Table 2.
Synopsis of data collected from 25 studies on NSAIDs and cannabinoid system interactions
| No. | Cyclooxygenase pathway (prostaglandins precursors, prostaglandins, COX inhibitors) | Cannabinoid (agonists, antagonists) administered | Experimental method used | The results of the study | Discussion | Authors |
|---|---|---|---|---|---|---|
| 1 | Indomethacin (p.o.) | delta9–THC delta9–THC–11–oic acid (p.o.) | The hot plate test (in mice) | 10 min after delta9–THC administration, a pronounced hyperalgesia was seen. Hyperalgesia could be inhibited by prior administration of either indomethacin or delta9–THC–11–oic acid. | The metabolite delta9–THC–11–oic acid inhibited eicosanoid synthesis whereas the parent drug (delta9–THC) elevated tissue levels of prostaglandins | Burstein SH, et al FASEB J. 1988 Nov;2(14):3022–6. [12] |
| 2 | Ibuprofen, aspirin, sulindac, acetaminophen, ketoprofen, naproxen | Rat cerebellar membrane preparation | The potency of ibuprofen as an inhibitor of anandamide metabolism was of the same magnitude as required for inhibition of COX2. Aspirin, sulindac, acetaminophen, ketoprofen and naproxen did not inhibit the anandamide metabolism. | The metabolism of anandamide might be affected, following the therapeutic doses of ibuprofen. | Fowler CJ, et al. Pharmacol Toxicol. 1997 Feb;80(2):103–7 [13] | |
| 3 | Indomethacin (i. th.) | HU–210 (p.o. and i.th.) | Tail flick and formalin test (in mice) Spinal microdialysis | Indomethacin reduced the HU 210 effect on pronociceptive prostaglandins production but did not potentiate the analgesic effect of HU–210 | HU–210 showed analgesic properties that are independent of its influence on the prostaglandin pathway. | Guhring H, et al. Eur J Pharmacol. 2001 Oct 19;429(1–3):127–34 [14] |
| 4 | Aspirin, indomethacin, celecoxib, ketorolac, acetaminophen diclofenac (p.o.) | delta9–THC, anandamide, arachidonic acid, ethanolamine, methanandamide, SR141716A,SR144528(i.p.) | The phenylbenzo–quinone writhing test (in mice) | After chronic treatment with delta9–THC the analgesic effect of diclofenac and acetaminophen decreased while the effect of aspirin, indomethacin, celecoxib, ketorolac was not detected. Chronic treatment with methanandamide did not alter the analgesic effects of the NSAIDs tested. Neither SR141716A, SR144528 blocked the effects of the NSAIDs tested. | The alteration of NSAIDs effects was not due to chronic administration of delta9–THC and might be due to pharmacokinetic mechanisms (some metabolites of delta9–THC might interfere with NSAIDs). Also it was stated that NSAIDs are not acting directly or indirectly at either the CB1R or CB2R. | Anikwue R, et al J Pharmacol Exp Ther. 2002 Oct;303(1):340–6 [15] |
| 5 | Indomethacin Prostaglandin E2(i. th) | AM251 (i.th.) | The formalin test (in spinally micro–dialyzed mice) | Indomethacin–induced analgesia was reversed by co–administration of AM251, but not by co–infusion of prostaglandin E2. | Indomethacin might acted by stimulation of CB1R or by increasing the level of endocannabinoids | Guhring H, et al. Eur J Pharmacol. 2002 Nov 15;454(2–3):153–63 [16] |
| 6 | Prostaglandin E2 Flurbiprofen (i. th) | AM251 (i. th) | The formalin test (in rats) | The analgesic effect of flurbiprofen (i.th.) was reversed by the co–administration of AM–251, but not by prostaglandin E2 | Endocannabinoids played a major role in mediating flurbiprofen–induced analgesia | Ates M, et al. Eur J Neurosci. 2003 Feb;17(3):597–604 [17] |
| 7 | Flurbiprofen Prostaglandin E2 (i.th.) | delta9– THC AM251 (i.th.) | The spinal super–perfusion model (in rats) | delta9 THC inhibited capsaicin induced CGRP release. Similarly, flurbiprofen inhibited spinal CGRP release. This inhibition was reversed by AM–251, but not by co–administration of prostaglandin E2 | The mechanism for flurbiprofen inhibitory effect on spinal CGRP release might be the shift of arachidonic acid metabolism towards endocannabinoids formation | Seidel K, et al. Neurosci Lett. 2003 Feb 27;338(2):99–102 [18] |
