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Role of Cannabinoids in Pain Management

January 2013

In book: Comprehensive Treatment of Chronic Pain by Medical, Interventional, and Integrative Approaches (pp.181-197)

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CReDO Science

It is a curious fact that we owe a great deal of our insight into pharmacological treatment of pain to the plant world. Willow bark from Salix spp. led to development of aspirin and eventual elucidation of the analgesic effects of prostaglandins and their role in inflammation. The opium poppy (Papaver somniferum) provided the prototypic narcotic analgesic morphine, the first 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 Δ9-tetrahydrocannabinol (THC), the major psychoactive ingredient in cannabis, in 1964. 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.

.1 Randomized controlled trials of cannabinoids in pain

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.1 (continued)

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181

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

Introduction

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

Management

Ethan B. Russo and Andrea G. Hohmann

1 8

E. B. Russo , M.D. (*)

GW Pharmaceuticals ,

20402 81st Avenue SW , Vashon , WA 98070 , USA

Pharmaceutical Sciences , University of Montana ,

Missoula , MT , USA

e-mail: ethanrusso@comcast.net

A. G. Hohmann , Ph.D.

Department of Psychological and Brain Sciences , Indiana University ,

101 East 10th Street , Bloomington , IN 47405 , USA

e-mail: hohmanna@indiana.edu

Key Points

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

1 recep-

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

1 receptors

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

2 receptors.

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

pharmaceutical development.

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

Medicine?

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/

GuidanceComplianceRegulatoryInformation/Guidances/

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

Neuropathic Pain

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

via CB

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

Mechanisms

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

2 mechanisms.

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

Descending modulation:

PAG (presynaptic GABAergic,

glutamatergic mechanisms

RVM (ON and OFF cells)

Nociceptive transmission

(VPL, amygdala, anterior

cingulate cortex)

Enteric nervous

system

Gut

Modulation

of propulation

Periphery

Nonneuronal:

CB1,CB2(immune cells,

inflammatory cells,

keratinocytes)

Pruritus

Limbs

Autonomic

Nerve

Vagus

Brain

Cord

Wind-up

Central

sensitization

Nociceptive

transmission

WDR, NS cell;

microglia ( by injury)

Contact dermatitisHyperalgesia

Allodynia

Primary afferent:

CB1;CB2( by injury)

Modulation

of secretion

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

involving CB

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 ] .

Cannabinoid-Opioid Interactions

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

Marinol

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. [

92 ]

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. [

94 ]

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. [

98 ]

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. [

95 ]

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. [

97 ]

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. [

120 ]

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. [

123 ]

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. [

76 ]

Marinol 40 Postoperative pain Single dose/DB No bene ﬁ t observed over placebo/Buggy

et al. [

77 ]

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. [

79 ]

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 [

85 ]

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. [

90 ]

Nabilone 96 Neuropathic pain 14 weeks/DBC vs.

dihydrocodeine

Dihydrocodeine more effective with

fewer AE/Frank et al. [

88 ]

Nabilone 13 Spasticity pain 9 weeks/DBC NRS decreased 2 points for nabilone

( p < 0.05)/Wissel et al. [

87 ]

Nabilone 40 Fibromyalgia 4 weeks/DBC VAS decreased in pain, Fibromyalgia

Impact Questionnaire, and anxiety over

placebo (all, p < 0.02)/Skrabek et al. [

89 ]

Sativex 20 Neurogenic pain Series of 2-week N-of-1

crossover blocks

Improvement with Tetranabinex and

Sativex on VAS pain vs. placebo

( p < 0.05), symptom control best with

Sativex ( p < 0.0001)/Wade et al. [

132 ]

Sativex 24 Chronic intractable pain 12 weeks, series of N-of-1

crossover blocks

VAS pain improved over placebo

( p < 0.001) especially in MS ( p < 0.0042)/

Notcutt et al. [

133 ]

Sativex 48 Brachial plexus avulsion 6 weeks in 3 two-week

crossover blocks

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. [

134 ]

Sativex 66 Central neuropathic pain

in MS

5 weeks Numerical Rating Scale (NRS) analgesia

improved over placebo ( p = 0.009)/Rog

et al. [

135 ]

(continued)

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

pain (Table

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

18.1 )

[ 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

pain

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. [

136 ]

Sativex 56 Rheumatoid arthritis Nocturnal dosing for 5

weeks

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. [

138 ]

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. [

139 ]

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

sessions (Table

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,

and thirst.

