AJA Asian Journal of Anesthesiology

Advancing, Capability, Improving lives

Editorial View
Volume 51, Issue 4, Pages 139-140
Hui-Bih Yuan 1 , Shung-Tai Ho 1
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Outline



Cannabinoids (CBs) are lipophilic compounds derived from cannabis. The major psychotropic CB delta-9-tetrahydrocannabinol was isolated in 19641 and the first CB receptor (CB1R) was discovered in 1990.2 CB signaling occurs via G-protein-coupled CB1Rs distributed throughout the body. Central neuronal CB1Rs modulate synaptic transmission and mediate psychoactivity including dysphoria, memory impairment, reduced concentration, disorientation, and motor incoordination.3 The second receptor (CB2R) was discovered in 1993.4 The distribution of CB2R is localized to the immune system such as mast cells, macrophages, and microglias, and it is thought to have immunosuppressive and anti-inflammatory activities.5 In parallel to opioid research, the discovery of endogenous CBRs led to the identification of endogenous cannabinoid or endocannabinoids (eCBs). They are rapidly synthesized de novo from postsynaptic membrane-lipid precursors by the stimulation of presynaptic neurotransmitter release; eCBs act as retrograde neurotransmitters, hyperpolarizing the presynaptic terminal and thus reducing further anterograde neurotransmitter release.3 The eCB system may further be manipulated by inhibitors of eCB hydrolysis or those of the putative CB re-uptake transporter.

Pain is a complex perception and there are several points in pain pathways on which CBs may exert actions. CBRs are found in all the nociceptive neuroanatomical pathways described. The principal actions of CB1R are to decrease presynaptic intracellular calcium concentrations and activate inward-rectifying potassium channels, thereby depressing neuronal excitability and reducing transmitter release. Peripheral CB1R normally mediates an inhibitory tone on nociceptive activity. Central CB1Rs may participate in descending supraspinal pain modulation via the midbrain periaqueductal gray and rostral ventromedial medulla. Analgesia may occur via presynaptic inhibition of GABAergic interneurons within the midbrain periaqueductal gray, which tonically inhibit descending antinociceptive pathways. Thus, CBs can modulate the activity of intrinsic on and off cells, thus controlling descending pain pathways in a manner similar to morphine.3

In an article in this issue of the Journal, Chiou et al6 presents a thorough review on the role of the CB system in pain relief. The current analgesic potential of CB agonists in humans is limited by unwanted psychoactivity, which is mediated by neuronal CB1R. Because CB2Rs are found mainly outside the central nervous system (CNS) and certain selective CB2R agonists have been shown to have antinociceptive properties, targeted CB2R activation may therefore have the merit of lacking CB1R-mediated CNS side effects. Anandamide and 2-arachidonoylglycerol are two intensively studied eCBs. They are synthesized on demand and are degraded rapidly. Thus, inhibitors of their degradative enzymes, fatty acid amide hydrolase and monoacylglycerol lipase, respectively, may be superior to direct CBR agonists as other promising targets for pain relief. All the above approaches were verified in various animal pain models but not in human clinical trials. AZD1940, a peripherally acting CB1R/CB2R agonist, did not show analgesic efficacy in the capsaicin pain model of 44 male healthy volunteers aged 20–45 years.7 Another clinical trial conducted by Eli Lilly, Indianapolis, IN, US, using a CB2R agonist Ly-2828360 for the treatment of osteoarthritis of knee, also failed to meet the primary endpoint.8 The outcome of the first Phase II clinical trial of PF-04457845, an irreversible fatty acid amide hydrolase inhibitor developed by Pfizer Global Research and Development, Sandwich, UK, once more had contradictory results from animal studies. Huggins and coworkers9 reported in Pain (2012) that, in a randomized, placebo-controlled study, chronic administration of PF-04457845 to patients with pain due to osteoarthritis of the knee, despite being very well tolerated overall and elevating the plasma levels of the eCBs significantly, failed to produce analgesia. No wonder, Chiou et al6 used a question mark in the title of their review article “Targeting the cannabinoid system for pain relief?”

At this time, sufficient data are not available to support a widespread use of the currently available CBs for analgesia. CBs are recommended only as a second-line therapy for pain and spasticity in multiple sclerosis patients. Sativex has received limited approval for the treatment of cancer pain and neuropathic pain in Canada. Possible psychotropic side effects, risk of abuse/dependence, and precipitation of psychotic disorders especially in younger adults limit the medical use of CBs. Although adverse effects of CBs in short-term use seem to be modest, research is needed to evaluate their adverse effects, including potential risk of infection, immunosuppression, and cancer, in case of long-term medical use. Analgesic effects of CBs are not sufficient for the management of severe pain conditions. Many clinical trials have provided negative or equivocal results. However, their other neurologic effects may be beneficial when used as coanalgesics or adjuvants for multimodal therapeutic approaches for individual patients or certain types of patient groups. Further studies also are warranted on CB synergism with opioid analgesics or non-steroidal anti-inflammatory drug (NSAID). Advances in cannabis research should ensure a future for these analgesics. However, there is still a long way to go to use cannabis as pain medicine.


References

1
Y. Gaoni, R. Mechoulam
Isolation, structure and partial synthesis of an active constituent of hashish
J Am Chem Soc, 86 (1964), pp. 1646-1647
2
L.A. Matsuda, S.J. Lolait, M.J. Brownstein, A.C. Young, T.I. Bonner
Structure of a cannabinoid receptor and functional expression of the cloned cDNA
Nature, 346 (1990), pp. 561-564
3
R.D. Hosking, J.P. Zajicek
Therapeutic potential of cannabis in pain medicine
Br J Anaesth, 101 (2008), pp. 59-68
4
S. Munro, K.L. Thomas, M. Abu-Shaar
Molecular characterization of a peripheral receptor for cannabinoids
Nature, 365 (1993), pp. 61-65
5
J.M. Walker, S.M. Huang
Cannabinoid analgesia
Pharmacol Ther, 95 (2002), pp. 127-135
6
L.C. Chiou, S.S.J. Hu, Y.C. Ho
Targeting the cannabinoid system for pain relief?
Acta Anaesthesiol Taiwan, 51 (2013), pp. 161-170
7
K. Huizar, C. Clarke, A. Zettergren, R. Karlsten, M. Segerdahl
Evaluation of the analgesic efficacy and psychoactive effects of AZD1940, a novel peripherally acting cannabinoid agonist, in human capsaicin-induced pain and hyperalgesia
Clin Exp Pharmacol Physiol, 40 (2013), pp. 212-218
8
A. Pereira, A. Chappell, J. Dethy, H. Hoeck, L. Arendt-Nielsen, S. Verfaille, et al.
A proof-of-concept (POC) study including experimental pain models (EPMs) to assess the effects of a CB2 agonist (LY2828360) in the treatment of patients with osteoarthritic (OA) knee pain
Clin Pharmacol Ther, 93 (2013), pp. s56-s57
Article  
9
J.P. Huggins, T.S. Smart, S. Langman, L. Taylor, T. Young
An efficient randomized, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee
Pain, 153 (2012), pp. 1837-1846

References

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