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Antihistamines

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Written by: Dr Jeremy Steinberg ā€“ created: 23 August 2021; last modified: 24 April 2025

This article is still missing information.


Both H1 and H2 receptors are involved in nociception and chronic pain. H1 and H2 antagonists have mild analgesic activity, especially in experimental conditions where pain is induced by histamine.[1] This article should be read in conjunction with that on histamine.

There is old research, mainly with first generation H1 antagonists (mainly diphenhydramineLink to NZF: 2042), showing analgesic effects in dysmenorrhoea, atypical head and facial pain, trigeminal neuralgia, and thalamic pain[2]. Diphenhydramine has also been shown to have an analgesic effect as an adjunct to opioids in refractory cancer pain.

The analgesic effects of histamine on the central nervous system and the algesic effects on the peripheral nervous system has lead to some interesting findings in research. In an animal model of neuropathic pain (peripheral axotomy[3]), pain behaviours were decreased with the administration of histidine (precursor to histamine). Knockout mice that have a histamine deficiency had higher pain behaviours. This was thought to be due to central effects. In this study the rats were also treated with loratadineLink to NZF: 1848, an H1 antagonist that doesn't pass through the blood brain barrier, and this also reduced pain behaviours. The combination was the most effective.

FexofenadineLink to NZF: 1844 is an H1 receptor centrally sparing antagonist. It therefore only acts on peripheral H1 receptors and has been found to decrease mechanical hypersensitivity in neuropathic pain models[4]. Fexofenadine also has selective COX-2 inhibitor activity which may also contribute to its analgesic effect.

BilastineLink to NZF: 1838 is another H1 antagonist available in NZ, and this agent has negligible passage through the blood brain barrier. CetirizineLink to NZF: 1840 has some passage centrally, but not as much as the first generation H1 antagonists.

For H2 antagonists, in an experimental animal model (tibial nerve transection[4]), the centrally permeable ranitidine reversed mechanical and cold allodynia. Famotidine on the other hand, which isn't centrally permeable, was completely ineffective. This is obviously contrary to the rule of histamine being analgesic in the central nervous system. The role of ranitidineLink to NZF: 749 induced analgesia may be due to different as yet unknown central activities.There are no CNS permeable H2 antagonists available in New Zealand. However another animal study (partial ligation of sciatic nerve) did show analgesic effects of peri sciatic nerve injection of famotidineLink to NZF: 745 through upregulation of Nav1.8 expression.[5]

Ketotifen is an H1 antagonist and mast cell stabiliser, but is only available from compounding pharmacies

There are many other studies that have been done, please see Obara et al.[1]

There is also research into the use of H3 antagonists as analgesics in neuropathic pain but none are approved for human use in New Zealand to my knowledge. [1]

Summary

Agent Class Potential BBB Penetration Portential Mechanism Preclinical Pain Models Clinical Conditions Quality of Evidence
Loratadine H1 Antagonist Minimal Peripheral H1 blockade; Anti-inflammatory (NF-ĪŗB/MAPK?) Neuropathic (chemical)[6] Limited for G-CSF-induced bone pain and Vinca neuropathy [6][7] Low
Cetirizine H1 Antagonist Low Peripheral H1 blockade; Anti-inflammatory; ?MAGL inhibition Inflammatory / OA (CFA model)[8] Itch (atopic dermatitis, high dose) Low
Fexofenadine H1 Antagonist Minimal (P-gp) Peripheral H1 blockade; Anti-inflammatory; ?Microglial inhibition Neuropathic (TNT[4], SNL+NPs[9]); Inflammatory (formalin, carrageenan)[10] Itch (atopic dermatitis) Low
Famotidine H2 Antagonist Low/Minimal Gastric acid suppression; ?Peripheral H2 blockade (Nav1.8)[5] Neuropathic (neuroma, SNL); Ineffective in TNT[4] Acid-related GI pain Strong for acid-related pain; low for everything else
Ranitidine H2 Antagonist Moderate Gastric acid suppression; Central & Peripheral H2 blockade Neuropathic (TNT);[4] Inflammatory (formalin); [11]Ineffective post-op[12] Acid-related GI pain Strong for acid-related pain; low for everything else
Ketotifen Mast Cell Stabilizer / H1 Antagonist Moderate MC stabilization; Peripheral & Central H1 blockade Inflammatory (formalin[10], CFA[13], endometriosis[14], joint contracture); Ineffective in SNI[13] IBS[15]; Cluster headache[16]; Neurofibroma pain/itch[17]; CWP (case series)[13] Low
Sodium Cromoglycate Mast Cell Stabilizer Minimal (Systemic) MC stabilization; Inhibition of central sensitization (central admin) Postoperative; [18]Sickle cell[19]; Central MC-driven sensitization models[20] IBS (pilot studies)[21] Low

