 ] and CB 2 mechanisms (Fig. 18.2 ). Indeed, path-
ological pain states have been postulated to arise, at least in
part, from a dysregulation of the endocannabinoid system.
Antinociceptive and Anti-in ﬂ ammatory Pain
Beyond the mechanisms previously mentioned, the ECS
plays a critical role in peripheral pain, in ﬂ ammation, and
hyperalgesia [ 43 ] through both CB 1 and CB
1 and CB
2 mechanisms are also implicated in regulation
of contact dermatitis and pruritus [ 44 ] . A role for spinal CB
mechanisms, mediated by microglia and/or astrocytes, is
also revealed under conditions of in ﬂ ammation [
45 ] . Both
THC and cannabidiol (CBD), a non-euphoriant phytocan-
nabinoid common in certain cannabis strains, are potent anti-
in ﬂ ammatory antioxidants with activity exceeding that of
184 E.B. Russo and A.G. Hohmann
Central nervous system
PAG (presynaptic GABAergic,
RVM (ON and OFF cells)
(VPL, amygdala, anterior
WDR, NS cell;
microglia ( by injury)
CB1;CB2( by injury)
Fig. 18.2 Cannabinoids suppress pain and other pathophysiological
(e.g., contact dermatitis, pruritis) and physiological (e.g., gastrointesti-
nal transit and secretion) processes through multiple mechanisms
1 and CB
2 receptors. Peripheral, spinal, and supraspinal
sites of cannabinoid actions are shown. In the periphery, cannabinoids
act through both neuronal and nonneuronal mechanisms to control
in ﬂ ammation, allodynia, and hyperalgesia. CB
1 and CB
2 have been
localized to both primary afferents and nonneuronal cells (e.g., kerati-
nocytes, microglia), and expression can be regulated by injury. In the
spinal cord, cannabinoids suppress nociceptive transmission, windup,
and central sensitization by modulating activity in the ascending pain
pathway of the spinothalamic tract, including responses of wide
dynamic range ( WDR ) and nociceptive speci ﬁ c ( NS ) cells. Similar pro-
cesses are observed at rostral levels of the neuraxis (e.g., ventropostero-
lateral nucleus of the thalamus, amygdala, anterior cingulate cortex).
Cannabinoids also actively modulate pain through descending mecha-
nisms. In the periaqueductal gray, cannabinoids act through presynaptic
glutamatergic and GABAergic mechanisms to control nociception. In
the rostral ventromedial medulla, cannabinoids suppress activity in ON
cells and inhibit the ﬁ ring pause of OFF cells, in response to noxious
stimulation to produce antinociception (Figure by authors with kind
assistance of James Brodie, GW Pharmaceuticals)
18518 Rol e of Cannabi noids in Pain Management
vitamins C and E via non-cannabinoid mechanisms [ 46 ] .
THC inhibits prostaglandin E-2 synthesis [
47 ] and stimulates
lipooxygenase [ 48 ] . Neither THC nor CBD affects COX-1 or
COX-2 at relevant pharmacological dosages [
49 ] .
While THC is inactive at vanilloid receptors, CBD, like
AEA, is a TRPV
1 agonist. Like capsaicin, CBD is capable of
inhibiting fatty-acid amide hydrolase (FAAH), the enzyme
which hydrolyzes AEA and other fatty-acid amides that do
not bind to cannabinoid receptors. CBD additionally inhibits
AEA reuptake [
50 ] though not potently. Thus, CBD acts as
an endocannabinoid modulator [ 51 ] , a mechanism that vari-
ous pharmaceutical ﬁ rms hope to emulate with new chemical
entities (NCEs). CBD inhibits hepatic metabolism of THC to
11-hydroxy-THC, which is possibly more psychoactive, and
prolongs its half-life, reducing its psychoactivity and attenu-
ating attendant anxiety and tachycardia [ 51 ] ; antagonizes
psychotic symptoms [
52 ] ; and attenuates appetitive effects
of THC [
53 ] as well as its effects on short-term memory [ 54 ] .
CBD also inhibits tumor necrosis factor-alpha (TNF- a ) in a
rodent model of rheumatoid arthritis [ 55 ] . Recently, CBD
has been demonstrated to enhance adenosine receptor A2A
signaling via inhibition of the adenosine transporter [ 56 ] .
Recently, GPR18 has been proposed as a putative CBD
receptor whose function relates to cellular migration [ 57 ] .
Antagonism of GPR18 (by agents such as CBD) may be
ef ﬁ cacious in treating pain of endometriosis, among other
conditions, especially considering that such pain may be
endocannabinoid-mediated [ 58 ] . Cannabinoids are also very
active in various gastrointestinal and visceral sites mediating
pain responses [ 59, 60 ] .
Cannabinoid Interactions with
Other Neurotransmitters Pertinent to Pain
As alluded to above, the ECS modulates neurotransmitter
release via retrograde inhibition. This is particularly impor-
tant in NMDA-glutamatergic mechanisms that become
hyperresponsive in chronic pain states. Cannabinoids
speci ﬁ cally inhibit glutamate release in the hippocampus
[ 61 ] . THC reduces NMDA responses by 30–40 % [ 46 ] .
Secondary and tertiary hyperalgesia mediated by NMDA
[ 62 ] and by calcitonin gene-related peptide [ 40 ] may well be
targets of cannabinoid therapy in disorders such as migraine,
ﬁ bromyalgia, and idiopathic bowel syndrome wherein these
mechanisms seem to operate pathophysiologically [ 63 ] ,
prompting the hypothesis of a “clinical endocannabinoid
de ﬁ ciency.” Endocannabinoid modulators may therefore
restore homeostasis, leading to normalization of function in
these pathophysiological conditions. THC also has numer-
ous effects on serotonergic systems germane to migraine
[ 64 ] , increasing its production in the cerebrum while decreas-
ing reuptake [
65 ] . In fact, the ECS seems to modulate the
trigeminovascular system of migraine pathogenesis at
vascular and neurochemical levels [
66– 68 ] .