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

cannabinoid administration.

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

(Table

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-

ble (Table

18.1 ).

Sativex® is a whole-cannabis-based extract delivered as

an oromucosal spray that combines a CB

1 and CB

2 partial

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

positive (Table

18.1 ). Additionally, an RCT of intractable

lower urinary tract symptoms in MS also demonstrated pain

reduction (Table

18.1 ).

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 [

165 ]

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

a CB

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

selective CB

2 agonist [ 195 ] . a -Pinene inhibits PGE-1 [ 196 ] ,

and linalool acts as a local anesthetic [

197 ] .

19318 Role of Cannabinoids in Pain Management

Summary

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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Computationally Rationalising the Conformational Dynamics of Pseudo-Endocannabinoid Receptors CB1 and CB2 with Cannabidiol

Preprint

Full-text available

Aug 2024

Ikechukwu Achilonu

This study provides a comprehensive analysis of the conformational dynamics of pseudo-endocannabinoid receptors (p-CBRs) CB1 and CB2 in response to ligand binding. The ligands studied include N-arachidonoyl dopamine (NADA), Cannabidiol (CBD), known agonists (FUB-MDMB and E3R), and inverse agonists (Taranabant and AM630). Using homology models based on crystal structures (PDB ID: 5U09 for CB1 and 5ZTY for CB2), molecular docking, and molecular dynamics (MD) simulations, the research validates the structural integrity and dynamic behaviours of these pseudo-receptors. Induced-fit docking revealed NADA as having the highest binding affinity for both receptors, with docking scores of −13.92 kcal/mol for CB1 and −13.32 kcal/mol for CB2, facilitated by key hydrogen bond interactions. MD simulations over 250 ns at ~298 K showed successful equilibration, indicating the most stable interaction for NADA, thereby further validating the models. CB1 and CB2 exhibited distinct conformational responses to ligands, with Cα RMSD and Cα RMSF analyses suggesting a more rigid binding pocket for CB1 and a flexible binding pocket for CB2. These findings highlight the significance of receptor behaviour and dynamics in the development of cannabinoid-based therapeutics, supporting the potential of CBD and NADA as modulators for CB1 and CB2, respectively.

Cannabinoids in neuropathic pain treatment: pharmacological insights and clinical outcomes from recent trials

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N Schmied Arch Pharmacol

Neuropathic pain, a complex and often devastating condition, poses significant challenges for its effective management. Despite promising research on various cannabis formulations and delivery methods for neuropathic pain, significant gaps remain in our knowledge. While inhaled cannabis shows analgesic effects and alternative delivery methods may improve bioavailability, oral formulations have yielded mixed results, often limited by small sample sizes and placebo effects. Therefore, further research is essential to optimize cannabis formulations, identify responder profiles to tailor treatments effectively, and, most critically, confirm the long-term safety and efficacy of cannabis-based therapies in managing NP. This review article aims to provide a comprehensive analysis of the therapeutic potential of cannabis-based medicines, with a particular focus on cannabinoids. This review, though not systematic, examines 11 clinical studies, specifically Randomised Clinical Trials) published from 2014 to 2024, highlighting the efficacy of numerous cannabis formulations, in alleviating neuropathic pain. Key findings show that cannabinoids can reduce pain perception, improve patient quality of life, and mitigate other symptoms associated with neuropathic pain. The synergistic effects of tetrahydrocannabinol and cannabidiol are discussed, emphasizing their ability to enhance analgesic effects, while potentially reducing the psychoactive side effects of tetrahydrocannabinol. This review emphasizes the importance of the personalized approach to improve therapeutic outcomes. Limitations of the existing research focusing on cannabis for neuropathic pain are limited by heterogeneity, lack of standardization, small sample sizes, and reliance on subjective outcomes, impacting the reliability and generalizability of findings. However, this exhaustive review aims to inform clinicians and researchers about the evolving role of cannabis in contemporary pain management strategies, illustrating the diverse pharmacological profiles of cannabinoids and their potential as adjunct therapies for neuropathic pain management.

