Farmakologiska kopplingar mellan petidin och prometazin

Fråga: Denna patient har haft ont i under höger arcus sedan galloperation för 5 år sedan. Orsaken till smärtan är okänd. Farmakologiskt hjälper bara petidin och prometazin (Prometazinhydrochloride injections). Tidigare hjälpte lidokaininjektioner.<br><br>Frågor: Finns det några farmakologiska kopplingar mellan petidin och prometazin? Förslag på läkemedel eller mekanismer som hypotetiskt kan öka möjligheterna att förstå situationen. Svaren kan vara av spekulativ karaktär då vi gärna vill ha ideér om hur man kan tänkas hjälpa patienten.

Svar: <br><b>SAMMANFATTNING</b><br><br>The property of decreasing intracellular cAMP and subsequently inhibiting the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline - which is considered to be the major effect of opioids in the nervous system - is partially shared by antihistamines like promethazine.<br><br><b>SVAR</b><br><br><b>Pethidine</b><br><br>Primary sensory neurons involved in pain sensation release predominantly substance P and glutamate in the dorsal horn of the spinal cord (1). The presynaptic action of opioids to inhibit neurotransmitter release is considered to be their major effect in the nervous system. Opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited (1, 2).<br> <br><b>Antihistamines</b><br><br>Antihistamines has been suggested to have direct analgesic activity (3). The exact mechanism of action for the analgesic action of antihistamines is unknown. However, many opioid and non-opioid mechanisms have been proposed. <br> <br>Activation of cyclic nucleotide, which acts as a second messenger in histaminergic neurotransmission, appears to be a possible mechanism for antihistaminic analgesia (4). Histamine is one of the most potent agents in stimulating cAMP accumulation into brain regions in animals and man. H1 antihistamines partially antagonize the histamine-induced stimulation of cAMP (4). Antihistamines might also augment the release of cyclic GMP, a CNS regulator of analgesia, which could then act as a central analgesic (3-5). <br> <br>Inhibition of substance P, an excitatory transmitter of pain pathways, and phospholipase A2, an intermediate for prostaglandin release and pain receptor sensitization, has been suggested (4). <br> <br>It has been suggested that antihistamine drugs can modulate the responses of the histaminergic and serotoninergic central pathways that are involved in nociception (4). It is known that histamine can stimulate nociceptors, and the serotoninergic system is also involved in the regulation of nociception. Antiserotonin activity has been observed at higher dose levels for promethazine.<br> <br>Antihistamines are known to possess anticholinergic effects and a cholinergic mechanism has a role in analgesia. In rats, antimuscarinic activity was observed at low dose levels for promethazine (4).<br>Noradrenergic pathways that are involved in nociception have also been described. <br>Antihistamines have been shown to block norepinephrine, dopamine and serotonin uptake in synaptosomes; and the increased availability of the amines causes a reduction in central pain response by some as yet undetermined mechanisms (4).<br> <br>A possible interaction at the opioid receptor site had been proposed (4, 6). Evidence suggests that endogenous opioids are involved in the control and modulation of nociception and in the antinociceptive actions of various drugs (4). It is speculated that antihistamines may facilitate the binding of opioids to the opioid receptor (4, 7), or replacement of opioids bound to nonspecific receptors by antihistamines, thereby making more opioid available for specific opioid receptor (4, 7).<br>

1. Chahl, LA. Opioids - mechanisms of action. Australian Prescriber, 1 July 1996. https://www.nps.org.au/australian-prescriber/articles/opioids-mechanisms-of-action
2. Meperidine, DrugBank, sökning gjord 2021-12-07. https://go.drugbank.com/drugs/DB00454
3. Santiago-Palma J, Fischberg D, Kornick C, Khjainova N, Gonzales G. Diphenhydramine as an analgesic adjuvant in refractory cancer pain. J Pain Symptom Manage. 2001 Aug;22(2):699-703. doi: 10.1016/s0885-3924(01)00311-6. PMID: 11495716.
4. Rumore MM, Schlichting DA. Analgesic effects of antihistaminics. Life Sci. 1985 Feb 4;36(5):403-16. doi: 10.1016/0024-3205(85)90252-8. PMID: 2578597.
5. Hui FW, Sun CJ, Tocus EC, Hanig JP. The effect of tripelennamine alone and in combination with opiates to produce antinociception in mice. Life Sci. 1983 Apr 4;32(14):1531-8. doi: 10.1016/0024-3205(83)90857-3. PMID: 6835002.
6. Raffa RB. Antihistamines as analgesics. J Clin Pharm Ther. 2001 Apr;26(2):81-5. doi: 10.1046/j.1365-2710.2001.00330.x. PMID: 11350529.
7. Bluhm R, Zsigmond EK, Winnie AP. Potentiation of opioid analgesia by H1 and H2 antagonists. Life Sci. 1982 Sep 20-27;31(12-13):1229-32. doi: 10.1016/0024-3205(82)90349-6. PMID: 6128651.