Although endocannabinoids do not bind to opioid receptors,
the ECS may nonetheless work in parallel with the endoge-
nous opioid system with numerous areas of overlap and
interaction. Pertinent mechanisms include stimulation of
beta-endorphin by THC [ 69 ] as well as its ability to demon-
strate experimental opiate sparing [ 70 ] , prevent opioid toler-
ance and withdrawal [ 71 ] , and rekindle opioid analgesia after
loss of effect [ 72 ] . Adjunctive treatments that combine opi-
oids with cannabinoids may enhance the analgesic effects of
either agent. Such strategies may permit lower doses of anal-
gesics to be employed for therapeutic bene ﬁ t in a manner
that minimizes incidence or severity of adverse side effects.
Clinical Trials, Utility, and Pitfalls
of Cannabinoids in Pain
Evidence for Synthetic Cannabinoids
Oral dronabinol (THC) has been available as the synthetic
since 1985 and is indicated for nausea associated
with chemotherapy and appetite stimulation in HIV/AIDS.
Issues with its cost, titration dif ﬁ culties, delayed onset, and
propensity to induce intoxicating and dysphoric effects have
limited clinical application [ 73 ] . It was employed in two
open-label studies of chronic neuropathic pain in case studies
in 7 [ 74 ] and 8 patients [ 75 ] , but no signi ﬁ cant bene ﬁ t was
evident and side effects led to prominent dropout rates (aver-
age doses 15–16.6 mg THC). Dronabinol produced bene ﬁ t in
pain in multiple sclerosis [ 76 ] , but none was evident in post-
operative pain (Table 18.1 ) [ 77 ] . Dronabinol was reported to
relieve pruritus in three case-report subjects with cholestatic
jaundice [ 78 ] . Dronabinol was assessed in 30 chronic non-
cancer pain patients on opioids in double-blind crossover
single-day sessions vs. placebo with improvement [ 79 ] , fol-
lowed by a 4-week open-label trial with continued improve-
ment (Table 18.1 ). Associated adverse events were prominent.
Methodological issues included lack of prescreening for can-
nabinoids, 4 placebo subjects with positive THC assays, and
58 % of subjects correctly guessing Marinol dose on test day.
An open-label comparison in polyneuropathy examined nabi-
lone patients with 6 obtaining 22.6 % mean pain relief after
3 months, and 5 achieving 28.6 % relief after 6 months, com-
parable to conventional agents [
80 ] . A pilot study of Marinol
in seven spinal cord injury patients with neuropathic pain saw
two withdraw, and the remainder appreciate no greater
ef ﬁ cacy than with diphenhydramine [ 81 ] .
186 E.B. Russo and A.G. Hohmann
Table 18.1 Randomized controlled trials of cannabinoids in pain
Agent N = Indication Duration/type Outcomes/reference
Ajulemic acid 21 Neuropathic pain 7 day crossover Visual analogue pain scales improved
over placebo ( p = 0.02)/Karst et al. [
Cannabis, smoked 50 HIV neuropathy 5 days/DB Decreased daily pain ( p = 0.03) and
hyperalgesia ( p = 0.05), 52 % with >30 %
pain reduction vs. placebo ( p = 0.04)/
Abrams et al. [
Cannabis, smoked 23 Chronic neuropathic pain 5 days/DB Decreased pain vs. placebo only at 9.4 %
THC level ( p = 0.023)/Ware et al. [
Cannabis, smoked 38 Neuropathic pain Single dose/DBC NSD in pain except at highest cannabis
dose ( p = 0.02), with prominent
psychoactive effects/Wilsey et al. [
Cannabis, smoked 34 HIV neuropathy 5 days /DB DDS improved over placebo ( p = 0.016),
46 % vs. 18 % improved >30 %, 2 cases
toxic psychosis/Ellis et al. [
Cannabis, vaporized 21 Chronic pain on opioids 5 days/DB 27 % decrement in pain/Abrams et al.
[ 118 ]
Cannador 419 Pain due to spasm in MS 15 weeks Improvement over placebo in subjective
pain associated with spasm ( p = 0.003)/
Zajicek et al. [
Cannador 65 Postherpetic neuralgia 4 weeks No bene ﬁ t observed/Ernst et al. [ 122 ]
Cannador 30 Postoperative pain Single doses, daily Decreasing pain intensity with increased
dose ( p = 0.01)/Holdcroft et al. [
Marinol 24 Neuropathic pain in MS 15–21 days/DBC Median numerical pain ( p = 0.02),
median pain relief improved ( p = 0.035)
over placebo/Svendsen et al. [
Marinol 40 Postoperative pain Single dose/DB No bene ﬁ t observed over placebo/Buggy
et al. [
Marinol 30 Chronic pain 3 doses, 1 day/DBC Total pain relief improved with 10 mg
( p < 0.05) and 20 mg ( p < 0.01) with
opioids, AE prominent/Narang et al. [
Nabilone 41 Postoperative pain 3 doses in 24 h/DB NSD morphine consumption. Increased
pain at rest and on movement with
nabilone 1 or 2 mg/Beaulieu [
Nabilone 31 Fibromyalgia 2 weeks/DBC Compared to amitriptyline, nabilone
improved sleep, decrease wakefulness,
had no effect on pain, and increased AE/
Ware et al. [
Nabilone 96 Neuropathic pain 14 weeks/DBC vs.
