Cannabinoids as Alternatives to Opioids in Pain Management
Myron Yaster MD and Vidya Chidambaran MD, MS
What are the opioid-induced side effects that cause you and your patients the most trouble? Respiratory depression? For society, sure. GI side effects like nausea, vomiting, and constipation? Ditto, particularly in the management of acute pain. Addiction/dependence? Again, absolutely. To pain specialists though, particularly those taking care of chronic or persistent post-surgical pain, tolerance and unresolved pain are amongst the most important.
To minimize some of these side effects, several non-opioid drugs are being used and/or co-administered including cannabinoids, despite inconclusive or negative findings in their benefit and risk analysis. Indeed, there are tons of patient testimonials to the beneficial efficacy of using cannabinoids in pain management. Unfortunately, clinical trials have been much less supportive. Today, we are going to focus on the molecular basis of why cannabinoids may work. I know that for many of you, just mentioning molecular biology, G Protein Coupled Receptors, and descending pain inhibitory pathways (Peri-Aqueductal Gray (PAG), rostral ventromedial medulla (RVM) and spinal cord), causes your eyes to glaze over and invoke nightmares of the coagulation cascade…Trust me, today’s article is worth your effort and should be discussed in much greater detail in the OR, on pain rounds, and in your journal clubs than Vidya and I can achieve in a PAAD. To make this bite of the apple more tasty (tolerable), we are going to break it into two parts. Today we will discuss the potential synergy of using cannabinoids with opioids. Tomorrow, we will discuss peripheral neuromodulation and how endogenous cannabinoids interact with these alternative pain therapies…think acupuncture, TENS, etc. Hopefully, these PAADs will be your entre into the science of how opioids and alternatives to opioid like the cannabinoids, work. Myron Yaster MD
Original article
Lee MT, Mackie K, Chiou LC. Alternative pain management via endocannabinoids in the time of the opioid epidemic: Peripheral neuromodulation and pharmacological interventions. Br J Pharmacol. 2023 Apr;180(7):894-909. PMID: 34877650
Opioids do their magic by binding to the opioid receptor family of receptors: mu, kappa, delta, and the nociceptin opioid (NOP) receptor. The mu is the most important opioid receptor and once activated neuronal inhibition occurs along the descending pain inhibitory pathway (Peri-Aqueductal Gray (PAG), rostral ventromedial medulla (RVM) and spinal cord). Activation, via Gi/o protein activation, leads to inhibition of adenylyl cyclase, activation of K+ channels and inhibition of Ca2+ channels which hyperpolarize the cell membranes of neurons and thereby prevent pain transmission. Interestingly, cannabinoids share the same cellular action mechanisms and a similar regional distribution in the descending pain inhibitory pathway. Hmmm…this overlap should/must have clinical implications for synergy.
You are all aware of mu agonists which we use therapeutically every day, like morphine, fentanyl, and oxycodone. Unless you live in states in which marijuana is legal, like Colorado, you may be less familiar with the cannabinoids, which include phytocannabinoids derived from marijuana and hemp, synthetic cannabinoids, and endogenous (ligand) cannabinoids (eCBs), which produce their physiologic effects by binding to CB1 and CB2 receptors in the descending pain inhibitory pathways mentioned above. Unfortunately, because marijuana remains a DEA federally classified schedule I drug, its use in medical practice remains very limited and many clinical trials using federal marijuana strains remain significantly flawed.
How do endogenous cannabinoids work? “Unlike classical neurotransmitters that are pre-synthesized, stored in vesicles of nerve terminals and are rapidly released following increases of intra-cellular calcium in nerve terminals. Anandamide (AEA) and 2-arachidononylglycerol (2-AG) are two major eCBs and are synthesized in postsynaptic neurons and travel retrograde to activate presynaptic cannabinoid CB1 receptors to inhibit neurotransmitter release. The synthesis and degradation of these two eCBs are enzymically regulated.”1 Inhibition of the degradation enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) for AEA and 2-AG, respectively prolongs the effects of the eCBs and are therefore targets of drug development.
In the laboratory, activation of the cannabinoid system results in pain relief and just like the opioids, repeated activation can result in tolerance. Concurrent activation of μ-receptors and CB1 receptors synergistically induce analgesia in preclinical laboratory studies. Co-administration theoretically could produce an opioid-sparing effect and reduce the development of tolerance. Although this synergy does occur in the laboratory, human clinical trials have been, well, underwhelming for acute, chronic, or cancer related pain.2, 3 “Furthermore, a history of cannabis use may actually increase the tendency of inpatient opioid use”.1, 4 In fact, clinical studies with FAAH inhibitors either did not show significant analgesia (Phase II trial in patients with osteoarthritic pain)5 or was terminated early due to side effects (you may remember the BIA 10-2474 trial associated with death of one participant and morbidity in others due to faulty research methods and non-FAAH target effects).6 Another novel pharmacological alternative worth mentioning is a positive allosteric modulator (PAM) of CB1 receptors which shows promise in animal studies to enhance eCB-CB1 receptor transmission at low or normal levels of eCBs, thus minimizing the occurrence of tolerance. We would urge all of you to keep your eyes and PAAD open as more and more studies are being performed to figure this out.
In tomorrow’s PAAD we will discuss peripheral neuromodulation and non-pharmacologic treatments in the management of pain. Have you had personal or professional experience using cannabinoids in the treatment of pain? Please send your responses to Myron who will post in the Friday Reader Response.
References
1. Lee MT, Mackie K, Chiou L-C. Alternative pain management via endocannabinoids in the time of the opioid epidemic: Peripheral neuromodulation and pharmacological interventions. British journal of pharmacology. 2023;180(7):894-909. doi:https://doi.org/10.1111/bph.15771
2. Babalonis S, Lofwall MR, Sloan PA, Nuzzo PA, Fanucchi LC, Walsh SL. Cannabinoid modulation of opioid analgesia and subjective drug effects in healthy humans. Psychopharmacology. 2019/11/01 2019;236(11):3341-3352. doi:10.1007/s00213-019-05293-1
3. Okusanya BO, Asaolu IO, Ehiri JE, Kimaru LJ, Okechukwu A, Rosales C. Medical cannabis for the reduction of opioid dosage in the treatment of non-cancer chronic pain: a systematic review. Systematic reviews. 2020/07/28 2020;9(1):167. doi:10.1186/s13643-020-01425-3
4. Dalal RS, Palchaudhuri S, Snider CK, Lewis JD, Mehta SJ, Lichtenstein GR. Preadmission Cannabis Use Is Positively Correlated With Inpatient Opioid Dose Exposure in Hospitalized Patients With Inflammatory Bowel Diseases. Inflammatory bowel diseases. 2020;27(4):500-506. doi:10.1093/ibd/izaa104
5. Huggins JP, Smart TS, Langman S, Taylor L, Young T. An efficient randomised, 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. 2012;153(9):1837-1846. doi:10.1016/j.pain.2012.04.020
6. Kaur R, Sidhu P, Singh S. What failed BIA 10–2474 Phase I clinical trial? Global speculations and recommendations for future Phase I trials. Journal of Pharmacology and Pharmacotherapeutics. 2016;7(3):120-126. doi:10.4103/0976-500x.189661