Recent advances in cannabidiol (CBD) extraction: a review of potential eco-friendly solvents and advanced technologies

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Apr 2025

Cannabinoids, particularly cannabidiol (CBD), have been gaining attention for their numerous potential health benefits and are employed in various industries. However, there are unresolved challenges in CBD extraction including low yields, impurity issues, and environmental concerns, suggesting the requirement for green methods. Hence, our review objectives are to assess the efficacy, and the impact of novel solvents used for CBD extraction, considering green and sustainable techniques. The traditional extraction methods such as maceration and Soxhlet extraction used for CBD extraction have limitations such as low efficiency, long extraction times, high energy consumption, and substantial CO₂ emissions, raising environmental concerns. Emerging green extraction techniques, such as supercritical fluid extraction, deep eutectic solvents, and microwave-assisted extraction, offer promising alternatives by reducing solvent use, minimizing processing time, and enhancing extraction yields. Supercritical CO2 extraction, utilizing supercritical fluids' unique properties offers efficient and safe CBD extraction. Emerging green solvents such as ionic solvents and deep eutectic solvents provide promising alternatives for CBD extraction due to their properties such as no or low toxicity compared to the traditionally used solvents. Pressurized liquid extraction, such as subcritical water extraction, and techniques like microwave-assisted and ultrasonic-assisted extraction provide rapid and efficient alternatives for CBD extraction. To fulfill the growing demand for CBD extracts, future research can aim at developing efficient and sustainable extraction techniques while reducing the potential degradation of CBD, removing impurities produced during extraction, and considering concepts of sustainability and the One Health approach.

Evaluating the effects of Cannabis reform on human security: A comparative case study of Jamaica and Saint Vincent and the Grenadines

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Feb 2025
EVAL PROGRAM PLANN

Stephen Johnson

Human security outcomes of cannabis decriminalisation are important for small island developing states. This study uses a convergent parallel mixed-methods research design and comparative case analysis of Jamaica and St. Vincent and the Grenadines to develop a results matrix to evaluate the human security outcomes of cannabis decriminalisation. The findings indicate that St. Vincent and the Grenadines' context-sensitive approach has been more effective in providing livelihood opportunities for traditional farmers. In comparison, Jamaica's reform, using a people-centred approach and supported by a revised four-point plan, has struggled to integrate traditional farmers into its regulatory framework. Both states demonstrated sensitivity to cannabis use through social justice via expungement legislation, and health security through medical access. However, challenges remain in measuring the impact on health security in St. Vincent and the Grenadines. Biennial surveys capturing key variables can address this deficit by identifying policy gaps and guiding adaptive approaches. The study contributes to the discourse on drug reform and evaluation methodology as the development of a results matrix can assess human well-being and establish benchmarks for evaluating state progress in enhancing human security. The findings offer insights for policymakers, stakeholders, and evaluators to establish a secure cannabis industry aligned with human security principles.

Cannabinoide zur Schmerzbehandlung

Chapter

Jan 2024

CANABIDIOL E SUAS POSSÍVEIS APLICAÇÕES TERAPÊUTICAS NA ODONTOLOGIA UMA REVISÃO DE LITERATURA

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Full-text available

Dec 2024

As propriedades terapêuticas da planta Cannabis sativa L. é de conhecimento popular desde os povos antigos e, devido a mudanças socioculturais, sua utilização para fins terapêuticos foi reduzida. Entretanto, nos últimos anos, a busca por pesquisas científicas sobre esses efeitos terapêuticos e o incentivo de seu uso tem crescido largamente em todo mundo. O objetivo desta revisão bibliográfica é apresentar a história da planta Cannabis com uso medicinal e evidenciar seus benefícios para a odontologia. Com base em artigos encontrados nas plataformas SciELO, Pubmed e Google acadêmico, foram reunidas informações a respeito da trajetória do uso da planta na medicina e como ela interage com o nosso organismo. Deste modo, as evidências demonstram muitos benefícios para odontologia, como tratamentos de mucosites orais, devido ao efeito antioxidante e anti-inflamatório dos derivados da planta, de doenças periodontais, também pelo potencial de combate a inflamação e pela capacidade antimicrobiana e dor orofacial, uma vez que são considerados analgésicos potentes. Em geral, esta coletânea sugere que as substâncias advindas da planta, como o canabidiol, possuem propriedades biológicas promissoras e o crescente interesse nas pesquisas sobre plantas medicinais e seus fitocompostos fomentam a divulgação e os estudos sobre as aplicações da Cannabis sativa L. em odontologia.