Dihydrocodeine more effective with
fewer AE/Frank et al. [
Nabilone 13 Spasticity pain 9 weeks/DBC NRS decreased 2 points for nabilone
( p < 0.05)/Wissel et al. [
Nabilone 40 Fibromyalgia 4 weeks/DBC VAS decreased in pain, Fibromyalgia
Impact Questionnaire, and anxiety over
placebo (all, p < 0.02)/Skrabek et al. [
Sativex 20 Neurogenic pain Series of 2-week N-of-1
Improvement with Tetranabinex and
Sativex on VAS pain vs. placebo
( p < 0.05), symptom control best with
Sativex ( p < 0.0001)/Wade et al. [
Sativex 24 Chronic intractable pain 12 weeks, series of N-of-1
VAS pain improved over placebo
( p < 0.001) especially in MS ( p < 0.0042)/
Notcutt et al. [
Sativex 48 Brachial plexus avulsion 6 weeks in 3 two-week
Bene ﬁ ts noted in Box Scale-11 pain
scores with Tetranabinex ( p = 0.002) and
Sativex ( p = 0.005) over placebo/Berman
et al. [
Sativex 66 Central neuropathic pain
5 weeks Numerical Rating Scale (NRS) analgesia
improved over placebo ( p = 0.009)/Rog
et al. [
18718 Rol e of Cannabino ids in Pain Management
Nabilone, or Cesamet
, is a semisynthetic analogue of
THC that is about tenfold more potent, and longer lasting
[ 82 ] . It is indicated as an antiemetic in chemotherapy in the
USA. Prior case reports in neuropathic pain [ 83 ] and other
pain disorders [ 84 ] have been published. Sedation and dys-
phoria are prominent associated adverse events. An RCT of
nabilone in 41 postoperative subjects dosed TID actually
resulted in increased pain scores (Table 18.1 ) [ 85 ] . An uncon-
trolled study of 82 cancer patients on nabilone noted
improved pain scores [ 86 ] , but retention rates were limited.
Nabilone improved pain ( p < 0.05) vs. placebo in patients
with mixed spasticity syndromes in a small double-blind trial
(Table 18.1 ) [ 87 ] , but was without bene ﬁ ts in other parame-
ters. In a double-blind crossover comparison of nabilone to
dihydrocodeine (schedule II opioid) in chronic neuropathic
18.1 ) [ 88 ] , both drugs produced marginal bene ﬁ t,
but with dihydrocodeine proving clearly superior in ef ﬁ cacy
and modestly superior in side-effect pro ﬁ le. In an RCT in 40
patients of nabilone vs. placebo over 4 weeks, it showed
signi ﬁ cant decreases in VAS of pain and anxiety (Table
[ 89 ] . A more recent study of nabilone vs. amitriptyline in
ﬁ bromyalgia yielded bene ﬁ ts on sleep, but not pain, mood,
or quality of life (Table 18.1 ) [ 90 ] . An open-label trial of
nabilone vs. gabapentin found them comparable in pain and
other symptom relief in peripheral neuropathic pain [ 91 ] .
Ajulemic acid (CT3), another synthetic THC analogue in
development, was utilized in a phase II RCT in peripheral
neuropathic pain in 21 subjects with apparent improvement
(Table 18.1 ) [ 92 ] . Whether or not ajulemic acid is psychoac-
tive is the subject of some controversy [ 93 ] .
Evidence for Smoked or Vaporized Cannabis
Few randomized controlled clinical trials (RCTs) of pain
with smoked cannabis have been undertaken to date [ 94– 97 ] .
One of these [ 96 ] examined cannabis effects on experimental
pain in normal volunteers.
Abrams et al. [ 94 ] studied inpatient adults with painful
HIV neuropathy in 25 subjects in double-blind fashion to
receive either smoked cannabis as 3.56 % THC cigarettes or
placebo cigarettes three times daily for 5 days (Table 18.1 ).
The smoked cannabis group had a 34 % reduction in daily
pain vs. 17 % in the placebo group ( p = 0.03). The cannabis
cohort also had a 52 % of subjects report a >30 % reduction
in pain scores over the 5 days vs. 24 % in the placebo group
( p = 0.04) (Table 18.1 ). The authors rated cannabis as “well
tolerated” due to an absence of serious adverse events (AE)
leading to withdrawal, but all subjects were cannabis experi-
enced. Symptoms of possible intoxication in the cannabis
group including anxiety (25 %), sedation (54 %), disorienta-
tion (16 %), paranoia (13 %), confusion (17 %), dizziness
(15 %), and nausea (11 %) were all statistically signi ﬁ cantly
more common than in the placebo group. Despite these
ﬁ ndings, the authors stated that the values do not represent
any serious safety concern in this short-term study. No dis-
cussion in the article addressed issues of the relative ef ﬁ cacy
of blinding in the trial.
Wilsey et al. [ 95 ] examined neuropathic pain in 38 sub-
jects in a double-blind crossover study comparing 7 % THC
cannabis, 3.5 % THC cannabis, and placebo cigarettes via a
complex cumulative dosing scheme with each dosage given
Table 18.1 (continued)
Agent N = Indication Duration/type Outcomes/reference
Sativex 125 Peripheral neuropathic
5 weeks Improvements in NRS pain levels
( p = 0.004), dynamic allodynia ( p = 0.042),
and punctuate allodynia ( p = 0.021) vs.
placebo/Nurmikko et al. [
Sativex 56 Rheumatoid arthritis Nocturnal dosing for 5
Improvements over placebo morning
pain on movement ( p = 0.044), morning
pain at rest ( p = 0.018), DAS-28
( p = 0.002), and SF-MPQ pain at present
( p = 0.016)/Blake et al. [
Sativex 117 Pain after spinal injury 10 days NSD in NRS pain scores, but improved
Brief Pain Inventory ( p = 0.032), and
Patients’ Global Impression of Change
( p = 0.001) (unpublished)
Sativex 177 Intractable cancer pain 2 weeks Improvements in NRS analgesia vs.
placebo ( p = 0.0142), Tetranabinex NSD/
Johnson et al. [
Sativex 135 Intractable lower urinary
tract symptoms in MS
8 weeks Improved bladder severity symptoms
including pain over placebo ( p = 0.001)
[ 200 ]
Sativex 360 Intractable cancer pain 5 weeks/DB CRA of lower and middle-dose cohorts
improved over placebo ( p = 0.006)/ [ 201 ]
188 E.B. Russo and A.G. Hohmann
once, in random order, with at least 3 day intervals separating
18.1 ). A total of 9 puffs maximum were
allowed over several hours per session. Authors stated,
“Psychoactive effects were minimal and well-tolerated, but
neuropsychological impairment was problematic, particu-
larly with the higher concentration of study medication.”