| 8 | Acetaminophen | Tissue Homogenate Experiments (Rat Purified FAAH Enzyme Assay, etc) | Acetaminophen, following deacetylation to p– aminophenol, was conjugated with arachidonic acid (FAAH dependent) to form the potent TRPV1 agonist AM404 that inhibited purified COX–1 and COX–2 and synthesis of prostaglandins | The study provided a molecular mechanism for the occurrence of the analgesic metabolite AM404 in the nervous system following treatment with acetaminophen | Hogestatt ED, et al. J Biol Chem. 2005 Sep 9;280(36):31405–12 [19] | |
| 9 | Ketorolac (s.c) | WIN55,212–2 (s.c.) | The acetic acid–induced–writhing test (in mice) | WIN 55,212–2 and ketorolac either alone or in combination produced dose dependent analgesia in the writhing test. | Isobolographic analysis showed additive interactions between WIN 55,212–2 and ketorolac. | Ulugol A, et al. Anesth Analg. 2006 Feb;102(2):443–7 [20] |
| 10 | Acetaminophen (p.o) | AM281 SR141716A (i.p.) | The hot plate test in rats | The analgesic activity of acetaminophen is antagonized by AM281 and SR 141716A | Paracetamol–induced analgesia might involve the cannabinoid system. | Ottani A, et al. Eur J Pharmacol. 2006 Feb 15;531(1–3):280–1 [21] |
| 11 | Ibuprofen (i.pl.) | Anandamide (i.pl.) AM251 AM630 | the formalin test (in rats) | Analgesic interaction between anandamide and ibuprofen was synergistic and completely antagonized by AM251 but only partially inhibited by AM630. | The combination of anandamide with ibuprofen produced synergistic analgesic effects involving both cannabinoid CB1R and CB2R. | Guindon J, et al. Pain. 2006 Mar;121(1–2):85–93 [22] |
| 12 | Ibuprofen Rofecoxib (in the hind paw) | Anandamide AM251 AM630 (in the hind paw) | Evaluation of mechanical allodynia and thermal hyperalgesia in neuropathic rats | Anandamide, ibuprofen, rofecoxib and their combinations significantly decreased mechanical allodynia and thermal hyperalgesia. The effects of these NSAIDs were not antagonized by AM251 or AM630. | Locally injected anadamide, ibuprofen, rofecoxib and their combinations decreased pain behavior in neuropathic animals. | Guindon J and Beaulieu P. Neuropharmacology. 2006 Jun;50(7):814–23 [23] |
| 13 | Acetaminophen (i.p.) | SR141716A SR144528 (i.p.) | The phenylbenzoquinone writhing test (in mice) | Analgesic effects of acetaminophen were not blocked by SR141716A and SR144528. | Acetaminophen in this test produced analgesia via a non–CB1, non–CB2 pain pathway | Haller VL, et al. Eur J Pharmacol. 2006 Sep 28;546(1–3):60–8 [24] |
| 14 | Arahidonic acid (i.v.) | Anandamide SR141716A (i.v.) | Tetrad model in mice (tests for analgesia, sedation, hypothermia and catalepsy) | Arachidonic acid produced the same profile of effects in tertrad as anandamide but neither substance was blocked by SR141716A. | The failure of SR141716A to antagonize the in vivo effects of anandamide suggested that non CB1R might be involved. | Wiley JL, et al. Life Sci. 2006 Dec 3;80(1):24–35 [25] |
| 15 | Ibu am–5 (the 6–methyl–pyridin–2–yl analogue of ibuprofen) | Tissue homogenate experiments or intact cell assays (in rats) | The compound Ibu am–5 inhibited rat brain anandamide hydrolysis by FAAH in a non–competitive manner. Ibu am–5 inhibited the binding of [3H]–CP55,940 to rat brain CB1Rs and to human CB2Rs more potently than ibuprofen. | The compound may be useful for the study of the therapeutic potential of combined fatty acid amide hydrolase–cyclooxygenase inhibitors. | Holt S, et al. Eur J Pharmacol. 2007 Jun 22;565(1–3):26–36 [26] | |
| 16 | NS–398, indomethacin, acetaminophen, SC–560 (intracisternal) | WIN55,212–2 (intracisternal) | Intra–articular injection of formalin in temporomandibular joint (in rats) | An ineffective dose of WIN 55,212–2 in producing analgesia by intracisternal administration became effective following intracisternal administration of NS–398, indomethacin, acetaminophen, but not following SC–560. | Potentiation of WIN55212–2 with a selective COX–2 inhibitor, indomethacin, or acetaminophen was observed. | Ahn DK, et al. Pain. 2007 Nov;132(1–2):23–32. [27] |