Anti-inflammatory effects of phytocannabinoids and terpenes on inflamed Tregs and Th17 cells in vitro

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Aug 2024
Exp Mol Pathol

Cannabidiol plus krill oil supplementation improves chronic stifle osteoarthritis in dogs: A double-blind randomized controlled trial

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Unveiling Colombia's medicinal Cannabis sativa treasure trove: Phenotypic and Chemotypic diversity in legal cultivation

Article

Aug 2024
PHYTOCHEM ANALYSIS

Introduction Cannabis sativa is a highly versatile plant with a long history of cultivation and domestication. It produces multiple compounds that exert distinct and valuable therapeutic effects by modulating diverse biological systems, including the endocannabinoid system (ECS). Access to standardized, metabolically diverse, and reproducible C. sativa chemotypes and chemovars is essential for physicians to optimize individualized patient treatment and for industries to conduct drug‐discovery campaigns. Objective This study aimed to characterize and assess the phytochemical diversity of C. sativa chemotypes in diverse ecological regions of Colombia, South America. Methodology Ten cannabinoids and 23 terpenes were measured using liquid and gas chromatography, in addition to other phenotypic traits, in 156 C. sativa plants that were grown in diverse ecological regions in Colombia, a hotspot for global biodiversity. Results Our results reveal significant phytochemical diversity in Colombian‐grown C. sativa plants, with four distinct chemotypes based on cannabinoid profile. The significant amount of usually uncommon terpenes suggests that Colombia's environments may have unique capabilities that allow the plant to express these compounds. Colombia's diverse climates offer enormous cultivation potential, making it a key player in both domestic and international medicinal and recreational C. sativa trade. Conclusion These findings underscore Colombia's capacity to pioneer global C. sativa production diversification, particularly in South America with new emerging markets.

Miscellaneous Psychotropic Drugs

Chapter

Jul 2024

This chapter includes psychotropic drugs used in veterinary psychiatry that do not belong to the families presented previously. It concerns venlafaxine (anxiolytic), trazodone (anxiolytic, antidepressant, and hypnotic), buspirone (anxiolytic), bupropion (antidepressant, also used in nicotine addiction in humans), methylphenidate (stimulant), NMDA antagonists, including ketamine (anesthetic, analgesic), dextromethorphan, and memantine (both anticompulsive), atomoxetine (stimulant used in the treatment of ADHD in humans), and finally cannabinoids (analgesics and anxiolytics in humans). None of these molecules exist as licensed veterinary medications.

The role of cannabis and cannabinoids in pain management

Chapter

Full-text available

Jan 2001

Ethan Budd Russo

The herb cannabis is derived from the Old World species Cannabis sativa L. Cannabis indica and C. ruderalis may also merit species status. Cannabis has a history as an analgesic agent that spans at least 4000 years, including a century of usage in mainstream Western medicine. Quality control issues, and ultimately political fiat eliminated this agent from the modern pharmacopoeia, but it is now resurgent. The reasons lie in the remarkable pharmacological properties of the herb and new scientific research that reveals the inextricable link that cannabinoids possess with our own internal biochemistry. In essence, the cannabinoids form a system in parallel with that of the endogenous opioids in modulating pain. More important, cannabis and its endogenous and synthetic counterparts may be uniquely effective in pain syndromes in which opiates and other analgesics fail.