Again, only cannabis-experienced subjects were allowed
entry. No withdrawals due to AE were reported, but 1 subject
was removed due to elevated blood pressure. No signi ﬁ cant
differences were noted in pain relief in the two cannabis
potency groups, but a signi ﬁ cant separation of pain reduction
from placebo ( p = 0.02) was not evident until a cumulative 9
puffs at 240 min elapsed time. Pain unpleasantness was also
reduced in both active treatment groups ( p < 0.01).
Subjectively, an “any drug effect” demonstrated a visual ana-
logue scale (VAS) of 60/100 in the high-dose group, but even
the low-dose group registered more of a “good drug effect”
than placebo ( p < 0.001). “Bad drug effect” was also evident.
“Feeling high” and “feeling stoned” were greatest in the
high-dose sessions ( p < 0.001), while both high- and low-
dose differentiated signi ﬁ cantly from placebo ( p < 0.05). Of
greater concern, both groups rated impairment as 30/100 on
VAS vs. placebo ( p = 0.003). Sedation also demarcated both
groups from placebo ( p < 0.01), as did confusion ( p = 0.03),
and hunger ( p < 0.001). Anxiety was not considered a promi-
nent feature in this cannabis-experienced population. This
study distinguished itself from some others in its inclusion of
speci ﬁ c objective neuropsychological measures and demon-
strated neurocognitive impairment in attention, learning, and
memory, most noteworthy with 7 % THC cannabis. No com-
mentary on blinding ef ﬁ cacy was included.
Ellis et al. [ 97 ] examined HIV-associated neuropathic
pain in a double-blind trial of placebo vs. 1–8 % THC can-
nabis administered four times daily over 5 days with a 2-week
washout (Table 18.1 ). Subjects were started at 4 % THC and
then titrated upward or downward in four smoking sessions
dependent upon their symptom relief and tolerance of the
dose. In this study, 96 % of subjects were cannabis-experi-
enced, and 28 out of 34 subjects completed the trial. The
primary outcome measure (Descriptor Differential Scale,
DDS) was improved in the active group over placebo
( p = 0.016), with >30 % relief noted in 46 % of cannabis sub-
jects vs. 18 % of placebo. While most adverse events (AE)
were considered mild and self-limited, two subjects had to
leave the trial due to toxicity. One cannabis-naïve subject
was withdrawn due to “an acute cannabis-induced psycho-
sis” at what proved to be his ﬁ rst actual cannabis exposure.
The other subject suffered intractable cough. Pain reduction
was greater in the cannabis-treated group ( p = 0.016) among
completers, as was the proportion of subjects attaining >30 %
pain reduction (46 % vs. 18 %, p = 0.043). Blinding was
assessed in this study; whereas placebo patients were inac-
curate at guessing the investigational product, 93 % of those
receiving cannabis guessed correctly. On safety issues, the
authors stated that the frequency of some nontreatment-lim-
iting side effects was greater for cannabis than placebo.
These included concentration dif ﬁ culties, fatigue, sleepiness
or sedation, increased duration of sleep, reduced salivation,
A Canadian study [ 98 ] examined single 25-mg inhala-
tions of various cannabis potencies (0–9.4 % THC) three
times daily for 5 days per cycle in 23 subjects with chronic
neuropathic pain (Table 18.1 ). Patients were said to be can-
nabis-free for 1 year, but were required to have some experi-
ence of the drug. Only the highest potency demarcated from
placebo on decrements in average daily pain score (5.4 vs.
6.1, p = 0.023). The most frequent AE in the high-dose group
were headache, dry eyes, burning sensation, dizziness, numb-
ness, and cough, but with “high” or “euphoria” reported only
once in each cannabis potency group.
The current studies of smoked cannabis are noteworthy
for their extremely short-term exposure and would be of
uncertain relevance in a regulatory environment. The
IMMPACT recommendations on chronic neuropathic pain
clinical trials that are currently favored by the FDA [ 29 ] gen-
erally suggest randomized controlled clinical trials of
12-week duration as a prerequisite to demonstrate ef ﬁ cacy
and safety. While one might assume that the degree of pain
improvement demonstrated in these trials could be main-
tained over this longer interval, it is only reasonable to
assume that cumulative adverse events would also increase
to at least some degree. The combined studies represent only
a total of 1,106 patient-days of cannabis exposure (Abrams:
125, Wilsey: 76, Ellis: 560, Ware 345) or 3 patient-years of
experience. In contrast, over 6,000 patient-years of data have
been analyzed for Sativex between clinical trials, prescrip-
tion, and named-patient supplies, with vastly lower AE rates
(data on ﬁ le, GW Pharmaceuticals) [ 28, 99 ] . Certainly, the
cognitive effects noted in California-smoked cannabis stud-
ies ﬁ gure among many factors that would call the ef ﬁ cacy of
blinding into question for investigations employing such an
approach. However, it is also important to emphasize that
unwanted side effects are not unique to cannabinoids. In a
prospective evaluation of speci ﬁ c chronic polyneuropathy
syndromes and their response to pharmacological therapies,
the presence of intolerable side effects did not differ in groups
receiving gabapentinoids, tricyclic antidepressants, anticon-
vulsants, cannabinoids (including nabilone, Sativex), and
topical agents [ 80 ] . Moreover, no serious adverse events
were related to any of the medications.
The current studies were performed in a very select subset
of patients who almost invariably have had prior experience
of cannabis. Their applicability to cannabis-naïve populations
is, thus, quite unclear. At best, the observed bene ﬁ ts might
possibly accrue to some, but it is eminently likely that candi-
dates for such therapy might refuse it on any number of
18918 Role of Cannabinoids in Pain Management
grounds: not wishing to smoke, concern with respect to intox-
ication, etc. Sequelae of smoking in therapeutic outcomes
have had little discussion in these brief RCTs [
28 ] . Cannabis
smoking poses substantial risk of chronic cough and bron-
chitic symptoms [ 100 ] , if not obvious emphysematous degen-
eration [ 101 ] or increase in aerodigestive cancers [ 102 ] . Even
such smoked cannabis proponents as Lester Grinspoon has
acknowledged are the only well-con ﬁ rmed deleterious physi-
cal effect of marihuana is harm to the pulmonary system
[ 103 ] . However, population-based studies of cannabis trials
have failed to show any evidence for increased risk of respira-
tory symptoms/chronic obstructive pulmonary disease [ 100 ]
or lung cancer [ 102 ] associated with smoking cannabis.