| 17 | Acetaminophen (I pl) | AM251 AM630 (I pl) | Evaluation of mechanical allodynia and hyperalgesia in neuropathic rats | Acetaminophen decreased mechanical allodynia and hyperalgesia dose–dependently. These effects were inhibited by the administration of AM251 and AM630 | The study suggested the implication of the endocannabinoid system in analgesia produced by acetaminophen | Dani M, et al. Eur J Pharmacol. 2007 Nov 14;573(1–3):214–5 [28] |
| 18 | Indomethacin (chronic treatment) (s.c.) | SWIN55,212–2 AM1241 Met–F–AEA (chronic treatment) (i.p.) | Streptozotocin (STZ)–induced neuropathic pain model | Chronic pretreatment with indomethacin progressively increased the analgesic effects of low doses of WIN 55,212–2, AM1241 and Met–F–AEA. | Indomethacin might potentiate the low doses of CB1 and CB2 agonists | Bujalska M. Pharmacology. 2008;82(3):193–200 [29] |
| 19 | Acetaminophen (p.o) | AM251 (i.p.) URB597 (i.p.) PMSF (s.c.) | thermal, mechanical and chemical pain tests | AM251 abolished the analgesic action of acetaminophen; inhibition of FAAH suppressed the analgesic effect of acetaminophen. | Two steps in acetaminophen–induced analgesia could be: FAAH–dependent metabolism of acetaminophen into AM404 and indirect involvement of AM 404 on CB1R stimulation. | Mallet C, et al. Pain. 2008 Sep 30;139(1):190–200. [30] |
| 20 | Diclofenac (s.c.) | URB597 (s.c.) | The acetic acid–induced writhing test (in mice) | Combinations of URB597 and diclofenac showed synergistic analgesic interactions. | According to isobolographic analysis, URB 597 and diclofenac acted synergistically in the writhing test | Naidu PS, et al. J Pharmacol Exp Ther. 2009 Apr;329(1):48–56. [31] |
| 21 | Acetaminophen (i.p.) morphine (s.c.), gabapentin(s.c.) and their combination | AM251 AM630 (s.c.) | The measure of hind paw hypersensitivity after acute compression of the mid–thoracic spinal cord | Pre–treatment with AM251 significantly diminished the analgesic effect of the acetaminophen + gabapentin combination. Both AM251 and AM630 reduced the efficacy of the acetaminophen + morphine combination. | Modulation of the endocannabinoid system might mediate the synergistic analgesic effects of acetaminophen combinations | Hama AT and Sagen J. Neuropharmacology. 2010 Mar–Apr;58(4–5):758–66. [32] |
| 22 | Aspirin (i.p.) | HU210 (i.p.) | hot–plate and formalin tests (in rats) | Low doses of HU210 significantly increased the analgesic effect of the sub–active dose of aspirin. SR141716A was ineffective per se and failed to modify analgesia induced by the HU210 plus aspirin combination. | Mutual potentiation of the analgesic effects of HU210 and aspirin might depend on an indirect participation of cannabinoid mechanism. | Ruggieri V, et al. Life Sci. 2010 Mar 27;86(13–14):510–7 [33] |
| 23 | R–flurbiprofen | Spinal cord microdialysis, after sciatic nerve injury in rats | R–flurbiprofen reduced glutamate release in the dorsal horn of the spinal cord evoked by sciatic nerve injury; also inhibited FAAH activity. | R–flurbiprofen improved the endogenous mechanisms to fend off the chronic neuropathic pain. | Bishay P, et al. PLoS One. 2010 May 13;5(5):e10628. [34] | |
| 24 | Nimesulide (i.th.) | AM251 (i.th.) | Evoked responses of rat dorsal horn neurons in rats Spinal micro–dialysis | Spinal, but not peripheral, injection of nimesulide significantly reduced mechanically evoked responses of dorsal horn neurons that were blocked by AM251. Spinal levels of endocannabinoids were not elevated. | Responses to nimesulide were dependent on CB1R, without an implication of anandamide or 2–AG. | Staniaszek LE, et al. Br J Pharmacol.2010 Jun;160(3):669–76. [35] |
| 25 | Ibuprofen (i.p.) associated with acetaminophen (p.o) | AM281 (i.p.) | Acetic acid writhing test and hot plate test (in mice) | Additive analgesic effect in writhing test and potentiation in hot plate test. Adding AM281 the additive effect in writhing test is decreased and the potentiation in hot plate test disappeared | Influencing the cannabinoid system might be responsible for a part of analgesic effect of acetaminophen–ibuprofen combinations | Costescu M, et al Basic and Clinical Pharmacology and Toxicology. 2010, 107, Suppl. 1, 1: 243 [35] |