TNT: tibial nerve transection. SNI: spared nerve injury. SNL: spinal nerve ligation. NP: nanoparticles.

Resources

Histamine histamine receptors and neuropathic pain relief - Obara 2019.pdf
The role of histamine in neuropathic pain
Histamine in neurogenic inflammation - Rosa 2013.pdf

See Also

References

  1. ā†‘ 1.0 1.1 1.2 Obara I, Telezhkin V, Alrashdi I, Chazot PL. Histamine, histamine receptors, and neuropathic pain relief. Br J Pharmacol. 2020 Feb;177(3):580-599. doi: 10.1111/bph.14696. Epub 2019 Jun 7. PMID: 31046146; PMCID: PMC7012972.
  2. ā†‘ Barris, Ralph W. (1952-01). "Use of Benadryl for Symptomatic Relief of "Thalamic Pain"". Neurology (in English). 2 (1ā€“2): 59ā€“59. doi:10.1212/WNL.2.1-2.59. ISSN 0028-3878. Check date values in: |date= (help)
  3. ā†‘ Yu, Jie; Lou, Guo-Dong; Yue, Jia-Xing; Tang, Ying-Ying; Hou, Wei-Wei; Shou, Wen-Ting; Ohtsu, Hiroshi; Zhang, Shi-Hong; Chen, Zhong (2013 Mar 13). "Effects of histamine on spontaneous neuropathic pain induced by peripheral axotomy". Neuroscience Bulletin (in English). 29 (3): 261. doi:10.1007/s12264-013-1316-0. PMC 5561842. PMID 23494529. Check date values in: |date= (help)CS1 maint: PMC format (link)
  4. ā†‘ 4.0 4.1 4.2 4.3 4.4 Khalilzadeh, Emad; Azarpey, Farzin; Hazrati, Reza; Vafaei Saiah, Gholamreza (2018-09). "Evaluation of different classes of histamine H1 and H2 receptor antagonist effects on neuropathic nociceptive behavior following tibial nerve transection in rats". European Journal of Pharmacology (in English). 834: 221ā€“229. doi:10.1016/j.ejphar.2018.07.011. Check date values in: |date= (help)
  5. ā†‘ 5.0 5.1 Yue, Jia-Xing; Wang, Ran-Ran; Yu, Jie; Tang, Ying-Ying; Hou, Wei-Wei; Lou, Guo-Dong; Zhang, Shi-Hong; Chen, Zhong (2014-10). "Histamine upregulates Nav1.8 expression in primary afferent neurons via H2 receptors: involvement in neuropathic pain". CNS neuroscience & therapeutics. 20 (10): 883ā€“892. doi:10.1111/cns.12305. ISSN 1755-5949. PMC 6493056. PMID 24990156. Check date values in: |date= (help)
  6. ā†‘ 6.0 6.1 Kamal, Noha; Abdallah, Mahmoud S.; Wahed, Essam Abdel; Sabri, Nagwa A.; Fahmy, Sarah Farid (2024 May 9). "Evaluation of the Effect of Loratadine versus Diosmin/Hesperidin Combination on Vinca Alkaloids-Induced Neuropathy: A Randomized Controlled Clinical Trial". Pharmaceuticals (in English). 17 (5): 609. doi:10.3390/ph17050609. PMID 38794179. Check date values in: |date= (help)
  7. ā†‘ Kirshner, Jeffrey J.; McDonald, Maxwell C.; Kruter, Flavio; Guinigundo, Andrew S.; Vanni, Linda; Maxwell, Cathy L.; Reiner, Maureen; Upchurch, Terry E.; Garcia, Jacob; Morrow, Phuong Khanh (2018-04). "NOLAN: a randomized, phase 2 study to estimate the effect of prophylactic naproxen or loratadine vs no prophylactic treatment on bone pain in patients with early-stage breast cancer receiving chemotherapy and pegfilgrastim". Supportive Care in Cancer (in English). 26 (4): 1323ā€“1334. doi:10.1007/s00520-017-3959-2. ISSN 0941-4355. Check date values in: |date= (help)