A very detailed analysis and comparison of mainstream
and sidestream smoke for cannabis vs. tobacco smoke was
performed in Canada [ 104 ] . Of note, cannabis smoke con-
tained ammonia (NH
3 ) at a level of 720 m g per 775 mg ciga-
rette, a ﬁ gure 20-fold higher than that found in tobacco
smoke. It was hypothesized that this ﬁ nding was likely attrib-
utable to nitrate fertilizers. Formaldehyde and acetaldehyde
were generally lower in cannabis smoke than in tobacco, but
butyraldehyde was higher. Polycyclic aromatic hydrocarbon
(PAH) contents were qualitatively similar in the compari-
sons, but total yield was lower for cannabis mainstream
smoke, but higher than tobacco for sidestream smoke.
Additionally, NO, NO
, hydrogen cyanide, and aromatic
amines concentrations were 3–5 times higher in cannabis
smoke than that from tobacco. Possible mutagenic and carci-
nogenic potential of these various compounds were men-
tioned. More recently, experimental analysis of cannabis
smoke with resultant acetaldehyde production has posited its
genotoxic potential to be attributable to reactions that pro-
duce DNA adducts [ 105 ] .
Vaporizers for cannabis have been offered as a harm reduc-
tion technique that would theoretically eliminate products of
combustion and associated adverse events. The Institute of
Medicine (IOM) examined cannabis issues in 1999 [ 106 ] ,
and among their conclusions was the following (p. 4):
“Recommendation 2: Clinical trials of cannabinoid drugs for
symptom management should be conducted with the goal of
developing rapid-onset, reliable, and safe delivery systems.”
One proposed technique is vaporization, whereby cannabis is
heated to a temperature that volatilizes THC and other com-
ponents with the goal of reducing or eliminating by-products
of combustion, including potentially carcinogenic polycyclic
aromatic hydrocarbons, benzene, acetaldehyde, carbon mon-
oxide, toluene, naphthaline, phenol, toluene, hydrogen cya-
nide, and ammonia. Space limitations permit only a cursory
review of available literature [ 107– 115 ] .
A pilot study of the Volcano vaporizer vs. smoking was
performed in the USA in 2007 in 18 active cannabis consum-
ers, with only 48 h of presumed abstinence [ 116 ] . NIDA
900-mg cannabis cigarettes were employed (1.7, 3.4, and
6.8 % THC) with each divided in two, so that one-half would
be smoked or vaporized in a series of double-blind sessions.
The Volcano vaporizer produced comparable or slightly
higher THC plasma concentrations than smoking. Measured
CO in exhaled vapor sessions diminished very slightly, while
it increased after smoking ( p < 0.001). Self-reported visual
analogue scales of the associated high were virtually identi-
cal in vaporization vs. smoking sessions and increased with
higher potency material. A contention was advanced that the
absence of CO increase after vaporization can be equated to
“little or no exposure to gaseous combustion toxins.” Given
that no measures of PAH or other components were under-
taken, the assertion is questionable. It was also stated that
there were no reported adverse events. Some 12 subjects pre-
ferred the Volcano, 2 chose smoking, and 2 had no prefer-
ence as to technique, making the vaporizer “an acceptable
system” and providing “a safer way to deliver THC.”
A recent [ 202, 117 ] examined interactions of 3.2 % THC
NIDA cannabis vaporized in the Volcano in conjunction with
opioid treatment in a 5-day inpatient trial in 21 patients with
chronic pain (Table 18.1 ). All subjects were prior cannabis
smokers. Overall, pain scores were reduced from 39.6 to
29.1 on a VAS, a 27 % reduction, by day 5. Pain scores in
subjects on morphine fell from 34.8 to 24.1, while in subjects
taking oxycodone, scores dropped from 43.8 to 33.6.
The clinical studies performed with vaporizers to date
have been very small pilot studies conducted over very lim-
ited timeframes (i.e., for a maximum of 5 days). Thus, these
studies cannot contribute in any meaningful fashion toward
possible FDA approval of vaporized cannabis as a delivery
technique, device, or drug under existing policies dictated by
the Botanical Guidance [ 32 ] . It is likewise quite unlikely that
the current AE pro ﬁ le of smoked or vaporized cannabis would
meet FDA requirements. The fact that all the vaporization tri-
als to date have been undertaken only in cannabis-experienced
subjects does not imply that results would generalize to larger
patient populations. Moreover, there is certainly no reason to
expect AE pro ﬁ les to be better in cannabis-naïve patients.
Additionally, existing standardization of cannabis product
and delivery via vaporization seem far off the required marks.
Although vaporizers represent an alternate delivery method
devoid of the illegality associated with smoked cannabis, the
presence of toxic ingredients such as PAH, ammonia, and
acetaldehyde in cannabis vapor are unlikely to be acceptable
to FDA in any signi ﬁ cant amounts. Existing vaporizers still
lack portability or convenience [ 28 ] . A large Internet survey
revealed that only 2.2 % of cannabis users employed vapor-
ization as their primary cannabis intake method [ 118 ] . While
studies to date have established that lower temperature vapor-
ization in the Volcano, but not necessarily other devices, can
reduce the relative amounts of noxious by-products of com-
bustion, it has yet to be demonstrated that they are totally
eliminated. Until or unless this goal is achieved, along with
190 E.B. Russo and A.G. Hohmann
requisite benchmarks of herbal cannabis quality, safety, and
ef ﬁ cacy in properly designed randomized clinical trials,
vaporization remains an unproven technology for therapeutic
Evidence for Cannabis-Based Medicines
Cannador is a cannabis extract in oral capsules, with differ-
ing THC:CBD ratios [ 51 ] . Cannador was utilized in a phase
III RCT of spasticity in multiple sclerosis (CAMS)
(Table 18.1 ) [ 119 ] . While no improvement was evident in
the Ashworth Scale, reduction was seen in spasm-associ-
ated pain. Both THC and Cannador improved pain scores in
follow-up [ 120 ] . Cannador was also employed for posther-
petic neuralgia in 65 patients, but without success
18.1 ) [ 121, 122 ] . Slight pain reduction was observed
in 30 subjects with postoperative pain (CANPOP) not
receiving opiates, but psychoactive side effects were nota-
Sativex® is a whole-cannabis-based extract delivered as
an oromucosal spray that combines a CB
1 and CB
agonist (THC) with a cannabinoid system modulator (CBD),
minor cannabinoids, and terpenoids plus ethanol and propyl-
ene glycol excipients and peppermint ﬂ avoring [ 51, 123 ] .