Cannabinoid Receptor Agonists Inhibit Glutamatergic Synaptic Transmission in Rat Hippocampal Cultures

Article

Full-text available

Jul 1996

Activation of cannabinoid receptors inhibits voltage-gated Ca ²⁺ channels and activates K ⁺ channels, reminiscent of other G-protein-coupled signaling pathways that produce presynaptic inhibition. We tested cannabinoid receptor agonists for effects on excitatory neurotransmission between cultured rat hippocampal neurons. Reducing the extracellular Mg ²⁺ concentration to 0.1 m m elicited repetitive, transient increases in intracellular Ca ²⁺ concentration ([Ca ²⁺ ] i spikes) that resulted from bursts of action potentials, as measured by combined whole-cell current clamp and indo-1-based microfluorimetry. Pharmacological characterization indicated that the [Ca ²⁺ ] i spikes required glutamatergic synaptic transmission. Cannabinoid receptor ligands inhibited stereoselectively the frequency of [Ca ²⁺ ] i spiking in the rank order of potency: CP 54,939 > CP 55,940 > Win 55,212-2 > anandamide, with EC 50 values of 0.36, 1.2, 2.7, and 71 n m , respectively. CP 55,940 was potent, but not efficacious, and reversed the inhibition produced by Win 55,212-2, indicating that it is a partial agonist. Inhibition of [Ca ²⁺ ] i spiking by Win 55,212-2 was prevented by treatment of cultures with active, but not heat-treated, pertussis toxin. Win 55,212-2 (100 n m ) inhibited stereoselectively CNQX-sensitive excitatory postsynaptic currents (EPSCs) elicited by presynaptic stimulation with an extracellular electrode, but did not affect the presynaptic action potential or currents elicited by direct application of kainate. Consistent with a presynaptic site of action, Win 55,212-2 increased both the number of response failures and the coefficient of variation of the evoked EPSCs. In contrast, cannabimimetics did not affect bicuculline-sensitive inhibitory postsynaptic currents. Thus, activation of cannabinoid receptors inhibits the presynaptic release of glutamate via an inhibitory G-protein.

Plasma Cannabinoid Pharmacokinetics following Controlled Oral Δ-Tetrahydrocannabinol and Oromucosal Cannabis Extract Administration

Article

Full-text available

Nov 2010

Sativex(®), a cannabis extract oromucosal spray containing Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), is currently in phase III trials as an adjunct to opioids for cancer pain treatment, and recently received United Kingdom approval for treatment of spasticity. There are indications that CBD modulates THC's effects, but it is unclear if this is due to a pharmacokinetic and/or pharmacodynamic interaction. Cannabis smokers provided written informed consent to participate in this randomized, controlled, double-blind, double-dummy institutional review board-approved study. Participants received 5 and 15 mg synthetic oral THC, low-dose (5.4 mg THC and 5.0 mg CBD) and high-dose (16.2 mg THC and 15.0 mg CBD) Sativex, and placebo over 5 sessions. CBD, THC, 11-hydroxy-THC, and 11-nor- 9-carboxy-THC were quantified in plasma by 2-dimensional GC-MS. Lower limits of quantification were ≤0.25 μg/L. Nine cannabis smokers completed all 5 dosing sessions. Significant differences (P < 0.05) in maximum plasma concentrations (C(max)) and areas under the curve from 0-10.5 h postdose (AUC(0→10.5)) for all analytes were found between low and high doses of synthetic THC and Sativex. There were no statistically significant differences in C(max), time to maximum concentration or in the AUC(0→10.5) between similar oral THC and Sativex doses. Relative bioavailability was calculated to determine the relative rate and extent of THC absorption; 5 and 15 mg oral THC bioavailability was 92.6% (13.1%) and 98.8% (11.0%) of low- and high-dose Sativex, respectively. These data suggest that CBD modulation of THC's effects is not due to a pharmacokinetic interaction at these therapeutic doses.

Cannabinoids in the management of difficult to treat pain

Article

Full-text available

Feb 2008
Therapeut Clin Risk Manag

Ethan Budd Russo

This article reviews recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms, as well as randomized clinical trials employing canna- binoids in pain treatment. Tetrahydrocannabinol (THC, Marinol ® ) and nabilone (Cesamet ® ) are currently approved in the United States and other countries, but not for pain indications. Other synthetic cannabinoids, such as ajulemic acid, are in development. Crude herbal cannabis remains illegal in most jurisdictions but is also under investigation. Sativex ® , a cannabis derived oromucosal spray containing equal proportions of THC (partial CB 1 receptor agonist ) and can- nabidiol (CBD, a non-euphoriant, anti-infl ammatory analgesic with CB 1 receptor antagonist and endocannabinoid modulating effects) was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis, and in 2007 for intractable cancer pain. Numer- ous randomized clinical trials have demonstrated safety and effi cacy for Sativex in central and peripheral neuropathic pain, rheumatoid arthritis and cancer pain. An Investigational New Drug application to conduct advanced clinical trials for cancer pain was approved by the US FDA in January 2006. Cannabinoid analgesics have generally been well tolerated in clinical trials with acceptable adverse event profi les. Their adjunctive addition to the pharmacological armamentarium for treatment of pain shows great promise.