  8. ā†‘ Andrei, Corina; Mihai, Dragos Paul; Nitulescu, Georgiana; Ungurianu, Anca; Margina, Denisa Marilena; Nitulescu, George Mihai; Olaru, Octavian Tudorel; Busca, Radu Mihai; Zanfirescu, Anca (2023 Nov 6). "Cetirizine and Levetiracetam as Inhibitors of Monoacylglycerol Lipase: Investigating Their Repurposing Potential as Novel Osteoarthritic Pain Therapies". Pharmaceuticals (in English). 16 (11): 1563. doi:10.3390/ph16111563. PMID 38004429. Check date values in: |date= (help)
  9. ā†‘ Tran, Quangdon; Pham, Thuy Linh; Shin, Hyo Jung; Shin, Juhee; Shin, Nara; Kwon, Hyeok Hee; Park, Hyewon; Kim, Song I.; Choi, Seoung Gyu; Wu, Junhua; Ngo, Van T. H. (2022-08). "Targeting spinal microglia with fexofenadine-loaded nanoparticles prolongs pain relief in a rat model of neuropathic pain". Nanomedicine: Nanotechnology, Biology, and Medicine. 44: 102576. doi:10.1016/j.nano.2022.102576. ISSN 1549-9642. PMID 35714922. Check date values in: |date= (help)
  10. ā†‘ 10.0 10.1 Anoush, Mahdieh; Mohammad Khani, Mohammad Reza (2015-06-01). "Evaluating the Anti-nociceptive and Anti-inflammatory Effects of Ketotifen and Fexofenadine in Rats". Advanced Pharmaceutical Bulletin (in English). 5 (2): 217ā€“222. doi:10.15171/apb.2015.030. ISSN 2228-5881. PMC 4517081. PMID 26236660.CS1 maint: PMC format (link)
  11. ā†‘ Mobarakeh, Jalal Izadi; Torkaman-Boutorabi, Anahita; Rahimi, Amir Abbas; Ghasri, Shahrooz; Nezhad, Reza Mohammad Ali; Hamzely, Arash; Khoshkholgh Sima, Baharak; Takahashi, Kazuhiro; Nunoki, Kazuo; Yanai, Kazuhiko (2011). "Interaction of histamine and calcitonin gene-related peptide in the formalininduced pain perception in rats". Biomedical Research (in English). 32 (3): 195ā€“201. doi:10.2220/biomedres.32.195. ISSN 1880-313X.
  12. ā†‘ Berthold, C. W.; Dionne, R. A. (1993-10). "Clinical evaluation of H1-receptor and H2-receptor antagonists for acute postoperative pain". Journal of Clinical Pharmacology. 33 (10): 944ā€“948. doi:10.1002/j.1552-4604.1993.tb01927.x. ISSN 0091-2700. PMID 8227466. Check date values in: |date= (help)
  13. ā†‘ 13.0 13.1 13.2 Meloto, Carolina B.; Ingelmo, Pablo; Perez, Eduardo Vega; Pitt, Rebecca; CĆ”rdenas, VĆ­ctor Hugo GonzĆ”lez; Mohamed, Nada; Sotocinal, Susana G.; Bourassa, Valerie; Lima, Lucas Vasconcelos; Ribeiro-da-Silva, Alfredo; Mogil, Jeffrey S. (2021 Jun 3). "Mast cell stabilizer ketotifen fumarate reverses inflammatory but not neuropathic-induced mechanical pain in mice". Pain Reports (in English). 6 (2): e902. doi:10.1097/PR9.0000000000000902. PMID 34104835. Check date values in: |date= (help)