It is approved in Canada for spasticity in MS and under a
Notice of Compliance with Conditions for central neuro-
pathic pain in multiple sclerosis and treatment of cancer pain
unresponsive to opioids. Sativex is also approved in MS in
the UK, Spain, and New Zealand, for spasticity in multiple
sclerosis, with further approvals expected soon in some 22
countries around the world. Sativex is highly standardized
and is formulated from two Cannabis sativa chemovars pre-
dominating in THC and CBD, respectively [ 124 ] . Each
100 m l pump-action oromucosal spray of Sativex yields 2.7
mg of THC and 2.5 mg of CBD plus additional components.
Pharmacokinetic data are available [ 125– 127 ] . Sativex
effects begin within an interval allowing dose titration.
A very favorable adverse event pro ﬁ le has been observed in
the development program [ 27, 128 ] . Most patients stabilize
at 8–10 sprays per day after 7–10 days, attaining symptom-
atic control without undue psychoactive sequelae. Sativex
was added to optimized drug regimens in subjects with
uncontrolled pain in every RCT (Table 18.1 ). An
Investigational New Drug (IND) application to study Sativex
in advanced clinical trials in the USA was approved by the
FDA in January 2006 in patients with intractable cancer pain.
One phase IIB dose-ranging study has already been com-
pleted [ 201 ] . Available clinical trials with Sativex have been
independently assessed [
129, 130 ] .
In a phase II study of 20 patients with neurogenic symp-
toms [ 131 ] , signi ﬁ cant improvement was seen with both
Tetranabinex (high-THC extract without CBD) and Sativex
on pain, with Sativex displaying better symptom control
( p < 0.0001), with less intoxication (Table 18.1 ).
In a phase II study of intractable chronic pain in 24
patients [ 132 ] , Sativex again produced the best results com-
pared to Tetranabinex ( p < 0.001), especially in MS
( p < 0.0042) (Table 18.1 ).
In a phase III study of brachial plexus avulsion ( N = 48)
[ 133 ] , pain reduction with Tetranabinex and Sativex was
about equal (Table 18.1 ).
In an RCT of 66 MS subjects, mean Numerical Rating
Scale (NRS) analgesia favored Sativex over placebo
(Table 18.1 ) [ 134 ] .
In a phase III trial ( N = 125) of peripheral neuropathic
pain with allodynia [ 135 ] , Sativex notably alleviated pain
levels and dynamic and punctate allodynia (Table 18.1 ).
In a safety-extension study in 160 subjects with various
symptoms of MS [
136 ] , 137 patients showed sustained
improvements over a year or more in pain and other symp-
toms [ 99 ] without development of any tolerance requiring
dose escalation or withdrawal effects in those who volun-
tarily discontinued treatment suddenly. Analgesia was
quickly reestablished upon Sativex resumption.
In a phase II RCT in 56 rheumatoid arthritis sufferers over
5 weeks with Sativex [ 137 ] , medicine was limited to only 6
evening sprays (16.2 mg THC + 15 mg CBD). By study end,
morning pain on movement, morning pain at rest, DAS-28
measure of disease activity, and SF-MPQ pain all favored
Sativex (Table 18.1 ).
In a phase III RCT in intractable cancer pain on opioids
( N = 177), Sativex, Tetranabinex THC-predominant extract,
and placebo were compared [ 138 ] demonstrating strongly
statistically signi ﬁ cant improvements in analgesia for Sativex
only (Table 18.1 ). This suggests that the CBD component in
Sativex was necessary for bene ﬁ t.
In a 2-week study of spinal cord injury pain, NRS of pain
was not statistically different from placebo, probably due to
the short duration of the trial, but secondary endpoints were
18.1 ). Additionally, an RCT of intractable
lower urinary tract symptoms in MS also demonstrated pain
The open-label study of various polyneuropathy patients
included Sativex patients with 3 obtaining 21.56 % mean
pain relief after 3 months (2/3 > 30 %), and 4 achieving
27.6 % relief after 6 months (2/4 > 30 %), comparable to con-
ventional agents [ 80 ] .
A recently completed RCT of Sativex in intractable can-
cer pain unresponsive to opioids over 5 weeks was performed
in 360 subjects (Table 18.1 ). Results of a Continuous
Response Analysis (CRA) showed improvements over pla-
cebo in the low-dose ( p = 0.08) and middle-dose cohorts
( p = 0.038) or combined ( p = 0.006). Pain NRS improved over
placebo in the low-dose ( p = 0.006) and combined cohorts
( p = 0.019).
19118 Rol e of Cannabino ids in Pain Management
Sleep has improved markedly in almost all Sativex RCTs
in chronic pain based on symptom reduction, not a hypnotic
effect [ 139 ] .