Clinical endocannabinoid deficiency (CECD): Can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?

Article

Full-text available

Feb 2004
NEUROENDOCRINOL LETT

Ethan Budd Russo

OBJECTIVES: This study examines the concept of clinical endocannabinoid deficiency (CECD), and the prospect that it could underlie the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome, and other functional conditions alleviated by clinical cannabis. METHODS: Available literature was reviewed, and literature searches pursued via the National Library of Medicine database and other resources. RESULTS: Migraine has numerous relationships to endocannabinoid function. Anandamide (AEA) potentiates 5-HT1A and inhibits 5-HT2A receptors supporting therapeutic efficacy in acute and preventive migraine treatment. Cannabinoids also demonstrate dopamine-blocking and anti-inflammatory effects. AEA is tonically active in the periaqueductal gray matter, a migraine generator. THC modulates glutamatergic neurotransmission via NMDA receptors. Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia. Cannabinoids have similarly demonstrated the ability to block spinal, peripheral and gastrointestinal mechanisms that promote pain in headache, fibromyalgia, IBS and related disorders. The past and potential clinical utility of cannabis-based medicines in their treatment is discussed, as are further suggestions for experimental investigation of CECD via CSF examination and neuro-imaging. CONCLUSION: Migraine, fibromyalgia, IBS and related conditions display common clinical, biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines.

Cannabis smoke condensate III: The cannabinoid content of vaporised Cannabis sativa

Article

Jun 2009

Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain: A double-blind placebo-controlled crossover trial

Article

Jan 2006

Enhancement of mu opioid antinociception by oral Delta(9)-tetrahydrocannabinol: Dose-response analysis and receptor identification

Article

May 1999

The antinociceptive effects of various mu opioids given p.o. alone and in combination with Delta-9-tetrahydrocannabinol (Delta(9)-THC) were evaluated using the tail-flick test. Morphine preceded by Delta(9)-THC treatment (20 mg/kg) was significantly more potent than morphine alone, with an ED50 shift from 28.8 to 13.1 mg/kg. Codeine showed the greatest shift in ED,, value when administered after Delta(9)-IHC (139.9 to 5.9 mg/kg). The dose-response curves for oxymorphone acid hydromorphone were shifted 5- and 12.6-fold, respectively. Methadone was enhanced 4-fold, whereas its derivative, I-alpha-acetylmethadol, was enhanced 3-fold. The potency ratios after pretreatment with Delta(9)-THC for heroin and meperidine indicated significant enhancement (4.1 and 8.9, respectively). Pentazocine did not show a parallel shift in its dose-response curve with Delta(9)-THC. Naloxone administration (1 mg/kg s.c.) completely blocked the antinociceptive effects of morphine p.o. and codeine p.o. The Delta(9)-THC-induced enhancement of morphine and codeine was also significantly decreased by naloxone administration. Naltrindole (2 mg/kg s.c.) did not affect morphine or codeine antinociception but did block the enhancement of these two opioids by Delta(9)-THC. No effect was seen when nor-binaltorphimine was administered 2 mg/kg s.c. before morphine or codeine. Furthermore, the enhancements of morphine and codeine were not blocked by nor-binaltorphimine. We find that many mu opioids are enhanced by an inactive dose of Delta(9)-THC p.o. The exact nature of this enhancement is unknown. We show evidence of involvement of mu and possibly delta opioid receptors as a portion of this signaling pathway that leads to a decrease in pain perception.

Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb (vol 30, pg 515, 2009)

Article

Dec 2009
TRENDS PHARMACOL SCI

Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of Delta(9)-tetra hydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetra hydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.

Phytomedicines in Western Europe

Chapter

May 1993

Varro E. Tyler

Role of Cannabinoids in Pain Management

Abstract and Figures

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