  14. ā†‘ Zhu, Tian-Hong; Zou, Gen; Ding, Shao-Jie; Li, Tian-Tian; Zhu, Li-Bo; Wang, Jian-Zhang; Yao, Yong-Xing; Zhang, Xin-Mei (2019-04-29). "Mast cell stabilizer ketotifen reduces hyperalgesia in a rodent model of surgically induced endometriosis". Journal of Pain Research (in English). 12: 1359ā€“1369. doi:10.2147/JPR.S195909. PMC 6500880. PMID 31118754.CS1 maint: PMC format (link)
  15. ā†‘ Balemans, D.; Aguilera-Lizarraga, J.; Florens, M. V.; Jain, P.; Denadai-Souza, A.; Viola, M. F.; Alpizar, Y. A.; Van Der Merwe, S.; Vanden Berghe, P.; Talavera, K.; Vanner, S. (2019-03-01). "Histamine-mediated potentiation of transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 signaling in submucosal neurons in patients with irritable bowel syndrome". American Journal of Physiology-Gastrointestinal and Liver Physiology (in English). 316 (3): G338ā€“G349. doi:10.1152/ajpgi.00116.2018. ISSN 0193-1857.
  16. ā†‘ Split, W.; Szmidt, M.; Prusiński, A.; Rozniecki, J. (1984). "[Effectiveness of ketotifen--a drug stabilizing mast cell membranes--in the treatment of chronic forms of Horton's headache]". Neurologia I Neurochirurgia Polska. 18 (2): 105ā€“109. ISSN 0028-3843. PMID 6207450.
  17. ā†‘ Riccardi, V. M. (1993-05). "A controlled multiphase trial of ketotifen to minimize neurofibroma-associated pain and itching". Archives of Dermatology. 129 (5): 577ā€“581. ISSN 0003-987X. PMID 8481017. Check date values in: |date= (help)
  18. ā†‘ Yasuda, Makoto; Kido, Kanta; Ohtani, Norimasa; Masaki, Eiji (2013 Mar 4). "Mast cell stabilization promotes antinociceptive effects in a mouse model of postoperative pain". Journal of Pain Research (in English). 6: 161. doi:10.2147/JPR.S41527. PMID 23503682. Check date values in: |date= (help)
  19. ā†‘ Vincent, Lucile; Vang, Derek; Nguyen, Julia; Gupta, Mihir; Luk, Kathryn; Ericson, Marna E.; Simone, Donald A.; Gupta, Kalpna (2013 Jun 17). "Mast cell activation contributes to sickle cell pathobiology and pain in mice". Blood (in English). 122 (11): 1853. doi:10.1182/blood-2013-04-498105. PMID 23775718. Check date values in: |date= (help)
  20. ā†‘ Kissel, Casey L.; KovĆ”cs, Katalin J.; Larson, Alice A. (2017 Jul 19). "Evidence for the modulation of nociception in mice by central mast cells". European journal of pain (London, England) (in English). 21 (10): 1743. doi:10.1002/ejp.1086. PMID 28722336. Check date values in: |date= (help)
  21. ā†‘ Philpott, Hamish; Gibson, Peter; Thien, Frank (2011 Apr 26). "Irritable bowel syndrome - An inflammatory disease involving mast cells". Asia Pacific Allergy (in English). 1 (1): 36. doi:10.5415/apallergy.2011.1.1.36. PMID 22053295. Check date values in: |date= (help)

Literature Review

Literature Review

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