The adverse event (AE) pro ﬁ le of Sativex has been quite
benign with bad taste, oral stinging, dry mouth, dizziness, nau-
sea, or fatigue most common, but not usually prompting dis-
continuation [ 128 ] . Most psychoactive sequelae are early and
transient and have been notably lowered by more recent appli-
cation of a slower, less aggressive titration schedule. While no
direct comparative studies have been performed with Sativex
and other agents, AE rates were comparable or greater with
Marinol than with Sativex employing THC dosages some 2.5
times higher, likely due to the presence of accompanying CBD
[ 28, 51 ] . Similarly, Sativex displayed a superior AE pro ﬁ le
compared to smoked cannabis based on safety-extension stud-
ies of Sativex [ 28, 99 ] , as compared to chronic use of cannabis
with standardized government-supplied material in Canada
for chronic pain [ 140 ] and the Netherlands for various indica-
tions [ 141, 142 ] over a period of several months or more. All
AEs are more frequent with smoked cannabis, except for nau-
sea and dizziness, both early and usually transiently reported
with Sativex [ 27, 28, 128 ] . A recent meta-analysis suggested
that serious AEs associated with cannabinoid-based medica-
tions did not differ from placebo and thus could not be attribut-
able to cannabinoid use, further reinforcing the low toxicity
associated with activation of cannabinoid systems.
Cannabinoid Pitfalls: Are They Surmountable?
The dangers of COX-1 and COX-2 inhibition by nonsteroi-
dal anti-in ﬂ ammatory drugs (NSAIDS) of various design
(e.g., gastrointestinal ulceration and bleeding vs. coronary
and cerebrovascular accidents, respectively) [ 143, 144 ] are
unlikely to be mimicked by either THC or CBD, which pro-
duce no such activity at therapeutic dosages [ 49 ] .
Natural cannabinoids require polar solvents and may be
associated with delayed and sometimes erratic absorption
after oral administration. Smoking of cannabis invariably pro-
duces rapid spikes in serum THC levels; cannabis smoking
attains peak levels of serum THC above 140 ng/ml [ 145, 146 ] ,
which, while desirable to the recreational user, has no neces-
sity or advantage for treatment of chronic pain [ 28 ] . In con-
trast, comparable amounts of THC derived from oromucosal
Sativex remained below 2 ng/ml with much lower propensity
toward psychoactive sequelae [ 28, 125 ] , with subjective
intoxication levels on visual analogue scales that are indistin-
guishable from placebo, in the single digits out of 100 [ 100 ] .
It is clear from RCTs that such psychoactivity is not a neces-
sary accompaniment to pain control. In contrast, intoxication
has continued to be prominent with oral THC [ 73 ] .
In comparison to the questionable clinical trial blinding
with smoked and vaporized cannabis discussed above, all
indications are that such study blinding has been demonstra-
bly effective with Sativex [ 147, 148 ] by utilizing a placebo
spray with identical taste and color. Some 50 % of Sativex
subjects in RCTs have had prior cannabis exposure, but
results of two studies suggest that both groups exhibited
comparable results in both treatment ef ﬁ cacy and side effect
pro ﬁ le [ 134, 135 ] .
Controversy continues to swirl around the issue of the
potential dangers of cannabis use medicinally, particularly
its drug abuse liability (DAL). Cannabis and cannabinoids
are currently DEA schedule I substances and are forbidden
in the USA (save for Marinol in schedule III and nabilone in
schedule II) [ 73 ] . This is noteworthy in itself because the
very same chemical compound, THC, appears simultane-
ously in schedule I (as THC), schedule II (as nabilone), and
schedule III (as Marinol). DAL is assessed on the basis of
ﬁ ve elements: intoxication, reinforcement, tolerance, with-
drawal, and dependency plus the drug’s overall observed
rates of abuse and diversion. Drugs that are smoked or
injected are commonly rated as more reinforcing due to more
rapid delivery to the brain [ 149 ] . Sativex has intermediate
onset. It is claimed that CBD in Sativex reduces the psycho-
activity of THC [ 28 ] . RCT AE pro ﬁ les do not indicate eupho-
ria or other possible reinforcing psychoactive indicia as
common problems with its use [ 99 ] . Similarly, acute THC
effects such as tachycardia, hypothermia, orthostatic hypoten-
sion, dry mouth, ocular injection, and intraocular pressure
decreases undergo prominent tachyphylaxis with regular
usage [ 150 ] . Despite that observation, Sativex has not dem-
onstrated dose tolerance to its therapeutic bene ﬁ ts on pro-
longed administration, and ef ﬁ cacy has been maintained for
up to several years in pain conditions [ 99 ] .
The existence or severity of a cannabis withdrawal syn-
drome remains under debate [ 151, 152 ] . In contrast to
reported withdrawal sequelae in recreational users [ 153 ] , 24
subjects with MS who volunteered to discontinue Sativex
after a year or more suffered no withdrawal symptoms meet-
ing Budney criteria. While symptoms such as pain recurred
after some 7–10 days without Sativex, symptom control was
rapidly reattained upon resumption [ 99 ] .
Finally, no known abuse or diversion incidents have been
reported with Sativex to date (March 2011). Formal DAL
studies of Sativex vs. Marinol and placebo have been com-
pleted and demonstrate lower scores on drug liking and simi-
lar measures at comparable doses [ 155 ] .
Cognitive effects of cannabis also remain at issue [ 155,
156 ] , but less data are available in therapeutic applications.
Studies of Sativex in neuropathic pain with allodynia have
revealed no changes vs. placebo on Sativex in portions of the
Halstead-Reitan Battery [
135 ] , or in central neuropathic pain
in MS [
134 ] , where 80 % of tests showed no signi ﬁ cant dif-
ferences. In a recent RCT of Sativex vs. placebo in MS
patients, no cognitive differences of note were observed
192 E.B. Russo and A.G. Hohmann
[ 157 ] . Similarly, chronic Sativex use has not produced
observable mood disorders.
Controversies have also arisen regarding the possible
association of cannabis abuse and onset of psychosis [ 156 ] .
However, an etiological relationship is not supported by epi-
demiological data [ 158– 161 ] , but may well be affected by
dose levels and duration, if pertinent. One may speculate that
lower serum levels of Sativex combined with antipsychotic
properties of CBD [
52, 162, 163 ] might attenuate such con-
cerns. Few cases of related symptoms have been reported in
SAFEX studies of Sativex.
