Cannabinoids as Alternatives to Opioids in Pain Management Part 2:
Myron Yaster MD and Vidya Chidambaran MD, MS
The search for alternatives to opioid therapies has become a health care priority. In yesterday’s PAAD we discussed the molecular biology of cannabinoids and their potential role as opioid alternatives in acute and chronic pain management. Today 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 opioids, 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
“The main principle of peripheral neuromodulation involves the application of electrical stimulation on the peripheral nerves to achieve therapeutic effects, including analgesia”.1 This stimulation occurs either directly, peripheral nerve stimulation (PNS) by placing electrodes near the target nerves, or transcutaneously through intact skin (TENS), or percutaneously (PENS) using acupuncture like needles, or via ultrasound guided percutaneous PNS (pPNS). When TENS is applied to an acupoint, it is referred to as transcutaneous acupoint electrical stimulation (TEAS). Several reports of long-term effects with PNS have been described in literature in the context of post-surgical pain (for example, sciatic – femoral pPNS for total knee arthroplasty to radial (LI4) TEAS for lower abdominal surgery and chronic pain conditions. In adult patients PNS is increasingly being used in chronic back pain.
In theory, peripheral nerve stimulation works by Melzack and Walls Gate theory of pain control.2 Nociceptive transmission via Aδ and C fibers can be interfered with by nonpainful stimuli on Aβ fibers, with the spinal dorsal horn as the “gate” to suppress pain transmission to the brain. However, this does not explain systemic analgesia or pain relief in other dermatomal areas that is seen with peripheral neuromodulation. Endogenous opioids may also be released with PNS within the brain and the descending pain inhibitory pathways (Peri-Aqueductal Gray (PAG), rostral ventromedial medulla (RVM) and spinal cord) producing naloxone sensitive pain relief. Again, not all the analgesia is naloxone reversible leading to the possibility on non-opioid mechanisms such as endogenous cannabinoids (eCB). eCB act at the CB1 receptors which are located in the same pain inhibitory pathways as the opioid receptors, and may modulate analgesia when neuromodulation with PNS, TENS or acupuncture are used.
Finally, peripheral neuromodulation may also involve an interaction between endogenous cannabinoids (eCBs) and the orexin system (hypocretin). The orexin system consists of two hypothalamic neuropeptides, orexin-A and orexin-B, and two receptors, OX1 and OX2. Orexins are well known to be involved in arousal, hormonal, metabolic and cardiovascular functions and also in pain regulation.1, 3, 4 Many of you know that orexins are involved in appetite stimulation and sleep/arousal. Their absence results in weight loss and narcolepsy.
As you may recall, in yesterday’s PAAD we discussed eCBs. In brief, “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 which are synthesized in postsynaptic neurons and travel retrograde to activate presynaptic cannabinoid CB1 receptors to inhibit neurotransmitter (GABA) release. The synthesis and degradation of these two eCBs are enzymically regulated.”1
“When orexin neurons in the lateral hypothalamus are activated by acute stress or median nerve stimulation at PC6 acupoint (MNS-PC6), orexins are released in the periaqueductal grey (PAG) to activate postsynaptic OX1 receptors, a GqPCR, resulting in the synthesis of the endogenous cannabinoid, 2-AG via a phospholipase C (PLC)–diacylglycerol lipase (DAGL) enzymatic pathway. 2-AG then produces retrograde inhibition of GABA release by activating CB1 receptors on GABAergic terminals, leading to disinhibition of the PAG excitatory neurons that project to the rostral ventromedial medulla (RVM). The activated RVM, in turn, sends inhibitory inputs to the spinal cord, culminating in the activation of the descending pain inhibitory pathway that is constituted by the PAG–RVM–spinal cord circuit and ultimately leading to analgesia”.1
In summary, the endocannabinoids (especially CB1 Positive Allosteric Modulators (PAM)) may become increasingly important in the treatment of acute and chronic pain AND limit opioid dose escalation and the development of tolerance. Further, neuromodulation of the descending pain inhibition pathways which involve endogenous opioids, orexin and cannabinoid pathways are increasingly becoming important as alternative non-pharmacologic treatments in chronic and resistant post-surgical pain.
Do you have clinical patient or personal experiences with these therapies in the management of acute, chronic, or persistant pain? If you do 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. Melzack R, Wall PD. Pain mechanisms: a new theory. Science. 11/19/1965 1965;150(699):971-979. Not in File.
3. Li S-B, de Lecea L. The hypocretin (orexin) system: from a neural circuitry perspective. Neuropharmacology. 2020/05/01/ 2020;167:107993. doi:https://doi.org/10.1016/j.neuropharm.2020.107993
4. Chiou LC, Lee HJ, Ho YC, et al. Orexins/hypocretins: pain regulation and cellular actions. Current pharmaceutical design. 2010;16(28):3089-100. doi:10.2174/138161210793292483