Immune function becomes impaired in experimental ani-
mals at cannabinoid doses 50–100 times necessary to produce
psychoactive effects [ 164 ] . In four patients smoking cannabis
medicinally for more than 20 years, no changes were evident
in leukocyte, CD4, or CD8 cell counts [ 155 ] . MS patients on
Cannador demonstrated no immune changes of note [
nor were changes evident in subjects smoking cannabis in a
brief trial in HIV patients [
166 ] . Sativex RCTs have demon-
strated no hematological or immune dysfunction.
No effects of THC extract, CBD extract, or Sativex were
evident on the hepatic cytochrome P450 complex [ 167 ] or on
human CYP450 [ 168 ] . Similarly, while Sativex might be
expected to have additive sedative effects with other drugs or
alcohol, no signi ﬁ cant drug-drug interactions of any type have
been observed in the entire development program to date.
No studies have demonstrated signi ﬁ cant problems in
relation to cannabis affecting driving skills at plasma levels
below 5 ng/ml of THC [ 169 ] . Four oromucosal sprays of
Sativex (exceeding the average single dose employed in ther-
apy) produced serum levels well below this threshold [ 28 ] .
As with other cannabinoids in therapy, it is recommended
that patients not drive nor use dangerous equipment until
accustomed to the effects of the drug.
Future Directions: An Array of Biosynthetic
and Phytocannabinoid Analgesics
Inhibition of Endocannabinoid Transport
and Degradation: A Solution?
It is essential that any cannabinoid analgesic strike a compro-
mise between therapeutic and adverse effects that may both be
mediated via CB
1 mechanisms [ 34 ] . Mechanisms to avoid
psychoactive sequelae could include peripherally active syn-
thetic cannabinoids that do not cross the blood-brain barrier or
drugs that boost AEA levels by inhibiting fatty-acid amide
hydrolase (FAAH) [ 170 ] or that of 2-AG by inhibiting monoa-
cylycerol lipase (MGL). CBD also has this effect [
50 ] and cer-
tainly seems to increase the therapeutic index of THC [
51 ] .
In preclinical studies, drugs inhibiting endocannabinoid
hydrolysis [ 171, 172 ] and peripherally acting agonists [ 173 ] all
show promise for suppressing neuropathic pain. AZ11713908,
a peripherally restricted mixed cannabinoid agonist, reduces
mechanical allodynia with ef ﬁ cacy comparable to the brain
penetrant mixed cannabinoid agonist WIN55,212-2 [ 173 ] . An
irreversible inhibitor of the 2-AG hydrolyzing enzyme MGL
suppresses nerve injury-induced mechanical allodynia through
1 mechanism, although these anti-allodynic effects
undergo tolerance following repeated administration [ 172 ] .
URB937, a brain impermeant inhibitor of FAAH, has recently
been shown to elevate anandamide outside the brain and sup-
press neuropathic and in ﬂ ammatory pain behavior without
producing tolerance or unwanted CNS side effects [ 171 ] .
These observations raise the possibility that peripherally
restricted endocannabinoid modulators may show therapeutic
potential as analgesics with limited side-effect pro ﬁ les.
The Phytocannabinoid and Terpenoid Pipeline
Additional phytocannabinoids show promise in treatment of
chronic pain [ 123, 163, 174 ] . Cannabichromene (CBC),
another prominent phytocannabinoid, also displays anti-
in ﬂ ammatory [ 175 ] and analgesic properties, though less
potently than THC [ 176 ] . CBC, like CBD, is a weak inhibi-
tor of AEA reuptake [ 177 ] . CBC is additionally a potent
TRPA1 agonist [ 178 ] . Cannabigerol (CBG), another phyto-
cannabinoid, displays weak binding at both CB
1 and CB
[ 179, 180 ] but is a more potent GABA reuptake inhibitor
than either THC or CBD [ 181 ] . CBG is a stronger analgesic,
anti-erythema, and lipooxygenase agent than THC [ 182 ] .
CBG likewise inhibits AEA uptake and is a TRPV1 agonist
[ 177 ] , a TRPA1 agonist, and a TRPM8 antagonist [ 178 ] .
CBG is also a phospholipase A2 modulator that reduces
PGE-2 release in synovial cells [ 183 ] . Tetrahydrocannabivarin,
a phytocannabinoid present in southern African strains, dis-
plays weak CB
1 antagonism [ 184 ] and a variety of anticon-
vulsant activities [ 185 ] that might prove useful in chronic
neuropathic pain treatment. THCV also reduced in ﬂ ammation
and attendant pain in mouse experiments [ 187 ] . Most North
American [ 187 ] and European [ 188, 189 ] cannabis strains
have been bred to favor THC over a virtual absence of other
phytocannabinoid components, but the latter are currently
available in abundance via selective breeding [ 124, 190 ] .
Aromatic terpenoid components of cannabis also demon-
strate pain reducing activity [ 123, 163 ] . Myrcene displays an
opioid-type analgesic effect blocked by naloxone [ 191 ] and
reduces in ﬂ ammation via PGE-2 [ 192 ] . b -Caryophyllene
displays anti-in ﬂ ammatory activity on par with phenylbuta-
zone via PGE-1 [ 193 ] , but contrasts by displaying gastric
cytoprotective activity [
194 ] . Surprisingly, b -caryophyllene
has proven to be a phytocannabinoid in its own right as a
2 agonist [ 195 ] . a -Pinene inhibits PGE-1 [ 196 ] ,
and linalool acts as a local anesthetic [
197 ] .
19318 Role of Cannabinoids in Pain Management
Basic science and clinical trials support the theoretical and
practical basis of cannabinoid agents as analgesics for
chronic pain. Their unique pharmacological pro ﬁ les with
multimodality effects and generally favorable ef ﬁ cacy and
safety pro ﬁ les render cannabinoid-based medicines promis-
ing agents for adjunctive treatment, particularly for neuro-
pathic pain. It is our expectation that the coming years will
mark the advent of numerous approved cannabinoids with
varying mechanisms of action and delivery techniques that
should offer the clinician useful new tools for treating pain.
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